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V o l u m e
3 4
-
N u m b e r
4
-
2 0 1 4
Tyrosine
kinase
receptor
Nephrin
CD2AP
Growth
Factors
PIP2
PIP3
PI3K
PDK1
mTOR2-Rictor
p -Thr308
p -Ser473
Akt
mTOR inhibitors
mTOR inhibitors
Rac1
Cytoskeletal
reorganisation
GLUT-4
translocation
TSC1-TSC2
Raptor-mTOR1
GSK3
FOXO
Gluconeogenesis
Degradation
of lipids
Protein
synthesis
Protein synthesis
Stimulation
Estimulación
Pro-apoptotic
factors
Cell cycle
inhibition
Cell cycle
maintenance
Cell cycle and Apoptosis
Blocking/Inhibition
Bloqueo/inhibición
Canaud et al. Nad Med 2013 Canaud et al. Nad Med 2013
Metabolism
Podocyte-specific
Específico de podocitos
mTOR INHIBITION AND AKT PROTEINS
HIDDEN SOURCES OF PHOSPHORUS
TREATING HYPONATRAEMIA ASSOCIATED WITH THE SYNDROME OF INAPPROPRIATE
ADH HYPERSECRETION
ANTIBODIES AGAINST THE M-TYPE PHOSPHOLIPASE A2 RECEPTOR IN MEMBRANOUS GN TREATED
WITH TACROLIMUS
Official Publication of the Spanish Society of Nephrology
Full version in English and Spanish at www.revistanefrologia.com
Revista Nefrología
Editor-in-Chief: Mariano Rodríguez Portillo
Executive editor of digital Nefrología: Roberto Alcázar Arroyo
Deputy editors: Andrés Purroy Unanua, Ángel Luis Martín de Francisco, Fernando García López,
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Subject editors (editors of thematic areas)
Experimental Nephrology
A. Ortiz*
J. Egido de los Ríos
S. Lamas
J.M. López Novoa
D. Rodríguez Puyol
J.M. Cruzado
Clinical Nephrology
M. Praga*
J. Ara
J. Ballarín
G. Fernández Juárez
F. Rivera
A. Segarra
Diabetic Nephropathy
F. de Álvaro*
J.L. Górriz
A. Martínez Castelao
J.F. Navarro
J.A. Sánchez Tornero
R. Romero
Hereditary Nephropathies
R. Torra*
J.C. Rodríguez Pérez
E. Coto
V. García Nieto
Chronic Kidney Disease
A.L. Martín de Francisco*
A. Otero
E. González Parra
I. Martínez
J. Portolés Pérez
CRF-Ca/P Metabolism
E. Fernández*
J. Cannata Andía
R. Pérez García
M. Rodríguez
J.V. Torregrosa
Arterial Hypertension
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L. Orte
R. Santamaría
A. Rodríguez Jornet
Nephropathy and
Cardiovascular Risk
J. Díez*
A. Cases
J. Luño
Quality in Nephrology
M.D. Arenas
E. Parra Moncasi
P. Rebollo
F. Ortega
Acute Renal Failure
F. Liaño*
F.J. Gainza
J. Lavilla
E. Poch
Peritoneal Dialysis
R. Selgas*
M. Pérez Fontán
C. Remón
M.E. Rivera Gorrin
G. del Peso
Haemodialysis
A. Martín Malo*
P. Aljama
F. Maduell
J.A. Herrero
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J.L. Teruel
Renal Transplantation
J. Pascual*
M. Arias
J.M. Campistol
J.M. Grinyó
M.A. Gentil
A. Torres
Paediatric Nephrology
N. Gallego
A.M. Sánchez Moreno
R. Vilalta
Nephropathology
J. Blanco*
I.M. García
E. Vázquez Martul
A. Barat Cascante
Evidence-Based Nephrology
Vicente Barrio* (Director de Suplementos), Fernando García López (Asesor de Metodología). Editores: María Auxiliadora Bajo, José Conde, Joan M. Díaz, Mar Espino,
Domingo Hernández, Ana Fernández, Milagros Fernández, Fabián Ortiz, Ana Tato.
Continued Training (journal NefroPlus)
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contents
V o l u m e
3 4
-
N u m b e r
4
-
2 0 1 4
CD2AP
4 - 2 014
Nephrin
Vo l u m e 3 4 - N u m b e r
Tyrosine
kinase
receptor
Growth
Factors
PIP2
PIP3
PI3K
PDK1
mTOR2-Rictor
p -Thr308
mTOR inhibitors
EDITORIAL COMMENT
mTOR inhibition, Akt proteins and chronic kidney disease
Eva Márquez, Julio Pascual
Rac1
Cytoskeletal
reorganisation
GLUT-4
translocation
TSC1-TSC2
Raptor-mTOR1
GSK3
FOXO
Gluconeogenesis
Degradation
of lipids
Protein
synthesis
Pro-apoptotic
factors
Protein synthesis
Stimulation
Estimulación
425 •
mTOR inhibitors
p -Ser473
Akt
Cell cycle
inhibition
Cell cycle
maintenance
Blocking/Inhibition
Bloqueo/inhibición
Canaud et al. Nad Med 2013
Canaud et al. Nad Med 2013
Metabolism
Podocyte-specific
Específico de podocitos
MTOR INHIBITION AND AKT PROTEINS
HIDDEN SOURCES OF PHOSPHORUS
TREATING HYPONATRAEMIA ASSOCIATED WITH THE SYNDROME OF INAPPROPRIATE ADH
HYPERSECRETION
ANTIBODIES AGAINST THE M-TYPE PHOSPHOLIPASE A2 RECEPTOR IN MEMBRANOUS GN TREATED
WITH TACROLIMUS
Official Publication of the Spanish Society of Nephrology
SHORT REVIEW
428 •
Renal function, nephrogenic systemic fibrosis and other adverse reactions associated with gadolinium-based contrast media
Ana Canga, Maria Kislikova, María Martínez-Gálvez, Mercedes Arias,
Patricia Fraga-Rivas, Cecilio Poyatos, Ángel L.M. de Francisco
Full version in English and Spanish at www.revistanefrologia.com
COVER IMAGES
See page 426 of this issue,
Nefrologia 2014;34(4):425-7.
Schematic and simplified view of
Akt action pathways.
SPECIAL ARTICLE
439 •
Treatment of hyponatremia induced by the syndrome of inappropriate antidiuretic hormone secretion: a multidisciplinary algorithm
Isabelle Runkle, Carles Villabona, Andrés Navarro, Antonio Pose, Francesc Formiga, Alberto Tejedor, Esteban Poch
ORIGINALS
451 •
Predictive factors for kidney damage in febrile urinary tract infection. Usefulness of procalcitonin
Elena Lucas-Sáez, Susana Ferrando-Monleón, Juan Marín-Serra, Ricardo Bou-Monterde, Jaime Fons-Moreno,
Amelia Peris-Vidal, Aurelio Hervás-Andrés
458 •
Cost analysis and sociocultural profile of kidney patients. Impact of the treatment method
Víctor Lorenzo-Sellares, M. Inmaculada Pedrosa, Balbina Santana-Expósito, Zoraida García-González,
Mónica Barroso-Montesinos
469 •
During the pre-dialysis stage of chronic kidney disease, which treatment is associated with better survival
in dialysis?
Francisco Caravaca, Raúl Alvarado, Guadalupe García-Pino, Rocío Martínez-Gallardo, Enrique Luna
477 •
Fluid therapy and iatrogenic hyponatraemia risk in children hospitalised with acute gastroenteritis: prospective study
Marciano Sánchez-Bayle, Raquel Martín-Martín, Julia Cano-Fernández, Enrique Villalobos-Pinto
483 •
Soy protein and genistein improves renal antioxidant status in experimental nephrotic syndrome
Mohammad H. Javanbakht, Reza Sadria, Mahmoud Djalali, Hoda Derakhshanian, Payam Hosseinzadeh, Mahnaz Zarei, Gholamreza Azizi, Reza Sedaghat, Abbas Mirshafiey
491 •
Evolution of antibody titre against the M-type phospholipase A2 receptor and clinical response in idiopathic membranous nephropathy patients treated with tacrolimus
Alfons Segarra-Medrano, Elías Jatem-Escalante, Clara Carnicer-Cáceres, Irene Agraz-Pamplona, M. Teresa Salcedo,
Naiara Valtierra, Elena Ostos-Roldán, Karla V. Arredondo, Juliana Jaramillo
SHORT ORIGINAL
498 •
Sumario_03.indd 3
Hidden sources of phosphorus: presence of phosphorus-containing additives in processed foods
Luis M. Lou-Arnal, Laura Arnaudas-Casanova, Alberto Caverni-Muñoz, Antonio Vercet-Tormo, Rocío Caramelo-Gutiérrez, Paula Munguía-Navarro, Belén Campos-Gutiérrez, Mercedes García-Mena, Belén Moragrera, Rosario Moreno-López,
Sara Bielsa-Gracia, Marta Cuberes-Izquierdo, Grupo de Investigación ERC Aragón
09/07/14 12:31
contents
Vo l u m e 3 4 - N u m b e r
4 - 2 014
REVIEW
507 •
Defining protein-energy wasting syndrome in chronic kidney disease: prevalence and clinical implications
Carolina Gracia-Iguacel, Emilio González-Parra, Guillermina Barril-Cuadrado, Rosa Sánchez, Jesús Egido,
Alberto Ortiz-Arduán, Juan J. Carrero
CLINICAL CASE
520 •
Hypersensitivity reactions to synthetic haemodialysis membranes
Rafael J. Sánchez-Villanueva, Elena González, Santiago Quirce, Raquel Díaz, Laura Álvarez, David Menéndez,
Lucía Rodríguez-Gayo, M. Auxiliadora Bajo, Rafael Selgas
LETTERS TO THE EDITOR
A) Comments on published articles
526 • Comment on “Kaposi´s sarcoma in the early post-transplant period in a kidney transplant recipient”
Francisco Coronel, Manuel Macía
526 •
Increase of ischaemic colitis incidence in haemodialysis
Borja Quiroga
B) Brief papers on research and clinical experiments
528 • Home haemodialysis: a right and a duty
Alejandro Pérez-Alba, J. Ramón Pons-Prades, Esther Tamarit-Antequera, Juan J. Sánchez-Canel, Vicente Cerrillo-García, Elena Renau-Ortells, Laura Salvetti, M. Ángeles Fenollosa-Segarra
530 •
Influence of glucose solutions on the development of hyperglycaemia in peritoneal dialysis. Behaviour of glycated haemoglobin and the lipid profile
Margarita Delgado-Córdova, Francisco Coronel, Fernando Hadah, Secundino Cigarrán, J. Antonio Herrero-Calvo
531 •
Results 5 years after living donor renal transplantation without calcineurin inhibitors
Gustavo Martínez-Mier, Sandro F. Ávila-Pardo, Marco T. Méndez-López, Luis F. Budar-Fernández,
Benjamín Franco-Ahumada, Felipe González-Velázquez
C) Brief case report
534 • Hepatitis C virus infection, interferon α and lupus; a curious combination
Pilar Auñón-Rubio, Eduardo Hernández-Martínez, Ángel Sevillano-Prieto, Enrique Morales-Ruiz
536 •
Baclofen neurotoxicity in a patient with end-stage chronic renal failure
Pablo Justo-Ávila, Luciemne Fernández-Antuña, M. Teresa Compte-Jove, Cristina Gállego-Gil
538 •
Achromobacter xylosoxidans in two haemodialysis patients
M. Eugenia Palacios-Gómez, Adoración Martín-Gómez, Sergio García-Marcos
539 • Methylmalonic acidemia with homocystinuria. A very rare cause of kidney failure in the neonatal period
Orlando Mesa-Medina, Mónica Ruiz-Pons, Víctor García-Nieto, José León-González, Santiago López-Mendoza,
Carlos Solís-Reyes
540 •
An uncommon cause of linfadenopathy in a kidney transplant patient: Cat-scratch disease
Cláudia Bento, La Salete Martins, André Coelho, Manuela Almeida, Sofia Pedroso, Leonídeo Dias, Ramon Vizcaíno, António Castro-Henriques, António Cabrita
542 •
Extreme hypocalcaemia and hyperparathyroidism following denosumab.
Is this drug safe in chronic kidney disease?
Ana E. Sirvent, Ricardo Enríquez, María Sánchez, César González, Isabel Millán, Francisco Amorós
Sumario_03.indd 4
09/07/14 12:31
http://www.revistanefrologia.com
© 2014 Revista Nefrología. Official Publication of the Spanish Nephrology Society
editorial comment
mTOR inhibition, AKT proteins and chronic kidney
disease
Eva Márquez, Julio Pascual
Servicio de Nefrología. Hospital del Mar. Institut Mar d’Investigacions Mediques. Red Temática de Investigación Renal (RedinRen).
Barcelona (Spain)
Nefrologia 2014;34(4):425-7
doi:10.3265/Nefrologia.pre2014.Apr.12381
D
espite up to 9 % of the population suffering from
some degree of chronic kidney disease (CKD), the
physiopathological pathways that participate in the
disease’s progression are still unknown in detail1. Podocytes, highly specialised glomerular epithelial cells, play
an essential role in maintaining the glomerular filtration
barrier. Precise regulation of actin cytoskeleton is necessary for this maintenance; its reorganisation produces
functional and morphological alterations that cause proteinuria. The Akt protein family are serine/threonine kinases that regulate metabolic, growth and cell survival factors
(Figure 1)2. Podocytes have a protective role against apoptosis3-6. Nephrin and CD2AP, essential for maintaining
cell structure and function, play a role in the regulation of
cell apoptosis7 and a possible function in the regulation of
cytoskeleton8, both Akt effects.
Canaud et al. have recently published the results of a study
in which they demonstrate, using experimental in vivo, in
vitro models and human biopsies, Akt2 activation as a protective mechanism in the podocyte against a reduction of
kidney mass9. The loss of Akt2 or the decrease in one of the
phosphorylations required for its activity [pAkt (Ser473)]
worsens podocyte injury, causing proteinuria. A failure
in its phosphorylation, blocking the mTOR2 complex by
sirolimus, could explain, at least in part, the undesirable
effects of this drug group observed in some transplant patients.
This study stands out methodologically for the use of genetically engineered animals. Its authors created knockout
(KO) animals for Akt2 and podocyte-specific KO, enabling
Correspondence: Julio Pascual
Servicio de Nefrología.
Hospital del Mar. Institut Mar d’Investigacions Mediques. Red Temática
de Investigación Renal (RedinRen). 08003 Barcelona. (Spain).
[email protected]
the evaluation of these cells’ significance in the evolution
of renal lesions. These animals, together with their respective and suitable controls, are subjected to a reduction of
kidney mass through subtotal nephrectomy or assessed at
13 months old as an ageing model. Similarly, they develop
a KO-specific mouse for Rictor, an essential component of
the mTOR2 complex.
An increase in Akt2 protein level, primarily present at a podocyte level, is observed in the reduction of kidney mass.
Its increase seems to be a protective mechanism against
damage, since, in relation to their respective controls, the
KO animals for Akt2 show podocyte injury with pedicel effacement associated with an increase in Rac1, increase in
apoptosis at a glomerular level, higher degree of glomerular lesion and as a result, higher albumin level. Similar
alterations are found in KO mice for Akt 2 specifically in
the podocytes, which confirms the significance of podocyte
Akt2 in renal function maintenance. However, not only the
absence of Akt2 causes renal alterations: phosphorylation
deficiency, as that observed in KO mice for Rictor, causes
equivalent alterations. The in vitro results reinforce the in
vivo findings. KO podocytes for Akt2 or treated with sirolimus show alteration of its cytoskeleton with redistribution
of actin fibres and appearance of adhesion foci.
The studies carried out on human biopsies show, in the
same way as in the animal model, that Akt2 is mainly expressed in podocytes. An increase of pAkt (Ser473) is also
observed at a glomerular level in patients with various
pathologies, mainly of vascular origin.
The study of transplant patients with different degrees of
renal dysfunction shows that only patients with severe
nephron reduction present proteinuria when undergoing
treatment with sirolimus. Patients with worse renal function show intense stains for pAkt (Ser473) and Rictor; this
is not the case for patients with worse renal function being
425
Eva Márquez et al. AKT in chronic kidney disease
editorial comment
Tyrosine
kinase
receptor
Nephrin
CD2AP
Growth
Factors
PIP2
PI3K
PIP3
PDK1
mTOR2-Rictor
p -Thr308
p -Ser473
Akt
Rac1
Cytoskeletal
reorganisation
GLUT-4
translocation
TSC1-TSC2
mTOR inhibitors
mTOR inhibitors
Raptor-mTOR1
GSK3
FOXO
Gluconeogenesis
Degradation of lipids
Protein
synthesis
Pro-apoptotic
factors
Protein synthesis
Stimulation
Cell cycle
inhibition
Cell cycle
maintenance
Blocking/Inhibition
Canaud et al. Nad Med 2013 Metabolism
Podocyte-specific
Figure 1. Schematic and simplified view of Akt action pathways
treated with sirolimus. This group shows greater cell apoptosis at a glomerular level and, clinically, the presence of
proteinuria. One of the most noteworthy findings is the correlation in time between sirolimus withdrawal, increase of
pAkt (Ser473) in renal biopsy and reduction of proteinuria.
With an excellent design in the in vivo and in vitro studies, this study identifies Akt2 as the central element in
the pathophysiology of podocyte injury in CKD. Severe
nephron reduction models were used, making the findings
potentially applicable to CKD of any aetiology. It was
recently demonstrated that the activation of Rac1 causes
alterations of podocyte cytoskeleton, leading to pedicel
effacement10. Canaud et al. showed that Akt2 reduction activates Rac1 causing cytoskeletal alterations.
firmed11,12. In addition, from the study by Canaud et al., it
can be concluded that there is another kinase, aside from
mTOR2, that phosphorylates Akt, since pAkt (Ser473) is
not totally absent in the KO model for Rictor. Akt analysis
is carried out through studies of total Akt, its isoforms and
pAkt (Ser473); however no study was undertaken on the
status of specifically Akt2 nor pAkt (Thr308) phosphorylation, which, although not dependent on the mTOR2 complex, would supply relevant information for the complete
evaluation of the functional status of Akt13. In addition, the
valuation of Rictor-mTOR2 in the various animal models
could contribute to clarifying its role and regulation. Surprisingly, in presence of sirolimus, modifications in molecules phosphorylated by the mTOR1 complex, not specifically studied, were not detected.
In this way, previous studies on podocytes and on other
experimental models which show that mTOR inhibitors
do not only block mTOR1, but also mTOR2, are reaf-
One of the most remarkable findings is that the defect in
Akt phosphorylation seems to explain, at least in part, the
development of proteinuria observed in transplant patients
426
Nefrologia 2014;34(4):425-7
Eva Márquez et al. AKT in chronic kidney disease
with poor renal function when an mTOR inhibitor is introduced 14. The patients were grouped into high and low
estimated glomerular filtration rate; renal function and
proteinuria prior to sirolimus introduction or duration of
treatment with sirolimus, data which would help to establish the possible predictive role of Akt on renal function
following the onset of treatment, were not explained. Studies on human renal biopsies show an increase in glomerular pAkt (Ser473) in various pathologies, but the Akt2
isoform was not specifically studied in any of the groups,
which would obviously be of interest in the context of the
present study.
Future research, in both animal and cell models, should
be directed at determining which are the stimuli causing
the elevation of Akt2, which could be specific to different
pathologies. This aforementioned study focused on established renal damage models, but the study of this pathway in models with early damage would be significant.
The prevalence of diabetic nephropathy and the role of the
PI3K/Akt pathway in its pathophysiology, including podocyte injury 3-6, make it a clear objective for furthering
analysis of the role of Akt2. In addition, in-depth research
on apoptosis mechanisms, regulation of the cell cycle (especially in the podocyte, terminally differentiated cell) and
modifications of cytoskeleton, all regulated by Akt, is necessary to understand the pathophysiological consequences
of the changes in this molecule.
In-depth research in these different fields would facilitate
the ability to define possible therapeutic targets which
would lead to the design of new drugs or the use of current drugs to stop, or even prevent, the development of
established renal damage.
Finally, findings in human biopsies open the door to new
clinical decision-making tools in the management of immunosuppression. With specifically designed studies,
it would be possible to confirm the probable prognostic
value of total Akt, its phosphorylations and its isoforms
when assessing post-transplant biopsies as a step prior
to converting to mTOR inhibitors. The study of possible
non-invasive markers associated with the results of this
study would result in an improvement in routine clinical
practice.
editorial comment
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et al. Rapamycin-induced insulin resistance is mediated by mTORC2 loss
and uncoupled from longevity. Science 2012;335(6076):1638-43.
13. Song G, Ouyang G, Bao S. The activation of Akt/PKB signaling pathway
and cell survival. J Cell Mol Med 2005;9(1):59-71.
14.Diekmann F, Budde K, Oppenheimer F, Fritsche L, Neumayer HH,
Campistol JM. Predictors of success in conversion from calcineurin inhibitor to sirolimus in chronic allograft dysfunction. Am J Transplant
2004;4(11):1869-75.
Sent to review: 30 Nov. 2013 | Accepted: 21 Apr. 2014
Nefrologia 2014;34(4):425-7
427
short review
© 2014 Revista Nefrología. Órgano Oficial de la Sociedad Española de Nefrología
Renal function, nephrogenic systemic fibrosis
and other adverse reactions associated with
gadolinium-based contrast media
Ana Canga1, Maria Kislikova2, María Martínez-Gálvez3, Mercedes Arias4,
Patricia Fraga-Rivas5, Cecilio Poyatos6, Ángel L.M. de Francisco2
1
Servicio de Radiodiagnóstico. Hospital Universitario Marqués de Valdecilla. Santander, Cantabria (Spain); 2 Servicio de Nefrología.
Hospital Universitario Marqués de Valdecilla. Santander, Cantabria (Spain); 3 Servicio de Radiodiagnóstico. Hospital José María
Morales Meseguer. Murcia (Spain); 4 Unidad de Diagnóstico por Imagen Galaria. Empresa Pública de Servicios Sanitarios. Complejo
Hospitalario Universitario de Vigo (Spain); 5 Servicio de Radiodiagnóstico. Hospital del Henares. Unidad Central
de Radiodiagnóstico. Madrid (Spain); 6 Servicio de Radiodiagnóstico. Hospital Universitario Dr. Peset. Valencia (Spain)
Nefrologia 2014;34(4):428-38
ABSTRACT
Nephrogenic systemic fibrosis is a fibrosing disorder that
affects patients with impaired renal function and is associated
with the administration of gadolinium-based contrast media
used in MRI. Despite being in a group of drugs that were
considered safe, report about this potentially serious adverse
reaction was a turning point in the administration guidelines
of these contrast media. There has been an attempt to
establish safety parameters to identify patients with risk
factors of renal failure. The close pharmacovigilance and strict
observation of current regulations, with special attention
being paid to the value of glomerular filtration, have reduced
the published cases involving the use of gadolinium-based
contrast media. In a meeting between radiologists and
nephrologists we reviewed the most relevant aspects currently
and recommendations for its prevention.
Keywords: Nephrogenic systemic fibrosis. Gadolinium. Magnetic
resonance. Adverse reactions.
Función renal, fibrosis sistémica nefrogénica y otras reacciones adversas asociadas a los medios de contraste basados en el gadolinio
RESUMEN
La fibrosis sistémica nefrogénica es un trastorno fibrosante
que afecta a pacientes con deterioro de la función renal y
se asocia a la administración de medios de contraste basados
en el gadolinio, empleados en la resonancia magnética. A pesar de tratarse de un grupo de fármacos que se consideraban
seguros, la notificación de esta reacción adversa, potencialmente grave, supuso un punto de inflexión en las pautas de
administración de estos medios de contraste. Se han intentado
establecer parámetros de seguridad a fin de identificar a los
pacientes con factores de riesgo por presentar insuficiencia
renal. La estrecha farmacovigilancia y el rigor en la observación de las normativas actuales, con especial atención al valor del filtrado glomerular, han reducido los casos publicados
relacionados con el uso de medios de contraste basados en
el gadolinio. En un encuentro entre radiólogos y nefrólogos
revisamos los aspectos más relevantes en la actualidad y las
recomendaciones para su prevención.
Palabras clave: Fibrosis sistémica nefrogénica. Gadolinio.
Resonancia magnética. Reacciones adversas.
INTRODUCTION
Since 1997, when it was reported by Cowper for the first
time1, a condition called nephrogenic systemic fibrosis (NSF)
Correspondence: Ángel L.M. de Francisco
Hospital Universitario Marqués de Valdecilla. Avda. Valdecilla, SN.
39008, Santander, Cantabria. (Spain).
[email protected]
428
has drawn the attention of nephrologists and radiologists
from all over the world. It has been defined as a fibrosing
disease that predominantly affects patients who have received
gadolinium-based contrasts, with an estimated glomerular
filtration rate (GFR) of less than 30ml/min/1.73m2 or those
on haemodialysis2,3. In this document, we aim to summarise
the clinical expression of NSF, the data known about different
gadolinium-based contrasts, the possibilities of identifying
Ana Canga et al. Nephrogenic systemic fibrosis
patients at risk in order to prevent its onset and the types of
treatment for this disease.
GADOLINIUM
Gadolinium-based contrast media (GBCM) are used in
magnetic resonance imaging (MRI) studies due to their
magnetic ability to change the position of the protons of
water molecules in tissues, which is a change that improves
the study’s diagnostic capacity. These contrast media act
by shorting the T1 and T2 relaxation time of the tissues to
which they are distributed, which fundamentally leads to an
increased signal in T1-weighted sequences. However, if the
GBCM concentration is high, T2 shortening is predominant,
which causes a decrease in the signal. Nine agents have
currently been approved and are available in Europe; their
characteristics are summarised in Table 1.
Structure and pharmacokinetics
Gadolinium (Gd) is a heavy metal with a high paramagnetic
capacity and which is not soluble in water. In its free form
(Gd3) it is very toxic, and as such, it is necessary to chelate
it with different organic ligands, creating gadolinium
chelates4. There is a certain tendency for the ion to separate
from the ligand in a process called chelation blocking 5.
If this process continues, there is transmetalation and
this causes NSF6. Transmetalation is a chemical reaction
whereby a secondary free metal with affinity for the
chelate allows gadolinium release (Gd3). In renal failure
patients, it decreases the renal elimination of GBCM;
its half-life is extended, which increases the possibility
of Gd3 dissociating from the chelate. This facilitates
the recruitment of circulating fibrocytes, triggering the
fibrosing reaction7,8. The structure of gadolinium chelates
may be linear or macrocyclic, with the latter being that
which shows higher thermodynamic stability constants.
Being hydrophilic compounds, they can be classified9 as
ionic and non-ionic, with the latter having lower osmolarity
for the same concentration (Table 1). Of all the agents, nonionic linear agents are the least stable and they increase the
risk of transmetalation. As such, they are associated with a
higher risk of NSF10,11.
In terms of the distribution after their intravenous administration
(Table 1), GBCM are classified into three types: non-specific
extracellular, mixed (hepatospecific extracellular and
intracellular distribution with a variable percentage of biliary
elimination) and intravascular (they remain in the intravascular
space for longer). The vast majority of GBCM used in daily
practice are from the first group12.
GD chelates have a molecular weight that ranges between
500 and 1,000Da, they are not bound to plasma proteins and
Nefrologia 2014;34(4):428-38
short review
are not lipophilic, which means that after their intravenous
administration, there is a distribution and balance within
the extracellular space. All of these characteristics help
to create the good glomerular filtration capacity of GD
chelates6. They are small molecules that leave the vascular
space quickly, with a half-life in plasma of around 15-30
minutes. They do not cross the blood-brain barrier or the cell
membrane, and as such, after leaving the vascular space,
they are distributed around the interstitial space. They are
eliminated, without being metabolised, through glomerular
filtration. In patients with normal renal function, 98% of
Gd is eliminated in urine in the first 24 hours13, and it is
not eliminated from or reabsorbed into the renal tubule14.
Pharmacokinetic studies have demonstrated its elimination
by glomerular filtration, extending the contrast’s halflife by more than 30 hours but without side effects
of nephrotoxicity. In renal failure patients, peritoneal
clearance of GBCM was 3.8ml/minute/1.73m2 with a T1/2
of 52.7 hours, which is not surprising, given the slow
clearance of peritoneal dialysis techniques. 75% of doses
administered were eliminated by peritoneal dialysis after
5 days and as such, peritoneal dialysis is not an effective
technique for eliminating contrast. After two haemodialysis
sessions, 95% of the gadolinium dose administered was
eliminated but there were no tests of its efficacy in the
removing the risk of NSF. However, we recommend that
patients on dialysis undergo haemodialysis less than two
hours after administration and another haemodialysis
session the next day. It is not routinely recommended in
non-dialysis patients6.
Dose and administration range
As a gadolinium atom modifies the relaxation times of many
neighbouring hydrogen nuclei, the contrast dose used is low,
Table 1. Classification of the different gadolinium-based
contrasts according to their distribution
Extracellular (non-specific)
•
Gadopentetate dimeglumine (Gd-DTPA)
•
Gadoteridol (Gd-HP-DO3A)
•
Gadodiamide (Gd-DTPA-BMA)
•
Gadoterate meglumine (Gd-DOTA)
•
Gadobutrol (Gd-BT-DO3A)
•
Gadoversetamide
Mixed (extracellular/hepatobiliary)
•
Gadoxetate disodium (Gd-EOB-DTPA)
•
Gadobenate dimeglumine (Gd-BOPTA)
Intravascular
•
Gadofosveset trisodium
429
short review
significantly lower than the quantity of iodine administered
for computerised tomography studies15. The most used
commercial preparations have a concentration of 0.5 molar
(0.5M), and as such, the standard administration dose is
0.1mmol/kg of weight, equivalent to 0.2ml/kg of contrast4.
High doses and increases in the accumulated dose increase
the risk of NSF6.
NEPHROGENIC SYSTEMIC FIBROSIS
NSF is an acquired fibrosing disorder that has been observed
in patients with severely impaired renal function. Although the
term “nephrogenic systemic fibrosis” was adopted in 2005, it
was recognised for the first time in 1997 and reported in the year
2000 by Cowper as a scleromyxedema-like illness in dialysis
patients1. In our country, Rodríquez Jornet et al. published
the first case in 2009, with a detailed pathological review
of the patient, and the macroscopic and microscopic images
are available at: http://www.revistanefrologia.com/modules.
php?name=articulos&idarticulo=129&idlangart=ES16. Table
2 displays the chronology and evolution of the term.
Epidemiology
NSF affects most cases of patients with impaired renal
function, particularly those with an estimated glomerular
filtration rate of less than 30ml/min/1.73m2 independently of
the origin of renal damage (acute, chronic or haemodialysis
patients)2,3, who are administered GBCM. According to
Zou et al., the two most affected groups are patients with
chronic renal failure (CRF) on dialysis (85% of cases) and
those with acute renal failure17. Another patient group that
may be affected are those with liver failure who have acute
hepatorenal syndrome18,19. It is well-known that not all risk
patients exposed to GBCM have a disease6.
NSF is more common in middle-aged patients (50-60 years
of age)20, although it may affect children and the elderly21,22.
There are no differences according to race or sex, or any
relationship with the cause or duration of CRF20.
Although various authors have reported different prevalences
in accordance with the population selected, it is currently
estimated that there is a mean incidence of 0%-18% in the
risk population23. There is a clear relationship between the
dose of GBCM used and the risk of NSF, with there being
a NSF incidence close to 0 after an exposure to a standard
dose15,24. Differences were also reported in the incidence of
NSF according to the characteristics of the molecule, with
a greater number of cases of NSF having been recorded
after exposure to non-ionic linear compounds. As we have
mentioned before, it seems that there is a greater risk of
incidence in the peritoneal dialysis patient group25.
430
Thanks to the knowledge of risk factors and the better
use of GBCM, the number of cases of NSF has decreased
significantly26. Since 2008, there have been no cases of any
CM being reported without these CM being replaced27. Many
hospitals have continued to use the same GBCM but have
changed the patterns of use.
Aetiopathogenesis
Although the exact pathogenesis of NSF continues to be
unknown, the only solid association identified in all patients
with NSF is renal failure, both in its chronic and acute forms,
and its presence is a sine qua non condition for the diagnosis
of the disease28. However, only a small percentage of the risk
population exposed to GBCM develops NSF, and cases of
NSF have also been reported without exposure to GBCM29.
Table 2. Chronology and evolution of the term
“nephrogenic systemic fibrosis”
2000
First report of NSF in the literature as a skin condition
“scleromyxedema-like” in dialysis patients1
2001
Nephrogenic fibrosing dermopathy is reported as a
new disease2
2003
The systemic involvement of the disease becomes
known for the first time24
2005
The term “nephrogenic systemic fibrosis” is recorded
for the first time72
2006
Two publications warn about the potential
relationship between gadolinium and NSF42,43
The FDA publishes its first public warning with regard
to this association72
2007
The FDA74 and the European Medicines Agency
(EMA)75 make it compulsory to introduce a warning
on the data sheets of GBCM
The European Society of Urogenital Radiology (ESUR)76
and the American College of Radiology (ACR)77
publish guidelines on the use of GBCM in patients
with renal failure
2011
An expert group publishes the first recommendations
for defining and diagnosing NSF28
FDA: Food and Drug Administration, NSF: nephrogenic systemic
fibrosis, GBCM: gadolinium-based contrast media.
Nefrologia 2014;34(4):428-38
Given that exposure to GBCM does not explain all cases
of NSF, other coadjuvant risk factors have been studied
that may contribute to its development, many of them
associated with situations of renal failure. Pro-inflammatory
factors: vessel injury, surgery, thrombosis, procoagulant
stages, severe infection, chronic hepatitis C, chronic liver
disease and liver transplantation, hyperparathyroidism and
hypothyroidism. Biochemical factors: acidosis, intravenous
iron, erythropoietin, calcium and phosphorus30.
Pathophysiological mechanisms
The two forms, free Gd ions and the chelate-Gd complex
may cause the release of cytokines, stimulating skin
macrophages (Gd-free ions) or peripheral blood monocytes
(chelate-Gd complexes). All of these processes (macrophage
activation, pro-inflammatory cytokine release, differentiation
of fibrocytes in blood, activation of fibroblasts, TGF-β
pathways, metallothionein, FGF-23 and Klotho protein)
stimulate fibroblasts30, a response that creates collagen
deposits and fibrosis by increasing transforming growth
factor beta 1 levels31. The presence of renal failure contributes
to the release of free GD3 by increasing transmetalation
in a uraemic environment and decreasing the glomerular
filtration rate32. A complete diagram with pathophysiological
mechanisms published by Chopra et al. is available at http://
www.hindawi.com/journals/ijn/2012/912189/fig1/30. Diagnosis
It presents clinically as a thickening and hardening of the
skin, associated with pain, muscle weakness, bone pain and
joint contractures, which causes severe disability3. Over time
there may be loss of flexibility, limited mobility and joint
contractures2,34. Lesions may appear in the form of plaques
(58%) with irregular edges and papules (32%), nodules (17%),
macules, vesicles, blisters, bullae and ulcers2,21,35,36. It typically
affects the legs, but may be found anywhere apart from the
face in most cases35. These skin lesions progress over time to
fibrotic skin surrounded by wrinkles, also known as “orange
peel”37. Most lesions are hyperpigmented and erythematous
(39%), but their colour can vary (purple, brown, yellow, pink,
orange-red, grey-brown)35,38. Sometimes these symptoms can
be confused and wrongly treated as cellulitis6. Kroshinsky
et al. published the case of a 46-year-old woman with CRF,
oedema in her legs and skin changes, who was examined and
a differential diagnosis was carried out, with macroscopic and
microscopic images of the dermis being created39. At the time
this condition was first reported, scientists thought that it was
just a skin disorder, but it is nowadays well-known that it
affects joints, the muscular system, the testicles, the kidney,
the heart and the dura mater31,40,41. Another sign of interest
is that it has similar symptoms to conjunctivitis in 75% of
cases6.
Nefrologia 2014;34(4):428-38
short review
The onset of symptoms is variable; it generally occurs
between two weeks and two months after exposure to GBCM.
However, delayed onset has also been reported, years after
exposure17.
The histological diagnosis is based on a skin biopsy where
skin fibrosis is observed, with thickened collagen bundles
and a variable quantity of elastic fibres and mucin. The
mediating cell is the circulating fibrocyte (CD34 and positive
procollagen I in the immunohistochemistry stain)28,42. In most
cases, the inflammatory cells are not present and on some
occasions, perivascular mononuclear infiltrate has been
observed43. Sanyal et al. carried out a histological review
of a clinical case with an electron microscope and energy
dispersive x-ray fluorescence44.
With regard to its association with GBCM, the first publications
are from 200645,46, with the presence of gadolinium in tissues
being demonstrated only one year later47,48. Under normal
conditions, GBCM are eliminated by glomerular filtration in
1-2 days.
Prognosis The natural outcome of NSF is not fully known. It has been
reported that in up to 5% of cases, it may have a fulminant
course20. A third will have a mild course without functional
limitation17. There is increased mortality after 24 months
of skin manifestations of NSF49. The true mortality rate
is unknown and is difficult to determine, given the high
prevalence of other comorbidities34.
Treatment
There is no evidence of effective treatment and only in
transplant patients has an improvement or a detention in the
progression of renal disease been achieved in the case of
acute renal failure50.
As mentioned above, GBCM molecular weight allows
glomerular filtration6 and given these characteristics, there is
the possibility of elimination with haemodialysis51. Several
authors have carried out studies that confirm the elimination
of various types of GBCM with three haemodialysis sessions
of three hours each. Based on these results, the European
Society of Radiology recommends carrying out nine hours
of haemodialysis over three sessions. However, gadofosveset
is an agent that is difficult to eliminate by haemodialysis due
to a large proportion of it being bound to serum albumin6.
Broome et al. presented a series with three patients who
developed NSF despite undergoing the previously indicated
haemodialysis sessions52. To present, no studies have been
carried out on continuous haemofiltration or continuous
venovenous haemodiafiltration.
431
short review
Most treatments proposed are still being researched
and they are currently yielding suboptimal results (oral
steroids, extracorporeal photopheresis, plasmapheresis,
thalidomide, cyclophosphamide, pentoxifylline, intravenous
immunoglobulin, interferon alpha and vitamin D, ultraviolet
radiation and etanercept)20. Recently, combined treatments
with imatinib and extracorporeal photopheresis have been
attempted53,54. The efficacy of treatment with alefacept was
also confirmed in three patients with NSF55. The improvement
in renal function (transplantation and resolution of acute
renal failure) may slow down and even reverse the process20.
However, in reality, no treatment has shown to be effective;
therefore, prevention is important.
PREVENTION OF NEPHROGENIC SYSTEMIC FIBROSIS
Identification of patients with chronic kidney disease
The classification of chronic kidney disease (CKD) followed
the initial publication of the National Kidney Foundation
through the Kidney Disease Outcomes Quality Initiative
(K-DOQI) guidelines56. The definition of CKD by K-DOQI
is as follows:
Renal damage for at least three months, defined by structural
or functional abnormalities of the kidney or without a
decrease in the GFR and shown by pathological changes or
renal damage markers (changes in the composition of blood
or urine or changes in images of the kidney).
The international organisation KDIGO (Kidney Disease
Global Outcomes; http://www.kdigo.org/) recommends using
prediction equations to calculate the GFR based on SCr. In
adults, the formulae most used are those of the Modification of
Diet in Renal Disease (MDRD) study and that of Cockcroft and
Gault58. There are certain circumstances in which the first is not
validated (Table 3) and in order to estimate the GFR, 24-hour
urine should be collected or studies of creatinine clearance in 24hour urine, iothalamate, iohexol or insulin should be carried out.
In any case, the estimation of GFR using the MDRD formula
is more accurate that SCr, and considering these limitations,
the doctor may obtain valid information about renal function.
Recently, KDIGO recommended a new formula for calculating
renal function, called CKD-EPI (Chronic Kidney Disease
Epidemiology Collaboration), which is more accurate than
MDRD for values close to 60ml/min59. Likewise, it updated
the CKD classification by incorporating the CGA concept: C:
cause of CKD, G: GFR incorporating groups 3a and 3b, and A:
albuminuria with three subgroups: A1 (<30mg/g of creatinine),
A2 (30-300) and A3 (>300)60 (Table 4).
There are occasionally no data on renal function. In patients
who have unknown renal function and who require an x-ray
examination with gadolinium, a series of parameters should be
considered, such as renal failure risk factors, which will mean
that the examination must be delayed until their exact renal
function is known (Table 5). The study of risk factors must be
part of the routine before using GBCM in any hospital.
GFR <60ml/min/1.73m2 for more than three months, with or
without renal damage.
IMMEDIATE ADVERSE REACTIONS TO GADOLINIUMBASED CONTRAST MEDIA
It is common in consultations for renal function to be studied
simply by measuring serum creatinine (SCr). However, and
although it is true that SCr is a good follow-up parameter
of the evolution of filtration, it is not always equivalent to
glomerular filtration. SCr also depends on factors other than
the GFR, such as tubular elimination and the generation
and extrarenal elimination of creatinine, which explains the
wide range for SCr in healthy individuals. Some studies57
show a high percentage of males and particularly of females
who have reductions in the GFR with normal SCr. Even
with creatinine ranges between 1.3 and 2.5mg/dl, there are
significant percentages of very severe renal failure (GFR
below 30ml/min/1.73m2). Therefore, the real prevalence of
individuals with renal failure appears to be higher than that
which can be determined by studying SCr. The results of
these observations are important. This “hidden” renal failure
may easily worsen due to the large amount of medications,
particularly in glomerular haemodynamics, such as nonsteroidal anti-inflammatory drugs, angiotensin-convertingenzyme inhibitors and other types of drugs. Likewise, patients
often undergo x-ray examinations when there is an inadequate
evaluation of renal function, based only on plasma creatinine.
GBCM are very safe drugs, with a low immediate adverse
reaction (IAR) rate of 0.07%-2.4%61-63, mostly of a
432
Table 3. Circumstances in which the MDRD (Modification
of Diet in Renal Disease) equation is not valid for
calculating the glomerular filtration rate
-
Age <18 or >70 years old
-
Severe malnutrition and obesity
-
Musculoskeletal disease
-
Paraplegia or tetraplegia
-
Vegetarian diet
-
Rapid changes in renal function
-
Pregnancy
-
Drugs that increase the values of creatinine: trimethoprim, cimetidine, some fibrates and certain cephalosporins Nefrologia 2014;34(4):428-38
short review
Table 4. Classification of chronic kidney disease57
Grade
Description
GFR (mL/min/1.73 m2)
1
Renal damage with a normal or high GFR
2
Renal damage with a slightly decreased GFR
60-89
3
Moderate decrease in GFR
3a
3b
59-30
29-16
4
Severe decrease in the GFR
15-29
5
Renal failure
>90
<15 (or dialysis)
GFR: glomerular filtration rate
mild nature, mainly nausea or headaches at the time of
injection.
Although all GBCM show quite a similar IAR incidence64,
there are differences in their occurrence that cannot seem
to be explained by their physicochemical characteristics65,66
(Table 6).
Among IAR to GBCM, we must highlight allergic reactions,
due to their relevance, which are defined as a type of
adverse reaction measured immunologically by antibodies or
lymphocytes, characterised by being specific and recurrent
if the patient is exposed to the drug again67. Two types of
allergic reaction to x-ray contrast media are distinguished
depending on the moment of presentation: immediate and
non-immediate or delayed68. Immediate allergic reactions are
measured by immunoglobin E; if a systemic allergic reaction
develops, there is anaphylaxis. This is caused by the release
of histamines and other mediators, causing symptoms that
may put the life of the patients at risk: laryngeal oedema,
angioedema, upper airway obstruction, urticarial, nausea,
vomiting, low blood pressure and/or shock.
The occurrence of allergic reactions to GBCM is unpredictable,
although it is known that its incidence increases in asthmatic
patients and in those with food allergies and/or medication
allergies58,69.
With regards to how to act against an allergic reaction to a
GBCM, Figure 1 displays an algorithm, which schematically
shows how to manage these emergency situations in the x-ray
diagnosis department.
LEARN FROM EVIDENCE
was created, which led to an overenthusiastic use of GBCM,
which were often used as replacements for iodinated contrasts
in computerised tomography or conventional angiography
studies in patients who were allergic to iodinated contrasts or
in those with renal failure and even in MRI, at doses much
higher than those recommended.
This use of GBCM, before NSF was reported, was carried out
without any type of control in terms of dose or administration
times and without taking any precautions in relation to the
renal function of patients.
The reporting of this delayed and potentially serious adverse
reaction marked a turning point that forced x-ray departments
to establish new guidelines aimed at protecting patients.
Although the initial information may have been confusing,
some evidence was clear and shed light with regard to the
measures to adopt to prevent disease: it was only reported
in patients with severe renal failure (GFR<30), its incidence
was related to the administration of high doses of gadolinium
and it was more common in patients with pro-inflammatory
symptoms.
Table 5. Chronic kidney disease risk factors
– Age >65 years old
– High blood pressure
– Diabetic
– History of cardiovascular disease
– Obesity
Clinical use and abuse
Since the introduction of GBCM in MRI, its applications
have been increasing daily, and it is now used in all organs of
the body. During the first few years, a false sense of security
Nefrologia 2014;34(4):428-38
– History of renal failure or some type of kidney disease (single kidney, renal transplantation or renal neoplasm)
– Direct family member with kidney disease 433
short review
Table 6. Percentage of immediate adverse reactions to gadolinium-based contrast media
Prince et al.65
Several authors
0.33 %
n=3371
Gadoteridol
(Prohance®)
Gadopentetate dimeglumine (Magnevist®)
0.05 %
n=66,157
Gadodiamide
(Omniscan®)
0.02 %
n=55,703
0.39 %
n=254
2.4 %
n=15 496
78
79
n=24,308
0.55 %
Gadobutrol
(Gadovist®)
Gadobenate dimeglumine
(Multihance®)
0.12 %
n=33,114
0.20 %
n=7490
0.06%
n=3097
0.40 %
Gadoterate meglumine
(Dotarem®)
Bruder et al.66
0.25 %
n=1208
n=14,29980
0.23 %
n=2201
0.76 %
n=23,53381
0.47 %
n=428
If after administration of gadolinium-based contrast...
DOUBTFUL SYMPTOMS
URTICARIA-ANGIOEDEMA
ANAPHYLAXIS
Use a pulse oximeter
Measure blood pressure/heart
rate
Measure blood pressure/
heart rate
Measure blood pressure/
heart rate
I.v. administration
1 hour in the unit
1 amp. (5mg) i.v. Polaramine®;
<12 years: 0.15-0.3mg/kg
1mg/kg i.v. Urbason®
0.3-0.5cc i.m. administration 1/1,000
EPINEPHRINE to the thigh
(children 0.1cc/10kg)
If after 1h symptoms persist,
extract tryptase in blood
Refer to the emergency
department
CALL THE ICU
Venous administration with saline solution
Trendelenburg position
Oxygen therapy (6-8lpm at 100%)
ADJUVANT THERAPY
40-80mg i.v. Urbason® (1-2mg/kg)
1 amp. (5mg) i.v. Polaramine®;
<12 years: 0.15-0.3mg/kg
Nebulised salbutamol if bronchospasm occurs
Consult the allergology service
Refer according to the ICU
Figure 1. Protocol for treating adverse reactions to gadolinium.
i.m.: intramuscular, i.v.: intravenous, ICU: intensive care unit.
434
Nefrologia 2014;34(4):428-38
Clinical limitations in the use of gadolinium-based
contrast media
The main limitation with regard to the use of GBCM in MRI
is the difficulty of knowing the GFR of patients, particularly
outpatients. In this regard, collaboration between the x-ray
department, which would have to routinely record renal
failure risk factors (Table 4) before carrying out the GBCM
study, and the doctor who requests the test, who must provide
information about the patient’s renal function and assess the
risk/benefit of the test requested for the patient. If any of the
risk factors of renal failure are confirmed or the GFR of the
patient cannot be excluded or assessed, it would be preferable
to postpone it until MDRD or CKD-EPI are determined in
another test.
Since gadolinium has been considered an agent the potentially
causes NSF, restrictive guidelines have been designed for its
administration (Table 7), with the most important aspects
being the possession of recent GFR data and the adjustment
of doses used in accordance with the latter (Table 8).
In 2010, the U.S. Food and Drug Administration (FDA)
established general precautions on the use of GBCM and
limited Magnevist®, Omniscan® and Optimark® GBCM in
patients with acute renal failure and high-risk severe CRF43.
Two years after the recommendations carried out by the
FDA, a 71% decrease was observed in MRI in patients with
MDRD 30ml/min/1.73m2 and a 99% increase was observed
in requests for SCr a month before carrying out MRI70. A year
before, the European Medicines Agency also contraindicated
the use of the aforementioned GBCM in patients with severe
renal failure, infants and those awaiting liver transplantation43.
short review
According to Bennet et al., in Denmark since 2007 and in the
United States since 2009, no new cases of NSF have been
published71.
The possibility of this adverse reaction occurring should not
limit clinical action. It is essential to find a balance between
the guarantee of patient safety and the carrying out of the tests
necessary for correct clinical management. As such, the need for
a test and its effectiveness will be discussed clinically, and other
diagnostic options will be taken into account, as well as alternative
contrasts. In short, the risk/benefit will be weighed up.
CONCLUSIONS
GBCM are a group of drugs with differentiated physiochemical
characteristics that are increasingly being used in diagnosis
by MRI.
Due to the fact that they were initially used without taking
patients’ renal function into account, and without an exact
knowledge of the toxic doses permitted, a series of adverse
effects appeared, and in particular, the predominantly
dermatological multiple organ fibrosing disorder subsequently
known as NSF, which discredited its use.
The reporting of this delayed and potentially severe adverse
reaction marked a turning point, since it made it compulsory
to establish consensuses to protect patients by assessing the
GFR and risk factors. All of this along with dose adjustment
have decreased the number of adverse reactions significantly
and in the last five years there have hardly been any published
cases with the use of gadolinium.
Table 7. Measures to avoid nephrogenic systemic fibrosis
development
Table 8. Administration of gadolinium adjusted to renal
function
- Know the possibility of this delayed adverse reaction to
identify it and warn about it
GFR >60mL/min
- Avoid the administration of gadolinium in patients
with a glomerular filtration rate <30mL/min (1% of the
population) 82
- Use the minimum dose diagnosed, respecting a 1
week interval to repeat an MRI with contrast. The
risk increases in patients with end-stage renal disease
from 1.5% with a single dose to 12.1% with a double
dose (frequently used in angiographic and oncological
studies)
- I n f o r m t h e p a t i e n t a b o u t t h e r i s k o f s u ff e r i n g
this adverse reaction and consider the possibility
o f i n t ro d u c i n g t h i s i n f o r m a t i o n i n t h e i n f o r m e d
consent
Nefrologia 2014;34(4):428-38
There are no limitations on the administration of Gd, but it is
necessary to always try and respect the measures with regard
to dose and administration time
GFR 30-60mL/min
It may be administered whenever the maximum measures of
safety are taken into account in the doses administered and
at intervals of 1 week between MRI
GFR <30mL/min
Do not administer Gd. Seek diagnostic alternatives
GFR: glomerular filtration rate, Gd: gadolinium.
435
short review
As for IAR, all GBCM have a low and similar incidence,
although there are some differences between them, with
gadodiamide having the lowest incidence 63,64,67. These
reactions, although they are generally mild, can occasionally
be severe and even fatal.
Patient protection is key when GBCM are used in x-rays. The
identification and selection of patients at risk, the assessment
of the risk and benefit and informing the patient about the
adverse effects are essential.
In most cases, it is necessary to assess the patient, make a
multidisciplinary decision, and in particular, treat every case
individually.
Conflicts of interest
The content of this review is based on an update of Working
Session presentations sponsored by GE Healthcare entitled
What happened to NSF? The current situation, which took
place at the XXXI SERAM Conference (Granada, 2012). The
publication of this review was carried out independently of
the Working Session sponsor.
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Sent to review: 27 Nov. 2013 | Accepted: 8 Apr. 2014
438
Nefrologia 2014;34(4):428-38
special articles
Treatment of hyponatremia induced by the syndrome
of Inappropriate antidiuretic hormone secretion:
a multidisciplinary algorithm
Isabelle Runkle1, Carles Villabona2, Andrés Navarro3, Antonio Pose4, Francesc Formiga5,
Alberto Tejedor6, Esteban Poch7
1
Servicio de Endocrinología. Hospital Universitario Clínico San Carlos. Madrid (Spain); 2 Servicio de Endocrinología. Hospital Universitari
de Bellvitge. L’Hospitalet de Llobregat, Barcelona (Spain); 3 Servicio de Farmacia Hospitalaria. Hospital General Universitario de Elche.
Elche, Alicante (Spain); 4 Servicio de Medicina Interna. Hospital Universitario de Santiago de Compostela. Santiago de Compostela, La
Coruña (Spain); 5 Servicio de Medicina Interna. Hospital Universitari de Bellvitge. L’Hospitalet de Llobregat, Barcelona (Spain); 6 Servicio de
Nefrología. Hospital General Universitario Gregorio Marañón. Madrid (Spain); 7 Servicio de Nefrología. Hospital Clínic. Barcelona (Spain)
Nefrologia 2014;34(4):439-50
ABSTRACT
Introduction: The syndrome of inappropriate antidiuretic hormone
secretion (SIADH) is the most frequent cause of hyponatremia in a
hospital setting. However, detailed protocols and algorithms for its
management are lacking. Our objective was to develop 2 consensus
algorithms for the therapy of hyponatremia due to SIADH in hospitalized
patients. Material and methods: A multidisciplinary group made up
of 2 endocrinologists, 2 nephrologists, 2 internists, and one hospital
pharmacist held meetings over the period of a year. The group worked
under the auspices of the European Hyponatremia Network and the
corresponding Spanish medical societies. Therapeutic proposals were
based on widely-accepted recommendations, expert opinion and
consensus guidelines, as well as on the authors’ personal experience.
Results: Two algorithms were developed. Algorithm 1 addresses acute
correction of hyponatremia posing as a medical emergency, and is
applicable to both severe euvolemic and hypovolemic hyponatremia.
The mainstay of this algorithm is the iv use of 3% hypertonic saline
solution. Specific infusion rates are proposed, as are steps to avoid or
reverse overcorrection of serum sodium levels. Algorithm 2 is directed
to the therapy of SIADH-induced mild or moderate, non-acute
hyponatremia. It addresses when and how to use fluid restriction,
solute, furosemide, and tolvaptan to achieve eunatremia in patients
with SIADH. Conclusions: Two complementary strategies were
elaborated to treat SIADH-induced hyponatremia in an attempt to
increase awareness of its importance, simplify its therapy, and improve
prognosis.
Keywords: Hyponatremia. SIADH. Antidiuretic hormone.
Tratamiento de la hiponatremia secundaria
al síndrome de secreción inadecuada de la hormona antidiurética:
algoritmo multidisciplinar
RESUMEN
Introducción: El síndrome de secreción inadecuada de la hormona antidiurética (SIADH) es la causa más frecuente de hiponatremia en el paciente hospitalizado. Sin embargo, faltan protocolos y algoritmos concretos
que faciliten su abordaje terapéutico. Nuestro objetivo fue el desarrollo
de dos algoritmos de tratamiento de la hiponatremia secundaria al SIADH
en el paciente ingresado. Material y método: Un grupo multidisciplinar
español compuesto por 2 especialistas en Endocrinología, 1 en Farmacia
Hospitalaria, 2 en Medicina Interna y 2 en Nefrología se reunieron durante un año, bajo la tutela del grupo español del European Hyponatremia
Network, y de las respectivas sociedades científicas españolas. Las pautas
terapéuticas propuestas fueron basadas en recomendaciones ampliamente aceptadas, la práctica de expertos, guías de consenso, así como en la experiencia clínica de los autores. Resultados: Se elaboraron dos algoritmos
de tratamiento. El Algoritmo 1 se dirige al tratamiento de la hiponatremia aguda como urgencia médica de abordaje inmediato, y es de aplicación al tratamiento de la hiponatremia grave tanto de tipo euvolémico
como hipovolémico. Se basa en el uso de sueros salinos hipertónicos al
3 % i.v., con pautas de infusión y monitorización. Se expone cómo evitar la hipercorrección de la natremia y cómo corregirla en su caso. El
Algoritmo 2 aborda el tratamiento de la hiponatremia no aguda leve o
moderada asociada al SIADH. Expone cómo y cuándo usar la restricción
hídrica, solutos, furosemida y tolvaptán, para alcanzar eunatremia en el
paciente con SIADH. Conclusiones: Se han elaborado dos estrategias complementarias para el tratamiento de la hiponatremia inducida por SIADH,
en un intento de fomentar la toma de conciencia acerca de esa patología,
simplificar su abordaje y su tratamiento y, así, mejorar su pronóstico.
Palabras clave: Hiponatremia. SIADH. Hormona antidiurética.
Correspondence: Esteban Poch
Servicio de Nefrología. Hospital Clínic.
Villarroel, 170. 08036 Barcelona. (Spain)
[email protected]
* In agreement with the authors and the editors, this paper has been published also in Medicina Clinica:
Med Clin (Barc) 2013;141(11):507.e1-507.e10. http://dx.doi.org/10.1016/j.medcli.2013.09.002
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INTRODUCTION
The Syndrome of Inappropriate Antidiuretic Hormone
Secretion (SIADH) is characterized by the presence of
hypotonic hyponatremia in a context of inadequately
diluted urine given the hypoosmolality in plasma, in the
absence of a low effective circulating volume. (either
with hypovolemia or hypervolemia). For its diagnosis,
the following conditions must be excluded: hypotension,
renal failure, adrenal insufficiency, severe hypothyroidism,
as well as non-osmotic physiologic stimuli of arginine
vasopressin (AVP) secretion. In SIADH, a lowering of
plasma osmolality (Posm) does not inhibit AVP secretion as
expected, and free water is inappropriately reabsorbed at
the level of the collecting duct of the nephron, thus inducing
further hemodilution and hyponatremia, concomitantly
with an inappropriately elevated urine osmolality (Uosm)1,2.
In the less frequent Syndrome of Inappropriate Antidiuresis
(SIAD), ADH secretion is inhibited, but an activating
mutation of collecting duct V2 receptors imitates excessive
ADH-induced water reabsorption3-5.
Major advances have taken place over the last few
years in our understanding of the negative consequences
of hyponatremia. Mild, chronic hyponatremia is not
asymptomatic. On the contrary, it is accompanied by mental
symptoms, impaired gait, falls6, fractures7-9, and possibly
osteoporosis10, as well as increased mortality9, 11-14. Severe
hyponatremia per se can be life-threatening, inducing
profound cerebral edema and potentially brain herniation
and death. Even once hyponatremia is corrected, complete
neurologic recovery can take weeks, and some patients
will have permanent neurologic sequelae as a consequence
of profound hyponatremia15. Yet overly rapid correction of
serum sodium can induce osmotic demyelination syndrome
(ODS). Adequate and prompt correction of hyponatremia
is thus imperative, avoiding and/or dealing immediately
with overcorrection, while assuring that eunatremia is
ultimately achieved.
Close to 30% of hospitalized patients are hyponatremic
at some time during their hospital stay 13,16,17 , yet
hyponatremia is often overlooked and undertreated, even
in its most severe forms. A correct diagnosis of the cause
of hyponatremia is per se associated with reduced inhospital mortality, as indicated by a lower death rate in
patients with hyponatremia in whom plasma and/or urine
Osmolality have been determined18. And specific treatment
directed towards correcting hyponatremia is accompanied
by a lower death rate.19
SIADH is considered to be the most frequent cause of
hyponatremia in a hospital setting 20. However, detailed
protocols and algorithms for its management are lacking.
A new class of therapeutic agents, the vaptans, is currently
available for the treatment of SIADH in the adult. They
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Isabelle Runkle et al. Treatment of SIADH
block the AVP-responsive V2 collecting duct receptors
that ultimately induce apical expression of aquaporin 2
channels through which water is reabsorbed following AVP
stimulus21. Tolvaptan is the only drug of its class authorized
by the European Medicines Agency, and is a selective V2receptor blocker. Its addition to the therapeutic arsenal
of 3% hypertonic saline solution, furosemide, solute, and
fluid restriction further warrants a specific guide to the
treatment of SIADH-induced hyponatremia.
Our objective was to develop two consensus algorithms
for the therapy of hyponatremia due to SIADH in
hospitalized patients. These algorithms address acute
correction of hyponatremia posing as a medical emergency
(Algorithm 1) and correction of mild or moderate, nonacute hyponatremia requiring less aggressive measures
(Algorithm 2).
MATERIALS AND METHODS
The algorithms were developed by a multidisciplinary
group made up of 2 Endocrinologists, 2 Nephrologists,
2 Internists, and 1 Hospital Pharmacist. Over the
period of a year, the group held meetings and worked
on-line, organized under the auspices of the European
Hyponatremia Network and the corresponding Spanish
Medical Societies.
Given the dearth of evidence in many aspects of the
management of hyponatremia, we have based the algorithms
we present on widely-accepted recommendations, expert
opinion and consensus guidelines 22, as well as on the
authors’ personal experience. Application of the protocol
should be flexible, and adapted to the specific needs of
each patient, as is always the case in clinical medicine.
EXPLANATION OF THE ALGORITHMS AND THEIR USE
The severity of the patient’s neurologic symptoms will
be the most important element to be considered when
choosing which algorithm to apply initially22, together with
other factors presented in tables 1 and 2. Aggressive and
prompt correction (Algorithm 1) is particularly important
in subjects with acute and/or severe symptomatic
hyponatremia indicative of substantial cerebral edema, in
patients with hypoxemia23-28, in children and in women of
child-bearing age27.
When applying either algorithm, medication that can
potentially cause hyponatremia must be discontinued
when feasible. Pain and nausea are potent stimuli of AVP
secretion and must be adequately treated. If the underlying
cause of SIADH-induced hyponatremia is not evident, a
Chest x-ray, brain, cervical and thoracic CT, and abdominal
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Table 1. Definitions
The Syndrome of Inappropriate Antidiuretic Hormone
Secretion
Euvolemic Hyponatremia :
- Rule out a low effective circulating volume (normal OP,
normal CVP, absence of orthostatic hypotension, ascites,
and edema)
- Rule out diuretic therapy
- Rule out adrenal and renal failure, severe hypothyroidism
- Rule out physiologic stimuli of ADH secretion (post-surgery,
pain, etc.)
and:
-SNa < 135 mmol/L
-Posm < 275 mOsm/Kg
-Uosm > 100 mOsm/Kg
-UNa > 40 mmol/L when sodium intake is adequate
OP: ocular pressure; CVP: central venous pressure; SNa: serum
sodium concentration; Posm: plasma osmolality; Uosm: urine
osmolality; UNa: urine sodium concentration.
ultrasound must be considered. If ordered, these diagnostic
tests should follow initial emergency correction of SNa and
improvement of patient’s symptoms if hyponatremia is
severe.
Application of Algorithm 1
In the setting of acute and/or severe hyponatremia with
symptoms indicative of profound cerebral edema,
the initial aim of this algorithm is reduction of said
edema, while avoiding overcorrection of serum sodium.
It is applicable to severe euvolemic or hypovolemic
hyponatremia per se, regardless of the cause, and thus
prior to diagnosis of its origin. The algorithm specifies
initial treatment of cerebral edema with 3% hypertonic
saline iv, monitoring of the subsequent rise in serum
sodium concentration (S Na), and avoidance or treatment
of overcorrection of hyponatremia.
Hypertonic saline solution
1. 3% Hypertonic saline is the mainstay of treatment.
The mainstay of therapy is the use of 3% hypertonic
saline solution (HSS) administered iv 29 , to assure
the movement of water from the intracellular to the
intravascular compartment following an osmotic
gradient, thereby reducing neuronal edema. A central
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venous line is unnecessary and can only delay treatment.
3% saline, if unavailable, can be prepared by adding 60
ml of 20% saline to 500 ml of 0.9% isotonic saline. The
resulting solution must be shaken before administration.
Immediately prior to initiating treatment, blood must be
drawn for determination of SNa, serum potassium (SK),
urea, creatinine and plasma osmolality (P osm ). Urine for
the determination of Na (U Na), K (U K) and U osm must be
obtained as soon as possible, without delaying initiation
of hypertonic saline administration. Hypoxemia must
be ruled out and corrected if detected, since it worsens
prognosis 23-28.
Infusion rate. We propose an initial iv infusion rate of
3% HSS at 0.5 ml/Kg/hour or 1-2 ml/Kg/hour depending
on the severity of the neurologic symptoms 30,31. Patients
in coma, or presenting with seizures, stupor or respiratory
distress, should be started on an initial infusion rate of 2
ml/Kg/hour In these patients, an alternative can be the
administration of an iv bolus of 100 ml of 3% HSS, that
can be readministered up to 2 more times at 10-minute
intervals, and stopped once the acute symptoms have
subsided 22,32. We do not advise the use of formulas to
estimate the quantity and rate of infusion, since these
calculations often lead to overcorrection 32-34 and can
needlessly complicate therapy.
As previously mentioned, treatment must be particularly
aggressive in children and in women of child-bearing
age 27 , given that their risk of severe hyponatremic
encephalopathy is higher, potentially leading to
subsequent brain herniation and death, or permanent
neurologic sequelae. This is also the case for patients with
acute hyponatremia. Patients who have recently ingested
large quantities of liquid (acute water intoxication) are at
special risk, since their neurologic symptoms and serum
sodium will often worsen as they continue absorbing
water from the gastrointestinal tract 35. We note that in
these patients, sodium levels in arterial blood are often
several mmol/L lower than in peripheral venous blood,
and thus the latter can underestimate the true degree of
hyponatremia36.
HSS can induce substantial water diuresis, favoring
overcorrection. Thus diuresis must be closely monitored
to detect frank polyuria (urine output of approximately 2
ml/Kg/hour) and the need to initiate corrective measures
directed towards relowering of SNa. These patients are
also candidates to receive 1 mcg of sc or iv desmopressin
directly upon detection of polyuria, thus preventing an
excessive rise in serum sodium32,37.
Specific treatment goals of hypertonic saline infusion.
In the treatment of patients with chronic hyponatremia
(of a duration of 48 or more hours), the maximum
recommended rise in SNa is currently 10 mmol/L in 24
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Table 2. Classification of hyponatremia according to severity of clinical symptoms
Severe
Symptoms
Outlinea
-
-
-
-
Moderate
Stupor
Coma
Convulsions
Respiratory Distress
-
-
-
-
-
Mild
Nausea
Vomiting
Disorientation
Somnolence
Confusion
-
-
-
-
-
Headache
Attention deficit
Memory impairment
Gait impairment
Cognitive impairment
Moderate/severe symptoms, usually:
[SNa] < 120 mmol/L
Mild/moderate symptoms, usually :
[SNa] > 120 mmol/L
See Algorithm 1: Acute therapy (medical emergency)
See Algorithm 2: Non-acute therapy
Therapeutic objective: Eunatremia (SNa > 135 mmol/L)
- Factors that favor the use of Algorithm 1:
Women of child-bearing age
Children
Brain tumors/hemorrhage
Hypoxemia (pO2a < 70mmHg)
SNa < 120 mmol/L
Usually < 48 hours duration
- Factors that favor the use of Algorithm 2:
Malnutrition
Hypokalemia
Frail elderly
SNa > 120 mmol/L
Usually > 48 hours duration
Laboratory evaluation: plasma and urine electrolytes and osmolality
General therapy. Correct hypoxemia
Consider the magnitude and speed of the reduction of SNa
SNa; serum sodium concentration; pO2a; partial pressure of oxygen in arterial blood.
a
hours, and 18 mmol/L in 48 hours, to avoid the appearance
of osmotic demyelination syndrome 22. Furthermore, a
4-6 mmol elevation in sodium levels is accompanied by
a reduction in cerebral edema of the order of 50%38. A
recent study found that patients presenting an initial SNa
below 120 mmol/L had a higher mortality rate if their
S Na rose less than 6 mmol/L over the first 24 hours of
treatment 39 . Thus, our aim should be to achieve an
increase in serum sodium of the order of 6 to 8 mmol over
a 24-hour period. Avoiding overcorrection is particularly
important in patients at a high risk of developing the
osmotic demyelination syndrome such as alcoholics,
patients who are malnourished, and those presenting
hypokalemia 40-42. In these patients maximum correction
rates should therefore be from 6 to 8 mmol/L and from 14
to16 mmol/L over 24 and 48 hours respectively. However,
in patients with acute hyponatremia S Na can rise more
quickly, without negative consequences.
Monitoring and discontinuing hypertonic saline
infusion. SNa should be repeated 2 hours after initiating
HSS infusion. If sodium levels have risen more than 6
mmol/L, saline infusion must be stopped, since S Na can
still rise after the infusion has been discontinued. If
serum sodium has increased 1 to 6 mmol/L, infusion can
be maintained at the same rate. If there is no increment
in SNa , the infusion rate should be increased by 50-100%,
taking into account the clinical status of the patient. If
bolus therapy has been used, sodium levels should be
monitored 30 minutes after the last bolus.
No other treatments that raise serum sodium levels should
be given concomitantly with hypertonic saline, with the
SNa should once more be monitored 2 hours later (4 hours
after initiation of saline infusion). If a patient has yet to
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exception of iv furosemide in patients with a history of
heart failure. Since the combination of hypertonic saline
and a loop diuretic will increase sodium levels more than
the use of hypertonic saline alone, the initial objective in
these patients should be a rise in SNa of approximately 4-5
mmol/L with hypertonic saline infusion.
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Hyponatremia with moderate/severe symptoms and/or a duration ≤ 48 hours
(SNa < 120 mmol/L)
Hypertonic saline
solution a,b,c
Nacl 3% (513 Mmol/L)
Severe symptoms
1-2 mL/kg/h or iv
bolus 100 ml
Moderate symptoms
0,5 mL/kg/h
Evaluate 2 hours
later
SNa Increase < 1 mmol/L
SNa Increase = 1-6 mmol/L
Maintain
infusion rate
Increase infusion rate
50%-100%
SNa Increase >6 mmol/L
Stop
hypertonic saline
infusion
Evaluate 2 hours later
SNa < 120 mmol/L
and/or SNa increase <2 mmol/L
from start
Severe
symptoms
SNa = 120-130 mmol/L
and/or SNa increase >6 mmol/L
from start
Moderate
symptoms
Consider mantaining
infusion rate and reevaluating
4-6 hours later
Stop hypertonic
saline infusion
Reevaluate patient:
- Clinical picture
- Diagnostic studies
- Complete lab work, imaging, etc.
- Treat underlying disease
SNa > 130 mmol/L and/or
SNa increase >8 mmol/L
from start
Consider relowering SNa to avoid
ODS:
- Oral fluids
- 5% dextrose solution (6 mL/kg/h
during 2 hours) followed by
measurement of Nap
- Desmopressin 1-2 μg sc or iv q 6-8
hours
Consider transition
to Algorithm 2
Consider oral treatment
Algorithm 1. Acute therapy.
a,b
Prepatation of 3% hypertonic saline solution: Add 60 ml of 20% NaCl saline solution to a 500 mL 0.9 % isotonic saline NaCl al 0,9%,
and shake well. Administer vía peripheral vein; c Consider furosemida 20 mg iv (history of heart failure)
Valorar transición
SNa: serum sodium concentration; ODS: osmotic demyelination syndrome; SC: subcutaneous; IV: Intravenous
a Algoritmo 2
present an increase of 2 mmol/L, and shows insufficient
clinical improvement, the rate of saline infusion should
again be increased, with SNa determined once more after
two hours. If the patient presents only moderate or mild
symptoms, the infusion rate can be maintained and SNa
repeated 4-6 hours later. In patients whose SNa has risen
over 6 mmol/L , saline infusion should be discontinued. If
SNa has risen over 8 mmol/L, corrective measures should
be initiated (see below). If the rise in SNa is between 2
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and 6 mmol/L, infusion should be maintained, and S Na
monitored every 2 hours until it has risen by 6 mmol/L.
One of the most important recommendations we can make
in the use of hypertonic saline is that the prescribing
physician personally supervise cessation of the iv infusion.
Once hypertonic saline infusion has been discontinued,
and until 24 hours have passed since the start of treatment,
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oral salt can be administered and fluid restriction
initiated in patients with SIADH. Other measures that
can potentially raise SNa should be avoided, to decrease
the risk of overcorrection. We include potassium chloride
(KCl) in this category: mild hypokalemia should not be
corrected until the following day, since KCl administration
will increase serum sodium levels.
Corrective Measures to Relower Serum Sodium
Relowering of serum sodium, following an excessive
rise, prevents ODS. The development of ODS has been
associated with an excessive rise in serum sodium over
a 24 or 48 hour period. ODS can induce death or leave
permanent neurologic sequelae. It is for this very reason
that the 2007 guidelines22 recommend a maximum serum
sodium increment of 10 mmol/L and 18 mmol/L in 24
and 48 hours respectively. However, a rapid reinduction
of hyponatremia has been shown to prevent ODS
symptoms 37,43,44 and has been successfully used to treat
patients that have developed ODS45-49.
Specific Measures
If S Na is overcorrected (S Na rise greater than 8 mmol/L
following discontinuation of HSS or SNa rise greater than
10 mmol/L 24 hours after initiation of therapy), measures
should be taken immediately to once again lower the SNa
level. These include oral liquids, 5% iv dextrose solution
(4-6 ml/Kg/hour for 2 hours with subsequent reevaluation
of S Na) and 1-2 mcg iv or sc desmopressin every 6
hours if and as needed 37. When using desmopressin, we
recommend a lower initial rate of dextrose infusion: 1.5 to
2 ml/Kg/hour, repeating SNa 2 hours later, and increasing
the dextrose infusion rate as necessary. A lowering rate of
1 mmol/L/hour has been recommended50. The association
of desmopressin to iv dextrose is particularly important in
patients who will not otherwise reabsorb large quantities
of water in the collecting duct, as is the case of patients
with primary polydypsia, and other patients with low
U osm. With low AVP levels, these patients will have few
patent aquaporin-2 channels, (reflected by a low U osm)
and desmopressin should be administered for dextrose
infusion to be useful. Iv furosemide can be administered
once the desired serum sodium level has been reached, to
put a halt to a further reduction in SNa.
Patients at high risk for overcorrection. Certain groups
of patients present a higher risk of overcorrection of serum
sodium than others, and must be more closely monitored.
These include patients in which the cause of hyponatremia is
transitory, e.g. hyponatremia-inducing medication which has
just been discontinued, or physiologic stimuli of AVP secretion
once the stimulus has passed32. Patients with an extremely low
salt intake prior to admission also fall into this category.
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Patients with adrenal failure, either primary or secondary,
are a separate case. They should receive high enough
hydrocortisone doses to cover their glucocorticoid and
mineralocorticoid needs. S Na can rise very quickly after
initiation of steroid therapy, particularly if high doses of
hydrocortisone are given, and especially if administered
by iv bolus, as when treating an adrenal crisis. In
these patients, if SNa rises by 8 mmol/L before 24 hours
have elapsed since the start of treatment, 1-2 mcg of
iv or sc desmopressin can be administered every 6-8
hours to prevent a further increment in S Na levels. In
many patients, however, the infusion of lower doses of
hydrocortisone will be sufficient (between 60-150 mg
daily 51, with or without an intial bolus of 50 mg iv) and
will induce a slower rate of correction of SNa levels. In
even milder cases, oral hydrocortisone can be given at a
dose of 20 mg tid.
Application of Algorithm 2
The aim of algorithm 2 is to achieve eunatremia in patients
with SIADH-induced mild or moderate hyponatremia not
posing as a medical emergency.
Correction of hypokalemia
If hypokalemia is present, Potassium Chloride supplements
should be given, taking care NOT to administer potassium
bicarbonate, or potassium supplements that result in the
generation of bicarbonate, since the latter will increase
renal sodium excretion, and can induce metabolic
alkalosis52.
Solute Administration
Patients with SIADH should have an adequate oral salt
intake. A hospital diet frequently provides less than
4 grams of sodium chloride a day. Furthermore, many
patients eat considerably less than what is provided, and
will have an even lower sodium intake. We recommend
the association of NaCl supplements, for a minimum
consumption of 5 to 8 grams of salt daily.
The administration of large amounts of solute can be
used for the treatment of SIADH – induced hyponatremia,
acting through the induction of increased renal obligatory
water clearance. In this case, oral salt supplementation
can range from 3 to 4 grams every 8 hours, and must
be even higher in exceptional cases. Close monitoring of
blood pressure is essential. Another solute that has been
given for the treatment of SIADH hyponatremia is oral
urea, at doses of 30 g a day, usually given in two 15 g
doses 53. Urea could be the therapy of choice in children
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with SIADH 54. However, its low palatability has limited
its use.
Fluid Restriction
Currently, fluid restriction is the cornerstone of treatment
of SIADH-induced hyponatremia not requiring urgent
intervention. By fluid restriction we mean the reduction
of all liquids administered to the patient, be it with iv
medication, oral liquids, or the intrinsic water content
of foods. To adequately initiate fluid restriction, iv
medication must be concentrated whenever feasible, and
non-essential oral and iv medication discontinued. Oral
liquid intake must be limited and foods with a high water
content eliminated from the diet (soups, mashed foods,
coffee, tea, gelatins, semi-liquid desserts, melons, citric
fruits, etc. ).
In our experience, the Furst formula 55 is useful in
predicting which patients will respond adequately, and is
calculated by dividing the sum of U Na and U K (mmol/L)
by SNa. Patients with a result less than 0,5 can be limited
to 1000 ml of total liquid intake, whereas those between
0,5 and 1 need to be limited to 500 ml of liquid a day.
Patients with a result of 1 or more will not respond to
fluid restriction, since their nephrons are not capable
of eliminating electrolyte-free water. In this case fluid
restriction to 500 ml daily is used to prevent worsening of
hyponatremia, not to correct it. The response of a specific
patient to fluid restriction is not constant, and can vary
from one day to another. Therefore, for a correct use of
the Furst formula, electrolytes must be measured in serum
and urine frequently. We consider a positive response to
be an average 2 mmol/L rise in S Na per day over a 2-day
period.
Fluid restriction is not practical in all patients, and
is simply incompatible with necessary medication or
artificial nutrition in others. Another group does not
tolerate or does not respond to the required fluid restriction.
Furthermore, fluid restriction to 500 ml makes meals less
palatable, and can worsen the nutritional status of the
patient if used for more than a few days. In these cases,
together with those presenting a Furst formula result of 1
or more, alternative therapies must be initiated.
Furosemide Therapy
Furosemide can be useful as a short-term treatment for
SIADH hyponatremia when the UOsm is sufficiently high,
as it induces an increase in renal free water clearance. For
this loop diuretic to be effective, UOsm must be over 350
mOsm/Kg, and preferably over 400 mOsm/Kg. Sodium
losses must be compensated by sufficient oral salt intake.
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Furosemide can be administered iv or orally, in doses
ranging from 20 mg iv every 8 to 24 hours, or 40 mg
every 8 to 24 hours p.o., although higher doses have
been successfully given56,57. The use of this loop diuretic
is particularly helpful in patients in whom SIADH will
presumably be of limited duration (days), as is the case of
patients with pneumonia or drug-induced SIADH when
the medication can be discontinued (table 3).
Furosemide can also be useful in patients with serum
sodium levels below 120 mmol/L presenting with
moderate or mild symptoms, sodium levels higher that
115 mmol/L, and a low risk for herniation (ie the elderly).
In this case serum sodium should be repeated 3 to 6 hours
after an iv dose.
Tolvaptan Therapy
We recommend the use of tolvaptan, the selective V2
receptor inhibitor58, in patients with SIADH who are not
candidates for fluid restriction or furosemide. The drug is
particularly useful in patients that will need treatment of
their hypotonic hyponatremia for several days, or longer,
as occurs in patients with chronic SIADH.
Initiation and monitoring of tolvaptan therapy. We
prefer to start tolvaptan in patients in whose Nap has
already risen above 119 mmol/L, since patients with
lower serum sodium levels seem to be at a higher risk
for overcorrection, in our experience as well as in that of
others (Dr. Volker Burst, University of Cologne, personal
communication).
Tolvaptan therapy must always be initiated while the
patient is hospitalized. Care should be taken to assure that
during the first day of tolvaptan administration patients
not only have free access to liquids, but also are actively
encouraged to drink ad libitum, since maximum aquaresis
is observed precisely on day 1, when excess circulating
water is greatest. Patients who have previously been on
fluid restriction are prone to not drinking as much as
they desire and must be closely monitored. If a patient
has a limited capacity to drink (ie oral or gastrointestinal
disease) 5% dextrose solution should be associated from
the start. Patients with a nasogastric tube will also need
increased liquids. In these cases, diuresis is helpful in
estimating increased fluid needs.
The initial recommended dose is of 15 mg p.o., although
several groups prefer to start treatment with 7.5 mg 59,60,
(Dr. Volker Burst, personal communication). It is
preferable to administer tolvaptan early in the morning (7
to 9 AM), to facilitate monitoring of the patient’s response,
and to assure adequate nocturnal rest. We recommend
measuring serum sodium, potassium and POsm as well as
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Moderate/mild symptoms and/or hyponatremia > 48 hours
Ensure minimum NaCl intake of 5 g p.o./day
(SNa ≥ 120 mmol/L)
(UNa+UK)/SNa <0.51 a
(UNa+UK)/SNa > 1a
(UNa+UK)/SNa = 0.51-1ª
Fluid Restric. < 1000 ml/dayc
Fluid Restric. Not Feasible b
Fluid restric. < 500 ml/dayc
Negative Response if SNa increases
< 2 mmol/L in 24 hours 2 consecutive days.
h f
TOLVAPTAN
15 mg/day
Discontinue fluid restrictiond,e
Reevaluate 6 hours laterg,h
SNa Increase ≤ 5 mmol/L from start
SNa Increase >5 mmol/L
Reevaluate 24 hours laterg,h
Consider discontinuing treatment and taking
corrective measures to avoid development of
ODS
- Oral fluids
- 5% Dextrose solution iv (6 ml/kg/h during 2
hours) followed by measurement of SNa
- Desmopressine 2 mcg SC o IV q.6.h.
- Skip the next dose of tolvaptan
Evaluate SNa increase and clincal status:
SNa increase ≤ 0,4 mmol/L/h
and
SNa < 128 mmol/L
or
SNa increase ≤ 8 mmol/L from start
Adapt TOLVAPTAN dose to responseg (if SNa < 135 mmol/L)
TOLVAPTANhf
30 mg/day
Reevaluate in 24 hours
SNa Increase ≤ 5 mmol/L
TOLVAPTAN
60 mg/day
SNa Increase > 5 mmol/L
Maintain TOLVAPTAN
30 mg/day
Reevaluate in 24 hours
Duration of treatment of SIADH
based on etiology (table 3)
Hospital discharge
Follow-up 1 week later
Follow-up 2-4 weeks later (consider etiology)
and 1 week after discontinuation
Algorithm 2. Non-acute treatment.
a
Furst H, et al. Am J Med Sci 2000;319(4):240-244; b Parenteral nutrition, or iv liquids that prevent fluid restricction, or patien
intolerance; c Consider furosemide if Osmou >350 mOsm/Kg; d The patient must be able to drink ad libitum; e See warnings on text;
f
Tolvaptan summary of characteristics (Samsca®). Laboratorios Otsuka. g Measure electrolytes and Osmolality in plasma and urine;
h
Measure diuresis and liquid intake every 6 horas. If balance excessively negative: take corrective measures; especially important in
patients with intial SNa< 125 mmol/L.
Available at URL: http://www.ema.europa.eu. Access: November 2011.
SNa: serum sodium concentration; UNa and UK =Urine concentrations of sodium and potassium mmol/L; Osmou: urine osmolality;
ODS: osmotic demyelination syndrome; SC: subcutaneous; IV: intravenous; SIADH: syndrome of inappropriate antidiuretic hormone
secretion.
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sodium, potassium and osmolality in urine at baseline,
and 6 hours after the initial dose, with monitoring of fluid
intake and diuresis every 6 hours.
Patients whose S Na has not increased by more than 5
mmol/L at 6-hours post-tolvaptan, and are drinking
freely can be monitored by fluid intake/diuresis alone,
with SNa repeated 24 hours after the initial dose. If at 6
hours from baseline, SNa has risen more than 5 mmol/L,
we recommend initiating corrective measures in order to
prevent an excessive rise in the 24-hour serum sodium
levels, , given that in our experience on day one of
tolvaptan therapy S Na will rise at nighttime, when the
patient`s fluid intake is low. These measures include an
increase in oral fluid intake, and 5% dextrose solution
iv infusion, at a rate of 3-4 ml/Kg/hour for 2 hours,
followed by a new determination of SNa. We have found
the association of desmopressin (iv or sc) to be useful in
avoiding overcorrection of S Na in spite of V2 blockade,
at doses of 2-4 mcg every 6 hours as needed. When
using desmopressin, we recommend starting with a lower
rate of dextrose infusion: 2 3ml /Kg/hour for 2 hours,
followed by measurement of S Na. The rate of infusion
is then increased every 2 hours as necessary to relower
sodium levels , with a goal of attaining a maximum
increment of 4 mmol/L over baseline. Patients whose
SNa has risen more than 5 mmol/L over the first 6 hours
should have S Na measured once more 12 hours from
baseline. Not all patients drink as needed and thus some
present a excessively negative fluid balance. They will
also require a new 12 h measurement of SNa.
If 24 hours following the first dose serum sodium
levels have increased more than 10 mmol/L, tolvaptan
should not be readministered on that day, and corrective
measures used as needed, although discontinuation of
tolvaptan administration is usually sufficient to relower
S Na to desired levels. The drug can be reintroduced on
the following day. If SNa has increased by less than 10
mmol/L, a new dose of 15 mg should be administered,
and S Na monitored on the following day. When the rise
in serum sodium levels is insufficient, the daily dose of
tolvaptan can be increased to 30 mg, with a maximum
dose of 60 mg/day. Experience with tolvaptan in Europe
is still somewhat limited, and its use will surely undergo
modifications in the future, particularly regarding doses.
Table 3. Probable duration of syndrome of inappropriate antidiuretic hormone secretion treatment as indicated by etiology
Etiology
Probable duration of SIADH
ADH-secreting tumors (ectopic SIADH) (oat-cell, etc.)
Function of the duration of the underlying disease
Medication-induced, with continued use of the
drug (carbamazepine, etc.)
Duration of treatment
Relative Risk of
chronic SIADH
1.0
1.0
Cerebral tumors
Function of the evolution of the underlying disease
0.8
Idiopathic SIADH of the elderly
Indefinite
0.8
Subarachnoid Hemorrhage
1-4 weeks
0.6
Stroke
1-4 weeks
0.5
Inflammatory Cerebral Lesions
Function of response to therapy
0.5
Respiratory Failure (COPD)
0.4
HIV Infection
0.2
Head Trauma
From 2-7 days to indefinite
0.2
Drug-induced, when the medication is
discontinued. (carbamazepine, etc.)
Function of the duration of treatment
0.1
Pneumonia
2-5 days
0
Nausea, pain, prolonged exercise
Variable, depends on the cause
0
Post-operative Hyponatremia
2-3 days
0
COPD: chronic obstructive lung disease; SIADH: Syndrome of onappropriate Antidiuretic Hormone Secretion; HIV: human
immunodeficiency virus.
Repoduced with author’s permission from Verbalis J. Managing patients with syndrome of inappropriate antidiuretic hormone
secretion. Endocrinol Nutr 2010;57(supl.2):30-40.
Nefrologia 2014;34(4):439-50
447
special articles
Tolvaptan: General Considerations. Tolvaptan has
important drug interactions which must be taken into
account before and during its use (Table 4). As a
substrate for cytochrome P450 3A4, circulating levels
of tolvaptan will increase when used with inhibitors,
and will drop when associated with inducers. Tolvaptan
at high doses (60 mgday) can increase serum digoxin
concentrations.
of more research directed towards gathering evidence
that can optimize therapy.
Tolvaptan should be used as monotherapy for SIADH,
and never be administered jointly with hypertonic
saline. On day 1 of use, it is preferable not to associate
potassium supplements, nor furosemide. Tolvaptan
should never be administered to a hypovolemic patient,
underlying the importance of a correct diagnosis of
SIADH. Tolvaptan is usually well tolerated, and in
our experience is very effective for attaining strict
eunatremia. However, intense thirst sometimes follows
its administration. When accompanied by the ingestion
of large quantities of liquid, thirst can lessen the
effectiveness of the medication, as can chronic pain.
Patients with SIADH type D (NSIAD due to an activating
V2 receptor mutation) will probably not respond to
tolvaptan treatment 61.
Duration of Treatment. Out-patient follow-up. The
duration of tolvaptan treatment is determined by the
persistence of the underlying cause of the patient’s
SIADH (Table 3). When discontinuing tolvaptan, a
progressive reduction in dose is always preferable
to abrupt withdrawal of the medication. In patients
discharged on tolvaptan therapy, we recommend
repeating SNa within a week, with new laboratory tests
2 to 4 weeks later, then monthly. In patients with
chronic SIADH, in our experience, the tolvaptan dose
can be progressively reduced once strict eunatremia is
achieved. Patients with particularly low maintenance
doses of tolvaptan may need higher doses once more
in situations of increased liquid administration, and /or
low salt intake, such as typically occurs with hospital
readmission.
CONCLUSIONS
Hyponatremia is a very common disorder, yet it remains
underdiagnosed, underappreciated, and often incorrectly
managed. Concrete roadmaps for the treatment of
hyponatremic patients are lacking. We have elaborated
two complementary strategies to treat SIADH-induced
hyponatremia in an attempt to increase awareness of its
importance, simplify its therapy, and improve prognosis.
In spite of the frequency and negative repercussions of
hyponatremia, there is a paucity of evidence in the field
of hyponatremia and its therapy. We are clearly in need
448
We hope that the application of this protocol will
simplify and help bring consistency to the treatment of
SIADH-induced hyponatremia, thus reducing morbidity,
and facilitating the accumulation of evidence.
Isabelle Runkle has worked as a consultant for Otsuka and has
given sessions sponsored by Otsuka, Amgen and Novartis.
Carles Villabona has worked as a consultant for Otsuka and
has given sessions sponsored by Novartis, Ipsen and Otsuka.
Andrés Navarro has worked as a consultant for Otsuka.
Antonio Pose has worked as a consultant for Otsuka,
Boehringer, MSD, Rovi and Almirall, and has given sessions
sponsored by Otsuka, Almirall, Boehringer, Novartis, Astra,
Bristol, Lilly, Bayer, Sanofi, Lacer and Novo.
Francesc Formiga has worked as a consultant for Otsuka and
has given sessions sponsored by Otsuka.
Alberto Tejedor has worked as a Nephrology consultant
for the Spanish Agency of Medicines and the European
Medicines Agency. He has been a consultant for Otsuka and
Astra Zeneca.
Esteban Poch has worked as a consultant for Otsuka and has
given sessions sponsored by Otsuka.
Table 4. Tolvaptan drug interactions
- Tolvaptan should be administerd with caution when used
together with CYP3A4 inhibidores (such as ketoconazol,
diltiazem, macrolides) since these drugs increase circulating
levels of tolvaptan.
- Tolvaptan action is reduced when co-administered with
CYP3A4 inducers (such as rifampicine, barbiturates) as well
as when co-administered with cylcosporine.
- Grapefruit juice can increase the activity of tolvaptan, and
should be avoided.
- No interactions have been observed with CYP3A4
substrates (such as warfarin or amiodarone).
- Circulating levels of lovastatin are increased.
- Doses of 60 mg increase digoxin levels, requiring that the
latter be measured.
Nefrologia 2014;34(4):439-50
special articles
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Sent to review: 1 Sep. 2013 | Accepted: 14 Apr. 2014
450
Nefrologia 2014;34(4):439-50
originals
Predictive factors for kidney damage in febrile urinary
tract infection. Usefulness of procalcitonin
Elena Lucas-Sáez1, Susana Ferrando-Monleón2, Juan Marín-Serra3, Ricardo Bou-Monterde4,
Jaime Fons-Moreno5, Amelia Peris-Vidal6, Aurelio Hervás-Andrés7
1
Departamento de Pediatría. Hospital de Manises. Valencia (Spain); 2 Departamento de Pediatría. Hospital La Ribera. Alzira, Valencia
(Spain); 3 Departamento de Pediatría. Hospital Clínico Universitario de Valencia (Spain); 4 Unidad de Epidemiología. Hospital La
Ribera. Alzira, Valencia (Spain); 5 Departamento de Pediatría. Hospital Clínico Universitario de Valencia. Universidad de Valencia
(Spain); 6 Servicio de Pediatría. Centro de Salud Serreria II. Valencia (Spain); 7 Departamento de Pediatría. Hospital Lluís Alcanyís.
Xátiva, Valencia (Spain)
Nefrologia 2014;34(4):451-7
Objective: To establish the utility of procalcitonin (PCT) and other
clinical and analytical parameters as markers of acute and permanent
renal damage in children after a first febrile urinary tract infection
(UTI). Methods: Retrospective multicentre study. Statistical study:
descriptive, receiver operating characteristic (ROC) curves and
multiple logistic regression. Results: 219 patients, aged between 1
week and 14 years (68% under 1 year). The mean PCT values were
significantly higher in patients with acute pyelonephritis with respect
to normal acute DMSA (4.8 vs 1.44; P=0.0001), without achieving that
signification for late affected DMSA (6.5 vs 5.05; P=0.6). The area
under the ROC curve for PCT was 0.64 (CI 95% 0.55-0.72) for acute
renal damage, and 0.62 (CI 95% 0.44-0.80) for permanent damage,
with optimum statistical cut-off values of 0.85 and 1.17ng/ml.
Multivariate analysis for acute renal damage only found correlation
with PCT (Odds Ratio [OR] 1.2 (CI 95% 1.06-1.4, P=0.005), and hours
of fever (OR for less than 6 hours of fever 0.4 (CI 95% 0.2-1.02,
P=0.05). In patients with renal scarring, PCT showed an OR 1.0 (CI
95% 0.9-1.1, P=0.6). Conclusions: PCT and the duration of fever were
the only parameters statistically associated with early renal damage.
PCT and renal scarring did not reach statistical significance.
Factores predictivos de daño renal en la infección febril del tracto
urinario. Utilidad de la procalcitonina
RESUMEN
Objetivo: Establecer la utilidad de la procalcitonina (PCT) y otros
parámetros clínicos y analíticos como indicadores de daño renal
agudo y permanente en niños tras una primera infección del tracto urinario (ITU) febril. Material y métodos: Estudio retrospectivo
multicéntrico. Estudio estadístico: descriptivo, curvas ROC y regresión logística múltiple. Resultados: 219 pacientes, con edades
entre 1 semana y 14 años (68 % menores de 1 año). Las medias
de PCT fueron significativamente mayores en pacientes con pielonefritis aguda respecto a aquellos con DMSA agudo normal (4,8
frente a 1,44; p = 0,0001), sin alcanzar significación para DMSA
tardío (6,5 frente a 5,05; p = 0,6). El área bajo la curva ROC de PCT
fue 0,64 (IC 95 % 0,55-0,72) para daño renal agudo y 0,62 (IC 95
% 0,44-0,80) para permanente; con puntos de corte óptimos de
0,85 y 1,17 ng/ml. El análisis multivariante para daño renal agudo
solo encontró correlación con PCT (odds ratio [OR] 1,2, IC 95 %
1,06-1,4; p = 0,005) y horas de fiebre (OR para < 6 h 0,4, IC 95 %
0,2-1,02; p = 0,05). En los pacientes con cicatriz, la OR para PCT fue
1,0 (IC 95 % 0,9-1,1; p = 0,6). Conclusiones: La PCT y la duración de
la fiebre fueron los únicos parámetros que se asociaron de forma
significativa a daño parenquimatoso agudo. No se observó relación estadísticamente significativa entre la PCT y la cicatriz renal.
Keywords: Procalcitonin. Acute renal damage. Permanent renal
damage. Febrile urinary tract infection.
Palabras clave: Procalcitonina. Daño renal agudo. Daño renal
permanente. Infección urinaria febril.
ABSTRACT
INTRODUCTION
Urinary tract infection (UTI) is one of the most common bacterial
infections in children, with an overall incidence of 3%-7%1-5.
Correspondence: Elena Lucas Sáez
Departamento de Pediatría.
Hospital de Manises.
Av. Generalitat Valenciana 50, 46940. Manises. Valencia. (Spain)
[email protected]
[email protected]
Lack of symptom specificity in younger patients, frequent
association with malformations of the urinary tract and
the possibility of permanent renal damage require multiple
complementary tests in daily practice.
There is no consensus in clinical practice protocols and guidelines
concerning the complementary examinations that should be
carried out following a first episode of febrile UTI and which
patients are at a greater risk of developing renal scarring4-8.
451
originals
Currently, renal scintigraphy with Tc 99m dimercaptosuccinic
acid (DMSA) is the gold standard for diagnosing acute and
permanent kidney damage9,10. However, this test is expensive,
is not available in all centres and requires the patient to
undergo radiation. Consequently, there is an attempt to find
an indicator that limits invasive tests to those patients at
greater risk.
Various molecules have been proposed as possible markers for
renal damage. Several studies have shown their usefulness for
interleukin (IL)-6, IL-8 and urine osmolality, a more discreet
usefulness for α tumour necrosis factor, N-acetylglucosamine
and IL-16, and low or no usefulness for other tubular
proteins11-13.
In recent years, the most studied marker was procalcitonin
(PCT), due to its rapid and specific response to serious
bacterial infections 14,15. It is a precursor of calcitonin
without hormone activity, with practically undetectable
values in physiological conditions and during viral
infections, and which increases rapidly and proportionally
in response to bacterial infection and its severity. The
increase occurs 2 hours after the onset of the infection,
reaches its maximum level at 12 hours and normalises in
2-3 days when the infection has subsided.
There are diverse studies concerning the usefulness of PCT
for diagnosing acute and chronic renal damage, whose
results are contradictory 16-27. The objective of our study
was to assess the usefulness of PCT and other analytical
(leukocytes, C-reactive protein [CRP], etc.) and clinical
(age, hours of fever, etc.) parameters as indicators of acute
and permanent renal damage in children after their first
episode of febrile UTI.
MATERIAL AND METHOD
It is a retrospective multicentre study carried out in four
hospitals in Valencia (Spain), collecting data from paediatric
patients admitted during their first episode of febrile UTI,
from 2006-2010.
Inclusion criteria were UTI diagnosis through positive urine
culture with a significant number of colonies according to the
collecting method, fever over 38ºC, leukocyte count above
the upper value of the normal range according to age and/or
CRP levels > 30 mg/l, with at least one PCT measurement
and previous early or late DMSA.
Those patients with known uropathy (including prenatal
ectasia) and those with a previous febrile UTI episode were
excluded.
The study was approved by the Ethics Committees of the
participating hospitals.
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Elena Lucas-Sáez et al. Procalcitonin, predictor of kidney damage
We recorded each patient’s clinical data (age, sex, fever
duration until blood analysis, highest fever reached and
related symptoms), the antibiotic treatment used and the
hours it took the patient to become afebrile following the
onset of that treatment. Analytical data included: leukocyte
and neutrophil count, CRP and PCT values, urine collection
method, bacterium identified in the urine culture, antibiotic
sensitivity and the same bacterium’s presence or absence in
the haemoculture.
The method for measuring PCT during the first years of the
study was semi-quantitative using the immunochromatographic
BRAHMS test (36 patients), and later using the BRAHMS
Kryptor compact electrochemiluminescence immunoassay
method (183 patients). Only quantitative PCT values were
used for the statistical analysis.
Regarding the imaging tests, we collected results from the
conventional ultrasound and acute and/or late phase DMSA.
The scintigraphic study was performed 3 hours after injecting a
weight-adjusted TC-DMSA dose, obtaining three planes. The
presence of focal or diffuse areas of uptake defects, without
evidence of cortical loss, was considered pathological.
In those cases in which cystography was performed (either
early pathological DMSA or dilation of the upper urinary
tract detected in ultrasound during admission), we recorded
the presence or absence of vesicoureteral reflux (VUR), the
degree and the uni/bilaterality.
Statistical analysis included the calculation of sensitivity (S),
specificity (Sp), positive predictive value (PPV), negative
predictive value (NPV) and calculation of the area below
the ROC curve. The χ2 test and the Student’s t-test were
performed to compare the categoric and quantitative variables,
respectively. Non-conditional logistic regression was used to
estimate the association between the variables of interest.
RESULTS
A total of 219 patients (131 girls and 88 boys) were included in
the study, aged between 1 week and 14 years, of which 149 (68%)
were younger than 1 and 18 were younger than 28 days (8.2%).
The median value of the fever’s development in hours
when performing blood analysis was 24 [1-96] and the
most common associated symptoms were gastrointestinal.
As regards the analytical results, the leukocyte median was
18,000/mm3 (3,900-41,600), CRP median 74mg/l (4.469) and
PCT median 1.16ng/ml (0.07-53.5) (Table 1).
The tendency for PCT medians to increase in patients with
normal and pathological DMSA, both in acute and late phase,
is shown in Figure 1.
Nefrologia 2014;34(4):451-7
The most common isolated bacterium was Escherichia coli
in 92.7% of cases.
Other bacteria were isolated in 16 patients (7.3%): 4 klebsiella
(25%), 3 Proteus, 3 enterobacteriaceae, 2 enterococci and 2
Citrobacter and 2 others.
7.5
In those patients with early pathological DMSA, late DMSA
was indicated a mininum of 9 months after performing
the previous DMSA. The presence of renal scarring was
interpreted in this context as secondary to acute damage,
however these changes may not necessarily be due to the
Table 1. Description of clinical and analytical data
Age
7 days – 14 years
Sex (M/F)
88/131
Fever duration (hours), median and
range
24 (1-196)
Related symptoms n (%)
Fever
219 (100%)
Vomiting or diarrhoea
88 (40%)
Irritability
29 (13%)
Urinary disorders
22 (10%)
Lumbar pain
9 (4%)
Analytical data (median and range)
Leukocytes (/mm3)
18,000 (3,900-41,600)
CRP (mg/l)
74 (4-469)
PCT (ng/ml)
1.16 (0.07-53.5)
CRP: C-reactive protein; PCT: procalcitonin.
Nefrologia 2014;34(4):451-7
3.0
0.0
Normal
Pathological
Late DMSA
12.5
Procalcitonin
Acute-phase DMSA was performed on all patients in the first
7 days after admission (late DMSA alone was performed on
2 patients); 142 patients presented alterations (64.8%). In the
cases with infection by a bacterium other than E. coli, the
percentage of scintigraphic acute-phase alterations was 53%.
4.5
1.5
The antibiotic guideline chosen in the majority of cases
was intravenous gentamicin (65%), with a mean fever
disappearance time of 32 hours after the onset of treatment.
Conventional ultrasound was performed on all patients, with
60 (27%) presenting disorders. Doppler Sonography was
carried out simultaneously in some centres (72 sonographs,
22 pathological alterations).
Acute DMSA
6.0
Procalcitonin
The urine collection method in continent patients was via midstream sampling. An adhesive bag was used on 60 incontinent
patients (35%), always obtaining two samples, and a sterile
technique was used on the remainder (urinary catheterisation
or suprapubic aspiration).
originals
10.0
7.5
5.0
2.5
0.0
Normal
Pathological
Figure 1. Procalcitonin values in patients with normal
and pathological dimercaptosuccinic acid in acute phase
(acute pyelonephritis) and late phase (scarring)
DMSA: dimercaptosuccinic acid.
The lower and upper limits of the box indicate the 25 and 75
percentiles. The line crossing the box is the median.
cause-effect of early injury. This was carried out on 99
patients, with 22 resulting pathological (22.8%).
Cystography was performed on 126 patients, of which 30
(23.8%) were diagnosed with VUR.
The most significant clinical and analytical data in children
with acute-phase pathological DMSA (acute pyelonephritis)
and in those with normal DMSA are recorded in Table 2. PCT
means were significantly higher in patients with acute-phase
pathological DMSA in respect to those unaffected (4.8 vs
1.44; P=.0001); this significance was not achieved for late
DMSA (6.5 vs 5.05; P=.6). Similarly, CRP averages behaved
with respect to early DMSA (112.8 vs. 70.24; P=.01) and late
DMSA (163.39 vs. 115; P=.06).
453
originals
The area below the PCT ROC curve for acute renal damage
was 0.64 (95% CI 0.55-0.72) and 0.62 for scarring (95% CI
0.44-0.80), establishing values of 0.85 and 1.17ng/ml as cutoff points (Figures 2 and 3). The values of S, Sp, PPV and
NPV for acute and chronic renal damage are presented in
tables 3 and 4, respectively.
Although the characteristics of the newborn subgroup may
differ to those of the rest of the study’s population, we
decided to include this group to maintain the homogeneity of
the participating centres and to guarantee, as far as possible,
sufficient statistical power in order to establish statistically
significant associations.
The multivariate analysis with respect to acute renal damage
only found association with PCT (Odds Ratio [OR] 1.2, 95%
CI 1.06-1.4; P=.005) and fever duration (OR for <6h 0.4,
95% CI 0.2-1.02; P=.05). Patients younger than one year
presented lower risk of scinitgraphic affectation, although
statistic significance was not achieved (OR 0.52, 95% CI
0.2-1.1; P=.08).
Despite the causal bacterium being E. coli in the majority
of patients, other bacteria were discovered in 16 of the
study population. It involves 8 males and 7 females, which
constitute 7% of the sample’s total, of which 9 (56%) were
younger than 1 year. Fever duration was <24 h (94%) in most
of patients, and < 6 hours (37.5%) in 6 patients. Regarding
the complementary tests, ultrasound was normal in 12 (75%)
and PCT was negative in 10 of these patients (62%).
No association with any of the studied factors was found in
the assessment of permanent renal damage. Specifically, OR
was 1.0 for PCT (95% CI 0.9-1.1, P=.6), and 0.4 in patients
younger than one (95% CI 0.1-1.4; P=.1).
DISCUSSION
The aim of this study was to assess the usefulness
of PCT and other analytical (leukocytes, CRP, etc.)
and clinical (age, hours of fever, etc.) parameters as
indicators of acute and permanent renal damage in
children after their first episode of febrile UTI. Our
study includes a considerably sized group with respect
to those studies published to date of patients diagnosed
with first episode of febrile UTI with high theoretical
possibility of acute scinitgraphic affectation due
to analytical alterations presented on admission
(leukocyte count above the upper value of the normal
range according to age and/or CRP levels >30mg/l). In
addition, DMSA, the gold standard for renal damage
diagnosis, both acute and permanent, according to
general recommendations at the time of the test, was
performed on all patients.
The percentage of acute-phase pathological DMSA was
64.8% in our series, very similar to the rest of the published
studies16,17,19,24,26,28. Contrary to what was expected 6, in the
cases of infection by bacterium other than E. coli, the
percentage of acute-phase pathological DMSA was lower
(53%), with 3 developing scarring (19%). The clinical and
analytical characteristics of this group of patients were
analysed, without finding any risk or confusion factor
justifying this result.
PCT has demonstrated its validity in the early diagnosis of
invasive bacterial infections, surpassing CRP14,15. As regards
UTI, PCT was the most studied marker and currently offers
the best results. Since Benador published his study in 1998,
numerous studies have tried to find a cut-off point for PCT
with could be related to both risk of acute parechymatous
damage and permanent scarring16.
The majority of publications, except for two, have shown
the usefulness of PCT, although with very inconsistent
S and Sp values 17,18,19-27. Although sample sizes are often
small, we highlight Leroy’s 2013 meta-analysis which
assesses 18 independent studies, thus obtaining a total of
Table 2. Comparison between normal and pathological acute-phase dimercaptosuccinic acid
Normal DMSA (n = 75)a
Pathological DMSA (n = 142)a
P
Age
5 months [7 days – 8 years]
7 months [3 months – 14.9 years]
0.005
Sex
40 % male
40 % male
1
24.3 %
7.7 %
0.3
17,700 [8,100-41,600]
18,100 [3,900-35,400]
0.4
79.24 (59.24)
112.8 (87.12)
0.01
1.44 (1.85)
4.8 (8.62)
0.0001
< 6 hours of fever
Mean leukocytes (/mm3) [range]
Mean CRP (mg/l) (SD)
Mean PCTb (ng/ml) (SD)
SD: standard deviation; DMSA: dimercaptosuccinic acid; CRP: C-reactive protein; PCT: procalcitonin.
a
Late DMSA was only performed in 2 cases; b Only PCT values were considered quantitative.
454
Nefrologia 2014;34(4):451-7
originals
1.0
1.0
0.8
0.8
0.6
0.6
Sensitivity
Sensitivity
0.4
0.4
0.2
0.2
0.0
0.00.20.40.6 0.81.0
0.0
0.00.20.40.60.81.0
1-Specificity
1-Specificity
Figure 2. ROC curve for procalcitonin in acute kidney
damage.
Figure 3. ROC curve for procalcitonin in renal scarring.
1,011 patients26. In this instance, PCT shows good results
for acute renal damage and low Sp for renal scarring.
calculating the area below the curve, optimal PCT values
of 0.85 and 1.17ng/ml were found as cut-off points, which
are similar to those proposed in other studies (1ng/ml in the
studies by Sheu and by Bressan, and 0.85ng/ml proposed by
Kotoula)24,23. However, our S, Sp, PPV and NPV values are
much lower than those discovered in these studies.
Our study, as well as providing a considerably larger
sample size than the majority of previous publications,
includes a multivariate analysis to independently determine
the association between the variables of interest and renal
involvement.
As regards acute renal damage, we found significantly higher
PCT averages in patients with pathological DMSA. After
With respect to renal scarring, the increase of PCT values did
not achieve statistical significance. The area below the ROC
curve was similar to that for acute damage, and for the same
PCT values as cut-off points, we found acceptable values of
Table 3. Diagnostic validity of procalcitonin with respect to Tc 99m dimercaptosuccinic acid in acute damage
PCT
S
Sp
PPV
NPV
>0.85 ng/ml
74
46
72
48
>1.17 ng/ml
67
61
77
49
Sp: specificity; PCT: procalcitonin; S: sensitivity; NPV: negative predictive value; PPV: positive predictive value.
Table 4. Diagnostic validiy of procalcitonin with respect to Tc 99m dimercaptosuccinic acid in renal scarring
PCT
S
Sp
PPV
NPV
>0.85 ng/ml
80
30
28
81
>1.17 ng/ml
80
37
31
84
Sp: specificity; PCT: procalcitonin; S: sensitivity; NPV: negative predictive value; PPV: positive predictive value.
Nefrologia 2014;34(4):451-7
455
originals
S, but very low E and PPV values. Our data, with respect
to the usefulness of PCT for diagnosing permanent renal
damage, did not allow room for recommendations made by
other authors16-27.
The authors declare that they have no conflicts of interest
related to the contents of this article.
In reference to the other markers studied, only CRP achieved
certain usefulness in the diagnosis of acute damage, similar
to the study by Kotoula23.
REFERENCES
The results of the multivariate analysis demonstrate that only
two factors were relevant: PCT and <6 hours of fever. Each
unit that increases PCT represents a 20% greater risk of acute
parenchymatous damage. In contrast, <6 hour fever duration
gave 60% protection.
Contrary to that expected, an age of <1 proved to be a
protecting factor for acute and chronic parenchymatous
affectation; however, statistical significance was not achieved.
The results of our study demonstrate certain usefulness of
PCT for predicting acute renal damage in patients undergoing
their first episode of febrile UTI. Although we cannot
establish PCT cut-off values in those patients with low PCT
levels, ultrasound normality and good initial evolution, the
performance of acute-phase DMSA could be prevented.
However, data obtained until now does not allow the use of
PCT as a predictor of renal scarring in these patients.
Our study has certain limitations. Firstly, it is a retrospective
study. Second, the urine collection method in a significant
percentage of cases was via perineal bag and not using
a sterile technique, as recommended in the latest clinical
practice guidelines. However, having two urine cultures, with
growth of the same bacterium and in significant number, as
well as urinalysis with inflammatory signs, minimises the
possibility of false positives.
Finally, of the 142 patients with acute-phase DMSA,
only 99 late DMSA were performed during the study,
since in some cases sufficient time had not elapsed for it
to be carried out (5 patients) or the initial scintigraphic
affectation was mild and clinical evolution satisfactory
(16 patients). Some patients were also lost to follow-up
(22 cases, 10% of the sample). Due to this small sample
of patients with renal scarring, we are not able to obtain
concluding statistical data.
CONCLUSIONS
PCT increase and <6 hour fever duration were the
only parameters which were significantly associated
with acute parenchymatous damage. No statistically
significant association was observed between PCT and
renal scarring.
456
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Sent to review : 30 Jan. 2014 | Accepted: 7 Apr. 2014
Nefrologia 2014;34(4):451-7
457
originals
Cost analysis and sociocultural profile of kidney
patients. Impact of the treatment method
Víctor Lorenzo-Sellares1, M. Inmaculada Pedrosa1, Balbina Santana-Expósito2,
Zoraida García-González3, Mónica Barroso-Montesinos4
1
Servicio de Nefrología. Hospital Universitario de Canarias. La Laguna, Santa Cruz de Tenerife (Spain); 2 Servicio de Evaluación de la
Calidad. Servicio Canario de Salud. Santa Cruz de Tenerife (Spain); 3 Servicio de Nefrología. Hospital Tamaragua. Puerto de la Cruz,
Santa Cruz de Tenerife (Spain); 4 Unidad de Apoyo a la Investigación. Hospital Universitario de Canarias. La Laguna, Santa Cruz de
Tenerife (Spain)
Nefrologia 2014;34(4):458-68
ABSTRACT
Background: The cost analysis of chronic kidney disease based
on individual data for treatment methods and components
has not been published in Spain. Objectives: a) To study the
health costs of a year of treatment with haemodialysis (HD),
deceased donor renal transplantation (RTx), renal-pancreas
transplantation (RPTx), and S4 and S5 advanced chronic
kidney disease (ACKD) b) Assess the potential relationship
between sociocultural diversity, costs and treatment method.
Methods: Observational study of: 1) 81 patients with ACKD
(53 S4 and 28 S5) 2) 162 with more than 3 months on HD
and 3) 173 with a Tx for more than 6 months (140 RTx and
33 RPTx). The costs were assessed in five categories: 1) HD
sessions, 2) drug intake, 3) hospitalisation, 4) outpatient care
and 5) transportation. We carried out a survey with sociodemographic parameters. Results: The financial impact of HD
was €47,714±18,360 (mean±SD), that of Tx €13,988±9970,
and that of ACKD €9654±9412. The cost of HD was the highest
in all financial items. The costs were similar between RTx
and RPTx. In ACKD, the greater the renal deterioration, the
greater the cost is (S4 €7846±8901 versus S5 € 13,300±9820,
P<.01). Tx patients had the best sociocultural status, while HD
patients had the worst profile. We did not find differences
in costs between the three sociocultural groups. Conclusions:
HD has the greatest financial impact in all items, five times
higher than the ACKD patient cost and three times than
the Tx patient cost. Optimising early prevention and Tx, if
appropriate, must be priority strategies. This analysis invites
us to think about whether sociocultural status can have an
influence on opportunities for Tx.
Keywords: Costs-of-illness. Economic evaluation. Advanced chronic
kidney disease. Hemodialysis. Kidney transplant. Diagnosis-related
groups. Sociocultural level.
Análisis de costes y perfil sociocultural del enfermo renal. Impacto
de la modalidad de tratamiento
RESUMEN
Antecedentes: El análisis del coste de la enfermedad renal crónica
basado en datos individuales, por componentes y modalidades terapéuticas no ha sido publicado en España. Objetivos: a) Estudiar
los costes sanitarios de un año de tratamiento con hemodiálisis
(HD), trasplante renal (TxR) de cadáver y reno-páncreas (TxRP), y de
la enfermedad renal crónica avanzada (ERCA) E4 y E5. b) Evaluar la
eventual relación entre disparidad sociocultural, costes y modalidad
de tratamiento. Métodos: Estudio observacional de: 1) 81 pacientes
con ERCA (53 E4 y 28 E5); 2) 162 con más de 3 meses en HD y 3) 173
con más de 6 meses Tx (140 TxR y 33 TxRP). Los costes se evaluaron
en cinco categorías: 1) sesiones de HD, 2) consumo farmacéutico, 3)
hospitalizaciones, 4) atención ambulatoria y 5) transporte. Se realizó una encuesta de parámetros sociodemográficos. Resultados: El
impacto económico de la HD fue de 47 714 ± 18 360 € (media ± DS),
el del Tx de 13 988 ± 9970 €, y el de la ERCA 9654 ± 9412 €. El coste
de la HD fue el más elevado en todas las partidas económicas. Los
costes fueron similares entre TxR y TxRP. En ERCA, a mayor deterioro renal, mayor coste (E4 7846 ± 8901 frente a E5 13.300 ± 9.820, p <
0,01). Los pacientes Tx tenían mejor estatus sociocultural, mientras
que los de HD presentaban el peor perfil. No encontramos diferencias en los costes entre los tres grupos socioculturales. Conclusiones:
La HD conlleva el mayor impacto económico en todas las partidas,
incrementando cinco veces el coste del paciente ERCA y tres veces
el del Tx. Optimizar la prevención precoz y el Tx, llegado el caso,
deben ser estrategias prioritarias. Este análisis invita a reflexionar
acerca de si el estatus sociocultural puede influir en ventajas de
oportunidades para el Tx.
Palabras clave: Coste de la enfermedad. Evaluación económica.
Enfermedad renal crónica avanzada. Hemodiálisis. Trasplante
renal. Grupos relacionados con el diagnóstico. Nivel sociocultural.
Impact of the 5008 monitor software update on total
Correspondence: Víctor Lorenzo Sellares
Hospital Universitario de Canarias. Llombet, 27. 38296 La Laguna.
(Spain).
Santa Cruz de Tenerife.
[email protected]
458
INTRODUCTION The population with chronic kidney disease (CKD) who require
renal replacement therapy (RRT) is constantly growing1,2. This
is fundamentally due to an increase in the elderly and diabetic
Víctor Lorenzo-Sellares et al. Cost analysis in kidney patients
population3. RRT is a major component of healthcare spending,
given that, although the volume of patients is lower than
0.1% of the population, the healthcare budget is 2.5% for this
population4. According to data of the EPIRCE (Chronic Renal
Failure Epidemiology in Spain) study, the Spanish population
that suffers advanced CKD (ACKD) stages (S) 4 and 5 is
approximately 0.3% (around 130,000 individuals)2, to which
we must add the 50,000 patients who are on RRT: 51% kidney
transplant patients (RTx), 44% on haemodialysis and 5% on
peritoneal dialysis (PD)5.
In healthcare economics, cost plays an important role,
especially in chronic diseases, such as CKD and diabetes,
given the ageing population and the progressive number
of exposed patients. Therefore, priority must be given
to addressing the high social and financial costs of
treatment 6 . However, the information available on a
national level is poor and is fundamentally focussed
on HD 7,8 . In any case, it is very difficult to compare
studies, since the cost estimation varies depending on
whether or not different direct and indirect components
are included. Likewise, there is usually wide variability
depending on the public or subsidised status of hospitals
and the different use of resources. It is even more
complicated to compare costs between countries with
different healthcare models, both in terms of financing
and in the provision of services 9-11.
Despite thesse difficulties, knowledge and analysis of costs
is both important and necessary6. With this information we
can achieve an overview of the effect of illness on the use of
resources. Furthermore, knowledge of the cost distribution
between the different components would allow us to identify
areas of inefficiency, in order to allocate resources better12.
Many studies have shown that RTx and PD are considerably
cost-effective when compared with HD13-16. In our setting, we
have heterogeneous information about the cost of HD and PD;
however, the cost of ACKD patient treatment has not been
analysed in our country and we do not have detailed data on
patients who have received transplants.
originals
with HD, RTx and RPTx. The study population comprised
the Northern Health Area of the province of Santa Cruz
de Tenerife, and the reference hospital was the Hospital
Universitario de Canarias (HUC). This region has a population
of approximately 400,000 inhabitants.
Study subjects
We evaluated three populations, who were initially surveyed
between November 2009 and December 2009, and we
finished collecting data in December 2011. Patients who
completed at least six months of follow-up were included in
the final analysis and the cost allocation was extrapolated to
one year. Those who were not followed up for six months
were excluded due to the study period being considered
to be too short. Likewise, exclusion criteria included the
following: 1) patients whose circumstances or illness may
have interfered with the study (for example, drug users and
individuals with cognitive deficiencies or disorders); 2) when
informed consent could not be obtained or was not given; 3)
a lack of adherence to medical recommendations or a lack
of collaboration from the patient or their responsible family
member.
The final study included:
1. In the HUC’s ACKD clinic follow-up: 81 patients, 53 S4
and 28 S5.
2. HD patients who had spent at least three months on this
form of RRT: 85 HUC patients and 77 patients from the
Hospital Tamaragua. These are two subsidised hospitals
with a dialysis cost established in an agreement.
3. Patients followed up in the HUC’s RTx clinic who had
received their transplant at least six months before: 140
patients with RTx and 33 with RPTx.
Our objective was to study the financial impact of treatment with
HD, deceased donor RTx and renal-pancreas transplantation
(RPTx), and the management of S4 and S5 ACKD (not yet
on dialysis). A secondary objective was to investigate the
demographic and sociocultural profile of this population and
its possible association with cost and method of treatment.
Healthcare costs
We defined “cost” as the consumption of goods and services
valued in monetary terms, to achieve a certain objective or
obtain a certain product. In order to estimate the cost, we
used the prevalence cost method, i.e., the direct healthcare
costs attributable to the illness in the study year17. These
were organised into five main categories: 1) HD sessions,
2) medication use, 3) hospitalisation, 4) outpatient care in
clinics, emergency departments and complementary tests and
examinations, and 5) transportation use.
MATERIAL AND METHOD
Design
Observational study of direct healthcare costs during one
year of treatment for patients affected by ACKD and on RRT
Haemodialysis sessions
For the specific cost of HD sessions, there are different
models depending on the country. The model applied in
our setting is the one most commonly used in Europe, i.e.,
a fixed amount per dialysis session, which is adjusted to a
Nefrologia 2014;34(4):458-68
459
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protocol of action. In the Official Canary Gazette18, for this
method, there is just one activity that is charged: the HD
session, with certain variability depending on the hospital
and the services. The cost of HD in accordance with the
agreement established included the cost of consumables,
with a supplement for special membranes accepted for 10%
of patients, repayment of non-disposable material, staff and
medication administered during the HD session, with the
exception of erythropoiesis-stimulating agents (ESA). As
such, we applied €146 for the HUC outpatient unit and
€158 for the Hospital Tamaragua. There was no difference
in reimbursement depending on the number of hours per
session or the method of treatment. Regular examinations
that were carried out on these patients were included in the
dialysis reimbursement, and as such, they were not included
under a different heading. The normal HD regimen in all
hospitals was four hours, three times a week.
Medication expenses
Information on the consumption of medications and diagnosis
material for self-monitoring was taken from clinical databases
and from surveys carried out on patients and/or their family
members. The cost was obtained by calculating the price
of each unit in euros and multiplying it by the dose. The
costs were obtained from different sources, such as the
Pharmaceutical College Medications Database. This expense
was expressed in euros/patient/day or year, as appropriate, in
the presentation of results. In this study, we did not consider
the discounts offered by many pharmaceutical companies in
a different format.
Hospitalisation
The volume of hospital admissions was obtained from
the two hospitals where the patients were admitted. We
recorded the total number of admissions over the study
period and applied the attributable fractions of morbidity
for each diagnosis code of the International Classification
of Diseases (ICD-9-CM) and their subsequent processing
by diagnosis-related group (DRG). DRG, as a patient
risk-adjusted system, incorporate a cost estimator, which
is a measure of the mean complexity of the patients, and
the “relative weight”, or level of resource consumption
attributable to each patient type or group19. The mean cost
of each DRG was obtained from the Ministry of Health and
Consumption’s Health Information System.
Outpatient care
Outpatient care includes hospital or primary care centre
consultations, vascular access for HD carried out in an
outpatient setting, and complementary and imaging studies.
460
Information on the use of these healthcare resources was
obtained from three sources: a review of clinical records, a
review of digital hospital records and a review of the survey
carried out on patients and/or their family members. To
allocate the cost of consultations and complementary studies,
we used the HUC invoicing tables, the reimbursement tables
established by the Canary Health System (SCS) and the
allocations for procedures published in the Official Canary
Gazette18.
Transportation
We must add the cost for use of transportation to hospitals
to that of the HD sessions. This expense was obtained from
the reimbursement tables established by the SCS for the
use of private cars, taxis, health buses, non-emergency
ambulances and emergency ambulances. We also recorded
the possible use of transport for travel to clinics or for
imaging tests.
Sociodemographic variables
We carried out a generic survey on patients and/or a
relative, according to the individual circumstances. The
following data were collected: age, sex, underlying disease,
educational level, employment status and work activity,
autonomy, family support, living environment (urban,
rural). Subsequently and with the aim of simplifying
the analysis, we summarised and grouped the scores in
accordance with the level of studies and work activity.
In this manner, patients were classified into three groups
of sociocultural status: 2 points: lower, 3 points: lowermiddle, >3 points: middle-upper.
Data analysis
The results of this study are fundamentally descriptive,
and as such, we have exclusively used basic statistics
tests. Given that the cost values were extreme in
some patients, there was an asymmetric distribution
towards high values. This is highlighted because
the mean was higher than the median, particularly
for the expenses of hospitalisation and consultation,
not used in many cases. For these types of data with
many extreme values, the median must be considered
to be a stronger comparison parameter; however, the
arithmetic mean is considered to be more informative
of the total cost for decision-making about health
policies 20-24 . Finally, we presented the results in both
formats, mean ± standard deviation (SD) and median
(interquartile range [IR]). The statistical analyses
were carried out with the SPSS 17.0 software for
Windows (SPSS Inc, Chicago, ILL).
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by transplantation, while this financial item in ACKD
is less than half the cost of that of the other methods
(Table 1).
RESULTS
When we analysed the annual cost by treatment method,
we found that the greatest financial impact was made by
HD, which was more than three times the cost of treatment
for transplant patients and almost five times that of ACKD
patients. The explanation seems simple: the higher cost
is represented by the HD technique, which is not used
in transplant patients or ACKD patients. In any case, the
cost in HD patients is higher in all financial items. Table
1 displays the mean (SD) and median (IR) of the detailed
costs by financial item and treatment method.
Hospitalisation costs
The financial impact of hospitalisation is less
that it may have seemed a priori. This is due to
the considerable proportion of patients not being
admitted, which thus reduces the mean cost. Again,
the highest financial impact was caused by HD, which
on average was double the cost of that of patients
with ACKD or transplant patients (Table 1). The
proportion of patients who were admitted at least
once was also maintained according to methods: 68%
of HD patients were admitted one or more times,
while this was only true of 41% and 40% of patients
with ACKD and transplant patients, respectively.
If we only consider the costs of those who were
hospitalised at least once, the financial impact
per treatment method is considerably diminished:
ACKD €13,339±€8,539, HD €17,655±€16,726 and
transplantation €12,193±€10,604.
Cost of haemodialysis sessions
With the model adopted, the cost of HD sessions was
practically identical for all patients according to the
subsidised hospital, independently of comorbidity,
sociocultural status or location of residence. Differences
were only observed in the small proportion of patients who
received more than three sessions per week. This cost, as
we have mentioned before, is combined in a reimbursement
stipulated by the SCS. The average patient/year cost was
almost €25,000 (Table 1).
Outpatient care
Costs for outpatient care are not very high and not as
disparate between methods, representing an average of
€1,000-€1,800 per year per patient.
Medication costs
The medication costs by treatment method also showed
the highest expense to be in HD, followed very closely
Table 1. Detailed costs by financial item and treatment method
HD sessions
Medication
Hospitalisation
Transportation
Outpatient
Care
Totals
Totals
ACKD
HD
Tx
Mean (SD)
24,572 (3,426)
0
24,572 (3,426)
0
Median (IR)
24,726 (22,922-26,228)
0
24,726 (22,922-26,228)
0
Mean (SD)
5,269 (3,672)
2,502 (1,883)
6,231 (4,438)
5,580 (2,775)
Median (IR)
4,616 (2,888-6,691)
2,073 (1,288-3,195)
5,600 (3,433-7,590)
4,925 (3,937-6,671)
Mean (SD)
7,748 (12,602)
5,434 (8,524)
11,987 (16,055)
4 863 (8,961)
Median (IR)
1,831 (0-10,428)
0 (0-8,379)
5,258 (0.000-15,833)
0 (0-5,575)
Mean (SD)
1,311 (2,800)
91 (145)
3,076 (3,856)
228 (411)
Median (IR)
80 (36-614)
46 (32-80)
646 (20-5197)
76 (51-173)
Mean (SD)
1,554 (1,747)
1,030 (1,087)
1,809 (2,353)
1,562 (1,202)
Median (IR)
1,003 (503-1,945)
654 (356-1237)
995 (396-2,116)
1,228 (723-2,013)
Mean (SD)
26,278 (22,030)
9,654 (9,412)
47,714 (18,360)
13,988 (9,970)
Median (IR)
19,026 (8,459-38,612)
5,623 (2,946-14,207)
41,120 (34,102-56,505) 10,516 (7,311-16,962)
Values in euros, expressed as the mean and standard deviation, and the median and interquartile range.
SD: standard deviation, ACKD: advanced chronic kidney disease, HD: haemodialysis, IR: interquartile range, Tx: renal transplantation.
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Transportation
The financial impact of transportation is minimal in ACKD
and transplant patients, while it is €3,000 in HD, since these
patients need to travel three times a week. This amount
represents 6% of the total cost of treatment and 12.5% of the
cost of HD.
Costs by renal transplantation method
Table 2 shows that the overall and detailed costs of a
year of treatment, from six months after transplantation
onwards, were not significantly different between RTx
and RPTx.
Costs by advanced chronic kidney disease stage
In this section, we observed major differences in terms of
costs and the degree of renal damage (Table 3). Expenses
for S5 patients were significantly higher than those for
S4 patients, particularly in terms of medication and
hospitalisation. That said, they continue to be around 30%
lower than those observed in HD, and similar to those
attributed to transplant patients.
Table 2. Detailed costs by financial item and type of
transplantation
Expenses
RTx
RPTx
Medication
5,495±2,882
5,940±2,269
Biochemical study
766±789
1,353±1,088
Outpatient Care
1,621±1,200
1,314±1,193
Hospitalisation
5,130±9,337
3,731±7,164
14,011±10,375
13,891±8,166
Totals
RTx: renal transplantation, RPTx: renal-pancreas transplantation.
Association between cost and sociocultural
parameters
Table 4 displays sociodemographic data by treatment method.
It shows that the degree of sociocultural deprivation is
considerable; this is defined as the group of circumstances
that are an obstacle to normal access to healthcare for people
who live in cultural and material poverty.
As such, we observed that transplant patients had a better
sociocultural position, while those on HD had a worse profile.
Around 85% of HD patients had not graduated from school
and had an unskilled job. Likewise, this analysis also showed
that autonomy and family support are parallel to sociocultural
level and, thus, they were higher in the transplant population.
In any case, in the transplant population, 65% of patients had
not graduated from school (Table 5). The ACKD population
had an intermediate profile. Overall, the lower sociocultural
profile, as can be imagined, was more apparent in rural areas
or towns.
When we analysed the detailed costs in the three sociocultural
groups, no relevant differences were found, even when they
were classified by treatment method. The transportation
expense was lower in patients of a higher sociocultural level,
which shows that they more frequently use their own means.
DISCUSSION
In this study, for the first time, we analysed the costs of
treatment of patients with S4 and S5 ACKD and RTx and
RPTx patients for a specific region, using individual data
and not overall budgets. As authors, we are aware that the
allocations to the different financial items are difficult to
extrapolate given variations in cost in the different regions
and the sudden budgetary changes that occur. However, the
proportional analysis of each item and each treatment method
may be useful.
The greatest obstacle in carrying out the study was the
impossibility of including PD, with the latter being a costeffective alternative for the sustainability of RRT21-23. At the
Table 3. Detailed costs by financial item and advanced chronic kidney disease stage
Expenses
S4
S5
P
Medication
2,090±1,285
3,264±2,530
<0.03
330±234
384±343
Outpatient Care
Biochemical study
1,091±1,202
928±871
Hospitalisation
4,004±7,702
8,348±9,649
<0.03
Totals
7,846±8,901
13,300±9,820
<0.01
S4: stage 4, S5: stage 5,
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Table 4. Sociodemographic data by treatment method
ERCA
HD
Tx
P
Number of patients
81
162
173
Age (years)
69 ± 13
68 ± 12
51 ± 13
Sex (M, %)
70
61
69
Diabetes (%)
43
46
23
79.0
84.6
64.7
0.001
2. Bachiller elemental
6.2
9.3
6.4
3. > Bachiller superior
14.8
6.2
28.9
Retired due to age
55.2
56.3
12.5
0.001
Retired due to illness
25.4
41.5
53.3
Active
19.4
2.2
34.2
1. Unskilled
62.5
85.0
44.8
0.001
2. Vocational professional
28.8
10.0
38.7
Level of studies Employment status
Work Activity
1. < SchGr
3. Graduate
8.8
5.0
16.6
Self-sufficient
81.5
69.8
90.8
0.001
Partial assistance
16.0
19.1
8.7
Full assistance
2.5
11.1
0.6
Family support
Low
16.0
30.2
4.6
0.001
Medium
40.7
47.5
17.3
High
43.2
22.2
78.8
Living environment
Rural
13.6
13.0
2.9
0.001
Town
55.6
38.9
52.0
City
30.9
48.1
45.1
Autonomy
ACKD: advanced chronic kidney disease, SchGr: school graduate, HD: haemodialysis, Tx: transplantation.
start of the study, the number of patients in our hospital was
low and although the incident rate grew, we quickly lost the
technique due to transplantation or due to the temporary or
definitive change to HD. Since we were not able to increase
the number of patients followed-up in time, we ceased to
analyse this treatment method. In general, the European series
estimate that the cost of PD is between the wide range of 30%70% less than that of HD13,22,24, which means that it is close
to RTx costs. However, a recent article by Lamas Barreiro25
questions the allocation of costs, reopening the debate on
the financial advantages of PD. In fact, the incorporation of
biocompatible supplements, polyglucose or automation raises
its price even above that of HD4.
Cost of renal replacement therapy by treatment
methods
Table 1 highlights that HD patients cost was almost five times
greater than that of ACKD and more than three times greater
than that of transplantation. A more detailed analysis by
financial items showed us that HD is mainly more expensive
due to the cost of HD sessions, but it is also more expensive
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in all financial items, particularly that of hospitalisation,
in which it is double the costs of the other two methods.
However, the hospitalisation cost of transplant patients is
very similar to that of ACKD patients.
Classically, RTx has been described as the most efficient
treatment option with the lowest cost from the second
year onwards. However, our data show that the financial
advantages of transplantation are detected at least after six
months. Haller et al.13 recently published a cost analysis in
Austria that was similar to ours. Despite being countries with
different structures and socioeconomic circumstances, the
costs during the second year of treatment were slightly lower
than in our study for HD (mean±SD: 40,000±10,900 vs.
47,700±18,400) and somewhat higher for RTx (17,200±13,000
vs. 14,000±10,000).
In the transplantation section, the costs between
the two methods (RTx and RPTx) were not majorly
d i ff e r e n t , s u g g e s t i n g t h a t R P T x d o e s n o t e n t a i l
a higher cost from the sixth month onwards.
Unfortunately, there are no other studies that allow
us to make comparisons.
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originals
Table 5. Renal replacement therapy method and sociocultural status
ACKD
HD
Tx
Lower
n
47
124
67
%
58.0%
77.5%
41.1%
n
18
21
34
%
22.2%
13.1%
20.9%
n
16
15
62
%
19.8%
9.4%
38.0%
Lower-Middle
Middle-Upper
Matrix table showing significant differences between methods and status (c2 p<.0001).
ACKD: advanced chronic kidney disease, HD: haemodialysis, Tx: transplantation.
With regard to ACKD patients in Spain, no data have been
published, and as such, ours may be a new precedent for
epidemiological estimation of this cost. According to the
results of the Spanish EPIRCE study 2, S4 and S5 CKD
prevalence is 0.27% (118,800 individuals) and 0.03% (13,200
individuals), respectively. Given these data and the annual
cost taken from our study, we can infer that, in the event
that all of these patients were detected and monitored in an
ACKD clinic, the annual financial amount for managing this
population in Spain would be no less than 1108 million euros.
Recently in the United States, Honeycutt et al.26 carried out a
macroepidemiological ACKD cost analysis. Annual costs were
$1,700 for patients in S2, $3,500 for S3 patients and $12,700
(around €10,000) for S4 patients, which demonstrates the
major increase in cost as the disease worsens. In our series we
also confirmed that, the greater the renal damage, the greater
the expense. The cost increased 59% between S4 and S5 (from
€7,846 to €13,300), and the greatest increase was observed
in medication and hospitalisation costs. It is notable that, in
spite of the enormous disparity between health systems, the
S4 cost in our series was only 20% higher than that published
by Honeycutt et al.26.
The costs of the lower financial impact sections (transportation
and outpatient care) were also greater for HD patients. The
only clear difference between transplant and ACKD patients
was in the medication section, where the transplant patient
costs were double the ACKD patient costs.
Treatment with haemodialysis
Allocating expenses attributable to HD is a complicated
issue. Most countries with structured public health services
pay HD costs, with a standard price per session being
assigned and minimum quality criteria being imposed. In
general, Spanish health services have adopted this model,
including the SCS. However, even within this model there
is variability in the options, depending on the hospital and
the type of subsidising4.
464
Some Spanish studies have gone further in addressing
the cost of HD, demonstrating that, although they were
carried out more than a decade ago, the costs did not differ
significantly from current costs27,28. In 2008, Parra Moncasi
et al.8 carried out a detailed study on the cost of HD in public
and subsidised hospitals. The subsidised hospital cost was
€32,872-€35,294, and it was 23% higher in public centres.
These costs are approximately 33% higher than those
reimbursed by the SCS, but they include expenses that we
allocate to other areas (dialysis and outpatient medication,
imaging diagnostics and transportation), which represent
40% of the cost in the study by Parra Moncasi8. Therefore,
we must assume that the reimbursement by the SCS for HD is
quite close to the real costs obtained by these authors8.
Outside our country, a Canadian study10 published in 2002
reported an overall annual HD cost in hospitals of €43,528
(95% confidence interval [CI] €40,528-€46,600) (dollar-euro
conversion: €0.85 = 1 American dollar). The cost analysis
was carried out with categories that were similar to our own,
although the price of the doctor was included under a different
heading. Specifically, the cost of HD was €22,688. In spite of
the innumerable differences between healthcare models and
structures, the specific cost of HD and its proportion of the
overall cost of treatment were similar to our study. Moreover,
other European studies, methodologically different, reported
an HD treatment cost that covered a wide range between
€20,000-€80,000/patient/year29,30. Our costs are somewhere
near the middle of this range, but unfortunately a more
in-depth comparison is impossible with the information
available to us. More recently, Icks et al.31 published a study
on the overall cost of HD in 2006 in a region of Germany,
analysing similar cost components to ours. The overall mean
cost was €54,777/patient/year, that is, 15% higher than in
our study, fundamentally due to the HD procedure (€30,029/
patient/year).
Hospital HD may considerably increase the cost, with around
€200 being allocated per session32, which results in an even
greater increase in the HD patient cost.
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Medication expenses
The medication expenses item was the third largest
by percentage, representing 13% of the total. We
must highlight that the medication expense has fallen
significantly in the last few years, because of cuts
generated by the financial crisis in Spain. In our previous
study7 the mean HD cost was €12,000 and in the current
study, it is €6,000, i.e., half that of the previous study.
ESA account for 35% the medication expense in HD. In
the previous study, we allocated a cost of around €11 for
every 1,000 units of erythropoietin, whereas in the current
study, it was €2.4, and it has subsequently continued to
decrease. Given that their use is almost universal and
the doses are within a narrow range for most patients,
the medication expense is quite homogenous in the HD
population.
The medication expense in ACKD was less than half that
in HD or transplantation. In 2002, Pons et al.30 published a
study of the medication costs in HD patients. The expense
per patient/year was €3,084 for S4 patients and up to
€4,224 for S5 patients, with ESA being responsible for
46.5% of these costs. These values are clearly higher than
those recorded in the study that we carried out seven years
later: €2,090 and €3,264, respectively, which illustrates
the downward adjustment of the prices in recent years.
The decrease in the cost of ESA is also explained mainly
by the decreased medication cost in this population.
In contrast to the decreased medication cost, particularly
due to the lowering of ESA prices, medication expense
has probably been the item with the greatest annual
increase on previous years, due to the incorporation into
the market of more expensive drugs, all related to mineral
metabolism: new phosphate binders, vitamin D receptor
activators, calcimimetics, etc. A patient who received
three of these products with a mean dose may account for
an expense of €25-30/day, i.e., an approximate increase
of 70%-80% on the overall daily medication cost.
Unfortunately, these financial approximations do not help
us much in carrying out future estimations for medication.
The imminent arrival of generic drugs to manage mineral
metabolism, the continuous downward re-negotiation of
prices and reductions or extensive regional competition
result in a margin of uncertainty that is impossible to
predict.
Hospitalisation expenses
As with our previous publication 7, we used the concept
of DRG to report hospitalisation costs. This tool should
be used as a reference and comparison framework in
evaluating the quality of healthcare and the use of services
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provided by the hospitals. This system was developed
by the government in order to establish a payment
system for hospitals in the United States. It is based on
a fixed quantity according to the specific DRG for each
patient treated. The classification was carried out using
international classification of disease codes (ICD-10) 19.
The aim of this classification was to group diseases in
order to assign a monetary value to each one, with the
objective of improving hospital expense management.
Although this method provides interesting information,
unfortunately we do not have comparative data in the
national setting for any RRT method, and we cannot
guarantee that the coding of data taken from medical
records is accurate to the real situation. We are only capable
of carrying out comparisons in terms of hospitalisation
rates and HD. The study published by Ploth et al.11 shows
hospitalisation rates that are almost equivalent to ours:
32% of patients did not require hospitalisation during
the study year. However, hospitalisation days vary a lot
between different series: the shortest average was reported
by Ploth et al.11: 5.7 days; in the series by Sehgal et al. 33,
it increases to two weeks per patient per year; while in
our study it was 18.7 days. However, there is nothing to
indicate that these may be reference parameters, given
the variability in circumstances that influence healthcare
in each region or hospital. In fact, we did not observe a
relationship between expenses, time and days hospitalised
and initial patient comorbidity and this was probably due
to socio-family circumstances or those related to different
kinds of health deficiencies that lead to admissions or
extended hospitalisation not explained strictly by medical
reasons.
Outpatient care
The poor representation of outpatient costs reflects the lead
role that nephrologists play in overall patient care, basically
becoming the patients’ GPs. Furthermore, analysis of this
aspect (consultations, complementary tests) shows enormous
variability, given the social and health insecurity of patients
in our setting, along with the alarming delays in appointments
for studies and consultations, added to the difficulty of travel
and family support, etc.
The relationship between the cost of treatment,
sociocultural factors and equal opportunities
The association between sociocultural factors and cost is
very difficult to establish, particularly in a chronic disease
population that is elderly and has major comorbidities. In
previous studies7,35, the cost of treatment was not clearly
associated with comorbidity ranges or with the group of
variables associated with sociocultural deprivation. This
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is not surprising given that elderly patients, almost all
of whom retired early, not having attended school and
having worked in unskilled jobs had the most precarious
health. But we must insist that, contrarily to what was
expected (at least by the authors), none of these factors
were associated with the cost of treatment. However, this
statement warrants a response: the study population was
very homogeneous in terms of sociocultural parameters,
including comorbidity. Table 4 eloquently illustrates that
more than two thirds of patients did not complete school
and their work activity was unskilled. This may explain
the lack of association between these parameters and cost.
Very extensive series may be required, which include a
more diverse population, in order to observe the effect
of sociocultural deprivation on costs; although in studies
carried out in the United States, we observed that the
association between sociocultural factors and costs was
weak in dialysis patients36.
With regard to sociocultural status and access to
transplantation, two extensive North American studies 37,38
reported that the most disadvantaged minorities had
fewer opportunities to receive a transplant, with a certain
inequality being observed in access to these programmes.
In our case, we also observed that patients who received a
transplant had the best sociocultural profile and that those
who were on HD had the worst profile, with the profile
being intermediate in ACKD patients.
A priori, we must explain that patients on the transplant
waiting list were younger and had better economic
and cultural opportunities. With the aim of explaining
this aspect, we carried out a logistic regression using
sociocultural status as a dependent variable in a dichotomous
format (sociocultural level: lower and middle-upper) and
adjusting for age. It is interesting that the relative risk of
the HD group was (odds ratio [95% CI]) 3.4 (2.0-6.1),
P=.002 times greater than in the transplant group. When
we created a matrix table that only included patients
younger than 65 years of age (to homogenise the age of
the groups), we also observed that transplant patients had
a better sociocultural environment than HD patients of a
similar age segment (X=19.2, P<.001).
Study limitations
Our study has limitations that we cannot avoid. Firstly, the
data obtained from interviews are not strictly accurate or
verifiable. Assuming this limitation, the surveys employed
were validated and used previously 35,39, although with
slight modifications in order to adapt them to the situation
of HD patients. The study population was not necessarily
representative of the national mean; although in age and
distribution by sex it was similar, the proportion of diabetic
patients was significantly higher and the sociocultural
466
environment probably has considerable interregional
differences.
The information obtained about the cost of treatment will be
difficult to extrapolate to other regions and populations in
absolute terms. The costs assigned to the different expense
sections undoubtedly vary between health services and
there is enormous variability in the allocation of expenses
in different hospitals. Furthermore, we should bear in mind
the cost reduction that there has been in some budgetary
items, particularly in medication. But it continues to be
very useful to have information about the costs between
treatment methods or between different budget allocation
items. In fact, we consider that the detailed information
by cost component may be used as a reference for future
studies or to carry out epidemiological estimations.
PD, despite its limitations, has demonstrated cost-effective
advantages compared to HD 21,23. Unfortunately, in our
study, we did not manage to recruit a minimum number of
patients to include this group.
CONCLUSIONS
We proved that the HD method is the most expensive
procedure in all financial items, whereas the cost of
ACKD patients and transplant patients is substantially
lower. The similar cost between RTx and RPTx is notable.
Unfortunately, the increase in age of the population that
develops end-stage renal disease is a definitive limitation
for access to transplantation. With these premises in mind,
action at an earlier age is vital for preventing prolonged
exposure to the adverse effects of chronic diseases,
particularly diabetes 40,41. In this regard, we should aim
to save financially by preventing kidney disease, both in
primary care and in specific ACKD clinics. When patients
reach advanced stages of the disease, early transplantation,
giving full prominence to the living donor programme,
must be an initiative that we must drive forward. Lastly,
in spite of the health system in Spain being universal and
supposedly egalitarian, this analysis invites us to think
about whether a lower sociocultural status may undermine
opportunities for access to renal transplantation.
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Sent to review: 21 Feb. 2014 | Accepted: 19 Apr. 2014
468
Nefrologia 2014;34(4):458-68
originals
During the pre-dialysis stage of chronic
kidney disease, which treatment is associated
with better survival in dialysis?
Francisco Caravaca, Raúl Alvarado, Guadalupe García-Pino, Rocío Martínez-Gallardo,
Enrique Luna
Servicio de Nefrología. Hospital Infanta Cristina. Badajoz (Spain)
Nefrologia 2014;34(4):469-76
ABSTRACT
Introduction: Specialised care of patients in advanced stages of
chronic kidney disease (CKD) is associated with better survival in
dialysis, but it is not known which treatments specifically favour
this outcome. Objectives: To analyse normal treatment in advanced
stages of CKD and establish which treatments are associated with
better survival in dialysis as well as their relationship with causes
of death. Material and method: Cohort, prospective observational
study of 591 patients who started dialysis (491 haemodialysis and 100
peritoneal dialysis), who had previously been controlled in the CKD
clinic. The treatments analysed were: antihypertensive treatments,
statins, platelet antiaggregants, xanthine oxidase inhibitors,
correction of metabolic acidosis, treatment with (calcium or noncalcium) phosphate binders, vitamin D (calcitriol or paricalcitol),
erythropoietin and the availability of an internal arteriovenous fistula
(IAVF). The independent association of each of these treatments
with mortality in dialysis was analysed using Cox regression models
adjusted for age, sex, pre-dialysis monitoring time, renal function
at the start of dialysis, comorbidity, serum albumin and C-reactive
protein, and with stratification of the type of dialysis. Results: With a
median follow-up period of 28 months, the total number of patients
who died was 191 (32%). In the multivariate models, we observed
that, in addition to age, the comorbidity index, serum albumin, predialysis treatment with angiotensin-converting-enzyme inhibitors
and/or angiotensin II receptor antagonists, correction of acidosis
with sodium bicarbonate and IAVF at the start of haemodialysis
were significantly associated with better survival in dialysis. We did
not observe differences in causes of death among the different
treatments analysed. Conclusion: These results suggest a potential
delayed benefit of some treatments in pre-dialysis stages on the
outcome of dialysis. Furthermore, beginning dialysis without an IAVF,
and therefore the need for intravenous catheters, worsens prognosis
in these patients.
¿Qué intervenciones terapéuticas durante el estadio prediálisis
de la enfermedad renal crónica se asocian a una mejor supervivencia en diálisis?
RESUMEN
Introducción: El cuidado especializado de los pacientes en estadios avanzados de la enfermedad renal crónica (ERC) se asocia a una mejor supervivencia en diálisis, pero se desconoce qué tratamientos favorecen
específicamente esta evolución. Objetivos: Analizar las intervenciones
terapéuticas habituales en el estadio de ERC avanzada y establecer cuáles de ellas se asocian a una mejor supervivencia en diálisis y su relación
con las causas de muerte. Material y métodos: Estudio de cohortes,
prospectivo y de observación, que incluyó a 591 pacientes que iniciaron
diálisis (491 hemodiálisis y 100 diálisis peritoneal), que habían sido controlados previamente en la consulta de ERC. Las intervenciones terapéuticas analizadas fueron: tratamientos antihipertensivos, estatinas, antiagregantes plaquetarios, inhibidores de la xantina-oxidasa, corrección de
la acidosis metabólica, tratamiento con captores de fósforo (cálcicos o
no), vitamina D (calcitriol o paricalcitol), eritropoyetina y disponibilidad
de fístula arterio-venosa interna (FAVI). La asociación independiente de
cada uno de estos tratamiento con la mortalidad en diálisis fue analizada mediante modelos de regresión de Cox con ajuste a edad, sexo,
tiempo de seguimiento prediálisis, función renal al inicio de diálisis, comorbilidad, albumina sérica y proteína C reactiva, y con estratificación
al tipo de diálisis. Resultados: Con una mediana de seguimiento de 28
meses, la cifra total de fallecidos fue de 191 (32 %). En los modelos multivariantes se observó que, además de la edad, el índice de comorbilidad
y la albúmina sérica, el tratamiento prediálisis con inhibidores de la enzima de conversión y/o antagonistas de los receptores de la angiotensina,
la corrección de la acidosis con bicarbonato sódico y la FAVI al inicio
de la hemodiálisis se asociaron de forma significativa con una mejor
supervivencia en diálisis. No se observaron diferencias en las causas de
muerte entre los diferentes tratamientos analizados. Conclusión: Estos
resultados sugieren un posible beneficio diferido de algunos tratamientos en estadios prediálisis sobre la evolución en diálisis. Además, el inicio
de hemodiálisis sin una FAVI, y por tanto la necesidad de utilización de
catéteres endovenosos, empeora el pronóstico de estos pacientes.
Keywords: Mortality. Dialysis. Angiotensin-converting enzyme
inhibitors. Pre-dialysis.
Palabras clave: Mortalidad. Diálisis. Inhibidores de la enzima de
conversión de la angiotensina. Prediálisis.
Correspondence: Francisco Caravaca
Servicio de Nefrología. Hospital Infanta Cristina.
Avda. Elvás, S/N. 06080, Badajoz. (Spain).
[email protected]
INTRODUCTION
Mortality remains very high in dialysis patients. Age and
comorbidity are the main determining factors of mortality in
469
originals
this population, but these factors can obviously not or hardly
be changed.
Francisco Caravaca et al. Pre-dialysis treatment and survival in dialysis
Table 1. Clinical characteristics and treatments received by
patients included in the study
An epidemiological feature of dialysis patients is the lack of
association between classic cardiovascular risk factors and
mortality1. Moreover, the few randomised studies carried out
in this population have not demonstrated clear benefits on
survival with the use of various drugs proven to be useful
in the non-uraemic population or with other therapeutic
measures based on sound pathophysiological principles2.
Total no. of patients
Moreover, some studies have warned us about the potential
risk of drugs commonly used in chronic kidney disease
(CKD), such as erythropoietin (EPO)3 or calcium salts4, which
adds even more difficulty and confusion to the management
of these patients.
Davies comorbidity index, absent/low to
medium/high
The specialised care of pre-dialysis patients in advanced
stages of CKD is unanimously considered to be a factor that
benefits survival in dialysis5,6. In these advanced chronic
kidney disease (ACKD) clinics, many treatments are usually
carried out, such as controlling blood pressure, correcting
over-hydration, metabolic acidosis, mineral and bone
disorders and anaemia, creating vascular access and choosing
when to start dialysis, etc., but the importance of each of
these treatments and the benefits they can bring in terms of
dialysis patient survival is unknown.
Serum albumin, g/dl
We carried out this prospective study with the objective of
analysing the normal treatments for ACKD and establishing
which of them are associated with greater survival in dialysis,
as well as their relationship with causes of death.
MATERIAL AND METHOD
We included 591 patients with the demographic and clinical
characteristics that are displayed in Table 1. Inclusion
criteria were as follows: having begun dialysis treatment at
the Hospital Infanta Cristina de Badajoz during the period
between October 1999 and January 2012, and having
previously been monitored in the ACKD clinic of the same
hospital. We did not exclude any patients.
We started haemodialysis (HD) in 491 patients and peritoneal
dialysis (PD) in 100. There were no pre-dialysis kidney
transplantations.
The information on the treatment that the patients were
receiving was obtained by anamnesis and a review of medical
records.
The treatments used during the pre-dialysis stage that were
analysed in this study were: treatment with angiotensinconverting enzyme inhibitors (ACEI) and/or angiotensin
receptor blockers (ARBs), diuretics, calcium channel
470
591
Age, years
61±15
Sex, male/female
329/262
Diabetes, %
32%
ACKD follow-up time, median days
318 (125-657)a
Patients with ACKD follow-up >90 days, %
83
255/274/62
HD/PD, no. patients
491/100
Glomerular filtration rate at the start of dialysis,
ml/min/1.73m2
7.8±1.8
C-reactive protein, mg/l
3.85±0.51
3.79 (1.35-9.03)a
ACEI/ARBs, %
73
Calcium channel blockers, %
50
Diuretics, %
60
Beta-blockers, %
23
Statins, %
53
Antiplatelet drugs, %
28
Xanthine oxidase inhibitors, %
23
Sodium bicarbonate treatment, %
46
Phosphate binder, %
91
Phosphate binder with calcium, %
71
Treatment with vitamin D, %
13
Treatment with EPO, %
71
AVF, % HD patients
51
ARBs: angiotensin receptor blockers, PD: peritoneal dialysis,
EPO: erythropoietin, ACKD: advanced chronic kidney disease,
AVF: arteriovenous fistula, HD: haemodialysis,
ACEI: angiotensin-converting enzyme inhibitors.
a
Median and interquartile range.
blockers, beta-blockers, statins, antiplatelet drugs, xanthine
oxidase inhibitors, correction of metabolic acidosis with
sodium bicarbonate, treatment with (calcium or noncalcium) phosphate binders, calcium salts, active vitamin D
(calcitriol or paricalcitol) and anaemia correction by EPO.
Furthermore, we included an internal arteriovenous fistula
(IAVF) in our treatment, and this was usable at the time
dialysis began.
The covariates included to adjust survival models were:
age, sex, Davies comorbidity index (three subgroups: no
Nefrologia 2014;34(4):469-76
comorbidity, mild to moderate, and severe comorbidity)
, diagnosis of diabetes mellitus, serum albumin
concentrations (bromocresol green, Advia Chemistry,
Siemens Healthcare Diagnostics) and C-reactive protein
(high sensitivity by chemiluminescence immunoassay
in the solid phase, Immulite, Siemens). As potential
confounding variables, we also included the glomerular
filtration rate (MDRD-4) at the start of dialysis and the
follow-up time in the ACKD clinic (greater or less than
90 days).
The lack of a functioning IAVF in patients included in
this study who started HD may have been due to one of
the following reasons: failure (thrombosis), its rejection
by the patient or insufficient pre-dialysis follow-up time.
Patients were followed-up with regard to their outcomes in
dialysis, with death due to all causes being the only study
event. The follow-up period began with the first dialysis
session and patients were censored (non-informative
censoring) for the end of data collection (September
2012), loss to follow-up and renal transplantation.
We also recorded the cause of death, establishing
five etiological groups: sudden death, death from
cardiovascular, infectious, tumour and other causes.
To analyse whether there was an association between the
different pre-dialysis treatments and survival in dialysis,
we used Kaplan-Meier curves (univariate study) and
Cox multivariate proportional hazards models, with the
calculation of the instantaneous hazard rates (hazard
ratio) and their 95% confidence intervals. Covariates
in multivariate models were selected automatically,
using the backwards progressive conditional elimination
process.
Due to the potential confounding by indication in the
inclusion of PD and HD patients, who not only had age
and comorbidity differences, but also had differences in
other characteristics that were not recorded as variables
but nonetheless had a potential influence on survival,
such as socio-economic and cultural level or the degree
of dependency, the analyses were stratified according to
the initial form of treatment (HD or PD).
The analysis of survival and stratification between PD
and HD was in any case considered by intention-to-treat,
independently of the time that the patient would have
remained on one or another dialysis technique.
For comparison of continuous variables between patients
who survived or died, we used Student’s t-test or the
Mann-Whitney test, depending on the characteristics of
the variable distribution. The χ2 test was used to compare
categorical variables between subgroups.
Nefrologia 2014;34(4):469-76
originals
The data were presented as a mean ± standard deviation or
the median and interquartile ranges. A P value less than .05
was considered to be statistically significant. For statistical
analyses and creating graphs, we used the SPSS version 15.0
software (SPSS, Chicago, USA) and STATA version 11.1
(Stata Corporation, Texas, USA).
RESULTS
Mortality in dialysis
With a median follow-up of 28 months (interquartile
ranges: 13-50 months), the total number of deaths was 191
(32%) and estimated median survival was 82 months (95%
confidence interval: 56-108 months).
The demographic, clinical and biochemical characteristics
of the patients who survived and died are displayed
in Table 2. As well as the factors that were very much
expected to be associated with mortality such as age,
comorbidity and serum albumin and C-reactive protein
concentrations, we note the low mean follow-up time
in the ACKD clinics of the patients who died (Table 2).
We also observed significant differences in pre-dialysis
treatments between those who survived and those who
died, which highlights the positive association between
survival and ACEI/ARBs, beta-blockers, statins, sodium
bicarbonate and phosphate binders, and even calcium
salts. By contrast, the association was negative for
survival with diuretics and at the limit of significance
with antiplatelet drugs. We did not observe differences
in the percentage of EPO, vitamin D or xanthine oxidase
inhibitor prescription between those who survived and
those who did not.
The glomerular filtration rate at which dialysis began was
significantly higher in patients who died and the percentage
of patients with an IAVF was significantly lower in this
same subgroup (Table 2).
Patients whose initial treatment was with PD had better
survival than those treated with HD (Figure 1), although it is
important to highlight again that there were major differences
between both subgroups with regard to age, comorbidity and
other factors that potentially influenced survival that were not
recorded in this study, such as socio-economic, cultural and
dependency levels.
Causes of death according to pre-dialysis treatments
Figure 2 displays the causes of death grouped into five
aetiological sections (sudden death, cardiovascular, infection,
tumour and other causes), according to the type of initial
dialysis and some treatments carried out in the pre-dialysis
471
originals
Table 2. Clinical characteristics and treatments received by patients who survived or died during the study period
Survivors
400
57±16
57
Deaths
191
70±10
54
<0.0001
ns
344 (133-704)a
257 (99-561)a
0.02
26
43
<0.0001
53/40/7
22/59/19
<0.0001
No. patients
Age
Sex, % males
Pre-dialysis follow-up time, days
Diabetes, %
Comorbidity index, % group absent/low to medium/high
comorbidity
Serum albumin, g/dl
C-reactive protein, mg/l
3.93±0.48
P
3.68±0.52
<0.0001
2.97 (1.03-7.37)
4.69 (2.30-15.11)
<0.0001
ACEI/ARBs, %
79
61
<0.0001
Diuretics, %
56
70
0.001
Calcium channel blockers, %
48
55
0.113
Beta-blockers, %
26
19
0.032
Statins, %
56
46
0.020
Treatment with EPO, %
71
71
ns
Treatment with vitamin D, %
14
13
ns
Antiplatelet drugs, %
26
33
0.06
Xanthine oxidase inhibitors, %
24
20
ns
Treatment with sodium bicarbonate, %
51
35
< 0.0001
Phosphate binders,%
93
86
0.008
Calcium binders, %
75
63
0.003
7.61±1.67
8.22±1.93
<0.0001
59 %
36 %
<0.0001
Glomerular filtration rate at the start of dialysis,
ml/min/1.73m2
Functioning AVF, % patients who started HD
a
a
ARBs: angiotensin receptor blockers, EPO: erythropoietin, AVF: arteriovenous fistula, HD: haemodialysis,
ACEI: angiotensin-converting enzyme inhibitors, ns: not significant.
a
Median and interquartile range.
stage. Those of cardiovascular and infectious origin were the
most common causes of mortality.
The only significant difference observed was between PD and
HD (P=.02), with there being an absence of sudden death
in PD patients and on the other hand, a greater proportion
of death from tumours, due to a lack of oncological control
of myeloma and leukaemia that were already related to the
origin of renal failure.
We did not observe significant differences in the cause of
death between those treated and those not treated with EPO,
vitamin D or calcium salts. The differences in the cause of
death between patients who began HD with or without an
IAVF were not significant either, although there was a higher
rate of death from infectious aetiologies in those who did not
possess an IAVF.
472
Analysis of survival and its association with the
study variables
In the Cox stratified regression analysis according to the
initial type of dialysis (Table 3) we observed that, as well as
age, the comorbidity index and serum albumin, pre-dialysis
treatment with ACEI/ARBs and the correction of acidosis
with sodium bicarbonate were positively associated with
survival in dialysis. We also note the positive and significant
association between the availability of an IAVF at the start
of HD and survival. By contrast, higher renal function at the
start of dialysis was associated with worse survival.
Figures 3 and 4 display the dialysis survival curves of the patients
who had been treated and those who had not been treated with
ACEI/ARBs during the pre-dialysis period. Figure 5 displays the
survival curves of patients who started HD with or without an IAVF.
Nefrologia 2014;34(4):469-76
1.0
Due to strong confounding by indication in this study, we
cannot claim that there is causality between the direct
therapeutic effects of these drugs and improved survival in
dialysis patients, even after adjustment with the confounding
variables, but we believe that the data provide information
that could prove useful in the prediction of outcomes in
dialysis patients.
PD
Survival
0.8
0.6
HD
The effect of treatment with ACEI or ARBs on ACKD or
dialysis patient survival is controversial. These drugs may
have positive effects on residual renal function, vascular
access and the uraemic myocardium7, which in turn may be
reflected in better survival8, although other studies have not
been able to demonstrate this benefit9.
0.4
0.2
0
Log-rank = 25.15
P<0.0001
0
50
100
150
200
Time on dialysis, months
HD n =491 270 123 56
PD n =100 57 22 11
18
6
5
Figure 1. Kaplan-Meier survival curves in patients who
started haemodialysis or peritoneal dialysis.
The number of patients in each group at the start of each
25-month period is also displayed.
PD: peritoneal dialysis, HD: haemodialysis, Log-rank: log rank
estimated by the Mantel-Haensel test.
DISCUSSION
Mortality in dialysis patients continues to be very high.
Some characteristics of CKD such as the growing severity
of its complications as renal failure progresses, as well as
accumulative adverse effects, some of them irreversible,
could help us to understand this disconcerting fact. As such,
the monitoring and treatment of the disease in less advanced
stages may have a major influence on the survival of patients
who reach more advanced stages.
This is a hypothesis that would explain better survival in
dialysis of patients who were monitored and treated in ACKD
clinics.
The results of this study show that there are various predialysis treatments that are significantly associated with
a better outcome in dialysis patients, but the only ones to
remain in the models adjusted for age, sex, comorbidity,
dialysis type and other prognosis markers were treatment
with ACEI/ARBs, metabolic acidosis correction with
sodium bicarbonate and the introduction of an IAVF in
those who began HD. By contrast, we did not observe that
any of the treatments analysed in adjusted models were
associated with a worse outcome or any specific cause of
death.
Nefrologia 2014;34(4):469-76
originals
The association between ACEI/ARBs use in pre-dialysis and
survival in PD and HD patients is an original result of this
study. A hypothesis to explain these findings may be based
on a potential survival bias, that is, patients who required,
tolerated and survived treatment with ACEI/ARBSs in
the pre-dialysis period form a select group with a greater
probability of survival in dialysis. However, this hypothesis
seems unlikely, since we also observed better pre-dialysis
survival in those treated with ACEI/ARBs (observations not
published).
Another hypothesis to explain this delayed association may be
related to a “legacy effect”. This term was originally coined to
PD
HD
ACEI/ARBs +
ACEI/ARBs EPO +
EPO Calcium +
Calcium Vitamin D +
Vitamin D AVF +
AVF 0
25
50
75 100
% died
n Sudden
n CV n Infection
n Tumour
n Other
Figure 2. Causes of death according to the dialysis type,
or some pre-dialysis treatments, or the availability of an
arteriovenous fistula in those who started haemodialysis.
ARBs: angiotensin receptor blockers, CV: cardiovascular,
PD: peritoneal dialysis, EPO: erythropoietin, AVF: arteriovenous
fistula, HD: haemodialysis, ACEI: angiotensin-converting
enzyme inhibitors.
473
originals
Table 3. Cox multivariate regression models on mortality in dialysis
Variable
Hazard ratio
IC 95 % hazard ratio
P
Age, years
1.036
1.022-1.051
<0.0001
Comorbidity index (0,1,2)
1.432
1.121-1.829
0.004
Serum albumin, g/dl
0.706
0.530-0.941
0.018
ACEI/ABRs (0.1)
0.660
0.487-0.895
0.007
Treatment with sodium bicarbonate (0.1)
0.723
0.530-0.985
0.040
IAVF (0.1)
0.678
0.494-0.931
0.016
Glomerular filtration rate at the start of dialysis, ml/min
1.100
1.021-1.185
0.013
ARBs: angiotensin receptor blockers, CI: confidence interval, IAVF: internal arteriovenous fistula, ACEI: angiotensin-converting
enzyme inhibitors.
Outside the model: sex, diabetes, C-reactive protein, calcium channel blockers, erythropoietin, vitamin D, antiplatelet drugs,
xanthine oxidase inhibitors, diuretics, beta-blockers, phosphate binders, calcium salts, time in advanced chronic kidney disease clinic
and statins (the latter was on the limit of significance, hazard ratio =0.748, P=.058).
describe the positive effect of good metabolic control during
the initial stages of diabetes on the subsequent outcome and
its complications. There has also been speculation about the
possibility that this same legacy effect could be achieved
with the control of high blood pressure or with the use of
ACEI/ARBs11, which is a benefit of survival that could be
maintained beyond drug interruption, and it is therefore more
difficult to appreciate it clinically.
Metabolic acidosis in CKD has negative effects on the state
of nutrition, mineral and bone disease and inflammation,
and is associated with worse survival12. The correction of
acidosis with sodium bicarbonate has demonstrated not
only that it improves the state of nutrition, but that it also
has very positive effects on maintaining renal function.
In this study, the correction of acidosis with sodium
bicarbonate was independently associated with better
survival in dialysis. However, the potential confounding by
indication also prevented the causality of this association
from being confirmed. Some confounding factors that may
influence this association are the decreased tendency for
acidosis of diabetic patients with CKD13, or the association
between acidosis and treatment with ACEI/ARBs due
to type IV renal tubular acidosis or the impossibility of
prescribing antacids in those who were treated for a brief
period of time in the ACKD clinic. All of these confounding
variables were taken into account in the multivariate
regression analyses (diagnosis of diabetes, ACEI/ARB
treatment and pre-dialysis follow-up time), and treatment
with bicarbonate maintained statistical significance.
Starting HD with an IAVF improved vital prognosis 14.
According to these studies, we also observed better survival
474
in patients with a functioning IAVF at the start of HD,
and this association was independent of other confounding
factors (age, sex, comorbidity, drugs, etc.)
Although the causes of death in those who initiated HD
with or without IAVF were not significantly different, a
greater percentage of deaths due to infection was observed,
perhaps in relation to the more frequent use of endovascular
catheters.
The renal function with which these patients started
dialysis was another determining factor of survival, but
to the contrary of what was expected, the association
was negative. In accordance with observations of other
authors 15, it is likely that a higher glomerular filtration
rate at the start of dialysis reflects a poor general patient
condition, higher intolerance to uraemia, especially that
related to states of over-hydration and the development of
heart failure. It is also important to point out that when a
patient from our study required the (urgent) non-scheduled
initiation of dialysis due to any of these complications,
the renal function figure that was taken was that of the
last scheduled test, and therefore, this higher glomerular
filtration rate would not reflect real renal function at the
time of the first dialysis session.
This study has limitations mainly derived from the
aforementioned confounding biases (indication and
survival). Although the effect of these biases aims to
correct itself by stratification and adjustment of the
models with the main confounding variables, we cannot
rule out the possibility of other variables that we have
not considered having a significant influence on the end
results.
Nefrologia 2014;34(4):469-76
originals
1.0
1.0
With ACEI/ARBs
0.8
0.6
Without ACEI/ARBs
0.4
0.2
0
0.6
Survival
Survival
0.8
0.2
Log-rank = 10.16
P=0.001
0
With ACEI/ARBs
0.4
0
Log-rank = 10.46
P=0.001
0
20 40
60 80 100 120
n=
358
Without ACEI/
ARBs
50
100
150
200
198 91 38 11 4
72 32 18 7 1
With ACEI/ARBs n =74
49
1711631
Without ACEI/ARBs n =26
20
126 431
With ACEI/ARBs
Figure 3. Kaplan-Meier survival curves in patients who
started peritoneal dialysis and were treated or not
with angiotensin-converting enzyme inhibitors and/or
angiotensin receptor blockers.
ARBs: angiotensin receptor blockers, ACEI: angiotensinconverting enzyme inhibitors, Log-rank: log rank estimated by
the Mantel-Haensel test.
Figure 4. Kaplan-Meier survival curves in patients
who started haemodialysis and were treated or not
with angiotensin-converting enzyme inhibitors and/or
angiotensin receptor blockers.
ARBs: angiotensin receptor blockers, ACEI: angiotensinconverting enzyme inhibitors, Log-rank: log rank estimated by
the Mantel-Haensel test.
Without ACEI/ARBs n =132
1.0
Another limitation is that all patients studied were from
the same hospital, with certain treatment criteria, which
prevents us from guaranteeing the reproduction of the
results with different treatment criteria.
These results suggest a potential delayed benefit (legacy
effect) of some treatment in pre-dialysis stages on the
subsequent evolution of dialysis patients. In addition,
starting HD without an IAVF, with the resulting need for
intravenous catheters, could be related to worse prognosis.
Nefrologia 2014;34(4):469-76
Started HD with AVF
Survival
In conclusion, there are differences in pre-dialysis
treatments of patients who survive or die on dialysis. The
most significant differences in models that are stratified to
the type of dialysis and to the main confounding factors
are: treatment with ACEI/ARBs, treatment with sodium
bicarbonate and having a usable IAVF at the time of the
first HD session.
0.8
0.6
0.4
0.2
0
Started HD without AVF
Log-rank = 22.44
P<0.0001
0 50 100150200
With FAV n =
248148 74 33 8 2
10 3
Whithout FAV n = 243122 49 23
Figure 5. Kaplan-Meier survival curves in patients
who started haemodialysis and had or did not have a
functioning arteriovenous fistula.
AVF: arteriovenous fistula, HD: haemodialysis, Log-rank: log
rank estimated by the Mantel-Haensel test.
475
originals
REFERENCES
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6. Bradbury BD, Fissell RB, Albert JM, Anthony MS, Critchlow CW,
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US hemodialysis patients in the Dialysis Outcomes and Practice
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7. Cravedi P, Remuzzi G, Ruggenenti P. Targeting the renin angiotensin system in dialysis patients. Semin Dial 2011;24:290-7.
8. Chan KE, Ikizler TA, Gamboa JL, Yu C, Hakim RM, Brown NJ.
Combined angiotensin-converting enzyme inhibition and re-
ceptor blockade associate with increased risk of cardiovascular
death in hemodialysis patients. Kidney Int 2011;80:978-85.
9. Ahmed A, Fonarow GC, Zhang Y, Sanders PW, Allman RM, Arnett DK, et al. Renin-angiotensin inhibition in systolic heart failure and chronic kidney disease. Am J Med 2012;125:399-410.
10. Holman RR, Paul SK, Bethel MA, Matthews DR, Neil HA. 10year follow-up of intensive glucose control in type 2 diabetes.
N Engl J Med 2008;359:1577-89.
11. Volpe M, Cosentino F, Tocci G, Palano F, Paneni F. Antihypertensive therapy in diabetes: the legacy effect and RAAS blockade. Curr Hypertens Rep 2011;13:318-24.
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13. Caravaca F, Arrobas M, Pizarro JL, Espárrago JF. Metabolic acidosis in advanced renal failure: differences between diabetic
and nondiabetic patients. Am J Kidney Dis 1999;33:892-8.
14. Pisoni RL, Arrington CJ, Albert JM, Ethier J, Kimata N, Krishnan
M, et al. Facility hemodialysis vascular access use and mortality
in countries participating in DOPPS: an instrumental variable
analysis. Am J Kidney Dis 2009;53:475-91.
15. Susantitaphong P, Altamimi S, Ashkar M, Balk EM, Stel VS,
Wright S, et al. GFR at initiation of dialysis and mortality in
CKD: a meta-analysis. Am J Kidney Dis 2012;59:829-40.
Sent to review: 15 Sep. 2013 | Accepted: 24 Apr. 2014
476
Nefrologia 2014;34(4):469-76
originals
Fluid therapy and iatrogenic hyponatraemia risk
in children hospitalised with acute gastroenteritis:
prospective study
Marciano Sánchez-Bayle1, Raquel Martín-Martín2, Julia Cano-Fernández1,
Enrique Villalobos-Pinto1
1
Sección de Pediatría. Hospital Niño Jesús. Madrid (Spain); 2 Servicio de Pediatría. CS Reina Victoria. Madrid (Spain)
Nefrologia 2014;34(4):477-82
doi:10.3265/Nefrologia.pre2014.May.12257
ABSTRACT
Objective: The purpose of this study is to analyse whether
the use of hypotonic fluids increases the risk of iatrogenic
hyponatraemia in children hospitalised with acute gastroenteritis
(AGE). Patients and methods: Prospective study carried out on 205
patients with ages ranging from 1 to 28 months and admitted
with a diagnosis of mild or moderate dehydration due to AGE
and treated with intravenous hypotonic fluids in a paediatric
department in Madrid (Spain). The degree of dehydration at
presentation was estimated using standard clinical measures. 198
children received 0.3 % glucosaline solution and in 7 patients,
with baseline hypernatraemia, 0.2 % gluco-hyposaline solution
was administered. We analysed the results according to whether
children were hyponatraemic, normonatraemic or hypernatraemic
at presentation. The blood and urine samples were analysed and
the concentration of sodium and fractional sodium excretion
(EFNa) before and after intervention were considered as outcome
measures. Results: The 205 patients included in the study were
distributed in 3 groups according to the baseline natraemia
results. In 37 cases we detected hyponatraemia (18.04%), in 133
cases isonatraemia (64.87%) and in 35 children hypernatraemia
(17.07%). After administering hypotonic fluids we detected a
significant difference between initial and final natraemia in all
groups; in the group with hyponatraemia, sodium increased
and in the groups with iso and hypernatraemia, sodium slightly
decreased. A significant correlation between the EFNa and the
evolution of natraemia was found. No cases of hyponatraemia
post-infusion were seen and there was no correlation between
free water administered and natraemia evolution. Conclusions:
Results show that the use of hypotonic fluids does not increase the
risk of hospital acquired hyponatraemia in hospitalised children
with normal renal function. Our children with gastroenteritis did
not develop hyponatraemia even though they were all treated
with hypotonic intravenous solutions.
Intravenous rehydration and acquired hyponatraemia in hospitalized
children with gastroenteritis: prospective study
RESUMEN
Objetivo: Determinar si la utilización de sueros hipotónicos supone
un riesgo en la aparición de hiponatremia iatrogénica en los niños
hospitalizados por gastroenteritis aguda (GEA). Pacientes y método: Estudio prospectivo realizado con 205 pacientes de edades
comprendidas entre 1 y 28 meses e ingresados con diagnóstico de
deshidratación leve o moderada por GEA para recibir sueroterapia
en la sección de lactantes de un hospital pediátrico de Madrid (España). El grado de deshidratación inicial se estimó con mediciones
clínicas estándar. El suero administrado fue glucosalino 0,3 % en
198 casos y en los 7 casos restantes, todos con hipernatremia inicial,
se administró suero glucohiposalino 0,2 %. Se analizó la respuesta
a los líquidos intravenosos según si el niño se hallaba normo, hipo
o hipernatrémico antes de iniciar el tratamiento. Las cifras de sodio
en sangre y la excreción fraccional de sodio (EFNa) se consideraron
como medidas de resultado. Resultados: Los 205 pacientes incluidos
en el estudio se distribuyeron en tres grupos según el resultado inicial de la natremia. En 37 casos se detectó hiponatremia (18,04 %),
en 133 niños isonatremia (64,87 %) y en 35 niños hipernatremia
(17,07 %). Después de administrar soluciones hipotónicas encontramos en todos los grupos diferencia significativa entre el sodio sérico
inicial y el final; en el grupo con hiponatremia el sodio subió y en
los grupos con iso e hipernatremia el sodio descendió ligeramente.
Se evidenció correlación significativa entre la EFNa y la evolución de
la natremia (Na sérico inicial – Na sérico final). No se detectó ningún
caso de hiponatremia posinfusión y tampoco se encontró correlación entre el agua libre administrada y la evolución de la natremia.
Conclusiones: En lactantes con funcionamiento renal normal no se
ha encontrado hiponatremia como resultado de la administración
de sueros hiposalinos intravenosos, hallándose diferencias significativas en la EFNa que indican el ajuste renal de la natremia.
Keywords: Gastroenteritis. Hyponatraemia. Hypotonic fluids.
Palabras clave: Gastroenteritis. Hiponatremia. Sueros hipotónicos.
Correspondence: Marciano Sánchez Bayle
Sección de Pediatría.
Hospital Niño Jesús. Menéndez Pelayo, 65. 28009 Madrid. (Spain).
[email protected]
[email protected]
INTRODUCTION
Acute gastroenteritis (AGE) is one of the most frequent
medical pathologies in the first years of life and it can lead
477
originals
to dehydration that requires the child’s hospitalisation and
the subsequent use of parenteral rehydration solutions. An
imbalance between the intake and loss of free water or serum
sodium can occur in AGE which can cause hyponatraemia,
in other words, a serum sodium level <135 mEq/l1. Ever
since Holliday and Segar initiated a parenteral rehydration
standard in 1957 that continues today, it is frequent to
use hypotonic fluid in the intravenous correction of water
deficit in children with AGE 2. Furthermore, in 1957,
Schwartz published the first case of a metabolic disorder
in which the anti-diuretic hormone (ADH) was released by
non-physiological stimuli, which would cause the retention
of electrolyte-free water followed by a high sodium
concentration in the urine with resulting hyponatraemia3.
When a loss of intravascular fluid occurs due to
dehydration, ADH is released, which forces the kidneys to
retain water even if suffering from hyponatraemia, since
the signalling for volaemic compensation takes priority
over the natraemia control mechanisms. Nausea, vomiting
and dehydration make up the non-osmotic stimuli for ADH
secretion and are present in AGE 4. Serious secondary
effects from the use of hypotonic fluids or from perfusion
rhythm were documented, since they can cause dilution
hyponatraemia with the risk of neurological repercussions
of variable severity5.
At present, higher levels of NaCl in hydration solutions are
recommended to prevent hyponatraemia, but there is the
possibility that these recommendations are not appropriate
in infants6.
Most electrolyte imbalances occur in the hospital and
among them, hyponatraemia is the most frequent. Children
have a particularly high risk of secondary hyponatraemia
and prognosis is worse than in later life.
This study aims to determine whether the use of hypotonic
fluids involves a risk for iatrogenic hyponatraemic in
children hospitalised due to AGE and to analyse whether
initial natraemia can predict the risk of developing
iatrogenic hyponatraemia in our series.
PATIENTS AND METHOD
This is a prospective study involving 205 patients aged
between 1 and 28 months, of which 23 were younger than
6 months. Patients were admitted with dehydration due
to AGE and/or intractable vomiting in order to receive
fluid therapy in the infant department of the Niño Jesus
Children’s Hospital, Madrid, from January to December
2010.
The reasons recorded for admittance and subsequent
parenteral rehydration were the combination of mild
or moderate dehydration and/or continuous vomiting,
478
Marciano Sánchez-Bayle et al. Fluid therapy and hyponatraemia
as well as insufficient intake of oral liquid during stay
in the emergency department. The initial degree of
initial dehydration was estimated using standard clinical
measurements, according to the Gorelick score7.
55 patients presented mild dehydration, and the remaining
155 patients were moderately dehydrated.
19 children were excluded from the study, the exclusion
criteria being: nephropathy, heart disease, chronic diseases,
hypothalamus-hypophysis pathology and also admittance
to the intensive care unit due to the seriousness of the
process. Informed consent was obtained and the hospital’s
ethical committee approved the study.
In order to determine whether baseline plasma sodium was
a subsequent risk indicator for dilution hyponatraemia,
response to intravenous fluids was analysed based on
three groups of baseline natraemia: normonatraemia,
hyponatraemia and hypernatraemia.
Hyponatraemia was defined as a sodium serum level
<135mmol/l; normonatraemia as 135-145mmol/l; and
hypernatraemia >145mmol/l.
A separate analysis of the results was carried out in
accordance with the classification of hyponatraemia,
isonatraemia or initial hypernatraemia.
Urine and blood samples were taken to determine sodium
levels and osmolality before starting fluid therapy and
before beginning oral feeding and/or administering any
oral liquid. The urine sample was taken as close to the
blood sample as possible.
Fractional sodium excretion represents the percentage of
sodium filtered that is finally excreted and is calculated in
all patients using the formula: sodium in urine x creatinine
in blood x 100/sodium in blood x creatinine in urine8. Free
water administered in ml / kg of weight and ml/hour was also
analysed. The difference between the volume of fluid infused
with saline solution and the volume of fluid infused with
isotonic saline solution was calculated in order to administer
the same amount of sodium chloride; all calculated in ml/hour
divided by the child’s weight (kg)9.
The solutions administered were 0.3 % glucosaline (0.3 %
saline solution with 5 % glucose) in 198 cases and 0.2 %
gluco-hyposaline (0.2 % saline solution with 5 % glucose) in
the 7 remaining cases, all with initial hypernatraemia. Fifteen
patients previously needed expansion with saline solution.
Fluid infusion included baseline requirements in addition to
estimated deficit.
Administration of fluids and/or oral solids restarted when
vomiting eased.
Nefrologia 2014;34(4):477-82
The statistical analysis was carried out using SPSS 15.0
commercial software. Basic data was expressed in means
and standard deviations for quantitative variables, and
in numbers and percentage for qualitative variables.
95 % confidence intervals (95 % CI) were calculated.
Comparisons between quantitative variables were made
using the Mann-Whitney test after verifying that they
were not adjusted to a normal distribution (KolmogorovSmirnov test). If distribution was normal, the Student’s
t-test was applied. The Pearson correlation coefficients
were calculated. Values of P<.05 were considered to be
statistically significant.
RESULTS
205 was the total number of patients admitted with a
diagnosis of mild/moderate dehydration caused by AGE
in 2010 and who were included in the study; 117 patients
were boys (57.03 %) and the remainder, girls. The degree of
dehydration was mild in 55 cases (26.82 %) and moderate
in 150 (73.17 %).
198 patients received 0.3 % saline solution (0.3 % saline
with 5 % glucose) and 7 patients, whose analysis showed
baseline hypernatraemia, received 0.2 % gluco-hyposaline
solution (0.2 % saline with 5 % glucose). Expansion with
saline solution was previously required in 15 patients.
The age range of the children was 1 to 28 months; average
age was 11.52 months and standard deviation (SD) 5.77.
Twenty-three patients (11.21 %) were younger than 6
months. Mean weight of the patients was 8.44kg, 1.85SD.
Mean infused volume/kg/hour was 5.51, 1.3SD. The
incidence of baseline hyponatraemia in these patients was
18.04 %.
In the initial analysis, we separated the patients into three
groups according to baseline natraemia: 37 hyponatraemic
patients (18.04 %), 133 normonatraemic patients (64.87 %)
and 35 hypernatraemic cases (17.07 %).
Mean baseline glycaemia was 99.42mg/dl (18.61SD), with
range 40-166mg/dl, and values <70mg/dl were found in 45
children (21.95 %).
In the first group, after administering 0.3 % saline solution,
serum sodium increased from 131.9mEq/l (2.07SD) to
135.6mEq/l (2.54SD). Serum sodium slowly reduced in the
second group, without resulting in hyponatraemia, from
139.18 (2.9SD) to 137.92 (2.5SD); and likewise reduced
in the third group from 150.17 (4.2SD) to 142.02mEq/l
(4.3SD). There were no cases of hyponatraemia postinfusion. Blood and urine tests were performed after an
average time of 12.34 hours (95 % CI 11.94-12.56) from
the onset of fluid therapy.
Nefrologia 2014;34(4):477-82
originals
Table 1 shows the results of the biochemical measurements
in blood at the time of diagnosis and at the end of
treatment, before beginning oral feeding.
Table 2 shows the evolution of natraemia in all the
study’s patients, depending on whether or not they had
initial hyponatraemia. An increase of serum sodium was
observed in those patients with initial hyponatraemia
and these patients had significantly lower fractional
sodium excretion compared to those without initial
hyponatraemia.
Shown in table 3 are the analytical results obtained in blood
and urine after beginning fluid therapy with hypotonic
solutions and in accordance with baseline natraemia:
hyponatraemia, isonatraemia and hypernatraemia. We
found significant difference between baseline and final
serum sodium in all groups: sodium increased in the
group with hyponatraemia, and slightly decreased in the
groups with isonatraemia and hypernatraemia.
Table 1. Initial and final analysis (before starting oral
feeding)
Baseline
M (SD)
Final
M (SD)
Na (mEq/l)
141.2 (5.8)
137.4 (4.1)
K (mEq/l)
4.2 (0.53)
3.9 (0.55)
Cl (mEq/l)
108.7 (8.5)
107.6 (5.8)
Urea (mg/dl)
38.4 (16.7)
18.5 (12.5)
Creatinine (mg/dl)
0.47 (0.13)
0.36 (0.08)
SD: standard deviation; M: mean.
Table 2. Comparison of initial and final sodium of each
group
Hyponatraemia
M (SD)
No hyponatraemia
M (SD)
Baseline Na(mEq/l)
131.9 (2.07)
141.8 (5.4)
Final Na (mEq/l)
135.6 (2.54)
138.9 (3.9)a
EFNa
0.15 (0.27)
0.59 (0.71)a
Free water
11.82 (3.88)
12.79 (10.8)
a
SD: standard deviation; EFNa: fractional sodium excretion;
M: mean.
Comparison of baseline and final sodium and EFNa between
the hyponatraemia group and the remainder.
a
P<.0001.
479
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Table 3. Fluid therapy according to natraemia
Na < 135
M (SD)
Na 135-145
M (SD)
Na > 145
M (SD)
Baseline Na (mEq/l)
131.9 (2.07)
139.18 (2.9)
150.17 (4.2)
Final Na (mEq/l)
135.6 (2.54)
137.92 (2.5)
142.02 (4.3)d
EFNa
0.15 (0.27)
0.58 (0.61)b
0.77 (0.55)c
Free water
11.82 (3.88)
12.69 (5.8)
13.3 (6.8)
Na/Creatinine Urinary
0.77 (0.45)
2.35 (2.5)
2.1 (2.8)
a
b
SD: standard deviation; EFNa: fractional sodium excretion; M: mean.
P=.012; bP=.009; cP=.023; dP<.0001.
a
The Pearson correlation coefficients between fractional
sodium excretion and the analysed variables were: 0.413
with baseline sodium (P=.01), 0.808 with sodium evolution
(P=.003) and there was no significance with infused free
water (r = 0.028).
DISCUSSION
This study evaluates parenteral treatment with hypotonic
saline solutions in mild and moderate dehydration of
paediatric patients hospitalised with AGE and the possible
link with the iatrogenic development of hyponatraemia,
which was not proved in our case.
Despite the recommendation and acceptance of solutions
taken orally to rehydrate children with mild or moderate
dehydration caused by AGE, it was observed that intravenous
fluids were frequently used in developed countries10,11.
Suitable tonicity of the solutions is a subject of controversy,
without which a consensus on the type of solution for the
most convenient maintenance in hospitalised children
would be reached. At the time of assessing and discussing
the results of the consulted literature, the studied paediatric
pathologies should have been considered 12, since the
baseline hydrosaline situation of the case of a child with
AGE differs to that of a critical patient or that of a child
who undergoes surgery. Hydroelectrolytic management
in the infant has to be performed cautiously due to the
immaturity of the renal function. Newborns have a high
percentage of total body water, with a higher percentage of
extracellular water and lower intracellular water percentage
than adults. This situation changes progressively with age
and the percentages of total, intracellular and extracellular
water normalise around 6-12 months of life13. The newborn
presents glomerular-tubular imbalance and a limited
capacity of concentration and dilution of urine. The excreted
sodium fraction is inversely proportional to gestational age
480
in the newborn and there is no aldosterone suppression due
to sodium load, which would explain the small adaptation
of the youngest infants to sodium excess14,15.
In 2007, the National Patient Safety Foundation16 in the
United States recommended changing parenteral saline
solutions from 0.18 % to 0.45 % to prevent hyponatraemia
in infancy. However, Coulthard17 warns about the risk of
developing hypernatraemia with the previous standard and
considers hypotonic solutions as more physiological at the
time of replacing the losses. Halberthal et al. recommend
the use of hypotonic solutions in patients with serum
sodium >140mmol/l 18. Curiously, the publications by
Moritz18, which group various studies on the subject from
2004 to 2011, indicate that the administration of hypotonic
fluids is dangerous and anti-physiological19,20.
Our results coincide with those presented in 2006 by
Sánchez Bayle at al. 21 The incidence of hyponatraemia
at the time of diagnosis was 18.04 % in our study and
there were no cases of iatrogenic hyponatraemia. The high
incidence of baseline hypoglycaemia in our patients leads
us to think that the use of a glucose-free solution would
aggravate baseline hypoglycaemia, with consequential
risks. As regards fractional sodium excretion, our results
show that it is significantly lower in children with baseline
hyponatraemia, which seems to demonstrate that renal
management of sodium is the essential physiological
mechanism for regulating and correcting natraemia.
Neville et al. 22,23 report an baseline hyponatraemia
incidence of 36 %, they recommend the use of 0.9 %
saline solution in the case of AGE and refer to the nonosmotic stimuli present in patients with AGE which could
be involved in iatrogenic hyponatraemia. Holliday and
Segar 24 did not consider that hospitalised patients were
submitted to numerous non-osmotic stimuli for ADH
secretion and considered that secondary hyponatraemia at
the rehydration standard proposed by them in 1957 would
Nefrologia 2014;34(4):477-82
be due to excessive administration of fluids. The results
obtained by Hoor et al.9 in their study using a sample of
1586 children concluded that hyponatraemia was due to
incorrect treatment in which more fluids were administered
than necessary. It is important to remember that natraemia
does not precisely reflect body sodium content and that
rather than the reduction of serum sodium, it more precisely
reflects the increase of total body water. True hyponatraemia
is associated with serum hypo-osmolality; therefore it is
necessary to understand plasma osmolality and also urine
osmolality to determine whether there is deterioration in
the capacity to excrete free water. However, Kannan et al.25
report 14.3 % iatrogenic hyponatraemia after administering
0.18 % saline solution, but patients with AGE were not
included in their study. Armon et al.26 consider that using
0.9 % solutions would not be protective. Caramelo et al.27,28
do not find association between more hypotonic solutions
and hyponatraemia in their study carried out on operated
adult patients and they emphasise the importance of renal
retention of water and the volume of fluid administered as
a mechanism to consider in hyponatraemia. Other studies
performed using critical patients or patients undergoing
surgery have conflicting conclusions29-31.
A limitation of our study is that it was undertaken in
one centre and future studies on the subject should be
recommended.
As a conclusion and in light of the significant disparity in
this field, we point out that it is not possible to accept the
conclusion that hyponatraemia is generated with hyposaline
maintenance solutions. Considering the high percentage
of children with hypoglycaemia, the use of hypo-sodium
solutions would protect against this hypoglycaemia, in
addition to not inducing hyponatraemia in a healthy kidney.
The monitoring of electrolytes before and during treatment
is necessary.
It is important to reconsider the frequent and in many
cases, unnecessary use of parenteral pathway in dehydrated
patients and those with acceptable oral tolerance and to
remember that oral rehydration is key, since it is associated
with less secondary effects and significantly reduces
hospital stay.
FUNDING
The present study has not received any type of funding.
Nefrologia 2014;34(4):477-82
originals
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3. Schwartz WB, Bennet W, Curelop S, Bartter FC. A syndrome of renal
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la gastroenteritis aguda en menores de 5 años: un enfoque basado
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Pediatr (Barc) 2010;72(3):220.e1-220.e20.
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W. Oral versus intravenous rehydration for treating dehydration
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nacido. Rev Child Pediatr 1994;65(4):234-40.
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pediátrica. México: Mosby/Doyma; 1996. p. 348.
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risk of hyponatraemia when administering intravenous infusions to
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0,18% to 0,45% saline do more harm than good? Arch Dis Child
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M. Intravenous fluid regimen and hyponatraemia among children: a
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et al. Fluid therapy in surgical patients: composition and influences
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Sent to review: 29 Aug. 2013 | Accepted: 15 May. 2014
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Nefrologia 2014;34(4):477-82
originals
Soy protein and genistein improves renal antioxidant
status in experimental nephrotic syndrome
Mohammad H. Javanbakht1, Reza Sadria2, Mahmoud Djalali1, Hoda Derakhshanian1,
Payam Hosseinzadeh1, Mahnaz Zarei1, Gholamreza Azizi3, Reza Sedaghat4, Abbas Mirshafiey2
1
Department of Cellular and Molecular Nutrition. School of Nutritional Sciences and Dietetics. Tehran University of Medical Sciences.
Tehran (Iran); 2 Department of Pathobiology. School of Public Health. Tehran University of Medical Sciences. Tehran (Iran); 3 Alborz
University of Medical Sciences. Imam Hassan Mojtaba Hospital. Karaj, Alborz (Iran);4 Department of Pathology. School of Medicine.
Shahed University. Tehran (Iran)
Nefrologia 2014;34(4):483-90
doi:10.3265/Nefrologia.pre2014.Jun.12051
ABSTRACT
Background and objectives: Nephrotic syndrome is a chronic
disease especially common in the childhood and adolescence.
Reactive oxygen species (ROS) and free radicals have significant
role in the pathogenesis of nephrotic syndrome. The aim of this
study was to evaluate the effect of soy protein and genistein (main
isoflavone of soybean) on renal antioxidant status of nephrotic
rats. Methods: This study was done for 8 weeks on 40 adult
male Sprague-Dawley rats divided into four groups of 10 rats
each. Study groups included: 1-Control, 2-Nephrotic syndrome,
3-Nephrotic syndrome+soy protein diet and 4-Nephrotic
syndrome+soy protein diet+genistein. Urine protein and urine
creatinine were measured. After homogenization of kidney,
total antioxidant capacities (TAC), activities of catalase enzyme,
the concentration of malondialdehydes (MDA) and carbolynated
proteins were determined spectrophotometrically. Pathological
examination was done on kidneys with light microscope. Cell
viability was evaluated with MTT assay on WEHI-164 fibro sarcoma
cell line. The MMP2 enzyme activity was evaluated in different
concentrations of genistein. Results: Total antioxidant capacity
was significantly increased in soy genistein. Catalase activity was
significantly increased in soy and soy genistein groups. Protein
carbonyl and MDA were significantly lower in soy and soy
genistein groups. The scores of pathological examination showed
significant improvement in soy and soy genistein groups. Genistein
decreased the proliferation of the WEHI-164 fibrosarcoma cell line.
Conclusion: It seems that soy protein decreases kidney damages
in nephrotic syndrome. Adding genistein to soy protein causes
improvements in antioxidant status of kidney tissue. Genistein
decreases proliferation of cell.
La genisteína y la proteína de soja mejoran el estado antioxidante
renal en el síndrome nefrótico experimental
Keywords: Antioxidant. Genistein. Nephrotic Syndrome. Rat. Soy.
Palabras clave: Antioxidante. Genisteína. Síndrome nefrótico. Rata. Soja.
Correspondence: Abbas Mirshafiey
Department of Pathobiology.
School of Public Health. Tehran University of Medical Sciences.
Poorsina Street. Enghelab Avenue. Tehran (Iran).
[email protected]
[email protected]
RESUMEN
Antecedentes y objetivos: El síndrome nefrótico es una enfermedad
crónica especialmente común en la infancia y la adolescencia. Las
especies reactivas del oxígeno (ERO) y los radicales libres desempeñan un papel importante en su patogénesis. El objetivo de este estudio es evaluar los efectos de la genisteína (principal isoflavona de
la soja) y la proteína de soja en el estado antioxidante renal de ratas
nefróticas. Métodos: Este estudio se llevó a cabo durante 8 semanas
con 40 ratas Sprague-Dawley machos adultas, que fueron divididas
en cuatro grupos de 10. Cada uno de los grupos de estudio incluía:
1 control, 2 con síndrome nefrótico, 3 con síndrome nefrótico más
una dieta a base de proteína de soja y 4 con síndrome nefrótico más
una dieta a base de proteína de soja más genisteína. Se midieron
tanto los niveles de proteína como de creatinina en orina. Tras la
homogenización del tejido renal, se calcularon mediante espectrofotometría la capacidad antioxidante total (CAT), la actividad de la
enzima catalasa, la concentración de malondialdehídos (MDA) y las
proteínas carboniladas. El examen patológico de los riñones se realizó con el microscopio óptico. Además, se evaluó la viabilidad celular
con un ensayo de MTT de la línea celular de fibrosarcoma WEHI-164.
También se evaluó la actividad de la enzima MMP2 con distintas concentraciones de genisteína. Resultados: La capacidad antioxidante
total aumentó significativamente en las ratas que tenían una dieta
de genisteína, al igual que la actividad de la catalasa en aquellas con
una dieta de soja y genisteína. En cambio, los grupos carbonilo de las
proteínas y los niveles de MDA fueron significativamente inferiores
en los animales con una dieta de soja y de genisteína. El examen
patológico reveló una mejora significativa en los grupos con dietas
de soja y de genisteína. Asimismo, la genisteína disminuyó la proliferación de la línea celular de fibrosarcoma WEHI-164. Conclusión:
Parece ser que la proteína de soja reduce los daños renales causados
por el síndrome nefrótico. La adición de genisteína a la proteína de
soja produce mejoras en el estado antioxidante del tejido renal. La
genisteína disminuye la proliferación celular.
INTRODUCTION
Nephrotic syndrome is a chronic disease mostly in the
childhood and adolescence.1 It is due to alterations in
483
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Mohammad H. Javanbakht et al. Soy-genistein improves renal antioxidant
the penetrability of the glomerular barrier, resulting
from the activities of proteases and a decline in the
synthesis of the proteoglycans. 2 These malfunctions
result in the emergence of a series of symptoms including
severe proteinuria, hypoalbuminemia, hyperlipidemia and
edema.3 Decreases of the glomerular blood flow and level of
glomerular filtration rate (GFR) result from vasoconstrictor
bioactive lipids (prostaglandin, thromboxane, plateletactivating factors (PAF)) and inhibition of nitric oxide
activity.2,3 There are several evidences available concerning
the roles of reactive oxygen species (ROS) and free radicals
in the pathogenesis of nephrotic syndrome.3,4 The sources
of ROS are the electron transport chain, oxidant enzymes,
phagocytosis and auto-oxidation from epinephrine. 2,4 Free
radicals have great contribution in the damages resulted in
DNA, proteins, carbohydrates and lipids destruction.5 ROS
results in lipid per-oxidation in the cellular and organelles
membranes. It leads to loss of cell’s structure and capacity to
transmit and produce energy, especially in the proximal tubules.
Meanwhile, ROS are produced in nephritis by the immunity
system, the infiltrated blood cells (polymorphonuclear,
leukocytes, and monocytes), podocytes and mesangial matrix
cells.2 There are various antioxidant defensive mechanisms
for protecting the cells against the harmful effects of ROS
and free radicals. Some of these defensive mechanisms are
superoxide dismutase (SOD), catalase (CAT), glutathione
peroxidase (GPX) and glutathione reductase (GR).6 In
nephrotic syndrome, the balance between the oxidant and
antioxidant is lost.3 Some studies showed the decreasing trend
in the activities of the antioxidant enzymes and vitamins C, E,
beta-carotene and total antioxidant capacity, while the MDA
level increased.7 In order to generate the nephrotic syndrome
experimental model in the rats, adriamycin and/or puromycin
amino nucleoside may be used, while their metabolisms
resulted cause formation of reactive oxygen species (ROS),
followed by appearance of severe proteinuria and decreased
kidney performance.8,9 The protective effects of some of
compounds against the oxidative damages are associated to
their capacity to increase the antioxidant enzymes expression.
Lack of foodstuffs containing antioxidant or suppression of
antioxidant enzymes worsens the kidney damages resulting
from free radicals.10 Soybean with the same protein quality
as animal proteins is considered the richest source of
isoflavones. Its isoflavones are Genistein, Daidzein and
Glystein. They have estrogenic effects, therefore they
are called phytoestrogens. 11 It has been observed that
foodstuffs containing soybean may have useful effects on
the cardiovascular and renal diseases.12 Scientists believe
that isoflavones, by their antioxidant nature, neutralize free
radicals and decrease inflammatory reactions.13 There have
been addressed several mechanisms concerning the effect of
soybean on the renal diseases; however, they have attributed
all the effect of soybean on kidney to its Genistein.10
In various studies, the roles of Genistein, as the major
soybean isoflavone, have been studied in a variety of
484
cellular mechanisms, e.g. 1) Apoptosis induction; 2) Cellular
differentiation; 3) Prevention of cellular reproduction; 4)
Controlling cell cycle progression; 5) Antioxidant effect; 6)
Repetitive effectiveness of the treatment-resistant anticancer
drugs; 7) Angiogenesis controlling; 8) Inhibiting osteoclast;
9) Controlling cellular immunity activity and its extension;
10) Mast-cell sustainability and decreased inflammation.14
The purpose of this study is to examine the effects of
Genistein as an isoflavone, together with the soybean protein,
on the glomerulosclerosis induced by adriamycin, and also
studying the potential cytotoxicity and preventive effects
of Genistein on cellular proliferation and activity of matrix
metalloproteinase (MMPs) on the WEHI-164 fibrosarcoma
cell lines.
MATERIALS AND METHODS
This study was done on 40 adult male Sprague-Dawley rats.
12-15 weeks old rats weighing 300±50g were obtained from
Iranian Pasteur Institute and housed under standard condition
of the animal room (temperature 25±3 centigrade degrees,
humidity 50%, 12-hour light and 12-hour darkness) with free
access to food and water. Then, they were randomly divided
into four groups, of 10 rats each. The study protocol was
approved by ethic committee of Tehran University of Medical
Sciences (TUMS) which conforms to the provisions of the
Declaration of Helsinki.
Study groups included
1. Control (C): no disease induction + chow diet.
2. Nephrotic Syndrome (NS): induction of disease + chow
diet.
3. Nephrotic syndrome receiving soy diet (NS+S): induction
of disease + soy protein diet + gavaged with carboxymethyle cellulose (CMC) as placebo.
4. Nephrotic syndrome receiving soy diet and genistein
(NS+S+G): induction of disease + soy protein diet +
gavaged with genistein diluted in CMC.
Diets
In order to provide soy protein diet, AIN-93M was followed
and casein protein was replaced with the same amount of soy
protein (soy protein as 14.1% of total energy). Due to the lack
of sufficient amount of methionine, it was added to soy diet
prohibiting methionine deficiency (Table 1)15.
Disease induction and intervention protocol
All animals obeyed their diet for 2 weeks (chow diet for
control and NS groups and soy diet for soy and soy-genistein
Nefrologia 2014;34(4):483-90
Table 1. Ingredients of soy diet
Ingredients
(g/kg diet)
Soy protein
140
Cornstarch
465
Sucrose
100
Cellulose
50
Soybean oil
40
Mineral mixture
35
Vitamin mixture
10
Dextrinized cornstarch
155
L-Cystine
1
Methionin
0.8
Choline bitartrate
2.5
Tert-Butylhydroquinone (mg)
8
groups). Then, the induction of nephrotic syndrome was
done by the intravenous injection of single dose of 8mg/
kg Adriamycin (Adriablastina, Farmitalia, Milan, Italy)
in all groups except control.8 The study continued for 6
other weeks with each group receiving its especial diet.
NS+S+G group also gavaged with 40mg/kg/day genistein
diluted in CMC, while NS+S rats received CMC alone. At
the end, the kidneys were brought out, washed with PBS
and the right one was transferred to formalin for pathology
examination and the left to sterile test tubes. The left
kidneys were kept in -80.
Determination of the Kidney Performance Status
Urine collections were done for each group. Urine protein
was measured colorimetrically by Pyrogallol-red kit (cat
no. 10-545 ZiestChem Diagnostics, Tehran Iran). Urine
creatinine was measured based on the Jaffe method (Pars
Azmoon Co. Tehran, Iran).
originals
The activities of catalase enzyme in supernatans were
determined by the HegoAebi’s method.17 the concentration
of malondialdehydes in supernatants were measured
spectrophotometrically with the thiobarbituric acid.18 The
carbolynated proteins in supernatants were determined
spectrophotometrically based on the reaction of carbonyl
group with 2,4 dinitrophenylhydrazine.19
Kidney histopathology
The severity and extensiveness of the glomerular damages
were assessed by pathological examination on tissue slices
with optical microscope. The severity of glomerulosclerosis
was evaluated by 8 parameters including hypercellularity,
lobular pattern, polymorphonuclear (PMN) infiltration,
atrophy of lumen, degenerative necrotic changes, hyaline
cast in lumens, interstitial leukocyte infiltration and
fibrosis. These parameters were categorized into scales
ranging from 0 to 3 (0=negative, 1=mild, 2=average,
3=severe).
Cytotoxicity Studies
Cell Culture
The WEHI-164 fibro sarcoma cell line obtained from Iran
Pasteur Institute was cultured in the media containing
L-Glutamine, 10% FBS, RPMI and 100Unit/mL Penicillin/
Streptomycin and incubated in 37ºC, saturated moisture and
5% CO2 pressure.
Evaluation of the oxidative stress parameters
Total antioxidant capacities (TAC) of the kidney tissues
were measured in supernatants with 2-2- Azino- bis- (3Ethyl benzthiazoline-6-Sulfonic acid) (ABTS) method. 16
Proliferation assay
Cell viability was evaluated with MTT assay. MTT
colorimetric test is based on the activity of the mitochondria
dehydrogenase enzyme of the living cells in reduction
of the MTT salt to the formazan non-solvable crystals,
which could not pass through the cells’ membrane. The
concentration of formazan is proportional to the number
of viable cells. 20 Some of the WEHI-164 fibro sarcoma
cell line was cultured in 96-cell plates with 8x103 cells
in a well (incubated for 4 hours under 37ºC). Genistein
suspended in RPMI was added to each well in 0, 1, 5, 10,
20, 40 & 80μg/well, concentrations. The plate was then
incubated for 48 hours in incubator (37ºC). The respective
supernatant was extracted. Two hundreds microlitres of
the MTT solution with 0.5mg/mL concentration in phenol
red-free media was added to each well and incubated for
another 2-4 hours. The supernatants were extracted and
200μL of DMSO was added to each plate as solvent of the
formazan crystals (purple precipitation). The plate light
absorption was read with 570nm wavelength and 630nm
reference wavelength by ELISA reader machine.
Nefrologia 2014;34(4):483-90
Kidney Tissue Homogenization
The frozen left kidneys were homogenized in buffer (PH=7/4
0.05% NaN3, 25mM Tris-Hcl, 2mM PMSF, 2mM EDTA) by
sonication. The sonication process was done in five minutes
with six cycles. After being centrifuged, the supernatants
were separated and transferred to -80˚C.
485
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Gelatinase Zymography
The mentioned-above cell line was cultured in 24-cell
plates with 4x10 4 cells in a well. They were incubated
for 4 hours allowing the cells to adhere to the plate and
reaching to proper density. Then various densities of
Genistein (0-400μg/mL) was added to each well and
incubated for 48 hours under 37ºC, saturated moisture
and 5% Co2 pressure. Separating the supernatants, they
were centrifuged to remove cellular debris and kept under
-20ºC until performing Zymoanalysis.
The MMP2 enzyme activity was evaluated based on the
method described elsewhere.21 In brief, Genistein-containing
supernatants were aliquoted and electrophorized with the
SDS-PAGE gel containing 0.5mg/mL of A gelatin (Merk
Germany) and the tris-borate as buffer for 3 hours (100V).
Then, the gel was washed with X-100 triton two times to
extract SDS and incubated for 24 hours in Tris-Hcl gelatinase
activation buffer, PH=7.4 containing 10mM Cacl2. After that,
the gel was immersed in Coomissie Brillient Blue-G-250 1%
(1% in 25% methanol and 10% acetic acid solved in water)
for two hours. MMP-2 activity resulted in gel proteolysis and
generation of brilliant bands on the blue background. The
activity of MMP-2 was measured by using the Alpha Ease
FC densitometry (Alpha Innotech- Miami, USA) comparing
width and density of the bands appeared on the gel.
Statistical Analysis
The data has been shown in Mean±SD. Statistical package for
the social sciences (SPSS, version 20, Chicago, IL) was used
for statistical analysis. Parametric data analysis was performed
by analysis of variance (ANOVA) and Post hoc test by
Tukey-HSD. While the non-parametric data were analyzed by
Mannwhitney & Kruskalwallis Tests. The data was considered
meaningful with P value less than 0.05.
RESULTS
The urine protein to creatinine ratio was not significantly
different among four groups at the beginning of the study
(P=0.16) (Table 2). At the end of the study, the urine
protein to creatinine ratio showed statistically significant
difference among four groups (P<0.001). The normal
group had the urine protein to creatinine ratio significantly
different from other three groups (P<0.001) (Tukey HSD
test). Disease induced groups including patients, soy and
soy genistein showed differences in the urine protein to
creatinine ratio but it was not significant. The urine protein
to creatinine ratio was obviously less than the patient
group in soy and soy genistein groups. The urine protein
to creatinine ratio in soy genistein group was even lesser
than it in soy group.
Figure 1 shows malondialdehyde, protein carbonyl, total
antioxidant capacity (TAC) and catalase enzyme activity in
the kidney tissue of animals. TAC was significantly different
among four groups (P=0.008). In post hoc comparison, tukey
HSD test showed significant difference between nephrotic
rats vs. control (P=0.036) and soy genistein (P=0.011).
The groups were significantly different in tissue catalase
activity (P<0.001). In multiple comparisons, the NS group
showed significant difference with control (P=0.045), soy
(P=0.014), and soy genistein (P<0.001). The amount of
protein carbonylated in kidney tissue was different between
groups (P=0.001). The protein carbonylated in kidney tissue
had significant difference between NS and control (P=0.01),
NS and soy (P=0.003), NS and soy-genistein (P=0.001).
Malondialdehyde in kidney tissue was significantly different
among groups (P<0.001) (Figure 1). The amount of
malondialdehyde in tissue was significantly different between
NS and control (P<0.001), NS and soy (P=0.004), NS and
soy-genistein (P=0.002).
The effect of genistein on cellular proliferation
As Figure 2 shows, the increase in the genistein
concentration accompanies with decrease in proliferation
of the WEHI-164 fibrosarcoma cell line, while the
decreased growth has been quite obvious under 5-80μg/
well density. In addition, we observed obvious increase in
MMP-2 activities at 10mg/mL concentration of genistein
(Figures 3 and 4). This effect was not shown in higher
concentrations.
Table 2. Urine protein creatinine ratio in group at the beginning and the end of study
Control
NS
NS+S
NS+S+G
P value
Urine protein creatinine ratio (mg/mg) at the beginning
2.91±1.21
4±1.02
4.74 ± 2.32
3.51±2.27
0.16
Urine protein creatinine ratio (mg/mg) at the End
3.84±1.24
63.90±7.30 53.35 ± 14.62 51.28±16.67
<0.001
NS: Nephrotic syndrome; NS+S: Nephrotic syndrome with soy diet; NS+S+G: Nephrotic syndrome with soy diet and genistein.
Data are expressed as mean±SD.
Analysis of variance (ANOVA) and Post hoc test by Tukey-HSD were used to detect differences in between the groups.
486
Nefrologia 2014;34(4):483-90
originals
Malondialdehyde
4.5
4
3.5
3
2.5
2
1.5
1
0.5
0
70
60
50
40
30
20
10
0
nmol/mL
g/dl
Total antioxidant capacity
Control
NS+S NS+S+G
NS
Control
NS+S NS+S+G
Catalase
Ku/mg pr
nmol/mg
Protein carbonyl
45
40
35
30
25
20
15
10
5
0
Control
NS+S NS+S+G
NS
NS
9
8
7
6
5
4
3
2
1
0
Control
NS+S NS+S+G
NS
Figure 1. Concentration of malodialdehyde and of protein carbonyl, total antioxidant capacity and catalase activity
in kidney tissue of four groups.
G: genistein; NS: nephrotic syndrome; S: soy.
Nefrologia 2014;34(4):483-90
the score of degenerative-necrotic changes (P=0.022). The
score for tubular atrophy was significantly different among
three groups (P<0.001). Its score was significantly lower in
soy-genistein group in comparison to NS group (P=0.001).
The soy and NS groups were significantly different based
Evaluation of cell proliferation
% of number of cells
Histopathological Findings
Table 3 shows the histopathological findings in different
parameters. We compared the parameters of only three
groups (NS, NS+S and NS+S+G). Hypercellularity
parameter was significantly different among three groups
(P<0.001) (Figure 5). The score of hypercellularity in NS
group was significantly higher than that of soy and soygenistein groups (P=0.022 and P=0.01, respectively). The
score of hypercellularity was also significantly lower in soy
soy-genistein group in comparison to soy group (P<0.001).
The score of lobular pattern was significantly different
among three groups (P<0.001). Scores were significantly
lower in soy-genistein group in comparison to soy (P<0.001)
and NS groups (P=0.001). The score of PMN infiltration
was significantly different among groups (P<0.001). Score
of PMN infiltration was significantly lower in soy-genistein
group in comparison to soy (P<0.001) and NS groups
(P=0.001). The score for degenerative-necrotic changes
was significantly different among three groups (P=0.001).
Its score was significantly lower in soy-genistein group in
comparison to soy (P=0.012) and NS groups (P=0.001). The
soy and NS groups were significantly different based on
120
100
80
60
40
20
0
0 12510
204080
Genistein concentration (mg/0,2mL [well])
Figure 2. WEHI-164 fibrosarcoma cell line proliferation
in different concentrations of genistein.
487
Relative expression of MMP-2 activity (%)
originals
160
140
120
Figure 4. Bands MMP-2 of WEHI-164 fibrosarcoma cell line
100
in different concentrations of genistein.
80
The score for interstitial fibrosis was significantly different
among three groups (P<0.001). Its score was significantly
higher in NS group in comparison to soy (P<0.001) and soygenistein groups (P=0.001).
60
40
20
0
0
5
DISCUSSION
This study showed adding genistein to soy protein can
decrease histological deteriorations in nephrotic syndrome.
Soy protein, with or without genistein, decreased
tissue malondialdehyde in nephrotic rats. Soy protein
increased catalase activity and diminished carbonylated
protein of kidney tissue in nephrotic syndrome. These
findings support the beneficial effects of soy protein in
nephrotic status. The beneficial effects of soy could be
associated to its copious isoflavone, genistein. Genistein
makes improvements in nephrotic syndrome through
its antioxidant effects. 10,11 Some findings support the
pivotal role of oxidative stress in nephrotic syndrome.
The imbalance between oxidant and antioxidant factors
causes the glomerular damage in renal diseases. 3 The
activities of antioxidant enzymes decrease in nephrotic
syndrome. Hence, the peroxidation products increase
in kidney diseases. Malodialdehyde and carbonylated
proteins are produced through peroxidation processes.
10 25 50 100 200 400
Genistein concentration (mg/mL)
Figure 3. MMP-2 activity of WEHI-164 fibrosarcoma cell
line in different concentrations of genistein.
on the score of tubular atrophy (P=0.002). The score for
hyaline cast was significantly different among three groups
(P<0.001). Its score was significantly lower in soy-genistein
group in comparison to soy (P<0.001) and NS groups
(P=0.001). The soy and NS groups were significantly
different based on the score of hyaline cast (P=0.016).
The score for leukocytes infiltration in interstitial was
significantly different among three groups (P=0.001). Its
score was significantly lower in soy-genistein group in
comparison to soy (P=0.021) and NS groups (P=0.001).
The soy and NS groups were significantly different based on
the score of leukocytes infiltration in interstitial (P=0.007).
Table 3. Score of microscopic findings of kidney histology in various groups
Control
NS
NS+S
NS+S+G
P value
Hypercellularity
0
1.41±0.13
0.97±0.02
0.31±0.10
< 0.001
Lobularity pattern
0
1±0
0.92±0.05
0.06±0.04
< 0.001
PMN infiltration
0
1±0
0.97±0.02
0.21±0.05
< 0.001
Degenerative-necrotic changes
0
2.08±0.36
1.62±0.14
0
0.001
Atrophy of tubules
0
1±0.12
0.1±0.10
0
< 0.001
Hyaline cast
0
2.20±0.25
0.62±0.16
0.28±0.11
< 0.001
Leukocytes infiltration
0
1.66±0.24
0.75±0.13
0.34±0.09
0.001
Interstitial tubules fibrosis
0
0.83±0.10
0
0.06±0.06
< 0.001
NS: Nephrotic syndrome; NS+S: Nephrotic syndrome with soy diet; NS+S+G: Nephrotic syndrome with soy diet and genistein;
PMN: polymorphonuclear.
Data are expressed as mean±SD.
Mannwhitney & Kruskalwallis Tests were used to detect differences in between the groups.
488
Nefrologia 2014;34(4):483-90
Figure 5. Representative light microscopic view
of histopathological slides of kidney in different groups.
C: control; G: genistein; NS: nephrotic syndrome; S: soy.
Previous studies showed that diets containing soy could decrease
proteinuria in comparison to casein protein diets.10,13 In the
process of nephrotic syndrome, serum albumin is lost through
kidneys. Serum albumin functions as a major antioxidant in
serum, hence albumin loss causes oxidative damage. In the
case of albumin loss, MDA as a product of oxidative damage
increases.3 Isoflavones mainly genistein restrict inflammation
with their antioxidative, anti inflammatory and anti necrotic
characteristics.13 The anti inflammatory effect of genistein
is through inhibition of cyclooxigenase expression and
myeloperoxidase activity. 22 Genistein decreases lipid
peroxidation and serum lipids.23 Oxidative stress induces NFkB and inflammatory cytokines expressions.24 Isoflavones
reacts with free radicals and neutralizes their effects.13 It
seems isoflavones decrease renal damage through reacting
with hydrochloric acid and peroxynitrate.10 More studies are
needed to analyze the angiotensin-II receptors expression,
TGF-β, NF-κB and strogen receptor beta to elucidate the
possible contribution of these mechanisms to the renoprotective effect of genistein. The lack of these data is one of
our limitations in this study.
In our study, urine protein creatinine ratio was slightly lower
in soy-genistein group than soy group, but this difference
was insignificant. It seems we would observe significant
difference in case of prolongation of the study. This
observation supports the notion that the effects of soy are
mainly due to its isoflavone, genistein.10,13 This study showed
that adding genistein to soy protein enhances antioxidative
status of kidney tissue, albeit insignificant. Some studies on
the histopathology of nephrotic syndrome showed that soy diet
in comparison to casein diet causes improvement in sclerotic
and fibrotic sequels.13 Another research showed mesangeal
and segmental proliferation with matrix expansion, capillary
blockade, fibrosis with adhesion between glomerular coils
and Bowman’s capsule, also mononuclear cells infiltration
Nefrologia 2014;34(4):483-90
originals
in interstitial space in case of receiving casein diet. But
glomerular damage and fibrosis were less in rats receiving
soy protein.10 A research showed that soy replaced in animal
protein improved glomerular filtration rate and glomerular
hypertension. It also decreased the incidence of diabetic
nephropathy.25 In the current study, adding genistein to soy
protein caused profound improvement in histopathology
of kidney. The improvement was so impressive that soygenistein group resembled to normal group. Researches on
the role of genistein in proliferation of malignant cell line
showed that genistein induces apoptosis and suppression of
cell proliferation through P53 pathway.26 Some researches
supported the role of genistein in cell cycle inhibition specially
breast and prostate cancer cell lines which are in consistent
to our results on fibrosarcoma cell line WEHI-164.27 Another
study on prostate cancer cell line showed inhibitory role
of genistein on the activity of MMP-2 enzyme.28 Matrix
metalloproteinases are inactive.29 Some factors like cancer
cell lines, cytokines and inflammatory factors disturb their
activity and balance.30
It is concluded from the results of current study that soy
protein diet causes impressive changes in oxidative status
markers and histopathological aspects of nephrotic syndrome.
This study showed that adding genistein as an isoflavone to
soy protein caused a greater improvement in this disease.
We can conclude that the effects of soybean on nephrotic
syndrome would be attributed to its isoflavone genistein.
Acknowledgments
This study was supported by undersecretary of research in Tehran
University of Medical Sciences (the grant number of 15438). We honestly
appreciate Karen pharma & food supplement company (Tehran, Iran) for
the donation of some food components.
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14. Polkowski K, Mazurek AP. Biological properties of genistein. A
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19. Castegna A, Drake J, Pocernich C, Butterfield DA. Protein carbonyl
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Sent to review: 2 Apr. 2013 | Accepted: 3 Jun. 2014
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short original
Hidden sources of phosphorus: presence of
phosphorus-containing additives in processed foods
Luis M. Lou-Arnal1, Laura Arnaudas-Casanova1, Alberto Caverni-Muñoz2,
Antonio Vercet-Tormo3, Rocío Caramelo-Gutiérrez1, Paula Munguía-Navarro1,
Belén Campos-Gutiérrez4, Mercedes García-Mena5, Belén Moragrera5,
Rosario Moreno-López6, Sara Bielsa-Gracia7, Marta Cuberes-Izquierdo8,
Grupo de Investigación ERC Aragón*
*Instituto Aragonés de Ciencias de la Salud. Zaragoza (Spain); 1 Servicio de Nefrología. Hospital Universitario Miguel Servet.
Zaragoza; 2 Servicio de Nutrición y Dietética. Alcer Ebro. Zaragoza (Spain); 3 Departamento de Tecnología de los Alimentos. Facultad
de las Ciencias de la Salud y del Deporte. Zaragoza (Spain); 4 Servicio de Nefrología. Hospital de Alcañiz. Teruel (Spain); 5 Servicio de
Nefrología. Hospital San Juan de Dios. Zaragoza (Spain); 6 Servicio de Nefrología. Hospital Militar de la Defensa. Zaragoza (Spain); 7
Servicio de Nefrología. Hospital Obispo Polanco. Teruel (Spain); 8 Servicio de Nefrología. Hospital de Tudela. Navarra (Spain)
Nefrologia 2014;34(4):498-506
ABSTRACT
Introduction and objectives: An increased consumption of processed
foods that include phosphorus-containing additives has led us to
propose the following working hypothesis: using phosphate-rich
additives that can be easily absorbed in processed foods involves
a significant increase in phosphorus in the diet, which may be
considered as hidden phosphorus since it is not registered in the
food composition tables. Materials and method: The quantity of
phosphorus contained in 118 processed products was determined
by spectrophotometry and the results were contrasted with
the food composition tables of the Higher Education Centre of
Nutrition and Diet, those of Morandeira and those of the BEDCA
(Spanish Food Composition Database) Network. Results: Food
processing frequently involves the use of phosphoric additives.
Correspondence: Luis M. Lou Arnal
Hospital Universitario Miguel Servet. Zaragoza. (Spain).
[email protected]
[email protected]
The products whose label contains these additives have a higher
phosphorus content and a higher phosphorus/protein ratio. We
observed a discrepancy with the food composition tables in terms
of the amount of phosphorus determined in a sizeable proportion
of the products. The phosphorus content of prepared refrigerated
foods hardly appears in the tables. Conclusions: Product labels
provide little information on phosphorus content. We observed
a discrepancy in phosphorus content in certain foods with respect
to the food composition tables. We should educate our patients
on reviewing the additives on the labels and on the limitation of
processed foods. There must be health policy actions to deal with
the problem: companies should analyse the phosphorus content
of their products, display the correct information on their labels
and incorporate it into the food composition tables. Incentives
could be established to prepare food with a low phosphorus
content and alternatives to phosphorus-containing additives.
Keywords: Food additives. Phosphorus intake. Phosphorus-protein
ratio. Hyperphosphatemia. Food analysis. Chronic kidney disease.
Phosphorus absortion. Food labelling. Food composition.
* Group members:
Hospital Universitario Miguel Servet: Dr. Luis Miguel Lou Arnal, Dr. Álex Gutiérrez Dalmau, Dr. Jesús Pérez y Pérez, Dr. Alejandro Sanz París, Dr. Laura
Arnaudas Casanova, Dr. Laura Sahdalá Santana, Dr. Beatriz Lardiés Sánchez, DUE Gloria Millán Asín, DUE Rosa Isabel Muñoz, DUE Gloria Pérez Sierra;
Hospital Clínico Universitario Lozano Blesa: Dr. Rafael Álvarez Lipe, Dr. José Antonio Gimeno Orna, DUE Mercedes Marcén Letosa, DUE Blanca Aznar
Arribas, DUE Inma Serrano; Hospital San Juan de Dios: Dr. Mercedes García Mena, Dr. Marta Luzón Alonso, Dr. Belén Moragrega, Dr. Elena Castillón,
DUE María Duran Andía, DUE María Carmen Sancho Alcázar, DUE Cristina Callizo Pequerul; Hospital Militar de la Defensa: Dr. Rosario Moreno López,
Dr. Raquel Abadía del Olmo; Hospital Comarcal de Alcañiz: Dr. Olga Gracia García, Dr. Belén Campos Gutiérrez, DUE Miriam Sorribas Marts; Hospital
Obispo Polanco de Teruel: Dr. Sara Bielsa Gracia; Hospital de Calatayud Ernest Lluch: Dr. M.ª José Aladren Regidor; Hospital de Tudela: Dr. Marta Cuberes
Izquierdo; Hospital San Jorge: Dr. Rafael Virto Ruiz, Dr. Carlos Bergua Amores; Alcer Ebro: Sr. Alberto Caverni Muñoz, Sra. Cristina Calles Merino, Sra.
Carmen Jiménez Cortes, Dr. Hana Maher Berlín.
498
Luis M. Lou-Arnal et al. Phosphorus-containing additives in CKD
Fuentes ocultas de fósforo: presencia de aditivos con contenido
en fósforo en los alimentos procesados
RESUMEN
Introducción y objetivos: El incremento del consumo de alimentos
procesados que incluyen aditivos con fósforo nos lleva a plantearnos
la siguiente hipótesis de trabajo: la utilización de aditivos ricos en
fosfatos fácilmente absorbibles en los alimentos procesados supone
un incremento significativo del fósforo contenido en la dieta, que
puede considerarse como fósforo oculto al no quedar registrado
en las tablas de composición de alimentos. Material y método:
Se determina la cantidad de fósforo contenido en 118 productos
procesados mediante espectrofotometría. Se contrastan los
resultados con las tablas de composición de alimentos del Centro
de Enseñanza Superior de Nutrición y Dietética, de Morandeira y de
la Red BEDCA. Resultados: El procesamiento de los alimentos con
frecuencia implica el uso de aditivos fosfóricos. Los productos en
cuya etiqueta figuran estos aditivos presentan un mayor contenido
en fósforo y una mayor ratio fósforo/proteínas. Apreciamos
discordancia con las tablas de composición de alimentos en la
cantidad de fósforo determinada en una parte importante de
los productos. El contenido en fósforo de alimentos refrigeradoselaborados apenas figura en las tablas. Conclusiones: El etiquetado
de los productos ofrece información escasa sobre el contenido
en fósforo. Apreciamos disparidad de contenido de fósforo en
determinados alimentos respecto a las tablas de composición de
alimentos. Deberíamos formar a nuestros pacientes en la revisión
de los aditivos en las etiquetas y en la limitación de los alimentos
procesados. Una aproximación al problema debe incluir actuaciones
de política sanitaria: las empresas deberían analizar el contenido
en fósforo de sus productos, reflejar este dato en el etiquetado
e incorporarlo en las tablas de composición de alimentos. Podrían
establecerse incentivos para elaborar alimentos con contenido bajo
en fósforo y alternativas a los aditivos que contienen fósforo.
Palabras clave: Aditivos alimentarios. Ingesta de fósforo,
Cociente fósforo/proteínas. Hiperfosforemia. Encuesta dietética.
Enfermedad renal crónica. Absorción de fósforo. Etiquetado de
los alimentos. Composición de los alimentos.
INTRODUCTION
High levels of phosphorus are related to the development
of arteriosclerosis and bone disease in patients with chronic
kidney disease (CKD)1. Phosphorus intake is also a public
health problem given its impact on cardiovascular risk in
the general population (“new cholesterol”)2-4. The wide and
growing use of these additives5, in relatively high quantities6,
without clear regulations in the labelling7,8 and usually
without their inclusion in the food composition tables means
that there is a high phosphorus contribution, which we can
consider to be “hidden phosphorus”9.
The dietary recommendations in CKD aim to obtain an
adequate protein contribution with reduced phosphorus intake,
which is a difficult balance to achieve. Additives provide
phosphorus without protein, which is something we should
consider in the dietary education of our patients. However,
it is difficult to know the real phosphorus contribution in the
Nefrologia 2014;34(4):498-506
short original
diet, given the limited information on the product labels and
the few and confusing data in the food composition tables10.
The main objective of this study was to provide information
about the real phosphorus content determined by
spectrophotometry in an extensive group of 118 natural
products and with different degrees of processing. As
secondary objectives, we aimed to indicate the differences and
contradictions with respect to the different food composition
tables and make nephrologists, dieticians and nursing staff
aware of this barrier in dietary education, in order to facilitate
practical training for our patients.
MATERIAL AND METHOD
Study design: descriptive cross-sectional study with analysis
of food product components.
We received financing of the Aragón Health Sciences Institute
over two years to determine phosphorus and protein in 118
fresh products with different degrees of processing.
In the first 52 products we analysed three different batches.
After verifying the reproducibility of the phosphorus
measurements, we acquired two batches of the following 66
products analysed and carried out a third test when the values
were conflicting (coefficient of variation [CV] [standard
deviation (SD/average value] ≥10%).
The detailed methodology of the study is displayed in a
previous publication10. Total phosphorus was determined
using molecular absorption spectrophotometry and total
protein content was determined by the Kjeldahl method. These
tests were carried out in the Aragón Food Technology and
Research Centre. The averages of the tests were considered
to be phosphorus measured. Protein content, which was more
standardised, was only measured in the first batch of each
product.
Expression of results
Phosphorus content was expressed in mg/100g of the product
and the protein content was expressed in g/100g of the
product. We added the calculation of the phosphorus [mg]protein [g] ratio due to its relevance in our patients11. The
Kidney Disease Outcomes Quality Initiative guidelines
recommend a dietary ratio of 10-12mg/g.
We reviewed the information on phosphorus and protein
content of the different food processed in the Moreiras food
composition table12, that of the Nutrition and Diet Higher
Education Centre13 and that of the BEDCA (Spanish Food
Composition Database) of the Ministry of Science and
Innovation, Spanish Food Safety and Nutrition Agency14.
499
short original
Statistical analysis
The description of quantitative variables was carried out
with their mean ± SD and the qualitative variables with the
distribution of frequencies. We carried out a phosphorus
content repeatability study in various foods, with two or
three repetitions for each sample. We calculated the mean,
SD, and the CV (CV=SD/mean) expressed as a % and the
repeatability interval (r=SDx2.8) for each set of repeated tests
of the same sample. Subsequently, we calculated the means
of all the previous tests in all the samples. We considered CV
values between phosphorus tests in the same sample <10% to
be acceptable. We considered P values <.05 to be statistically
significant. We analysed the data with the SPSS version 15.0
software.
RESULTS
The results obtained in our tests are shown in Tables 1, 2 and
3. For a comparison, the data of the food composition tables
are expressed in Table 4.
Of the 118 products analysed, 50 (43.2%) contained
phosphorus additives, according to the labels. The mean
phosphorus value in the total samples was 162.1 (range
21.4-790.3) mg/100g, the mean SD was 9.93mg/100g, the
mean CV was 6.7% and the mean repeatability interval (r)
was 29.3mg/100g (this implies that 95% of the time, a new
test, repeated again, did not differ by more than 29.3mg/dl
from the mean of the previous tests). In values below the
median, the mean of the phosphorus tests in the total sample
was 120.3 (range 21.4-160.6) mg/100g, the mean of the SD
was 8.7mg/100g, the mean of the CV was 7.9% and the
mean repeatability interval (r) was 24.6mg/100g. In values
above the median, the mean phosphorus test in the total
sample was 205.3 (range 161.2-790.3) mg/100g, the mean
SD was 10.3mg/100g, the CV mean was 5.4% and the mean
repeatability interval (r) was 28.38mg/100g. The CV was
significantly lower (5.3% vs. 7.9%; P=.016) in products with
values above the median phosphorus content. There were no
significant differences in the r value.
In dairy products, the high phosphorus content is known,
which increases in processed milk. Soy milk contributes half
the phosphorus with a similar amount of proteins, and as
such, it may be used in some patients, although we must bear
in mind the problem of its palatability. Cheeses for melting
and grating have phosphorus-containing additives in the form
of melting salts. It must be noted that in fresh cheeses such
as Burgos, the most tolerated in the dietary recommendations
for our patients, we detected a high phosphorus-protein ratio
in the six samples taken in two products (between 18.9 and
20.4mg/g), which is much higher than that displayed in
two of the tables (13.7mg/g). Overall, the products without
phosphorus additives have a phosphorus-protein ratio of
500
10.2mg/g and those that contain these additives have a ratio
of 15.3mg/g.
Within cereals, simple products, such as Marie biscuits or white
bread have a reasonable phosphorus-protein ratio of between
11.7 and 12.1mg/100g. Different brands of sliced bread may
or may not include phosphorus additives, with a 23% increase
in phosphorus content in those that contain them. “Spongy”
products, such as cupcakes, or sobao cakes have a high
phosphorus content, since their dough requires phosphoruscontaining additives, while products such as croissants reduce
the phosphorus quantity since they do not include these
additives. Products without phosphorus-containing additives
have a phosphorus-protein ratio of 11.4mg/g and those that
contain these additives have a ratio of 25.7mg/g. The tables
display contradictory values for Marie biscuits, sobao cakes,
croissants and chocolate cookies.
The phosphorus-protein ratio in sausages decreases as the
quality of the products increases, since they require fewer
preservatives and flavouring. Specific products such as cooked
ham, which do display the absence of phosphates on their
labels effectively have a significant reduction in phosphorus
content, of around 33%. Products that we may recommend
to our patients, such as cold meats that are low in fat and
salt, may have phosphorus-containing additives to give them
texture and taste. Products without phosphorus-containing
additives have a phosphorus-protein ratio of 10.2mg/g and
those that contain these additives have a ratio of 15.5mg/g.
The tables do not provide information about products without
phosphates, and some low-phosphorus values in smoked and
chopped bacon, chorizo and fuet salami are surprising, as well
as contradictory data for chorizo, cooked ham and Bologna
sausage.
The results for meat products and fish were reported
in a previous study10. In summary, we can say that the
phosphorus-protein ratio is higher in processed meat products
(15.83mg/g) than in breaded products (11.04mg/g) and frozen
products (10.5mg/g), and is lower in fresh (8.41mg/g) and
refrigerated meat products (8.78mg/g). Fresh white fish has
a phosphorus-protein ratio of 8.58g/g while in frozen white
fish, it increases by 22% (10.3mg/g) and in breaded white
fish, by 46% (12.54mg/g). The information in the tables is
poor and confusing, without reference to the brands analysed.
We should highlight the reasonable phosphorus content in
oily fish such as fresh salmon, frozen salmon and frozen
swordfish (between 10.29 and 11.92mg/g), data that coincide
with the table values for salmon (phosphorus-protein ratio
between 12 and 12.9mg/g), although there are conflicting
values for swordfish (phosphorus-protein ratio of 29.8mg/g
in the Moreiras table).
The wide diversity of refrigerated-prepared foods makes a
systemic evaluation difficult. Their phosphorus content hardly
appears in the tables, and the information is conflicting and
Nefrologia 2014;34(4):498-506
short original
Table 1. Results of the phosphorus and protein composition of foods and the phosphorus-protein ratio according to the
tests by the Aragón Agri-Food Research Centre. Dairy products, cereals and cold meats
Phosphorus
mg/100
CITA
Protein
mg/100
CITA
CITA
phosphorusprotein ratio
Phosphoruscontaining additive
on the label
Dairy products
Hacendado whole milk
Hacendado whole milk with calcium
Yo soy milk
Danone natural yogurt
Actimel prebiotic yogurt
Danet custard
Burgos fresh cheese
Hacendado own label fresh cheese
Hochland cheese slices
Entrepinares grating cheese
83.2±7
105±5
43.6±4
85.7±4
65.7±4
104.7±9
216.7±16
200.2±19
790.3±7
447.2±6
3.2
3.8
3.6
3.2
2.8
3.5
10.6
10.6
14
21
26
27.3
12.1
26.8
23.5
29.6
20.4
18.9
56.5
21.3
No
E451
No
No
No
E450
No
No
E452
E341
Cereals
Hacendado Marie biscuits
White bread
Bimbo sliced white bread
Hacendado sliced white bread
Bella Easo non-iced fairy cakes
Martínez Sobao cake
Bella Easo croissants
Doughnuts
Bimbo “Tigretón” Swiss roll
Mcennedy chocolate cookies
81.3±5
98.2±5
119.5±11
97.1±1
181.1±18
147±8
90.2±1
85.7±1
102.3±8
221.7±12
6.7
8.4
9.5
8.7
4.8
5.3
8.6
5.8
4
7.2
12.1
11.7
12.5
11.2
37.8
27.8
10.5
16.5
29.2
30.8
No
No
E341
No
E450
E450
No
E341
E450
E451
Cold meats
Campofrío smoked bacon
Eroski chopped pork
Carrefour extra chorizo
Valle Alagón extra Iberian chorizo
Los Alcores extra fuet salami
Campofrío cooked ham
Casa Tarradellas extra cooked ham
Bonatur Argal cooked ham without phosphates
Carrefour cooked ham without phosphates
Valle Alagón fattened Iberian ham loin
Los Alcores cured Longaniza sausage
Carrefour Bologna sausage
Bonnatur Argal turkey breast
El Pozo fat-free and salt-free turkey breast
Juán Luna extra salchichón sausage
Monter Hacendado extra salchichón sausage
Iglesias Iberian salchichón sausage, Salamanca
250.1±2
216.3±18
228.2±12
245.4±19
320.8±26
258.1±14
270.8±1
187.4±14
172.4±7
268.1±23
275.9±21
172.3±37
231.2±19
263.4±9
228.5±63
273.4±38
225.9±18
13.1
9.85
21.3
26.2
28.1
19.2
19
20.1
19
30.6
30.1
14.4
16.6
14.6
16
21.4
26.3
19.1
22
10.7
9.4
11.4
13.4
14.2
9.3
9.1
7.33
9.2
11.9
13.9
18
14.3
12.8
8.6
E451
E451
E450
No
No
No
No
No
No
No
No
E451
E451
E451
E450-E451
E450-E451
No
CITA (Agri-Food Technology and Research Centre): phosphorus values by spectophotometry and protein values by the Kjeldahl
method tested in the Aragón Agri-Food Research Centre.
Nefrologia 2014;34(4):498-506
501
short original
tests by the Aragón Agri-Food Research Centre. Fresh, refrigerated, frozen, breaded and processed meats.
Phosphorus
mg/100
CITA
Protein
mg/100
CITA
CITA phosphorusprotein
ratio
Phosphoruscontaining
additive on
the label
184±4
185.5±2
213±8
178.2±2
22.17
23.15
24.08
20.44
8.3
8.01
8.85
8.72
No
No
No
No
181.12±29
171.9±8
217±23
241.2±24
204.67±7
185.25±3
153.37±28
136.83±9
155.5±9
223.03±5
144.7±5
22.2
21.6
24.65
28.4
23.57
21.8
17.38
14.69
19.54
23.32
15.27
8.15
8.2
8.82
8.49
8.68
8.49
8.82
9.31
7.96
9.56
9.48
No
No
No
No
No
No
No
No
No
No
No
170±37
175±8
14.09
18.59
12.07
9.41
No
No
Meat in breadcrumbs
La Cocinera frozen chicken nuggets
Frinka frozen chicken nuggets
Burger King chicken fillet
Hacendado frozen chicken nuggets
Eroski frozen chicken nuggets
103.90±2
117±16
179.3±10
132.77±11
162.20±3
10.98
10.42
16.22
11.60
13.71
9.46
11.47
11.05
11.45
11.83
No
E450-631
--E450
E450
Processed meats
Mackein barbecue chicken wings
Burger King fried chicken leg and wings
Casa Matachín refrigerated chicken meatballs
Eroski Basic frozen chicken croquettes
Hacendado frozen chicken croquettes
Martínez Loriente marinated turkey breasts
Carrefour turkey and cheese Flamenquín croquettes
Oscar Mayer turkey Frankfurter
Carrefour refrigerated chicken roti
Carrefour refrigerated chicken wrap
Hacendado frozen meatballs
Refrigerated breaded pork steak with cheese
Oscar Mayer Classic Wiener Frankfurter
Jumbo Cheese Oscar Mayer Frankfurter
Carrefour French toast sandwiches
139.3±12
206.8±6
152.7±7
44.7±7
74.43±13
205±16
251.60±10
221.1±4
273.73±30
259.27±10
108.47±1
171.9±10
211.1±8
262.3±10
272.2±20
21.95
30.46
15.69
4.34
4.70
13.80
13.23
11.13
12.80
11.14
10.8
12.77
11.33
13.08
10.4
6.35
6.79
9.73
10.3
15.84
14.86
19.02
19.86
21.39
23.27
10.04
13.46
18.62
20.05
26.17
No
--No
No
No
E450-451
E450-451
E451
E451
E339
E450
E451-322
E451
E451-340
E450-451
Fresh meat
Simply pork loin
Simply beef
Simply chicken breast
Simply skinless chicken leg
Refrigerated meat
Simply pork loin
Eroski pork loin
Eroski Natur Selection pork loin
Eroski Natur Selection sirloin
Martínez Loriente loin fillet/scallops
Simply beef
Martínez Loriente beef/pork mince
Martínez Loriente beef/pork burger
Eroski skinless chicken leg
Carrefour chicken breast
Martínez Loriente chicken/turkey sausages
Frozen meats
Martínez Loriente frozen loin chop
Carrefour skinless chicken drumsticks
CITA: phosphorus values by spectophotometry and protein values by the Kjeldahl method tested in the Aragón Agri-Food Research
Centre.
502
Nefrologia 2014;34(4):498-506
short original
tests by the Aragón Agri-Food Research Centre. Fresh, frozen and breaded fish and surimi.
PhosphorusCITA phosphoruscontaining
protein ratio
additive on the
label
Phosphorus
mg/100
CITA
Protein
mg/100
CITA
Fresh fish
Simply hake
Simply squid
Simply salmon
154.32±8
78.23±9
176.23±7
18.36
9.26
17.14
8.41
8.42
10.28
No
No
No
Frozen fish
Findus skinless hake
Mascatto hake fillets
Eroski catfish fillet
Pescanova salmon pieces
Eroski salmon
Carrefour frozen swordfish
Simply Aligator squid rings
Carrefour squid rings
Eroski squid rings
Simply Aligator cleaned squid
125.1±9
162.37±11
131.10±8
213.3±18
213.21±12
208.5±6
101.42±9
78.33±9
146.10±9
53.12±6
16.93
17.08
11.49
20.14
20.09
17.49
11.50
7.27
11.27
8.62
7.39
9.51
11.40
10.59
10.6
11.92
8.78
10.77
12.96
6.15
No
No
E451
No
No
No
No
E338
No
No
Breaded fish
Pescanova fish burgers
Pescanova breaded hake pieces
Findus breaded hake fillets
Carrefour hake nuggets
Pescanova egg-battered hake fillets
Pescanova hake surfers
Pescanova stewed cod
Hacendado squid rings
Eroski fried squid rings
Pescanova Caprichos fried squid rings
Eroski breaded crab claw surimi
Pescanova breaded crab claw surimi
Frudesa surimi
68.3±11
145.4±8
118.8±4
103.67±8
157.6±18
162.3±6
137.3±3
78.3±3
114.6±9
122.5±12
42.60±3
58.00±5
28.30±1
9.30
9.72
12.15
9.87
12.03
11.24
12.60
7.25
7.28
6.49
5.84
5.76
5.39
7.31
14.96
9.51
10.50
13.10
14.44
10.90
10.8
15.65
18.98
7.29
10.07
5.25
E635
E451
No
No
No
E450
E450
E339
E450
E450
E450
E450-E635
E450-E635
Refrigerated/prepared
Carrefour cannelloni bolognese
Eroski fresh refrigerated spaghetti carbonara
Eroski noodles
Eroski frozen vegetable lasagne
Buittoni Piacere vegetable tortelloni
Casa Tarradellas ham and cheese pizza
Casa Tarradellas Neapolitan pizza
Buitoni Prosciuto e Fromaggio frozen pizza
Casa di Mama Prosciuto Funghi frozen pizza
Hacendado ham and cheese pizza
Hacendado refrigerated tuna pies
Hacendado frozen patties
La Cocinera frozen tuna patties
Seleqtia lentils, duck and mushrooms
Carrefour refrigerated Valencian-style paella
Cheese panini
66.37±1
49.20±5
67.90±12
54.10±3
112.30±5
195.20±12
170.30±11
166.60±8
210.10±14
193.83±4
72.17±4
62.10±8
69.00±5
87.00±3
76.43±7
203.33±9
4.16
3.84
5.29
3.40
8.31
13.47
11.71
10.67
8.92
12.96
7.26
6.48
7.63
4.97
5.74
13.09
15.95
12.82
12.84
15.90
13.51
14.49
14.54
15.61
23.55
14.96
9.94
9.58
9.05
17.51
13.32
15.53
E452
No
E452
E339-E631
No
E451
E451
No
E452
E451
E450
No
No
No
No
No
21.43±6
28.20±9
1.20
0.67
17.86
42.09
No
No
Sauces
Hacendado tomato sauce
Kraft mayonnaise
CITA: phosphorus values by spectophotometry and protein values by the Kjeldahl method tested in the Aragón Agri-Food Research
Centre.
Nefrologia 2014;34(4):498-506
503
short original
Table 4. Phosphorus-protein ratio according to the values of the food composition tables. Dairy products, cereals, cold
meats, refrigerated-frozen products and fish.
CESNID phosphorusprotein ratio
Moreiras phosphorusprotein ratio
BEDCA phosphorusprotein ratio
Dairy products
Whole milk
Soy milk
Natural yogurt
Prebiotic yogurt
Custard
Burgos fresh cheese
Cheese slices
Grating cheese
27.7
--25.7
30
26.5
13.7
47.8
25.4
27.9
--45.9
--26.1
40
58.5
20.3
30.1
14.7
29.7
--29.7
13.7
56.5
21.6
Cereals
Marie biscuits
White bread
Sliced bread
Non-iced fairy cakes
Sobao cakes
Croissants
Doughnuts
Chocolate cookies
12.7
10.8
12.5
37.9
--16.5
15.6
13.2
27.1
13.7
9.8
22.1
10.3
15.7
13.3
27.1
12.7
10.8
12.5
37.9
--12.7
13.3
13.2
Cold meats
Smoked bacon
Chopped pork
Chorizo
Extra fuet
Cooked ham
Cooked ham without phosphates
Pork loin
Longaniza sausage
Bologna sausage
Cold turkey meat
Salchichón sausage
8.1
--12
5.1
12.8
--6.4
--7.1
--11.5
11.1
11.4
7.3
5.1
5
--3.6
--11.4
9.2
10.1
8.3
11.4
10
7.8
11.4
--5.3
6.4
11.4
17.7
10.1
Refrigerated-frozen
Frozen pizza
Meat cannelloni with white sauce
Lasagne with white sauce
Spaghetti
Pasta filled with meat
Pasta filled with cheese
Meat pie
Tuna pasty
Paella
21.8
7.5
14.7
15
14.9
9.1
3.1
-----
18.3
17.6
14.8
15.8
14.9
9.1
-------
21.8
7.5
14.7
15
14.9
--8.5
51.1
5.9
Fish
Salmon
Swordfish
16.8
20.1
12
14.5
13.6
29.8
BEDCA: Spanish Food Composition Database, CESNID: Nutrition and Diet Higher Education Centre food composition table,
Moreiras: Moreira O food composition table.
504
Nefrologia 2014;34(4):498-506
confusing. In general, they have additives and high amounts
of phosphorus, although, in some cases the phosphorusprotein ratio would mean they could be included to a
limited extent in our patients’ diets: meatballs and chicken
croquettes, pies and tuna patties, fresh spaghetti and fideuà.
We also found that some simple pizzas (romana, cooked ham
and cheese pizza) do not contain excessively high quantities
of phosphorus. Products without phosphorus additives have a
phosphorus-protein ratio of 13.3mg/g and those that contain
these additives have a ratio of 18.7mg/g.
DISCUSSION
The increased consumption of processed foods, with the
extensive use of phosphorus additives, complicates dietary
management of CKD patients. The diverse application of these
additives (pH regulators, antioxidants, protein stabilisers,
flavour enhancers, colour enhancers, melting salts in cheeses,
dough enhancers and baking powder) means that they may
contribute up to a third of dietary phosphorus15. Leon et
al., in supermarkets in the US, detected that almost 50%
of foods have phosphorus-containing additives, increasing
the phosphorus quantity by 67mg/100g. The presence of
additives is common in refrigerated-frozen and packaged
products, cereals and yogurts, and in general, the products
that contain them are cheaper16.
Current regulations make phosphorus contribution
estimations difficult: producers are not required to display
their quantities on the labels, variable quantities are allowed,
since they can set their limit according to maximum amounts
and the contribution of these additives is not clearly defined
in the food composition tables17. Therefore, we must interpret
the phosphorus contribution calculation with caution by
dietary survey18, and we recommend questionnaires that
record the normal intake of different foods and their form of
preparation19.
In the dietary education of CKD patients, we must be aware
of this extra contribution in the form of hidden phosphorus20.
Some authors are optimistic and consider that by recognising
the problem, we can provide better options21. However, poor
knowledge of the phosphorus content of many products limits
our actions, which do not usually go beyond recommending
intake of non-processed foods. This option is increasingly
complicated, since in modern society, processed foods
surround our patients, making regular access to natural foods
difficult. We must study more specific dietary interventions
that include information about phosphorus-containing
additives. Of the list of additives authorised, only a few are
a source of phosphorus and they are displayed on labels
with a letter and number format: phosphoric acid (E338),
phosphates (E339, E340, E341, E343), diphosphates (E450),
triphosphates (E451) and polyphosphates (E452). Sullivan
et al. achieved a moderate but significant decrease in serum
Nefrologia 2014;34(4):498-506
short original
phosphorus levels of 0.6mg/dl, by adding data on phosphoruscontaining additives to patient dietary information22.
Other factors complicate the limitation of phosphorus
contributions. The quantities permitted are relatively high,
since their limits are designed more to avoid fraud than being
based on a dietary risk; in some products (refrigerated, frozen
and packaged foods in supermarkets), the regulations allow
phosphorus-containing additives without a specific indication
thereof on the list of ingredients23 and in other processed
products (pizza, tortellini, cheese paninis, etc.), it is surprising
that there are no phosphorus-containing additives on the
labels. This may be due to current legislation, which according
to the “General regulations for labelling, presentation and
advertising of foodstuffs”, it is not compulsory to declare in
the list of ingredients additives from an ingredient if they do
not have a technological function in the final product. This
means that in prepared or pre-cooked products, there may
be prepared dough with phosphorus-containing additives,
melted cheese with phosphates, crab sticks with phosphates,
etc. whose phosphorus content is not listed on the labels.
In this study on 118 products, we aim to provide complete
information about the phosphorus content of the processed
products reviewed in previous studies10,24, displaying data
on the normal foods in our setting, noting the differences
with fresh food and the discrepancy with food composition
tables. We consider it important to remark that nephrologists,
nutritionists and nephrology nursing staff should be aware of
these barriers in order to recognise a potential for the reduction
of phosphorus, while maintaining protein intake. Intake of
natural foods that are not pre-cooked and the phosphorus
content of some soft drinks (particularly cola) are important
aspects that we should consider25.
The study limitations are those that are unavoidable in any
approach to this problem. It was a cross-sectional study carried
out in a specific geographic area, new products often appear
and at any time there may be changes in the processing of the
food, which may alter its phosphorus content (the quantities
permitted according to current legislation are indicated with
“up to xxx grams of P205 per kg or litre”, with a generally
high level that may be variable). These limitations highlight
the importance of the need for dietary advice clinics and
prospective studies to assess whether we can adopt truly
effective measures.
We must be aware of the excessive phosphorus contribution
of phosphorus additives without protein contribution. Patients
must be provided with this information at dietary advice clinics,
and must individually become accustomed to reviewing
product labels; prospective studies are recommended to
assess the effectiveness of the measures. It is obvious that
this problem requires healthcare policy actions, such as
changes to the labelling that make it compulsory to display
the real phosphorus content of the product and encourage the
505
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preparation of products with a low phosphorus content and
alternatives to phosphorus additives.
REFERENCES
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de alimentos. Madrid: Ediciones Pirámide (Grupo Anaya SA); 2011.
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Ministerio de Sanidad y Política Social [accessed August 26, 2010].
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2012].
16. León J, Sullivan C, Sehgal A. The prevalence of phoshorus-containing
food additives in top selling food in grocery stores. J Ren Nutr
2013;23:265-70.
17.Uribarri J. Phosphorus homeostasis in normal health and in chronic
kidney disease patients with special emphasis on dietary phosphorus
intake. Semin Dial 2007;20(4):295-301.
18. Murtaugh M, Filipowicz R, Baird B, Wei G, Greene T, Beddhu S. Dietary
phosphorus intake and mortality in moderate chronic kidney disease:
NHANES III. Nephrol Dial Transplant 2012;27:990-6.
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Association of dietary phosphorus intake and phosphorus to protein
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20. Cupisti A, Ferretti V, DÁlesandro C, Petrone I, Di Giorgio A, Meola M,
et al. Nutritional knowledge in hemodialysis patients and nurses: focus
on phosphorus. J Ren Nutr 2012;22:541-6.
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al. Effect of food additives on hyperphosphatemia among patients
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et al. Fuentes ocultas de fósforo: presencia de aditivos con contenido en
fósforo en los alimentos procesados. Diálisis y Trasplante 2013;34:1549.
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Shinaberger CS, et al. Understanding sources of dietary phosphorus
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Sent to review: 30 Dec. 2013 | Accepted: 7 Apr. 2014
506
Nefrologia 2014;34(4):498-506
originals
Evolution of antibody titre against the M-type
phospholipase A2 receptor and clinical response
in idiopathic membranous nephropathy patients
treated with tacrolimus
Alfons Segarra-Medrano1, Elías Jatem-Escalante2, Clara Carnicer-Cáceres3,
Irene Agraz-Pamplona1, M. Teresa Salcedo4, Naiara Valtierra1, Elena Ostos-Roldán1,
Karla V. Arredondo1, Juliana Jaramillo1
1
Servicio de Nefrología. Hospital Universitari Vall d’Hebron. Barcelona (Spain); 2 Escuela de Doctorado. Universidad Autónoma
de Barcelona (Spain); 3 Servicio de Bioquímica. Hospital Universitari Vall d’Hebron. Barcelona (Spain); 4 Servicio de Anatomía
Patológica. Hospital Universitari Vall d’Hebron. Barcelona (Spain)
Nefrologia 2014;34(4):491-7
doi:10.3265/Nefrologia.pre2014.Jun.12536
ABSTRACT
Introduction and objectives: The level of circulating antibodies
against M-type phospolipase A2 receptor has been reported as
having a significant correlation with clinical activity in idiopathic
membranous nephropathy. However, the usefulness of monitoring
antibody titre as a predictor of clinical response following the
onset of treatment has not been formally analysed. The predictive
value of the evolution of anti-PLA2R antibody titre on the clinical
response of idiopathic membranous nephropathy patients treated
with tacrolimus is analysed in the following study. Patients and
Method: 36 patients with nephrotic syndrome secondary to
idiopathic membranous nephropathy with immunosuppressive
treatment indication criteria were treated with tacrolimus in
monotherapy. The level of anti-PLA2R antibodies was determined
before treatment and at 3, 6, 9 and 12 months after the onset
of treatment. The study analysed the predictive value of the
reduction in antibody titre and the relative and absolute
reduction in antibody titre at 3 and 6 months over the period
until remission and on the probability of remission at 6, 9 and
12 months. Results: The relative reduction in the anti-PLA2R
antibody titre was significantly greater in those patients with
remission and it preceded the clinical response. No association
was observed between the antibody titre prior to treatment and
the mean response time or the response at 12 months. Reduction
in antibody titre is significantly associated with the time until
Correspondence: Elías Jatem Escalante
Escuela de Doctorado.
Universidad Autónoma de Barcelona. Idumea, 08035. (Spain).
[email protected]
[email protected]
signs of remission. Relative reduction in anti-PLA2R antibody
titre at 3 months had a high sensitivity and specificity to predict
the response at 6 and 9 months, but not at 12 months; however
the relative reduction in the antibody titre at 6 months had a
high sensitivity and specificity for predicting the response at 12
months. Conclusion: In patients with IMN associated with antiPLA2R antibodies, the monitoring of antibody titre following
the onset of treatment is useful for estimating the time period
until remission and predicting the probability of remission at 12
months.
Keywords: Anti PLRA2 antibodies. Idiopathic membranous
nephropathy. Tacrolimus.
Evolución del título de anticuerpos contra el receptor tipo M de
la fosfolipasa A2 y respuesta clínica en pacientes con nefropatía
membranosa idiopática tratados con tacrolimus
RESUMEN
Introducción y objetivos: Se ha descrito que el nivel de anticuerpos
circulantes contra el receptor tipo M de la fosfolipasa A2 tiene
correlación significativa con la actividad clínica de la enfermedad
en la nefropatía membranosa idiopática (NMI). Sin embargo,
la utilidad de la monitorización del título de anticuerpos como
predictor de respuesta clínica tras el inicio del tratamiento no ha
sido formalmente analizada. En el siguiente estudio se analiza
el valor predictivo de la evolución del título de anticuerpos antiPLA2R sobre la respuesta clínica en enfermos con NMI tratados
con tacrolimus. Pacientes y métodos: 36 enfermos con síndrome
491
originals
nefrótico secundario a NMI, con criterios de indicación de
tratamiento inmunosupresor, fueron tratados con tacrolimus en
monoterapia. Se determinó el nivel de anticuerpos anti-PLA2R
antes del tratamiento y a los 3, 6, 9 y 12 meses tras su inicio. Se
analizó el valor predictivo de la pendiente de reducción en el título
de anticuerpos y de la reducción absoluta y relativa en el título de
anticuerpos a los 3 y 6 meses sobre el tiempo hasta la remisión y
sobre la probabilidad de remisión a los 6, 9 y 12 meses. Resultados:
La reducción relativa en el título de anticuerpos anti-PLA2R
fue significativamente mayor en los enfermos que presentaron
remisión y precedió a la respuesta clínica. No se apreció asociación
entre el título de anticuerpos previo al tratamiento con el tiempo
medio de respuesta o la respuesta a los 12 meses. La pendiente de
reducción en el título de anticuerpos se asoció significativamente
con el tiempo hasta la evidencia de remisión. La reducción relativa
en el título de anticuerpos anti-PLA2R a los 3 meses tuvo una
elevada sensibilidad y especificidad para predecir la respuesta a
los 6 y 9 meses, pero no a los 12 meses, mientras que la reducción
relativa en el título de anticuerpos a los 6 meses tuvo una elevada
sensibilidad y especificidad para predecir la respuesta a los 12
meses. Conclusión: En enfermos con NMI asociada a anticuerpos
anti-PLA2R, la monitorización del título de anticuerpos tras el
inicio del tratamiento es útil para estimar el período de tiempo
hasta la remisión y para predecir la probabilidad de remisión a
los 12 meses.
Palabras clave: Anticuerpos anti-PLA2R. Nefropatía membranosa
idiopática. Tacrolimus.
INTRODUCTION
Idiopathic membranous nephropathy (IMN) is an antibodymediated disease caused by IgG and C3 deposits in the
subepithelial space of the glomerular basement membrane1,2.
There is currently agreement that patients with normal renal
function who suffer from nephrotic syndrome for more than
6-12 months after diagnosis are candidates for receiving
immunosuppressive therapy. The drugs whose efficacy has
been proven in randomised clinical trials and which are
considered the drugs of choice as the first line of treatment
are alkylating agents combined with steroids and calcineurin
inhibitors3,4. Both treatments have proven similar efficacy in
inducing nephrotic syndrome remission and preserving renal
function, but they have some limitations. Firstly, around 20%
of patients may be resistant to one or both drugs3-13. Secondly,
the available evidence suggests that after starting therapy, the
probability of a response progressively increases with time,
even beyond the period of exposure to the drug5-13, and there
is currently no variable that allows us to predict whether the
patient will respond or not to the treatment or the time at which
the response will occur. Recently, the M-type phospholipase
A2 receptor has been identified as one of the target antigens of
the autoimmune response in IMN patients14-16 and it has been
reported that circulating antibodies against the latter (anti492
Alfons Segarra-Medrano et al. Anti-PLA2R titre and evolution of IMN
PLA2R), present in approximately 70%-75% of patients,
have a significant correlation with the clinical activity of the
disease17,18. As such, the evolution the anti-PLA2R antibody
titre after the start of treatment could be useful for predicting
the response. Some evidence indicates that after treatment
with rituximab the reduction in the antibody titre precedes
the remission of proteinuria 19. However, the usefulness
of monitoring the antibody titre as a predictor of clinical
response has not been formally analysed and there are no data
on the evolution of the anti-PLA2R antibody titre in patients
treated with tacrolimus.
In this study, repeated measurements of the anti-PLA2R
antibody titre were carried out before and during the 12
months following the start of treatment in patients with IMN
who received tacrolimus, with the objective of analysing the
predictive value of the anti-PLA2R antibody titre evolution
on the clinical response.
PATIENTS AND METHOD
We included a total of 36 patients who fulfilled the
following criteria: 1. Age >18 years old. 2. Nephrotic
syndrome caused by IMN confirmed by renal biopsy.
3. Exclusion of secondary aetiologies. 4. Anti-PLA2R
antibody titres >20RU/ml at the time of diagnosis. 5.
Immunosuppressive therapy criteria due to persistence of
the nephrotic syndrome after 6 months of symptomatic
treatment with angiotensin receptor blockers, statins,
diuretics and a low-sodium diet, in accordance with the
treatment guidelines3,4. 6. Normal renal function, as defined
by a CKD-EPI (Chronic Kidney Disease Epidemiology
Collaboration) value >60ml/min/1.73m2.
The renal biopsies were stained with haematoxylin and
eosin, PAS, methenamine silver and Masson’s trichrome
stainings for the morphological analysis and we carried out
immunofluorescence studies with antibodies against IgA, IgG,
IgM, C3, fibrinogen and light chains. The diagnosis of IMN
was carried out in the presence of a compatible morphological
pattern, associated with evidence of subepithelial IgG and C3
deposits in the immunofluorescence.
At the time of diagnosis, patients received treatment with
angiotensin-converting-enzyme inhibitors or angiotensin
II receptor blockers, a low-sodium diet and treatment for
dyslipidaemia with statins. After a 6-month observation
period and after observing no spontaneous remission, all
patients received monotherapy with tacrolimus at an initial
dose of 0.06mg/kg/day, which was subsequently adjusted to
maintain target levels of 7ng/ml-9ng/ml after 12 hours. No
patient had previously received immunosuppressive therapy.
Treatment with tacrolimus was maintained for three months
after evidence of remission or a maximum of 12 months in
Nefrologia 2014;34(4):491-7
cases in which patients had not shown remission at the end
of this period. After evidence of total or partial remission, the
tacrolimus dose was reduced at a rate of 30% per month until
total suppression or recurrence.
Per protocol, all patients were tested monthly until there
was evidence of remission, and if there was remission, they
were tested every 2-3 months until suppression of treatment,
evidence of recurrence or the absence of a response after
12 months. In all patients included, serum samples were
extracted before and after the start of treatment every three
months until the end of the first year. These samples were
used to determine the anti-PLA2R antibody titre by ELISA
(Euroimmun, Lübeck, Germany; linearity: 6-1500RU/ml;
lower limit of detection 0.6RU/ml).
The outcome variables were the probability of obtaining
total or partial remission in the course of the 12 months
following the start of treatment, the time period between the
start of treatment and evidence of remission, the evolution
of the antibody titre during the observation period and the
percentage of patients who had a negative antibody titre at the
end of the 12-month observation period.
Definitions:
- Complete remission: proteinuria <0.3g/day, albumin
>3.5g/dl and glomerular filtration rate >60ml/min/1.73m2.
- Partial remission: >50% reduction in baseline proteinuria,
with the last test showing <3.5g/day and with a glomerular
filtration rate >60ml/min/1.73m2.
- No response: absence of complete or partial remission 12
months after the start of treatment.
- Negative antibody titre: anti-PLA2R antibody titre
<20RU/ml.
This study followed the parameters of the Declaration of
Helsinki. All patients gave their written informed consent and
the study was approved by the hospital’s bioethics committee.
Statistical analysis
The results are expressed as a mean and standard deviation
for the variables with normal distribution and as a median
and quartiles for variables whose distribution is not normal.
The differences in proportions were analysed using the χ2
test or Fisher’s exact test. The analysis of the antibody titre
evolution over time was carried out using analysis of variance
for repeated measurements. In order to study the predictive
value of the reduction in the antibody titre on the response, we
calculated the absolute and relative reduction of the antibody
titre after 3 and 6 months in relation to the baseline value, as
well as the reduction slope in the antibody titre during the
follow-up period, expressing it in RU/ml/month. We carried
out a univariate analysis to identify the variables associated
Nefrologia 2014;34(4):491-7
originals
with the probability of remission during the 12-month
observation period through the Kaplan-Meier method,
using the log-rank test for comparison between groups. The
relationship between the reduction slope in the antibody titre
and time until evidence of remission was calculated using a
simple linear regression. Using ROC curves, we analysed
the anti-PLA2R antibody titre reduction value after 3 and 6
months that had the greatest sensitivity and specificity for
identifying patients in remission after 3, 6, 9 and 12 months.
Differences were considered to be statistically significant
when p was <.05. The version 20.0 SPSS statistical software
was used.
RESULTS
Table 1 summarises the baseline clinical and biochemical
characteristics of the total number of patients included in the
study in terms of their response to treatment after 12 months.
No significant variables were observed in any of the variables
analysed between those patients who responded and those
who did not.
Over the 12 months of follow-up (Figure 1), the probability
of remission increased progressively over time, with a 40%
probability after 6 months, 60% after 9 months and 69.4%
(25/36 patients) after 12 months. Of the total number of
patients in remission, 9 (25%) showed complete remission and
16 (75%) showed partial remission. The median time between
the introduction of treatment and evidence of remission
was 8.5 months (interquartile range: 5.5-9.6 months). The
percentage of patients who entered total or partial remission
without treatment with tacrolimus after 12 months was 28%
(7/25). The mean tacrolimus dose was 0.05±0.017mg/kg/
day and the mean level was 7.9±1.9ng/ml without significant
differences being observed between those who responded and
those who did not. During the observation period, there was
no recurrence in any patient when tacrolimus therapy was
discontinued.
Figure 2 displays the evolution of the antibody titre according
to the response to treatment in the total group of 36 patients
studied. In relation to the baseline value, in the group of
patients, the relative reduction in the antibody titre at the end
of the 12-month observation period was 61.3±37% (p:.004).
There were no differences in the baseline antibody levels
between patients who entered remission and those who did
not. Following treatment, the antibody titre after 3, 6, 9 and
12 months was significantly lower in those who showed total
or partial remission (F: 25.9, p:.000) than in those who did not
respond to treatment. The mean anti-PLA2R antibody titre
at the time of remission was 17.4±8.3RU/ml. Twenty of the
25 (80%) patients who entered remission had an anti-PLA2R
antibody titre <20RU/ml at the time of remission. Figure 3
displays the evolution of the anti-PLA2R antibody titre and
proteinuria in patients who did not respond to treatment.
493
originals
Table 1. Baseline clinical and biochemical characteristics and therapeutic response
N
Total
Remission
No remission
36
25
11
P
Sex (male) n (%)
25 (69.4)
17 (68)
8 (72.7)
0.91
Age (years)
49.5±15.1
51.5±15.3
42.3±17.8
0.13
Total cholesterol (mg/dl)
339.2±83.1
331.8±66.4
355.36±33.1
0.31
Albumin (g/dl)
2.1±0.42
2.06±0.53
2.19±0.53
0.44
Creatinine (mg/dl)
0.98±0.2
1±0.19
0.95±0.25
0.62
eGFR (ml/min/1.73m2)
114±21
108±26
120±20.7
0.30
Proteinuria (g/24 h)
11.3±3.2
10.5±2.9
12.8±3.5
0.22
Anti-PLA2R antibody titre (RU/ml)
Time since diagnosis (months)
Diabetes n (%)
225±81
222.4±98
231±92
0.43
10.7±3.14
10.6±2.8
10.8±4.5
0.85
3 (8.3)
2 (8)
1 (9)
0.58
High blood pressure n (%)
7 (19.4)
5 (20)
2 (18.1)
0.74
Smokers n (%)
6 (16.6)
4 (16)
2 (18.1)
0.74
Ischaemic heart disease n (%)
Body mass index n (%)
2 (5.5)
1 (4)
1 (9)
0.86
24.9±4.9
24.8±4.9
25.1±5.1
0.49
eGFR: estimated glomerular filtration rate.
We can observe a statistically significant reduction in
the antibody titre between the baseline level and the
third month (18.5±4.8%, p:.037) and an accumulated
21.4±13.6% reduction in the antibody titre after 12 months.
The reduction slope in the antibody during the 12-month
follow-up in patients who did not respond to treatment was
7.53±5.50RU/ml/month. Over the course of the follow-up
period, we did not observe significant changes in urine
protein excretion.
Probability of remission (%)
1.0
0.8
0.6
0.4
0.2
0.0
0.0 2.04.06.08.0
10.012.0
Time (months)
Figure 1. Probability of remission and time in the sample
studied.
494
Figure 4 displays the evolution of the anti-PLA2R antibody
titre and proteinuria in patients who showed remission. The
relative reduction in the antibody titre preceded the decrease
in proteinuria and it was statistically significant from the
third month. The relative reduction in the antibody titre was
35±18.4% after 3 months, 60±16.4% after 6 months, 70±12%
after 9 months and 78.9±14.2% after 12 months. The reduction
slope in the antibody titre during the observation period in
patients who responded to treatment was -21.5±3.78RU/
ml/month. Using a simple regression analysis, we observed
a statistically significant relationship between the antibody
titre reduction rate and the time until remission (Table 2).
Table 3A summarises the value of relative reduction in the
antibody titre after three months on the prediction of response
to treatment after 6, 9 and 12 months. Table 3B summarises
the value of the relative reduction in the antibody titre after 6
months on the prediction of the response to treatment after 9
and 12 months. It can be observed that the relative reduction in
the antibody titre after 3 months has increased sensitivity and
specificity for predicting the response after 6 and 9 months
but not after 12 months, while the relative reduction in the
antibody titre after 6 months has an increased sensitivity and
specificity for predicting the response after 9 and 12 months.
DISCUSSION
In this study, we carried out repeated measurements of the
anti-PLA2R antibody titre before and during the 12 months
following the start of treatment in patients with IMN who
received tacrolimus as the first line of treatment, with the
objective of analysing the predictive value of the evolution
Nefrologia 2014;34(4):491-7
originals
of the anti-PLA2R antibody titre on the clinical response.
The patient group included a non-selected sample of patients
with IMN associated with anti-PLA2R antibodies, who were
treated by following the same protocol, after an extended
period of symptomatic treatment starting at diagnosis in
accordance with recommendations of different guidelines3,4.
The observation period was 12 months, which is the
maximum period in which monotherapy with tacrolimus was
maintained if no response was observed. Both the probability
of remission observed over time and the percentage of
patients in remission after 12 months observed in our patients
were very similar to those reported in previous studies with
calcineurin inhibitors11-13. For these reasons, the results
observed in our patients could be applied to other patient
groups with IMN who receive tacrolimus.
250.0
200.0
150.0
100.0
50.0
0.0
Start 3 months 6 months 9 months 12 months
Time (months)
Remission
No remission
Figure 2. Anti-PLA2R antibody titre and remission in the
sample studied.
The error bars represent the mean ± the standard error of the
mean.
250.0
The results of our study provide the following data of clinical
interest. Firstly, similarly to the data reported after treatment
with rituximab19,20, our results indicate that in patients treated
with tacrolimus, the reduction in the anti-PLA2R antibody
titre after the start of treatment precedes the remission
of proteinuria and is related to the clinical response. The
evidence of a progressive reduction in the antibody titre was
highly predictive of remission, while persistence of high titres
was associated with the persistence of nephrotic syndrome,
250.0
200.0
200.0
150.0
150.0
*
100.0
100.0
50.0
50.0
0.0
0.0
Start 3 months 6 months 9 months 12 months
Time (months)
Proteinuria (gr/24h x 10)
Figure 3. Evolution of proteinuria and the anti-PLA2R
antibody titre in patients without remission in the
observation period.
For the purposes of graphic representation and in order to
standardise the measurement scales, proteinuria values are
represented as g/day x 10.
mean.
Nefrologia 2014;34(4):491-7
*
Start
3 months 6 months 9 months 12 months
Time (months)
Proteinuria (g/24 h x 10)
Figure 4. Evolution of proteinuria and the
anti-PLA2R antibody titre in patients with remission in the
observation period.
For the purposes of graphic representation and in order to
standardise the measurement scales, proteinuria values are
represented as g/day x 10.
mean.
495
originals
Table 2. Relationship between the antibody titre reduction slope and the time until remission in patients who responded
to the treatment
(Constant)
Reduction slope
b
ET
T
Sig
95% confidence interval for β
22.1
1.354
16.3
0.000
19.344
24.976
–0.61
0.051
-10.5
0.000
–0.688
–0.461
Reduction slope expressed in RU/ml/month.
R2: 0.84, P:.000.
with statistically significant differences in the antibody
titre between patients with and without a response,
which were evident from the third month and they were
maintained throughout the whole observation period.
Furthermore, in patients who responded to treatment,
the antibody level reduction rate was associated with the
speed of the clinical response. Both data indicate that
monitoring the anti-PLA2R antibody titre after the start
of treatment is useful in clinical practice and it may have
two practical implications. The first is that the antibody
titre reduction rate after the start of treatment may be used
as an estimator of the response time. The second is that
the relative reduction in the antibody titre after 3 and 6
months may serve as a guide for predicting the response
probability. Given that the available evidence indicates
that the response to treatment with tacrolimus increases
progressively with the drug exposure time13 and that none
of the baseline clinical or biochemical characteristics allow
the probability of response to treatment to be calculated,
in patients who show late responses, a relative reduction
value in the antibody titre equal to or greater than 50%
after 6 months may be a useful criterion when making the
decision to maintain immunosuppressive therapy, while the
persistence of reductions lower than this figure after 6 and
9 months has to suggest a high probability of resistance to
treatment.
IMN is an antibody-mediated glomerulopathy. In
approximately 70% of cases, these antibodies are
directed against the M-type phospholipase A2 receptor.
In 30% of cases, the antibodies are not identified either
in their circulating form or deposited in the glomerular
basement membrane. The identity of antibodies in the
immune deposits responsible for glomerular damage
and dysfunction in these cases is at present uncertain.
Calcineurin inhibitors (cyclosporine and tacrolimus)
induce downregulation of a series of cytokines
synthesised by T helper cells (Th1 and Th2) and antigenpresenting cells, particularly interleukin 2, which
amongst other functions is involved in the activation
of B lymphocytes and the subsequent production
of antibodies 21 . This would be the key mechanism
Table 3. Value of the relative reduction in the level of anti-PLA2R antibodies in relation to the baseline level in the 6, 9
and 12 month remission prediction
A
Value of the relative reduction in the anti-PLA2R antibody titre after 3 months in the 6, 9 and 12-month remission prediction
Remission time
Value
Sensitivity %
Specificity %
ABC
P
6 months
35%
87
93
0.98±0.01
0.000
9 months
30%
86
85
0.92±0.04
0.000
12 months
29%
60
70
0.71±0.08
0.004
B
Value of the relative reduction in the anti-PLA2R antibody titre after 6 months in the 9 and 12-month remission prediction
Remission time
Value
Sensitivity%
Specificity %
ABC
P
9 months
50%
93
95
0.97±0.02
0.000
12 months
45%
87
98
0.96±0.02
0.000
496
Nefrologia 2014;34(4):491-7
through which calcineurin inhibitor therapy induces
the reduction observed in the anti-PLA2R titres and its
correlation with remission.
In summary, our data indicate that in patients with IMN,
the reduction slope in the anti-PLA2R antibody titre is
significantly associated with the time until evidence of
remission. Furthermore, the relative reduction in the antiPLA2R antibody titre after 3 months is very sensitive and
specific for predicting the response after 6 and 9 months, but
not after 12 months, while the relative reduction in the antibody
titre after 6 months has a high sensitivity and specificity for
predicting the response after 9 and 12 months. These data may
be useful in the clinical follow-up of patients after the start
of therapy and they may be particularly important in cases
in which, as has been recently proposed22,23, we consider the
anti-PLA2R antibody titre as the base for treatment decisions.
REFERENCES
1. Donadio JV, Torres VE, Velosa JA, Wagoner RD, Holley KE, Okamura M, et al. Idiopathic membranous nephropathy. Kidney Int
1988;33:708-15.
2. Kerjaschki D. Pathomechanisms and molecular basis of membranous
glomerulopathy. Lancet 2004;364:1194-6.
3. Fulladosa X, Praga M, Segarra A, Martínez Ara J. Glomerulonefritis
membranosa. Nefrologia 2007;27(Suppl 2):70-86.
4. KDIGO Clinical Practice Guideline for glomerulonephritis idiopathic
membranous nephropathy. Kidney Int Suppl 2012;2:186-97.
5. Donadio JV, Holley KE, Andersons CF, Taylor WF. Controlled trial of
cyclophosphamide in idiopathic membranous nephropathy. Kidney
Int 1974;6:431-9.
6. Ponticelli C, Zucchelli P, Passerini P, Cesana B, Locatelli F, Pasquali S,
et al. A 10-year follow-up of a randomized study with methylprednisolone and chlorambucil in membranous nephropathy. Kidney Int
1995;48:1600-4.
7. Ponticelli C, Altieri P, Scolari F, Passerini P, Roccatello D, Cesana B,
et al. A randomized study comparing methylprednisolone plus chlorambucil versus methylprednisolone plus cyclophosphamide in idiopathic membranous nephropathy. J Am Soc Nephrol 1998;9:44450.
8. Jha V, Ganguli A, Saha TK, Kohli HS, Sud K, Gupta KL, et al. A
randomized, controlled trial of steroids and cyclophosphamide in
adults with nephrotic syndrome caused by idiopathic membranous
nephropathy. J Am Soc Nephrol 2007;18:1899-904.
originals
9. Hofstra JM, Branten AJ, Wirtz JJ, Noordzij TC, du Buf-Vereijken PW,
Wetzels JF. Early versus late start of immunosuppressive therapy in
idiopathic membranous nephropathy: a randomized controlled trial.
10. van den Brand JA, van Dijk PR, Hofstra JM, Wetzels JF. Long-term
outcomes in idiopathic membranous nephropathy using a restrictive
treatment strategy. J Am Soc Nephrol 2014;25:150-8.
11. Cattran DC, Greenwood C, Ritchie S, Bernstein K, Churchill DN,
Clark WF, et al. A controlled trial of cyclosporine in patients with
progressive membranous nephropathy. Kidney Int 1995;47:1130-5.
12. Cattran DC, Appel GB, Hebert LA, Hunsicker LG, Pohl MA, Hoy WE,
et al. Cyclosporine in patients with steroid resistant membranous
nephropathy: A randomized trial. Kidney Int 2001;59:1484-90.
13. Praga M, Barrio V, Juárez GF, Luño J; Grupo Español de Estudio de la
Nefropatía Membranosa. Tacrolimus monotherapy in membranous
nephropathy: a randomized controlled trial. Kidney Int 2007;71:92430.
14.Beck LH Jr, Bonegio RG, Lambeau G, Beck DM, Powell DW, Cummins TD, et al. M-type phospholipase A2 receptor as target antigen
in idiopathic membranous nephropathy. N Engl J Med 2009;361:1121.
15. Qin W, Beck LH Jr, Zeng C, Chen Z, Li S, Zuo K, et al. Anti-phospholipase A2 receptor antibody in membranous nephropathy. J Am Soc
Nephrol 2011;22:1137-43.
16.Hoxha E, Harendza S, Zahner G, Panzer U, Steinmetz O, Fechner
K, et al. An immunofluorescence test for phospholipase-A2-receptor
antibodies and its clinical usefulness in patients with membranous
glomerulonephritis. Nephrol Dial Transplant 2011;26:2526-32.
17.Hofstra JM, Beck LH Jr, Beck DM, Wetzels JF, Salant DJ. Anti-phospholipase A receptor antibodies correlate with clinical status in
idiopathic membranous nephropathy. Clin J Am Soc Nephrol
2011;6:1286-91.
18.Kanigicherla D, Gummadova J, McKenzie EA, Roberts SA, Harris S,
Nikam M, et al. Anti-PLA2R antibodies measured by ELISA predict
long-term outcome in a prevalent population of patients with idiopathic membranous nephropathy. Kidney Int 2013;83:940-8.
19.Beck LH Jr, Fervenza FC, Beck DM, Bonegio RG, Malik FA, Erickson
SB, et al. Rituximab-induced depletion of anti-PLA2R autoantibodies
predicts response in membranous nephropathy. J Am Soc Nephrol
2011;22:1543-50.
20. Bomback AS, Derebail VK, McGregor JG, Kshirsagar AV, Falk RJ,
Nachman PH. Rituximab therapy for membranous nephropathy: a
systematic review. Clin J Am Soc Nephrol 2009;4:734-44.
21. Cattran DC, Alexopoulos E, Heering P, Hoyer PF, Johnston A, Meyrier
A, et al. Cyclosporin in idiopathic glomerular disease associated with
the nephrotic syndrome: Workshop recommendations. Kidney Int
2007;72:1429-47.
22.Hofstra JM, Wetzels JF. Anti-PLA2R antibodies in membranous
nephropathy: ready for routine clinical practice? Neth J Med
2012;70:109-13.
23. Hofstra JM, Fervenza FC, Wetzels JF. Treatment of idiopathic membranous nephropathy. Nat Rev Nephrol 2013;9:443-58.
Sent to review: 18 Mar. 2014 | Accepted: 3 Jun. 2014
Nefrologia 2014;34(4):491-7
497
review
Defining protein-energy wasting syndrome
in chronic kidney disease: prevalence
and clinical implications
Carolina Gracia-Iguacel1, Emilio González-Parra2, Guillermina Barril-Cuadrado3,
Rosa Sánchez4, Jesús Egido2, Alberto Ortiz-Arduán2, Juan J. Carrero5
1
Servicio de Nefrología. IIS-Fundación Jiménez Díaz. En el Centro Santa Engracia. Fundación Íñigo Álvarez de Toledo. Madrid (Spain);
2
Servicio de Nefrología. IIS-Fundación Jiménez Díaz. Universidad Autónoma de Madrid (Spain); 3 Servicio de Nefrología. Hospital
Universitario de la Princesa. Madrid (Spain); 4 Servicio de Nefrología. Hospital de Segovia (Spain); 5 Servicio de Nefrología. Karolinska
Institutet. Estocolmo (Sweeden)
Nefrologia 2014;34(4):507-19
ABSTRACT
The presence of malnutrition in chronic kidney disease (CKD) is
well-known. The discovery in the last 15 years of pathophysiological
mechanisms that lead to this process, such as anorexia, the
increase of protein catabolism and inflammation, has created
the need for a new name by the International Society of Renal
Nutrition and Metabolism (ISRNM): protein-energy wasting
syndrome (PEW). This document’s objectives are to propose
the use of the term “desgaste proteico energético” (DPE) as a
more accurate translation of the English term and to update the
pathogenic mechanisms involved that are inherent to DPE (PEW).
We simultaneously review the latest epidemiological evidence
that highlight the relevance of malnutrition and its impact both
on mortality and morbidity in CKD. Finally, we point out the
need to redefine DPE (PEW) diagnostic criteria so that they are
applicable to the Spanish population with CKD. We do not think
that the criteria established by the ISRNM can be extrapolated to
different populations, as is the case, for example, with interracial
anthropometric differences.
Keywords: Protein-energy wasting syndrome. Chronic kidney
disease.
Correspondence: Carolina Gracia Iguacel
IIS-Fundación Jiménez Díaz. En el Centro Santa Engracia.
Fundación Íñigo Álvarez de Toledo. Madrid (Spain).
[email protected]
Definiendo el síndrome de desgaste proteico energético en la
enfermedad renal crónica: prevalencia e implicaciones clínicas
RESUMEN
La presencia de malnutrición es bien conocida en la enfermedad renal crónica (ERC). El descubrimiento en los últimos 15 años de los
mecanismos fisiopatológicos que desencadenan este proceso, tales
como la anorexia, el aumento del catabolismo proteico y la inflamación, ha generado la necesidad de una nueva denominación por la
Sociedad Renal Internacional de Nutrición y Metabolismo (ISRNM):
protein energy wasting syndrome (PEW). Los objetivos de este documento son proponer la utilización del término «desgaste proteico
energético» (DPE) como una traducción más fiel del término anglosajón y actualizar los mecanismos patogénicos implicados que son
inherentes al DPE. Simultáneamente revisamos las últimas evidencias
epidemiológicas que ponen de manifiesto la relevancia de la malnutrición y su impacto tanto en la mortalidad como en la morbilidad en
la ERC. Por último, destacamos la necesidad de redefinir los criterios
diagnósticos del DPE para que sean aplicables a la población española con ERC. Los criterios establecidos por la ISRNM creemos que no
son extrapolables a diferentes poblaciones, como ocurre por ejemplo
con las diferencias antropométricas interraciales.
Palabras clave: Síndrome de desgaste proteico-energético.
Insuficiencia renal crónica.
INTRODUCTION
Chronic renal failure is characterised by nutritional
disorders and systemic inflammation, which is
accompanied by an increased catabolism, increasing
507
review
morbidity and mortality. Nutritional disorders have been
reported in the literature with numerous and confusing
terms such as malnutrition, sarcopenia, cachexia and the
malnutrition-inflammation-atherosclerosis syndrome.
These terms describe a part of the problem but do not
cover the many mechanisms that influence patient health
and prognosis. In 2008, the International Society of
Renal Nutrition and Metabolism (ISRNM) proposed that
the term protein-energy wasting (PEW) be adopted as a
unifying nomenclature and the starting point for a better
knowledge and treatment of these problems in uraemic
patients. The term PEW does not translate easily to
Spanish and the Nutrition Working Group of the Spanish
Society of Nephrology (S.E.N.) proposes to use the
term “desgaste proteico energético” (DPE) as the most
accurate translation of the English term.
The PEW syndrome is very common in kidney patients
and it causes a deterioration in their quality of life and
decreases short-term survival. However, regrettably, many
hospitals still do not incorporate measures to evaluate
and monitor the nutritional state of patients. Likewise,
adequate nutrition is a strategy that is sometimes forgotten
in the management of kidney patients.
We c a n d e f i n e t h e P E W s y n d r o m e a s a s i n g l e
pathological condition in which purely nutritional
disorders converge with catabolic conditions. Both are
pathophysiologically related, they are enhanced by each
other and they create a vicious circle, which makes it
difficult to distinguish between the two components in
clinical practice. A diagnostic and therapeutic approach
in patients with PEW must be multifactorial and we
must try to treat each and every factor that we can
identify, since nutritional repletion is insufficient as
the only treatment, as it does not slow down underlying
proteolysis. With the intention of providing a current
view of all catabolic disorders covered by the PEW
syndrome, we reported the main concepts, mechanisms
and implications of this state.
Carolina Gracia-Iguacel et al. Protein-energy wasting in CKD
i.e., the disorders derived from the deficiency of macroand micronutrients2.
By “undernourishment”, we mean a body composition
disorder characterised by an excess of extracellular
water, frequently associated with a decrease in muscle
and fat tissue, hypoproteinaemia and potassium
deficiency, which interferes with the normal response of
the patient to their disease and treatment. “Protein-calorie
undernourishment” is caused whenever daily needs are not
covered by the diet. It is often reversed with the recovery
of intake and the resolution of the underlying problem.
Protein-calorie undernourishment can be divided into
three main clinical syndromes:
1. Marasmus or calorie undernourishment: this
develops gradually after months or years of insufficient
energy intake. The patient appears cachexic, with
a generalised loss of muscle mass and an absence
of subcutaneous fat. The result is a generalised
consumption syndrome (emaciation syndrome),
with major weight loss, generally normal visceral
protein reserves and a worsening of anthropometric
measurements.
2. Kwashiorkor, protein or hypoalbuminaemic
undernourishment: this begins and develops much
quicker and it is regulated by hormones and cytokines,
which act by decreasing organic visceral protein
deposits. Cytokines such as interleukin (IL)-1 and
tumour necrosis factor (TNF) mediate in the immune
response of the patient to stress and cause changes
in the acute phase reactants, such as fibrinogen at
the expense of albumin. Decreased production, along
with an exacerbated catabolism leads to marked
hypoalbuminaemia. Recently, gut microbiota has been
implicated in Kwashiorkor.
3. Mixed: very common in hospitalised patients. It
usually occurs in previously undernourished subjects
who suffer an intercurrent acute condition, causing
protein-calorie undernourishment.
CONCEPT AND TERMINOLOGY
PEW 1 is defined as a pathological state where there
is a continuous decrease or wasting of both protein
deposits and energy reserves, including a loss of fat and
muscle. Before introducing this new concept into our
terminology, we should briefly consider the malnutritionundernourishment concept and its difference with
other terms such as the wasting syndrome, in order to
understand the unifying nature of the term PEW.
The defining feature of undernourishment is weight loss.
Survival during fasting is related to the already existing
fat storage volume. Changes in body composition are
reflected as a severe increase in extravascular water, a
decrease in fat deposits and a decrease in lean body mass.
It is important to highlight that weight may increase
during a severe acute disease, due to fluids passing into
the third space. Abnormalities in uraemia in a certain
manner reflect mixed malnourishment, although it
presents with a moderate intensity and is not the result of
an intercurrent acute condition, but rather, a low-intensity
chronic inflammation.
The term “malnutrition” covers pathological states caused
both by an excess and a deficiency of nutrients. However in
uraemia, it is generally used to refer to undernourishment,
The term “cachexia” represents a complex metabolic
syndrome associated with a chronic disease and it
is characterised by a gradual loss of muscle tissue,
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Nefrologia 2014;34(4):507-19
accompanied or not by concomitant losses of fat reserves.
Cachexia, however, represents an extreme degree of
intake that is rarely observed in advanced chronic kidney
disease (CKD).
The term “wasting” was proposed by the World Health
Organization in 1988 3 and is defined as an involuntary
loss of weight of more than 10% on the baseline value
in the absence of an opportunistic infection, a tumour
disease or chronic diarrhoea. It is a multifactorial
syndrome and it is occasionally difficult to know the
main cause. It is characterised by a disproportionate loss
of lean mass due to specific abnormalities in metabolism
as part of the body’s defence mechanism in response to a
stress situation. When this situation is sustained, it leads
to a depletion of proteins, especially musculoskeletal
proteins, and is not recovered with intake, since this
whole process is due to cellular metabolic changes.
It is very important to adopt common terminology is
Spanish and we believe that the concept of DPE agreed
on by the S.E.N. Nutrition Group accurately captures
the spirit of the ISRNM’s nomenclature PEW. This term
describes the mechanisms involved and consequently
allows us to identify therapeutic targets, use the
appropriate monitoring methods and choose the most
effective therapeutic approach. We recognise that the
term “wasting” is less clinically severe than “emaciation”,
which may occur in patients with chronic kidney disease.
However, in the choice of terms and acronyms, we must
consider the advantage, using simpler language, of
instilling in healthcare professionals the need to identify
and treat these catabolic disorders. The terminology
DPE avoids including terms such as malnutrition of
catabolism, with the aim of not giving more importance
to any one of the components. In these disorders, both
undernourishment and muscle catabolism converge
and are pathophysiologically related, and as such, it is
impossible to distinguish one from the other in clinical
practice. Therefore, DPE implies both accelerated protein
(muscle) and energy (fat) loss.
MECHANISMS INVOLVED IN PROTEIN-ENERGY
WASTING
The disorders involved in renal failure malnutrition have
recently been revised by the ISRNM4. Anorexia5 and the
increase in protein catabolism6 result in an energy imbalance,
with the final result of an increase in energy wasting7 and in
the intake of energy storage sources.
Other pathophysiological mechanisms in CKD PEW are
metabolic acidosis8, endocrine disorders9,10, inflammation11,12
and the activation of the ubiquitin-proteasome systems
(UPS)13,14. At the same time, other aspects such as a restrictive
Nefrologia 2014;34(4):507-19
review
diet, the loss of amino acids and micro-macronutrients15 due
to dialysis techniques, blood loss, volume overload16 and
other psychosocial factors change the energy balance.
Muscle mass loss (wasting)
The term sarcopenia defines a situation of major loss of
muscle mass and strength and a multifactorial aetiology,
where an intake deficiency may occur, as well as hormonal
disorders, neuropathic damage, metabolic disorders and
the presence of uraemic toxins 17. It is a type of chronic
muscular atrophy and in CKD, it is associated with PEW,
limiting the independence of the patient and their quality
of life. It compromises vital organs, with respiratory,
musculoskeletal and heart muscle deterioration 18 .
Decreased intake, metabolic acidosis, physical inactivity,
diabetes and sepsis are associated factors in CKD that
Table 1. Causes of developing protein-energy wasting in
chronic kidney disease
a) Decrease in intake and increase in loss of nutrients
-Anorexia
-
Restrictive diets
-
Losses of amino acids in dialysis
-
Blood loss
b)
Increased catabolism
-
Metabolic acidosis
-
Endocrine disorders: insulin resistance, hypothyroidism,
decreased testosterone levels, changes in growth hormone
IGF1
-
Inflammation, oxidative stress increase
-
Activation of proteolytic systems such as the ubiquitinproteasome and caspase systems
-
Accumulation of uraemic toxins
-
Activation of proinflammatory cytokines: IL-6, TNF-α
(cachectin), IL-1 β, TGF-β
-
Increased energy wasting
IIGF1: insulin-like growth factor 1; IL: interleukin;
TGF: transforming growth factor; TNF: tumour necrosis factor.
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review
increase muscle proteolysis through increased catabolism,
activation of different intracellular signals of muscle cell
apoptosis and decreased synthesis. Several studies have
shown significant atrophy of muscle fibres in CKD 19-21
(Table 1).
One of the main mechanisms by which PEW is associated
with muscle atrophy in uraemia is increased UPS-mediated
protein catabolism and the activation of musculoskeletal
myostatin. The UPS system degrades muscle proteins
and myostatin is a member of the transforming growth
factor β family, which inhibits cellular proliferation and
muscle synthesis22. Intracellular activation of the caspase
pathway and myostatin stimulate protein degradation,
providing the substrate for the UPS and cell apoptosis.
The extensive tissue damage leads to an increase in
circulating actin, which may consume gelsolin (the
protein that assembles and disassembles actin) and other
proteins such as the vitamin D binding protein, which
have a protective role23.
High circulating actin and low circulating gelsolin levels
in patients on haemodialysis are associated with an
increased risk of mortality. Increased protein catabolism
and an accumulation of uraemic toxins would alter gelsolin
synthesis, leading to a loss in the ability to assemble
actin, platelet activation, endothelial dysfunction and an
increased susceptibility to infectious complications24.
Another mechanism recently reported is resistance to
insulin. Insulin-like growth factor 1 would activate the
phosphoinositide 3-kinase pathway, altering protein
metabolism and favouring an overregulation of myostatin
with a decreased proliferation of satellite muscle cells25.
PROTEIN-ENERGY WASTING DIAGNOSTIC CRITERIA
PROPOSED BY THE INTERNATIONAL SOCIETY OF
RENAL NUTRITION AND METABOLISM
An important development is the consideration of the
PEW syndrome as a single pathological condition in
which undernourishment and hypercatabolism converge.
An effective therapeutic approach to PEW cannot only
be carried out by nutritional repletion, since this would
not resolve proteolysis. A syndrome of a multifactorial
origin requires diagnostic criteria and comprehensive
therapy. The ISRNM has recommended diagnostic
criteria (Table 2). It is necessary to fulfil at least
one criterion in three of the four categories proposed
(biochemical, body mass, muscle mass and intake
criteria) 1 (Table 2).
These criteria are initially attractive due to their
multifactorial scope (analytical, anthropometric and
nutritional), but when we try to apply them to clinical
510
practice, they become confusing. Leinig et al. 26 did not
find any patient who had abnormalities in three of the
four categories specified by the ISRNM and when the
PEW syndrome was defined as abnormalities in two of the
four sections, a prevalence of 17% was found, which is
abnormally low if we compare it with the 65% prevalence
when it is diagnosed by subjective global assessment
(SGA). Another example of the questionable validity of
these criteria is found in the study by Drechsler et al. 27,
in which they analysed the relationship between PEW
and cardiovascular mortality and mortality from other
causes in a cohort of 1255 diabetic patients on regular
haemodialysis. They observed that no patient fulfilled the
PEW criteria proposed by the ISRNM. In this case, the
authors redefined the ISRNM criteria, considering there
to be PEW if the body mass index (BMI), albumin and
serum creatinine were below the median in the patients
studied. This article has limitations resulting from the
Table 2. Diagnostic criteria for protein-energy wasting
proposed by the International Society of Renal Nutrition
and Metabolism1
Biochemical criteria
Serum albumin <3.8g/dl (determined by bromocresol green)
Prealbumin/transthyretin <30mg/dl (only for patients on
dialysis)
Serum cholesterol <100mg/dl
Body mass
Body mass index <23kg/m2 (except in some geographic
areas)
Non-intentional weight loss of >5% of weight in 3 months
or >10% in 6 months
Body fat <10% of body mass
Muscle mass
Muscle mass loss >5% in 3 months or >10 % in 6 months
Decrease of the muscle area of the arms >10 % in relation to
the 50th percentile of the reference population
Generation/occurrence of creatinine
Dietary intake
Protein intake measured by the protein catabolism rate
<0.8g/kg/day in dialysis or <0.6g/kg/day in patients with
stages 2-5 CKD
Calculated energy wasting <25kcal/kg/day for at least 2
months
CKD: chronic kidney disease.
Nefrologia 2014;34(4):507-19
fact that the whole study population was diabetic, with a
consequential association with obesity, and as such, after
the adjustments, there was a 16% prevalence of PEW.
We believe that the ISRNM criteria have limitations
that we must take into account. In prospective studies,
these criteria should still demonstrate their superiority
to other possible diagnostic combinations before their
implementation becomes widespread. Recent observations
illustrate this by suggesting, in a population of 570
patients on haemodialysis, that only the presence of
hypoalbuminaemia had a similar or higher mortality
prediction value than the sum of several malnutrition
markers proposed by the ISRNM 28. However, we often
forget that the prediction of mortality does not necessarily
equate to a diagnosis of malnutrition, and the cut-off points
suggested are often based on survival analysis. Secondly,
the cut-off points of the parameters proposed derive from
American populations, and this leads us to wonder whether
or not they can be extrapolated to other geographic areas
and lifestyles such as those of Europe, Asia, or in our case,
Mediterranean countries. Thirdly, the dialysis population
is increasingly older and it is difficult to separate the
nutritional and body composition changes that occur with
age from malnutrition resulting from uraemia. For these
reasons, it is logical to think that the PEW diagnostic
criteria in CKD must be adapted and altered in different
demographic contexts (age, race), clinical situations
(obesity, diabetes, moderate and advanced CKD, dialysis
and transplantation) and contextual situations (lifestyle,
geographic location and culture)29.
In conclusion, although the criteria proposed by the ISRNM
reinforce the complex nature of the PEW syndrome, they
are based on tests/measurements that may be questionable
individually-speaking 30 and, moreover, their diagnostic
or prognostic validity have still not been demonstrated.
However, we consider that highlighting, for the first time
in this definition, the multifactorial nature of PEW and
the need to use different complementary nutritional state
markers has been an important step forward.
PREVALENCE OF PROTEIN-ENERGY WASTING
In the dialysis population, PEW traditionally has a wide
prevalence of 18%-75% 26 . Without a doubt, the
imprecision of these figures prevents us from drawing
valid conclusions. One of the problems is the variety of
assessment and monitoring tools and of cut-off points that
have been used to obtain these figures. Hypoalbuminaemia
has been defined in the literature with figures of <4, <3.8
or <3.5g/dl, with the added difficulty of its estimation
being changed according to the methodology employed
(bromocresol purple or bromocresol green). As such,
we should not be surprised that prevalence varies to a
Nefrologia 2014;34(4):507-19
review
great extent with the methodology employed for its
estimation. We are given an example of this by two
studies in Brazil 26 and Europe 28. The prevalence of PEW
varied between 23% and 74%, depending on whether it
was defined by biochemical tools (albumin, creatinine),
anthropometric tools (arm perimeter, BMI) or nutritional
tools (SGA, energy/protein intake). The same occurs with
other multi-centre studies, such as those carried out in
the United States, in which a prevalence of 38% 31 has
been reported. Lastly, and no less importantly, PEW
prevalence in different countries is a reflection of the
economic situation, the degree of development and the
prevalence of malnutrition in the general population,
making it impossible to refer to a general prevalence in
the dialysis population. This also applies to prevalence
in different regions, with varying resources, of the same
city or country.
In Spain, the first studies on the prevalence of
malnutrition date back to 1994 and in 29 patients on
chronic haemodialysis the nutritional state was analysed
using anthropometric measurements such as the triceps
skin fold, arm muscle circumference, BMI, visceral
proteins (albumin), the normalised protein catabolic
rate (nPCR) and protein intake 32. They observed that in
a sizeable proportion of patients (65%), the reduction
of fat and protein reserves was greater than that which
the relative body weight indicated (only deficient in
38%). In the same year, the first and only tables of
anthropometric parameters of a Spanish population on
haemodialysis were published (761 patients) 33,34 . In
the sample studied, prevalence of malnutrition defined
according to anthropometric parameters and biochemical
markers (albumin, transferrin, lymphocyte count) was
52% in males and 46% in females. The predictors of
malnutrition were old age, comorbidity index, male
sex, time on haemodialysis and nPCR. The multi-centre
Dialysis Outcomes and Practice Pattern Study (DOPPS)
displayed major differences between countries in the
monitoring of nutritional parameters, with Spain being
one of the most deficient in the recording of these
parameters 35. As such, the nPCR was only recorded in
20% of dialysis units in Spain, compared with 90% in
Germany and furthermore, there was only a nutritionist
in 20% of units in Spain, compared with 85% in the
United Kingdom. In contrast, there were no significant
differences in the results of serum albumin (3.98g/dl),
creatinine (9.1mg/dl) and BMI (23.9kg/m 2 ) with the
other European countries. However, the prevalence of
moderate malnutrition according to the SGA scale was
lower in Spain that in other countries such as France
(11% versus 18%).
We must point out that the aforementioned studies included
stable patients, and as such, there was a bias to eliminate
critically or acutely ill patients, who probably had PEW.
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review
This leads us to believe that PEW prevalence may even be
greater than that which we outline here. As such, in a recent
analysis of our unit, we observed PEW prevalence, according
to ISRNM criteria, of 37%, which increased to 41.1%
when patients were followed up for two years36. Although
the sample size was relatively small, the study included all
patients in the dialysis unit (without exclusions) and we used
all the ISRNM PEW criteria.
The latest S.E.N. advanced CKD nutrition guidelines
published in 200837 recommend assessing the nutritional state
using nutritional, biochemical, anthropometric and proteinenergy intake tests.
CLINICAL IMPLICATIONS
The mortality rate of CKD patients, particularly
cardiovascular mortality, is higher than in the general
population 38-41. This high mortality rate persists in spite
of correcting traditional cardiovascular factors, such as
hypotension, dyslipidaemia, left ventricular hypertrophy
and improving dialysis techniques 42 . PEW may be
considered a new risk factor, underlying the phenomenon
of reverse epidemiology, where markers that in the general
population are associated with a lower probability of
cardiovascular events, such a decreased BMI or low
cholesterol levels, are associated with a higher presence
of cardiovascular disease and lower survival in dialysis
patients43.
The presence of PEW in renal patients leads to the activation
of compensatory mechanisms and the deregulation of others,
which affects different organs and systems, including
the immune, endocrine, musculoskeletal, adipose tissue,
haematopoietic and gastrointestinal systems and causes
poor adaptation to the inflammatory cascade activation44,45,
leading to an increase in overall mortality (Table 3).
Protein-energy wasting and cardiovascular mortality
In patients with advanced CKD, malnutrition and
the presence of PEW are significantly related to
cardiovascular mortality 46,47 . Nutrients are necessary
for the body to function correctly. Dietary restrictions
in uraemic patients that limit potassium, phosphorus or
sodium intake, amongst others, may lead to deficiencies
of other essential nutrients if there is no dietary advice
from healthcare staff. Essential nutrients are necessary
for tissue synthesis and energy production, whilst being
coenzymes in most enzymatic reactions in the body.
Specific nutritional deficiencies, such as selenium,
magnesium or vitamin D deficiencies, so common
in kidney patients, have negative consequences on
the antioxidant and anti-inflammatory capacity and
on mineral and bone metabolism. As such, PEW is
associated with a higher risk of infection and death due
to infectious causes29,48. Deficiency of vitamins A, K and
D is associated with greater cardiovascular mortality in
haemodialysis patients 49,50. Up to 80% of haemodialysis
Table 3. Underlying clinical impacts of the protein-energy wasting syndrome that lead to higher mortality
Presence of protein energy wasting
Clinical implications
Nutritional: deficiency of micronutrients, vitamins (D, A, K), selenium and
magnesium. Increased oxidative stress, endothelial dysfunction, increased
vascular calcification
Cardiovascular mortality
Immune system: immune response disorder, with increased susceptibility to
infections and a delay in the healing of wounds
Inflammation and infection
Endocrine system: hypothyroidism, insulin resistance. Decreased production
of anti-inflammatory cytokines and adiponectins. Increase in advanced
glycosylation products
Inflammation and infection
Activation of pro-inflammatory cytokines: CRP, IL-6, IL-1. Endothelial
dysfunction and acceleration of the atherogenic process
Mortality-reverse epidemiology
Sarcopenia: increased actin levels. Muscle weakness, musculoskeletal system
disorder
Decreased quality of life. Increased hospitalisation
CRP: C-reactive protein, IL: interleukin.
512
Nefrologia 2014;34(4):507-19
patients have a vitamin K deficiency due to insufficient
intake (140µg/day versus 200µg/day in healthy patients).
Subclinical hepatic vitamin K deficiency increases
vitamin K-dependent non-carboxylated inactive proteins
and may contribute to an increased risk of bone fractures
and vascular calcification. Vitamin K supplements
(menaquinone-7) decrease non-carboxylated proteins
in haemodialysis patients and prolonged treatment can
increase vascular elasticity51-53.
PEW promotes increased muscle catabolism in uraemic
patients, both due to the lack of circulating nutrients and
due to the combined effect of systemic inflammation,
metabolic acidosis, uraemic toxins and other factors.
The result is a loss of muscle mass, which also affects
the muscle tissue of the arteries and heart, with direct
associations being found between malnutrition, arterial
stiffness and abnormalities in myocardial structure.
Continuous vascular distension resulting from salt and
water overload aggravates this process and promotes
ventricular hypertrophy. An example of how pure
undernourishment leads to cardiovascular system
abnormalities is found in the Minnesota experiment,
conducted in 1944 during World War II. The aim
was to better understand the pathophysiology of the
undernourishment to which the Jews were subjected
in the concentration camps. 36 volunteers underwent
a controlled reduction in intake that resulted in a total
loss of 25% of their weight. Undernourishment caused a
decrease in cardiac volume of 17%, with reduced cardiac
output, bradycardia, hypotension, and a decrease in
peripheral oxygenation and in myocardial contractility54.
Hypoalbuminaemia is the most common and most
frequently used biomarker for measuring PEW in dialysis
and it is a powerful prognostic marker of morbidity and
mortality 55,56. Furthermore, hypoalbuminaemia has been
associated with the de novo development and recurrence
of congestive heart failure in patients on haemodialysis
and peritoneal dialysis 57. In the 4D study carried out in
a cohort of 1255 diabetic haemodialysis patients, we
investigated the effect of PEW on mortality after four
years. The presence of PEW (defined as BMI 26.7kg/
m 2 , serum albumin <3.8g/dl and creatinine <6.8mg/
dl) doubled the risk of overall mortality, death due to
infections and sudden death of cardiac origin, but it was
not related to a higher incidence of heart attacks. The
presence of non-arteriosclerotic cardiovascular disease in
this study was greater in patients with PEW as a cause of
the cardiovascular events27.
The hormonal abnormalities associated with uraemia,
such as subclinical hypothyroidism 58 or low T3
syndrome 59 , are associated with inflammation and
malnutrition 60 and may contribute to cardiovascular
disease. As such, an independent association has been
Nefrologia 2014;34(4):507-19
review
observed between hypothyroidism and cardiovascular
mortality in haemodialysis patients61,62. In patients with
subclinical hypothyroidism and failure, the administration
of synthetic T3 improved the neuroendocrine profile,
with a significant decrease in levels of norepinephrine
and B-type natriuretic peptide (pro-BNP) compared
to the placebo. Furthermore, we observed an increase
in diastolic volume of the left ventricle with increased
cardiac output, without observing an increase in preload63.
The decreased synthesis of other anabolic hormones such
as testosterone 64 is also associated with greater muscle
loss 65, endothelial dysfunction 66, anaemia, resistance to
erythropoietin67 and mortality68.
PROTEIN-ENERGY WASTING, INFECTION AND
HOSPITALISATION
Uraemia is considered to be acquired immunodeficiency
state69 and patients with CKD have a high risk of infection70.
In the HEMO study, infection was the first cause of death
(23%) and the risk of death associated with an infection
during hospitalisation was 15%. The factors that predispose
CKD patients to infection according to the HEMO study
were old age, hypoalbuminaemia, immunosuppressive
therapy and catheters as vascular access 71. In parallel,
in the DOPPS 29 study, infection was the cause of 55%
of death in haemodialysis patients and it was related to
hypoalbuminaemia, low nPCR and cachexia.
The definition of the malnutrition status according to the
concept of PEW leads to a deficiency of the immune system
and an abnormal response in the patient, and as such, it is
associated with greater susceptibility to infections and a
slow recovery from injuries 72. The deficiency of certain
micro-macronutrients favours a state of immunodeficiency.
Some amino acids such as arginine and glutamine act and
favour the immune response 73. A severe zinc, vitamin
B6 (pyridoxine), vitamin C and folic acid deficiency 74-76
alters the immune response, decreases the production
of antibodies, causes polymorphonuclear leukocyte or
lymphocyte dysfunction and delays the scarring and
curing of injuries. Haemodialysis patients with PEW are
exposed to a greater risk of infection and its complications,
increasing mortality 77. For example, in infection by the
hepatitis C virus, the presence of hypoalbuminaemia and
a high result in the MIS (malnutrition inflammation score)
scale is independently associated with active infection and
increased viral replication78.
In hospitalised patients, a deficient nutritional state delays
recovery, prolongs hospitalisation, increases the rate of
infections and re-admissions and increases dependency
upon discharge and the need for institutionalisation.
In dialysis patients with prolonged and complicated
hospitalisation, there is a rapid decrease in albumin and
513
review
weight loss, particularly in those who have previously
been undernourished, elderly patients and those with
comorbidities and anorexia 79. The recommendations of
the guidelines on the prevention and management of
hospital undernourishment may be useful in hospitalised
patients with CKD, since they include the use of
supplements and parenteral nutrition to improve the
nutritional situation 80.
PROTEIN-ENERGY WASTING AND INFLAMMATION
Several studies have observed an independent association
between inflammatory conditions, commonly measured
by an increase in C-reactive protein (CRP), IL6, IL1
and TNF-α, with the risk of cardiovascular mortality in
haemodialysis patients81 and in the general population82.
Inflammation is associated with both anorexia and an
increased protein catabolism 83,84 and it seems to be the
connection that explains the relationship between PEW
and mortality in CKD.
The relationship between malnutrition and inflammation
in patients with CKD may be one of the causes of mortality
associated with malnutrition. Moreover, PEW may also be
the result of chronic inflammatory states in patients with
renal failure85,86.
PROTEIN-ENERGY WASTING AND QUALITY OF LIFE
An aspect that is sometimes underappreciated by
nephrologists, but which is increasingly important in
clinical practice, is the impact of nursing on the degree of
patient functionality. The impact of CKD on overall patient
functioning can be recorded in quality of life surveys such
as PROs (patient-reported outcomes) and Qo1 (health
related quality of life) surveys, which assess the mental
and functional state of the patient. CKD is associated with
a poor QoL and this leads to a higher risk of mortality87.
QoL has also been related to malnutrition markers, where
worse values for QoL are associated with low levels of
albumin, plasma creatinine, loss of LBM (lean tissue,
mainly muscle tissue) and a high percentage of fat88. An
improved QoL has become one of the objectives in dialysis
patients.
The prevalence of mental states of depression and anxiety
is high in dialysis patients 89. They face situations such
as hospitalisation, anxiety due to changes in dialysis,
dietary and water restrictions and the adaptation of
dialysis to their daily lives. The fear of inability,
disability and a lower life expectancy are at the heart
of these changes in frame of mind. New methods and
tools are being developed to measure depression and
514
anxiety and it has been acknowledged that anxiety is
under-diagnosed 90.
REVERSE EPIDEMIOLOGY IN RENAL FAILURE:
IMPLICATIONS OF NUTRITIONAL STATE
In the evaluation of morbidity and mortality
risk factors in CKD patients, we often observe
paradoxically opposed trends to those observed in the
general population. A clear example is obesity, which
in observational studies, appears to be a protective
factor against mortality in the final stages of CKD.
This is what is known as the reverse or paradoxical
epidemiology uraemic obesity phenomenon. The
cause of these reverse epidemiology phenomena is
the devastating effect that PEW has on short-term
survival, which does not leave enough time for other
traditional risk factors to act in long-term mortality 91 .
The most striking examples of this include the
case of hypercholesterolaemia, which has a reverse
association with mortality in uraemic patients. When
patients are divided according to whether they do or
do not have PEW, we observe that in the presence
of PEW, hypercholesterolaemia is a protective factor,
while in the absence of PEW, it is a risk factor. In a
situation of energy consumption affecting the patient,
cholesterol temporarily becomes a marker of the
body’s fat reserves, and when there is more fat, the
patient can resist this energy consumption for longer.
The same reasoning applies to the paradox of obesity.
Dialysis patients, independently of the method used, have
an inversely proportionate relationship between BMI
and mortality 92, differing from the general population,
in which this relationship is U-shaped (both extremes,
malnutrition and obesity have increased mortality)93. In
this instance, obesity involves an excess energy state that
helps patients resist PEW. However, long-term obesity is
a risk factor related to inflammation, atherosclerosis and
calcification, for example94. This is due to the endocrine
nature of adipocytes and the ability to regulate these
processes by cytokine and adipocytokine secretion 95 .
Endocrinologically active fat, fundamentally that which
accumulates in the abdomen, promotes these processes.
As such, the amount of total fat (reflection of the health
of energy reserves) and abdominal fat (participating in
obesity-associated risk) may have opposite effects on
patient risk96.
Another explanation of the reverse epidemiology of BMI
in uraemia is the inability of the BMI to distinguish
between muscle mass, body fat distribution (abdominal
versus peripheral) and hypervolaemia. Therefore, we
were recently able to observe that a BMI >30kg/m 2 was
not capable of distinguishing excess body fat in 65%
Nefrologia 2014;34(4):507-19
of dialysis patients 43. Recent studies highlight that the
type and distribution of fat, more than the total fat, is a
determining factor of risk97. Specifically, the accumulation
of abdominal fat is a risk factor and is associated with
greater secretion of pro-inflammatory adiponectins 98 .
It has been reported that both leptin and visfatin are
activators of cardiovascular disease and are endothelial
dysfunction risk factors 99,100. Observational studies based
on creatinine kinetics suggest that the protective effect of
BMI in haemodialysis patients is due to its indication of
greater muscle mass 101. In dialysis patients, it is perhaps
necessary to conserve both tissues, fat and muscle. In
this respect, a low arm muscle circumference percentile
as an indicator of muscle mass and a low triceps skin
fold as an indicator of fat tissue are related in equal
measure to higher mortality in haemodialysis patients 102.
Lastly, the risk of mortality increases whenever BMI,
creatinine and weight progressively decrease, but if
weight decreases and creatinine increases, the risk of
mortality is reduced 103.
CONCLUSION
The term protein-energy wasting or PEW attempts
to unite in one sole pathological condition the many
nutritional and catabolic disorders that occur in CKD
and which lead to a gradual and progressive loss of
both muscle and fat mass. It is a common syndrome,
particularly from stage 4-5 CKD, which is present in
30%-60% of dialysis patients. The clinical consequences
of PEW may be severe and require rapid and effective
treatment, since it is associated with increased overall
and cardiovascular mortality, an increased number of
review
infections and admissions and many other comorbidities.
The devastating effect of PEW causes paradoxical
epidemiologies that are explained by competition
between short- and long-term risk factors.
Acknowledgements
ISCIII-RETIC REDinREN/RD06/0016 and 12/0021, PIE13/00051, Spanish
Society of Nephrology, Swedish Research Council, Research Activity Intensification programme (ISCIII).
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KEY CONCEPTS
1. Protein-energy wasting is defined as a pathological
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2. The pathophysiological mechanisms involved
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Nefrologia 2014;34(4):507-19
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Sent to review: 8 Mar. 2014 | Accepted: 14 Apr. 2014
Nefrologia 2014;34(4):507-19
519
clinial case
Hypersensitivity reactions to synthetic
haemodialysis membranes
Rafael J. Sánchez-Villanueva1, Elena González1, Santiago Quirce2, Raquel Díaz1,
Laura Álvarez1, David Menéndez1, Lucía Rodríguez-Gayo1, M. Auxiliadora Bajo1, Rafael Selgas1
1
Servicio de Nefrología. Hospital Universitario La Paz. Madrid (Spain); 2 Servicio de Alergología. Hospital Universitario La Paz. Madrid
(Spain)
Nefrologia 2014;34(4):520-25
ABSTRACT
Undergoing a haemodialysis (HD) session poses a certain risk of
hypersensitivity adverse reactions as large quantities of blood
are in contact with various synthetic materials. Hypersensitivity
reactions to ethylene oxide and non-biocompatible membranes,
such as cuprophane, have been described in HD. Cases of
hypersensitivity with biocompatible membranes, such as
polysulfone, and even polysulfone-polyvinylpyrrolidone, have
also been reported. In this article we describe six cases of
mostly early-stage hypersensitivity reactions to HD occurring
in our department, characterised by malaise, desaturation,
bronchospasm and arterial hypotension, with good response
to the session’s temporary suspension and with reappearance
in subsequent sessions that used a synthetic dialyser. No
hypersensitivity reactions reappeared in successive observations
when the sessions were carried out using a cellulose membrane.
Keywords: Haemodialysis. Allergy. Polysulfone. Hypersensitivity
reaction. Anaphylaxis. Eosinophilia.
INTRODUCTION
Undergoing a haemodialysis (HD) session poses a
certain risk of hypersensitivity adverse reactions as large
quantities of blood are in contact with various synthetic
materials. These hypersensitivity reactions associated with
the HD technique have been traditionally categorised into
Correspondence: Rafael J. Sánchez Villanueva
Hospital Universitario La Paz. Paseo Castellana, 261.
28046 Madrid. (Spain).
[email protected]
[email protected]
520
Reacciones de hipersensibilidad a membranas sintéticas de
hemodiálisis
RESUMEN
La realización de una sesión de hemodiálisis (HD) supone un cierto
riesgo de aparición de reacciones adversas de hipersensibilidad, al
estar en contacto abundantes cantidades de sangre con diferentes
materiales de origen sintético. En HD han sido descritas reacciones
de hipersensibilidad al óxido de etileno y a membranas no
biocompatibles como el cuproamonio. También se han comunicado
casos de hipersensibilidad con membranas biocompatibles como la
polisulfona, e incluso con polisulfona asociada a polivinilpirrolidona.
En este artículo queremos describir seis casos acontecidos en nuestro
servicio de reacciones de hipersensibilidad mayoritariamente
temprana a la sesión de HD, caracterizados por mal estado general,
desaturación, broncoespasmo e hipotensión arterial, con buena
respuesta a la suspensión temporal de la sesión y con reaparición
en sesiones posteriores siempre que se utilizase un dializador
sintético. Todas tienen en común no haberse dado de nuevo en
sucesivas observaciones cuando las sesiones fueron realizadas con
una membrana de celulosa.
Palabras clave: Hemodiálisis. Alergia. Polisulfona. Reacción de
hipersensibilidad. Anafilaxia. Eosinofilia.
two types: type A or hypersensitivity reactions, which tend
to occur immediately, and type B or non-specific reactions,
which tend to start later1.
Hypersensitivity reactions to ethylene oxide and nonbiocompatible membranes, such as cuprophane, have
been described in HD2-4. Cases of hypersensitivity with
biocompatible membranes, such as polysulfone, and even
polysulfone-polyvinylpyrrolidone, a compound used to
prevent possible adverse reactions produced by the interaction
of the polysulfone membrane with platelets and plasma
proteins, have also been reported5-7.
Rafael J. Sánchez-Villanueva et al. Hypersensitivity reactions to membranes
In this article we would like to describe 6 cases of adverse
reactions to synthetic HD membranes in our department since
2011, with particular intensity between May and July 2013.
CLINICAL CASES
Case 1
A 58-year-old male patient, positive for hepatitis C virus
(HCV), with chronic renal failure (CRF) secondary to adult
hepatorenal polycystic disease, on the HD programme from
1996 to 2000, the year in which he received a cadavericdonor kidney transplant. Functioning transplant until May
2010, when he restarted HD due to stage 4-5T chronic
allograft dysfunction secondary to chronic humoral
rejection in the biopsy. The patient usually received highflux polysulfone dialyser by predilution online (Helixone ®
FX-800, FMC). He had no known history of allergies. In
July 2011, due to supply problems, the dialyser was changed
to high-flux polyamide (Polyflux® 210H, Gambro). After
being connected for 20 minutes, we noted oppressive
chest pain accompanied by hypotension (blood pressure
[BP] 80/40 mmHg) and 88% desaturation. Pulmonary
auscultation did not reveal wheezing. After returning
the circuit and prescribing high-flow oxygen, the patient
improved spontaneously. After stabilising the vital signs
(BP 130/70 and 94% baseline oxygen saturation), the
session was restarted and ultrafiltration reduced, without
further complications.
In the following HD session, after being connected for 20
minutes, he presented the same symptoms as in the previous
session (chest pain with hypotension and 78% oxygen
saturation). The patient was returned to and prescribed
high flow oxygen and 1g intravenous (IV) paracetamol.
He improved noticeably following this treatment and
consequently the HD session was restarted, finishing
without complications.
Given a suspicion of adverse reaction to the dialyser,
we decided to change it in the following session to a
polynephron membrane (Elisio TM-21H, Nipro). When
he had been connected for 35 minutes, he experienced
central chest pain, holocranial headache and abdominal
pain. Pulmonary auscultation did not reveal wheezing.
BP was 80/50mmHG, for which reason we returned to the
patient. High doses of oxygen and 1g IV paracetamol were
prescribed, with which the patient improved and 30 minutes
after presenting symptoms, the HD session was restarted,
which was completed without complications.
Complementary tests (troponin I and electrocardiogram
[ECG]) found no significant differences with respect to
earlier tests. The analysis of the third session only showed
leucopoenia (2,300 leukocytes/ml) with normal formula, the
Nefrologia 2014;34(4):520-25
clinical case
same magnitude of thrombocytopenia as previously (54,000
platelets/ml), slightly elevated C-reactive protein (CRP)
(11.5mg/l) and increase of D-dimer (8,544ng/ml; 2,117ng/
ml in June 2011). Therefore, a computed tomography
angiogram of the pulmonary arteries was requested, which
showed pulmonary thromboembolism.
Given a suspicion of possible allergy to synthetic membranes,
we decided to perform the next HD session using cellulose
triacetate (SureFlux®-21UX, Nipro). The patient did not
present symptoms in either this session or in any subsequent
session to date.
Case 2
An 80-year-old female with CRF of multifactorial aetiology,
on HD since May 2012. The patient had no known history
of allergies. She regularly underwent HD using Helixone®
FX-80 from the start.
On 14 September 2012, an hour and a half into dialysis,
she experienced sweating, tachypnoea and dyspnoea; 78%
oxygen saturation was observed, overcome using highflow oxygen. Maintained BP. Pulmonary auscultation did
not reveal wheezing. Analysis showed mild leukocytosis
(12,500 leukocytes with normal formula), normal troponin
I with CRP 8mg/l, with no other noteworthy findings. ECG
was similar to previous tests. 20 minutes after presenting
symptoms, spontaneous improvement of the patient was
observed, finishing HD without complications. Post-HD
thoracic radiography was performed, which did not show
consolidations, effusion or vascular redistribution; it only
showed the known increased cardiothoracic index.
After this incident, HD sessions ran without problems
for a month, until 17 October 2012, when the patient
experienced sweating and significant dyspnoea during HD,
with 76% oxygen saturation. Pulmonary auscultation did
not reveal wheezing. The patient was administered oxygen
at 5bpm, 200mg of IV hydrocortisone and 2 salbutamol
inhalations 15 minutes apart. BP: 115/55mmHg. ECG was
performed with sinus rhythm 98bpm, with no changes from
the previous ECG. Analysis showed 19,000 leukocytes/
ml, 75% neutrophils (remainder of normal formula), CRP
18mg/l, negative troponin I, with no further alterations. On
re-examining the patient, we examined the pruritus that had
appeared on the lower limbs since the start of the session.
Saturation improved to 98%, but the patient subsequently
presented hypotension of 65/31mmHg, for which reason
the circuit was returned and the session suspended. She was
transferred to the Emergency department for observation,
being discharged without symptoms the next day.
Given the patient’s symptoms, we decided to change
the filter to Poliflux ® 210H for the next HD session.
521
clinical case
Subsequent sessions ran without complications. On 24
October 2012 (third session with Poliflux), 1h from
finishing HD, she experienced general discomfort,
sweating, dyspnoea and hypotension (87/36mmHg).
Pulmonary auscultation did not reveal wheezing. 200mg
of hydrocortisone was administered, with complete
disappearance of the symptoms. The filter was changed
again to ElisioTM-21H for subsequent HD sessions, which
ran without complications. On 7 June 2013, eight months
later, the patient presented dyspnoea and non-irradiated,
oppressive central chest pain 30 minutes into dialysis.
BP: 210/75mmHg. 90% oxygen saturation with oxigen
nasal cannula. Physical examination revealed general
hypoventilation, with wheezing in all lung fields. Despite
administering 300mg of hydrocortisone, the patient
persisted with general wheezing; therefore we decided to
stop HD and disconnect the whole system. An additional
200mg of hydrocortisone, 40mg of IV methylprednisolone
and ipratropium bromide inhalation were administered.
The patient’s clinical symptoms improved progressively,
with respiratory symptoms disappearing. For this reason
we decided to continue the HD session using SureFlux®21UX; the patient remained asymptomatic. Only CRP
21.6mg/l and haemoglobin 8.6g/dl stood out in the
analysis, for which reason 2 red blood cell concentrates
were transfused. ECG did not show changes from previous
tests.
SureFlux ®-21UX dialyser was kept for subsequent HD
sessions, with no complications to date.
Case 3
A 75-year-old male with stage 4 CRF, admitted to
cardiology due to complete auricular-ventricular block
requiring implantation of a pacemaker, along with
symptoms of decompensated heart failure and secondary
reduced renal function. The patient had no known history
of allergies.
On 28 May 2013, we opted for the patient’s acute
HD treatment. Conventional HD using Helixone ®
FX-100 Classix was prescribed. 15 minutes into the
session, the patient suddenly experienced dyspnoea,
72% oxygen saturation and clinical signs of severe
bronchospasm. The blood pump was stopped and
300mg of hydrocortisone and high-flow oxygen were
administered. We decided to interrupt the HD session
and, given the suspicion of adverse reaction to the
dialyser, the blood was removed from the circuit.
After 15 minutes the patient was asymptomatic. HD
was not required until 16 June 2013, when a session
was carried out using FX-100. After 15 minutes the
patient experienced the same symptoms as previously
and oxygen saturation reduced to 80%. The blood
522
pump was stopped and 300mg of hydrocortisone, 40mg
of methylpredisolone and high-flow oxygen were
administered. It was decided not to return the circuit’s
blood, changing the dialyser to SureFlux ® -21UX. The
patient slowly started to improve until symptoms
completely disappeared, finishing the session with the
new dialyser, and with no further complications to date.
Case 4
A 48-year-old male, positive for human immunodeficiency
virus and HCV, diagnosed with CRF of multifactorial
origin, with no known history of allergies, who had
stopped follow-up consultations and was admitted due
to worsening renal function (Cr 15mg/dl), secondary to
chronic diarrhoea of 6 months progression and sustained
hypotension (70/40mmHg). During admission, the right
jugular vein was channelled and one HD session was
carried out on 16 July 2013. The Helixone ® FX-100
Classix dialyser was used. Two hours into treatment he
experienced sudden dyspnoea, with 78%-80% oxygen
saturation, presenting general hypoventilation with bibasal
crackles and wheezing in both hemithorax in pulmonary
auscultation. We decided to interrupt treatment and not
return the system. Saturation rose to 98% following
administration of high-flow oxygen and 100mg IV
hydrocortisone, with pulmonary auscultation without
pathological sounds and improvement of respiratory
dynamic. The patient was transferred from the department,
for which reason we lost the follow-up.
Case 5
A 70-year-old male, solitary right kidney, with history of
stage 5 CRF secondary to nephrosclerosis, with no known
allergies, was admitted in June 2013 as scheduled for
myocardial revascularisation due to chronic ischaemic heart
disease expressed as lesion of the left coronary trunk and
three vessels. During admission he presented multiple postoperative complications, requiring continuous techniques
of kidney replacement therapy during his stay in the
resuscitation unit using a polysulfone dialyser (Aquamax®
HF-12, Baxter). After his transfer to the medical ward,
periodic HD sessions with Helixone® FX 100 Classix were
prescribed. 20 minutes into the first session, the patient
experienced hypotension (80/40mmHg), dyspnoea and
bronchospasm symptoms. After stopping the blood pump
and returning the system, 200mg of hydrocortisone and
high-flow oxygen were administered; the patient improved
progressively. 20 minutes into the next HD session using
the same filter, the clinical symptoms repeated. For this
reason we decided to carry out subsequent HD sessions
using cellulose triacetate (SureFlux ®-21UX), with no
complications to date.
Nefrologia 2014;34(4):520-25
Case 6
An 83-year-old female patient, diagnosed with stage 5
CRF secondary to chronic pyelonephritis, admitted due to
worsening renal function in the context of diarrhoea. The
patient had no known history of allergies. Given the lack
of improvement of the renal function, we decided to begin
HD on 11 July 2013 using Helixone® FX-100 Classix.
After 30 minutes of conventional HD, the patient presented
symptoms of arterial hypotension, dyspnoea and 60-80%
oxygen desaturation, accompanied by poor peripheral
perfusion. High doses of oxygen and fluid therapy were
administered, with improvement of BP, but not the clinical
situation; therefore we decided to stop the HD session. After
suspending dialysis, saturation returned to baseline values
and the patient improved clinically. In subsequent sessions,
the filter was replaced by SureFlux®-21UX, with no new
complications to date.
DISCUSSION
We present a six-case series of mostly early-stage
hypersensitivity reactions to an HD session, characterised
by general malaise, desaturation, bronchospasm when
determined, and arterial hypotension. There was good
response to the session’s temporary suspension and
reappearance of reactions in subsequent sessions which
used a synthetic dialyser. No hypersensitivity reactions
reappeared in successive observations of sessions using
a cellulose membrane. No patients had a history of
allergies and no causal relationship with the administered
medication was found.
As a peculiarity in the first two cases, there was the
apparent saturation of the hypersensitivity mechanism
for the dialyser that caused the reaction; that is, the
reaction only occurred in the first moments and it was
possible to resume HD using the previous dialyser,
without complications. The remaining cases showed
greater reaction severity and there was no other choice
but suspension of HD. These cases were a learning
curve for professionals in recognising the situation. The
genesis of apparent universal hypersensitivity to synthetic
membranes was also common among those patients in
which a different membrane from the same group was
tried. This procedure was not performed in some patients
given the severity of their previous symptoms. After
presenting symptoms, all patients were submitted to one
or several HD sessions using a cellulose dialyser with
no similar complications, centring the hypersensitivity
process on the dialyser.
The hospital’s allergologists admitted, after evaluating
the cases, that they could be classified as serious
hypersensitivity reactions to the polysulfone dialyser.
Nefrologia 2014;34(4):520-25
clinical case
We also attributed a certain epidemic character to the entire
episode, due to the study being concentrated in two years,
July 2011-July 2013, especially between May and July
2013. After this date, despite using the membrane in 90 %
of our population, there was no reoccurrence of a similar
case. The cases were notified to the Spanish Agency of
Medicines as adverse reactions and they informed us that
they had not received any similar correspondence. There
are still yet to be further notifications on this matter.
Traditionally hypersensitivity reactions to a dialyser have
been considered as rare events (4 out of every 100,000
sessions); however, at the end of the 1980s, Nicholls et al.
carried out a study in the United Kingdom and highlighted
that the problem could be of greater significance 8. Type
A hypersensitivity reactions regularly occurred in the
first minutes of the HD session after blood came into
contact with components of the extracorporeal circuit.
These processes are mediated by preformed antibodies
and, in the most serious cases, can cause dyspnoea,
hypertension, unconsciousness, cardiac arrest and death.
Given the suspicion of this adverse reaction, immediate
action consists of stopping the blood pump, disconnecting
the entire extracorporeal circuit, and administering highflow oxygen, as well as short-acting antihistamines and
corticosteroids, hydrocortisone and starting assisted
respiration where necessary. Type B hypersensitivity
reactions, much less frequent, usually occur after the
first 30 minutes of the HD session. Clinical signs are less
specific, such as chest and back pain, and do not require
the HD session to be interrupted.
Bigazzi et al. described how, in the presence of contaminated
fluid and through high-flux membranes, there could be
back-filtration of pyrogens into the blood compartment.
This causes hypersensitivity reactions at the start of the
session in patients dialysed using these membrane types9.
In the case of our patients, all were dialysed using highly
permeable membranes and ultrapure water in accordance
with European Pharmacopoeia standards 10. Complying
with these regulations, with periodic monthly checks,
and the absence of reactions in sessions immediately
performed using another highly permeable, non-synthetic
dialyser, make it very unlikely that it is the triggering
mechanism of a hypersensitivity reaction.
The majority of adverse reactions occurred between
May and July 2013 in the patients’ first HD session
using modified polysulfone dialysers. Cases of severe
reactions to polysulfone have been described5,6, as well as
hypersensitivity crossed to other types of membrane such
as polycarbonate and polymethyl methylcrylate11. These
reactions to polysulfone could be different depending
on its manufacturer. Therefore, HD sessions using other
synthetic dialysers were attempted in cases 1 and 2
without success.
523
clinical case
Another point of interest is the different sterilisation
method of the dialysers. Müller et al. reported that vapoursterilisation could increase the dialyser’s biocompatibility
in comparison to sterilisation using ethylene oxide 12.
Golli-Bennour et al. affirmed that the membranes sterilised
using vapour increased the viability of the endothelial
cells compared to sterilisation methods using radiation or
ethylene oxide13. In addition, they showed that, according
to the sterilisation method, the concentration of serum
malondialdehyde, used as a maker for lipid peroxidation,
increased substantially with respect to healthy patients
when the dialyser’s sterilisation was by gamma radiation
or ethylene oxide. However, other authors have reported
that vapour sterilisation does not seem to have an effect
on the freeing of pro-inflammatory cytokines, such as
interleukin-1. In our patients, membrane sterilisation was
heterogeneous; FX and Poliflux dialysers are sterilised
using vapour, while cellulose triacetate and Eliseo
dialysers are sterilised using gamma rays, making it
difficult to establish a causal relationship.
A key finding in the cases in our department is that all
hypersensitivity reactions disappeared after changing
the dialyser to cellulose triacetate. Urbani et al. showed
differences between the helixone and cellulose triacetate
dialysers when they were studied through proteomics 14.
Abundant proteins involved in the blood-dialyser
interaction were found on the helixone membrane, such
as ficolin-2 and fibrinogen fragments. Other authors
had already demonstrated the absorption of ficolin-2
in polisulfone dialysers, which could contribute to the
complement’s activation, leukocyte adhesion and, at worst,
blood coagulation 15,16. In addition, it was published that
cellulose triacetate induces less hypersensitivity reactions,
probably due to less activation of the platelet membrane
(GpIIb/IIIa), producing less aggregation disease 17. The
mechanisms making our patients sensitive to the described
synthetic dialysers and not to the cellulose triacetate
dialyser are not clear. Therefore we are designing specific
ex vivo response studies on immunocompetent cells for
those patients who showed allergic reaction to synthetic
dialysers, as well as cross-sectional response studies on
hypersensitivity with various HD membranes.
Adverse reactions to dialysers are a severe complication
intrinsic to the therapy itself. The nephrologists should be
alert to this possibility, acting immediately faced with mere
clinical suspicion and referring the patient to the allergy
department to complete the study as soon as possible.
Acknowledgements
The authors thank Dr. Rafael Pérez García for his revision and correction
of this article.
524
REFERENCES
1. Daugirdas JT, Ing TS. First-use reactions during hemodialysis: a
definition of subtypes. Kidney Int Suppl 1988;24:S37-43.
2. Caruana RJ, Hamilton RW, Pearson FC. Dialyzer hypersensitivity
syndrome: possible role of allergy to ethylene oxide. Report of 4
cases and review of the literature. Am J Nephrol 1985;5:271-4.
3. Lemke HD, Heidland A, Schaefer RM. Hypersensitivity reactions
during haemodialysis: role of complement fragments and
ethylene oxide antibodies. Nephrol Dial Transplant 1990;5:264-9.
4. Bommer J, Ritz E. Ethylene oxide (ETO) as a major cause of
anaphylactoid reactions in dialysis (a review). Artif Organs
1987;11:111-7.
5. Arenas MD, Gil MT, Carreton MA, Moledous A, Albiach B.
[Adverse reactions to polysulphone membrane dialyzers durind
hemodialysis]. Nefrologia 2007;27:638-42.
6. Ohashi N, Yonemura K, Goto T, Suzuki H, Fujigaki Y, Yamamoto
T, et al. A case of anaphylactoid shock induced by the BS
polysulfone hemodialyzer but not by the F8-HPS polysulfone
hemodialyzer. Clin Nephrol 2003;60:214-7.
7. Bacelar Marques ID, Pinheiro KF, de Freitas do Carmo LP, Costa
MC, Abensur H. Anaphylactic reaction induced by a polysulfone/
polyvinylpyrrolidone membrane in the 10th session of
hemodialysis with the same dialyzer. Hemodial Int 2011;15:399403.
8. Nicholls AJ. Hypersensitivity to hemodialysis: the United Kingdom
experience. Artif Organs 1987;11:87-9.
9. Bigazzi R, Atti M, Baldari G. High-permeable membranes and
hypersensitivity-like reactions: role of dialysis fluid contamination.
Blood Purif 1990;8:190-8.
10. European Pharmacopeia. Haemodialysis solutions, concentrated,
water for diluting. 3rd ed. 1997.
11. Tanoue N, Nagano K, Matsumura H. Use of a light-polymerized
composite removable partial denture base for a patient
hypersensitive to poly(methyl methacrylate), polysulfone, and
polycarbonate: a clinical report. J Prosthet Dent 2005;93:17-20.
12.Muller TF, Seitz M, Eckle I, Lange H, Kolb G. Biocompatibility
differences with respect to the dialyzer sterilization method.
Nephron 1998;78:139-42.
13.Golli-Bennour EE, Kouidhi B, Dey M, Younes R, Bouaziz C, Zaied
C, et al. Cytotoxic effects exerted by polyarylsulfone dialyser
membranes depend on different sterilization processes. Int Urol
Nephrol 2011;43:483-90.
14.Urbani A, Sirolli V, Lupisella S, Levi-Mortera S, Pavone B, Pieroni
L, et al. Proteomic investigations on the effect of different
membrane materials on blood protein adsorption during
haemodialysis. Blood Transfus 2012;10 Suppl 2:s101-12.
15. Mares J, Thongboonkerd V, Tuma Z, Moravec J, Matejovic M.
Specific adsorption of some complement activation proteins to
polysulfone dialysis membranes during hemodialysis. Kidney Int
Nefrologia 2014;34(4):520-25
2009;76:404-13.
16. Mares J, Richtrova P, Hricinova A, Tuma Z, Moravec J, Lysak D,
et al. Proteomic profiling of blood-dialyzer interactome reveals
involvement of lectin complement pathway in hemodialysisinduced inflammatory response. Proteomics Clin Appl
clinical case
2010;4:829-38.
17. Kuragano T, Kuno T, Takahashi Y, Yamamoto C, Nagura Y,
Takahashi S, et al. Comparison of the effects of cellulose
triacetate and polysulfone membrane on GPIIb/IIIa and platelet
activation. Blood Purif 2003;21:176-82.
Sent to review: 3 Apr. 2014 | Accepted 15 May. 2014
Nefrologia 2014;34(4):520-25
525
letters to the editor
A) COMMENTS ON PUBLISHED ARTICLES
Comment on “Kaposi´s
sarcoma in the early
post-transplant period
in a kidney transplant
recipient”
Nefrologia 2014;34(4):526
To the Editor,,
We have read the article by Ercam
et al. in the Clinical Case Section of
Nefrologia about a case of Kaposi’s
sarcoma in a transplant recipient.1 Renal
transplantation and immunosuppressive
medication used for it leads to a high
rate of tumors and among them Kaposi’s
sarcoma is common. There is extensive
literature on the development of
malignancies after renal transplantation,
so the description of another case does
not seem to justify its publication.
However, what seems novel and so
the authors justify its interest is the
prematurity of the Kaposi´s sarcoma
development (only 4 months after
renal transplantation), together with the
authors statement that this would be
the first reported case with this precocity.1
In 1990 we published a case of
Kaposi’s sarcoma associated with
renal transplant developed 4 years after
kidney transplant2 and in which the skin
lesions stabilized after withdrawing
immunosuppressive medication. In the
discussion of the case we pointed out
references describing cases in 1979 and
the time of appearance of the tumor
could be even after three months of
transplantation.3 Interestingly before
the time of our communication there
have been published some references
describing cases where tumor appear
between first and 4 months after renal
transplantation.4,5
It is true that most of the cases described
in the literature the time elapsed from
transplant to tumor development are
longer than that of Ercam et al. and
526
the well documented case by this
authors is unusual on this matter,
however it is also true that we get
used to refer recent references in
our publications, without taking into
account some previous periods. To
be fair we should not forget that
it is not easy to find past issues,
either completely or it abstract.
Finally note that these circumstances
should encourage us to avoid
statements like “the first or only
case or reference” given the lack of
access to all available information.
Conflict of interest
The authors declare that they have
no conflicts of interest related to the
contents of this article.
1. Ercan Z, Demir ME, Merhametsiz O, Yayar O, Ulas T, Ayli MD. Kaposi´s sarcoma
in the early post-transplant period in a
kidney transplant recipient. Nefrologia
2013;33(6):861-2.
2. Ambrojo P, Coronel F, Macia M, Gutierrez Marcos F, Sanchez Yus E. Sarcoma de
Kaposi asociado a trasplante renal. Actas
Dermo-Sif 1990;81(9):576-8.
3. Harwood AR, Osoba D, Hofstader SL,
Goldstein MB, Cardella CJ, Holecek MJ, et
al. Kaposi´s sarcoma in recipients of renal
transplants. Am J Med 1979;67:759-65.
4. Qunibi W, Akhtar M, Sheth K, Ginn HE,
Al-Furayh O, DeVol EB, et al. Kaposi´s sarcoma: the most common tumor after renal
transplantation in Saudi Arabia. Am J Med
1988;84(2):225-32.
5. Little PJ, Farthing CF, Al Khader A, Bunuan
H, Haleem A. Kaposi’s sarcoma in a patient
after renal transplantation. Postgrad Med J
1983;59:325-6.
Francisco Coronel1, Manuel Macía2
Servicio de Nefrología. Ex Jefe de sección.
Hospital Clínico San Carlos. Madrid (Spain);
2
Servicio de Nefrología. Hospital Universitario
Ntra. Sra. de Candelaria. Santa Cruz de
Tenerife (Spain).
Correspondence: Francisco Coronel
Comunidad de Baleares, 1.
Las Rozas. 28231, Madrid. (Spain).
[email protected]
1
Increase of ischaemic
colitis incidence in
haemodialysis
Nefrologia 2014;34(4):526-7
To the Editor,
Ischaemic colitis (IC) is a disease with
an increasing incidence in haemodialysis (HD) patients, due to their changing
profile (significantly older, with more
cardiovascular disease and with increased survival in relation to the past)1.
Despite the fact that IC can be secondary to vascular thrombosis or mesenteric vasospasm, the most frequent aetiology in HD patients is low output, which
occurs during the session usually as a
consequence of a lowering of blood
pressure.
The case published by Gutiérrez-Sánchez et al.2, despite concerning a patient who had only been on HD for
two months, presented many of the
classic characteristics of patients
with non-occlusive ischaemic colitis: high vascular risk patient with
hypotensive episode who developed
rectorrhagia and abdominal pain2. In
the study recently published by our
group involving the most cases of
non-occlusive IC in HD, the factors
associated with suffering this disease
were older age, diabetes mellitus
(DM), cardiovascular history (such
as peripheral vascular disease), time
on dialysis and resistance to erythropoietin. This last parameter is shown
to be an independent predictor in
multivariate analysis (together with
DM and time on HD), demonstrating
the association of this symptom with
inflammation and, consequently,
with atherosclerosis3. In a published
study that included incident patients
on dialysis (HD and peritoneal dialysis), the risk factors associated with
suffering from non-occlusive IC were
similar, apart from time on dialysis.
However, on studying the various
Nefrologia 2014;34(4):526-44
techniques, the authors found that the
patients on peritoneal dialysis had a
1.5 times increased risk of suffering
from this condition, despite being
younger and having less comorbidity, which they associated with exposure to solutions with a high dextrose
content4.
In this case series, the authors found
80 % mortality; this contrasts to our
study in which mortality in the acute
episode was 59 %. However, we performed a case-control study with patients who survived the acute episode
over an average of 56 months (± 69).
We found that the patients with non-occlusive IC had significantly lower survival, attributable to the condition being
the result of these patients’ high cardiovascular risk. In fact, the causes of
death were divided into infectious and
cardiovascular. To date, the only study
that compared survivors of non-occlusive IC with patients on HD was that
by Bassilios et al., which showed identical survival in both groups, probably
because it only included in the analysis
those patients who survived more than
three months5.
As regards treatment, as was the case
in the abovementioned study, it is usual
Nefrologia 2014;34(4):526-44
to administer wide-spectrum antibiotic
therapy and have a wait-and-see approach; surgery is opted for in the minority of cases (only 33 % in our study),
which is likely due to the patients’ profile (elderly, with cardiovascular risk,
etc.). In fact, our results only revealed
significant differences in age (younger) when we compared candidates for
surgery with those in which a conservative approach was maintained. Previous studies have shown that the delay
in carrying out surgery following diagnosis is associated with an increase in
mortality6.
As a result, it seems reasonable to establish a more conservative ultrafiltration
profile in patients at high risk of suffering from non-occlusive IC, due to its
harmful consequences in HD patients
Martín-Navarro JA, López-Quiñones Llamas
M. Ischaemic colitis in haemodialysis.
Nefrologia 2013;33(5):736-7.
3. Quiroga B, Verde E, Abad S, Vega A,
Goicoechea M, Reque J, et al. Detection
of patients at high risk for non-occlusive
mesenteric ischemia in hemodialysis. J
Surg Res 2013;180(1):51-5.
4. Li SY, Chen YT, Chen TJ, Tsai LW, Yang
WC, Chen TW. Mesenteric ischemia in
patients with end-stage renal disease:
a nationwide longitudinal study. Am J
Nephrol 2012;35(6):491-7.
5. Bassilios N, Menoyo V, Berger A, Mamzer
MF, Daniel F, Cluzel P, et al. Mesenteric
ischemia in hemodialysis patients: a casecontrol study. Nephrol Dial Transplant
2003;18:911-7.
6. Bender JS, Ratner LE, Magnuson TH,
Zenilman ME. Acute abdomen in the
hemodialysis patient population. Surgery
1995;117:494-7.
The authors declare that they have no
conflicts of interest related to the contents of this article.
1. Valentine RJ, Whelan TV, Meyers HF.
Nonocclusive mesenteric ischemia in renal patients: recognition and prevention
of intestinal gangrene. Am J Kidney Dis
1990;15:598-600.
2. Gutiérrez-Sánchez MJ, Petkov-Stoyanov V,
Borja Quiroga
Servicio de Nefrología. Hospital General
Universitario Gregorio Marañón. Madrid.
(Spain).
Correspondence: Borja Quiroga
Hospital General Universitario Gregorio Marañón.
Doctor Esquerdo, 46. 28007, Madrid. (Spain).
[email protected]
527
B) BRIEF PAPERS ON RESEARCH AND CLINICAL EXPERIMENTS
Home haemodialysis:
a right and a duty
Nefrologia 2014;34(4):528-9
doi:10.3265/Nefrologia.pre2014.Feb.12476
To the Editor,
There is a growing interest in home
haemodialysis (HHD) both in Spain’s
neighbouring countries and in the
United States. This interest has arisen
out of the limitations of the conventional three-weekly therapy sessions,
shown in studies such as HEME1,
in order to increase the survival of
stage 5 chronic kidney disease patients. There is an increasing number
of publications that back home therapies in terms of quality of life2, blood
pressure management, reduction of
left ventricular hypertrophy, calcium-phosphorus control, anaemia, nutritional state and lower morbidity and
mortality4,5, when compared to classic
treatment plans; there are also studies
supporting this treatment for its reduction of costs6.
For this reason, we think it opportune to present our experience in
implementing a short daily HHD
programme. Between March 2008
and November 2013, we included
10 patients (3 in 2008, 0 in 2009, 1
in 2010, 1 in 2011, 4 in 2012 and 1
in 2013); 50% were females, with
an average age of 61 (range: 38-81),
distance to the centre 42 km (range:
0-122 km) and remained in the technique for 32 ± 17 months. As regards
the origin of the patients: five came
from outpatient consultations, three
were on peritoneal dialysis and two
from a peripheral centre. In terms
of the programme exits, there were
two deaths and two transplants. No
patient required a change of renal replacement therapy and there were no
losses in the training period.
In terms of morbidity, we had two
hospitalisations in 2008, one in 2009,
two in 2010, none in 2011, one in
2012 and six in 2013 (we should
point out that half of the hospitalisations were scheduled). The reasons
for admission were: three cardiovas-
cular, two infectious (associated with
vascular access, in 2008 and 2010),
one neoplasia, one digestive, two due
to vascular access of non-infectious
cause (insertion of tunnelled catheter
and closure of fistula aneurysm) and
three due to other causes (scheduled
nephrectomy, herniorrhaphy and clinical deterioration).
The prescribed haemodialysis plan
and the results obtained are presented
in Table 1 and Figure 1.
Regarding drugs, we used:
- Antihypertensives: 43% did not
require any antihypertensive drug,
53% required one drug, and only
4%, two or more.
- Phosphate binders: the use of a
binder was not required in 47%
of the monthly checks; only one
type of binder was needed in 35%
of cases, predominantly calcium
over non-calcium based binders;
while a combination of various
types of binders was required in
the remaining cases. Although the
average calcium carbonate dose
Table 1. Description of the results
Incidence
Prevalence
No.hospitalisationsª
2008
3
3
2
2009
0
3
1 (1)
2010
1
3
2 (1)
2011
1
4
0
2012
4
7
1
2013
1
6
6 (4)
Total
10
Qs ml/min
323.33
338.88
348.61
327.08
317.26
306.89
12 (6)
Mean
322.68±25.98
Qd ml/min
Time min/session
No. sessions/week
Std Kt/V
Hb g/dl
EPO UI/kg/week
Phosphorus mg/dl
PTH pg/ml
MAP mmHg
%Weight gain
Albumin g/dl
685
130.7
5.63
3.2
12.1
118.34
4.38
271.95
89.43
1.8
4.4
705.55
129.4
5.66
3.05
12.02
88.5
4.56
278.66
93.19
2.5
4.19
737.5
132.9
5.75
3.07
11.62
42.54
4.98
297.29
95.07
2.3
4.24
631.25
130
5.97
3.33
11.23
38.54
4.97
292.18
86.62
1.9
4.03
586.3
130.6
5.76
3.27
10.64
62.58
4.82
390.56
86.93
1.3
4.17
533.03
143.9
5.08
2.98
11.3
80.31
4.58
360.51
91.18
1.5
4.17
619.85±128.03
134.76±18.7
5.56±0.6
3.15±0.4
11.3±1.1
69.34±71.8
4.73±1.2
324.89±171.4
90.27±14.7
1.8±1.4
4.16±0.3
PTH: parathyroid hormone.
ª Scheduled hospitalisations in brackets.
528
Nefrologia 2014;34(4):526-44
used initially was high, 3829.8mg/
day, there was subsequently a progressive substitution for calcium
acetate, averaging 815.16mg/day.
The other binders used were: aluminium hydroxide 77.66mg/day
(one-off use and not used at present), 2478.83mg/day of sevelamer
and 909.66mg/day of lanthanum
carbonate.
- Calcimimetic or vitamin D analogues: their use was not required
for controlling parathyroid hormone values in 15% of cases; only
paricalcitol was used in 40% of
cases, cinacalcet in 21%, and a
combination in the remaining cases (24%). The average cinacalcet
dose used was 28.9mg/day, and
3.84µg/week of paricalcitol.
- EPO: average dose was 69.34±71,
85UI/kg/week.
It must be highlighted that we did not
observe any microbiological or chemical contamination in the checks carried
out. In terms of technical complications, it must be noted that when dialysis treatment could not be carried out
on the planned day, the patient took an
un-planned break or went to hospital,
on three occasions; we believe this fact
to be anecdotic considering that more
than 6000 sessions were undertaken in
the study’s period.
The results obtained in clinical-analytical and morbidity and mortality terms
surpass, or are at least comparable to,
the standard quality of care objectives,
with no incidences observed in relation to the patients’ safety. In addition,
the technique has enabled a considerable improvement in patients’ quality
of life. For these reasons, we consider
that the patient has a right to the option
of HHD, and therefore it is our duty to
offer it. We believe that to do so, we
must broaden patient selection criteria,
not being led by preconceived ideas and
strengthening the physical substrate in
order to implement these programmes.
100
90
80
70
60
50
1. Eknoyan G, Beck GJ, Cheung AK, Daurgidas
JT, Greene T, Kusek JW, et al. Effect of dialysis
dose and membrane flux in maintenance hemodialysis. N Engl J Med 2002;347(25):20109.
2. Finkelstein FO, Schiller B, Daoui R, Gehr
TW, Kraus MA, Lea J, et al. At-home short
daily hemodialysis improves the long-term
health-related quality of life. Kidney Int
2012;82(5):561-9.
3. Daugirdas JT, Chertow GM, Larive B, Pierratos A, Greene T, Ayus JC, et al. Effects of
frequent hemodialysis on measures of CKD
mineral and bone disorder. J Am Soc Nephrol
2012;23(4):727-38.
4. Kjellstrand C, Buoncristiani U, Ting G, Traeger
J, Piccoli GB, Sibai-Galland R, et al. Survival
with short-daily hemodialysis: Association of
time, site, and dose of dialysis. Hemodial Int
2010;14(4):464-70.
5. Johansen KL, Zhang R, Huang Y, Chen SC,
Blagg CR, Goldfarb-Rumyantzev AS, et al.
Survival and hospitalization among patients
using nocturnal and short daily compared to
conventional hemodialysis: a USRDS study.
Kidney Int 2009;76(9):984-90.
6. Komenda P, Gavaghan M, Garfield S, Poret
A, Sood M. An economic assessment model
for in-center, conventional home, and more
frequent home hemodialysis. Kidney Int
2012;81:307-13.
7. MATCH.D group. Method to assess treatment
choices for home dialysis (MATCH-D). Available at: http://homedialysis.org/match-d.
40
Alejandro Pérez-Alba, J. Ramón Pons-Prades,
Esther Tamarit-Antequera,
Juan J. Sánchez-Canel, Vicente Cerrillo-García,
Elena Renau-Ortells, Laura Salvetti,
M. Ángeles Fenollosa-Segarra
30
20
10
0
Std Kt/V AVF
Hb
Iron
Ca
Extended range
- AVF+CAT
- P 5.1-5.5
- PTH 301-500
P
CaxP
PTH
Target range
Figure 1. Percentage of the quality indicators obtained.
Alb: albumin; PTH: parathyroid hormone.
Nefrologia 2014;34(4):526-44
MAP
%G
Alb
de Castellón. (Spain).
Correspondence: Alejandro Pérez Alba
Hospital General de Castellón.
Avenida Benicasim, s/n. Castellón
de La Plana,12004. (Spain)..
[email protected]
[email protected]
529
IInfluence of glucose
solutions on the
development of
hyperglycaemia in
peritoneal dialysis.
Behaviour of glycated
haemoglobin and the
lipid profile
Nefrologia 2014;34(4):530-1
doi:10.3265/Nefrologia.pre2014.Mar.12394
Sr. Director:
Peritoneal dialysis (PD) is a technique
that exposes the patient to glucose
solutions and may cause metabolic
complications,
such
as
central
obesity, hypertriglyceridaemia and
hyperglycaemia. Glucose absorbed
from the peritoneal cavity may lead to
the development of insulin resistance
(IR) and de novo diabetes1. Furthermore,
exposure to glucose degradation
products (GDP) leads to structural and
functional damage of the peritoneal
membrane2. In a study by Fortes et al.,
PD patients had higher fasting glucose,
glycated haemoglobin (HbA1C) and
estimated IR rate using the HOMA-IR
index3 than haemodialysis patients. In
addition, patients who receive dialysis
with glucose-free dialysate show a
lower absorption of glucose, lower
weight gain and fat accumulation,
and improved IR and dyslipidaemia4;
furthermore, the use of icodextrin
leads to increased adipocytokines in
the plasma of PD patients, without
changes in cholesterol levels, but with
a reduction in triglycerides5. In a study
aimed at observing differences in the
lipid profile of 22 non-diabetic patients
on PD between 6 and 48 months
compared to a control group of a similar
age, there were significantly higher
levels of very low-density lipoproteins,
cholesterol bound to low-density
lipoproteins and triglycerides, and
significantly lower levels of cholesterol
bound to high-density lipoproteins
compared to the control group6; using a
72-hour continuous glucose-monitoring
system, they studied the effect of PD
530
glucose solutions on patient glucose
levels and they observed that the
percentage of glucose levels above
90mg/dl was influenced by high
glucose concentrations in the fluids and
the high transporter state. However, a
Spanish study recently published that
non-diabetic PD patients did not have
a significant increase in HOMA-IR
levels, or modifications to these values
after one year of treatment on PD, or
statistically significant changes in the
lipid profile7.
We carried out a retrospective
observational study with 39 non-diabetic
PD patients of the Hospital Clínico San
Carlos de Madrid, 26 on continuous
ambulatory PD and 13 on automated
PD, of 61+14 years of age, in which
we analysed baseline glucose and lipids
(total cholesterol and triglycerides)
before beginning PD and after 1, 3, 6,
12, 18, 24, 30 and 36 months using the
technique, and a prospective 12-month
study in 18 of the patients, also analysing
HbA1C. We studied time on PD, the type
of PD, the type of transporter and use
of solutions with a high glucose load
(two or more exchanges at 2.3%) or a
low load (fewer than two at 2.3% and/
or icodextrin). We only used fluids with
a high glucose load in 6 patients and we
did not use 3.86%-4.25% solutions in
any patient. The type of transporter was
high (medium-high, high) in 16 and low
(medium-low, low) in 23.
We did not find significant differences
between the pre-PD glucose means
and those found over the 36 months of
follow-up (Table 1), which remained
at normal levels throughout the study.
Cholesterol levels rose suddenly in the
sixth month with respect to baseline
values (171±45 vs. 193.5±46mg/
dl; P=.008), without changes in the
triglyceride figures and with normal
levels being maintained in both
factors throughout follow-up. In the
prospective study with 18 patients, we
did not observe significant differences in
glycaemia evolution: baseline 103±14
vs. 105±17 after 1 month, 112±14
after 3 months, 108±20 after 6 months
and 104±14mg/dl after 12 months. No
significant differences were observed
in HbA1C: baseline 5.5±0.5 vs. 5.5±0.5
after 1 month, 5.4±0.6 after 3 months,
5.7±0.8 after 6 months and 5.4±0.6%
Table 1. Evolution of glycaemia in peritoneal dialysis.
Par 1
Par 2
Par 3
Par 4
Par 5
Par 6
Par 7
Par 8
Glycaemia
No.
Mean±SD
Baseline
39
93.8±13.8
1 month
39
99.5±16
Baseline
39
98.8±13.8
3 months
39
104.9±18
Baseline
37
98.6±14
6 months
37
101±16.4
Baseline
31
97.9±14
12 months
31
98±11.2
Baseline
27
98±14.9
18 months
27
98.9±12.2
Baseline
23
97.8±14.9
24 months
23
100.2±1.2
Baseline
17
96.3±12.7
30 months
17
97.7±8.14
Baseline
13
94.4±8.9
36 months
13
97±14.1
P
0.77
0.05
0.38
0.55
0.81
0.52
0.72
0.58
SD: standar desviation.
Nefrologia 2014;34(4):526-44
after 12 months. Glycaemia and HbA1C
do not seem to change in accordance
with the glucose load. There is a good
correlation between glucose and HbA1C.
High transporters have higher glucose
values after one month on PD (P=.039),
but not of HbA1C.
During the first years in which
PD has been reported, and on the
basis of the glucose load that was
contributed to obtain sufficient
ultrafiltration, it was considered
to be a dialysis technique with a
potential diabetogenic effect. It
is possible that in these first few
years, due to a lack of knowledge
about the deleterious effect that
glucose contribution has on the
peritoneum with the development
of GDP 2, the relatively common
use of very hypertonic solutions,
which furthermore did not use
bicarbonate as a buffer, may have
caused some cases of diabetes.In the
last decade since the introduction
of solutions in dual chambers with
a mixture of lactate and bicarbonate
or bicarbonate alone, with which
the formation of GDP is minimal
and use of 3.86%-4.25% glucose
PD dialysate is practically nil, the
induction of diabetes and even
the development of moderate
hyperglycaemia, as our study
shows, have become anecdotal. The
increase in lipids reported in some
articles 6 is not relevant in our study
in terms of its maintenance over
time and it has not been confirmed
by other authors 7.
In conclusion, our non-diabetic PD
patients treated with glucose solutions
did not show changes in their glucose
levels throughout the 36 months on
dialysis. HbA1C was unchanged after
a year on the technique. The potential
development of diabetes in PD was not
confirmed by our results.
1. Szeto CC, Chow KM, Kwan BCH, Chung
KY, Leung CB, Li PKT. New-onset hyperglycemia in nondiabetic Chinese patients
started on peritoneal dialysis. Am J Kidney
Dis 2007;49:524-32.
2. Kim YL, Cho JH, Choi JY, Kim CD, Park
SH. Systemic and local impact of glucose and glucose degradation products
in peritoneal dialysis solution. J Ren Nutr
2013;23(3):218-22.
3. Fortes PC, de Moraes TP, Mendes JG,
Stinghen AE, Ribeiro SC, Pecoits-Filho R.
Insulin resistance and glucose homeostasis in peritoneal dialysis. Perit Dial Int
2009;29:S145-8.
4. Cho KH, Do JY, Park JW, Yoon KW. Effect
of icodextrin dialysis solution on body
weight and fat accumulation over time
in CAPD patients. Nephrol Dial Transplant
2010;25:593-9.
5. Furuya R, Odamaki M, Kumagai H, Hishida
A. Beneficial effects of icodextrin on plasma level of adipocytokines in peritoneal
dialysis patients. Nephrol Dial Transplant
2006;21:494-8.
6. Johansson AC, Samuelsson O, Attman
PO, Haraldsson B, Moberly J, Knight-Gibson C, et al. Dyslipidemia in peritoneal
dialysis-relation to dialytic variables. Perit
Dial Int 2000;20:306-14.
7. Sánchez-Villanueva R, Estrada P, del
Peso G, Grande C, Díez JJ, Iglesias
P, et al. Análisis repetido de la resistencia insulínica estimada mediante
índice HOMAIR en pacientes no diabéticos en diálisis peritoneal y su
relación con la enfermedad cardiovascular y mortalidad. Nefrologia
2013;33(1):85-92.
Margarita Delgado-Córdova1,
Francisco Coronel2, Fernando Hadah2,
Secundino Cigarrán3,
J. Antonio Herrero-Calvo2
1
Universidad Autónoma de Chile.
Santiago de Chile (Shile); 2 Servicio de
Nefrología. Hospital Clínico de San Carlos.
Madrid. (Spain).; 3 Sección de Nefrología.
Hospital da Costa. Burela, Lugo (Spain).
Nefrologia 2014;34(4):526-44
Correspondence: Francisco Coronel
C/ Comunidad de Baleares 1, Las Rozas,
28231 Madrid, (Spain).
[email protected]
Results 5 years after
living donor renal
transplantation without
calcineurin inhibitors
Nefrologia 2014;34(4):531-4
To the Editor,
Calcineurin inhibitor-based (CNI)
immunosuppression regimens have
improved the outcomes of renal transplantation. Unfortunately, the use of
CNI has been associated with interstitial fibrosis and tubular atrophy,
affecting graft function and graft survival1. In order to avoid exposure to
CNI, agents such as sirolimus (SRL)
have emerged as new therapeutic
options. Therapeutic strategies with
SRL include the minimisation, suspension, elimination and total absence of CNI2.
Experiences with CNI-free SRL/mycophenolate mofetil (MMF)/ST immunosuppression have not obtained
sufficient acute rejection (AR) prophylaxis 3. The introduction of induction therapy improved AR rates
and short-term efficacy (1-3 years)
with contradictory results 4-7. We previously reported excellent and satisfactory results after 1 and 3 years
without CNI 8,9 and we now present
an observational and retrospective
study of efficacy and safety after 5
years of the SRL/MMF/ST regimen
compared with cyclosporine (CS)/
MMT/ST and selective induction
with basiliximab in 41 patients enrolled between May 2004 and January 2005.
The study design has previously been
reported in detail8. In this report, the
results were analysed in two populations: the intention-to-treat (ITT)
population, which included all patients with a functioning graft, and
the population on treatment (OT),
which included patients who were
maintained on the same original study
immunosuppression regimen.
531
The demographic data of patients are
displayed in Table 1. Five-year patient survival was 90% in the SRL
group and 80.9% in the CS group
(p=ns). The causes of death in the
SRL group were cardiovascular (n=1)
and infectious (n=1), which was similar to the CS group: cardiovascular
(n=2), infectious (n=2) and gastrointestinal bleeding (n=1). Five-year
graft survival was 80% for SRL and
76.1% for CS (p=ns). The causes of
graft loss in the SRL group were:
graft thrombosis (n=1), de novo glomerulonephritis (n=1), urological
complications (n=1) and a lack of
adherence to treatment (n=1). In the
CS group they were: graft thrombosis (n=1), de novo glomerulonephritis (n=1), lupus (n=1), chronic kidney
disease (n=1) and death with a functioning graft (n=1).
Eight patients (40%) from the SRL
group and 3 (14%) from the CS group
received basiliximab induction. After
5 years, there was a decrease in the
dose of CS (133±29.9mg/day, range
120-200) and of SRL (1.75±0.66mg/
day, range 1-3) compared to 12
months
after
transplantation
(205.7±66mg/day and 3.2±1.7mg/day
CS and SRL, respectively). The mean
dose of MMF was higher in the CS
group (1218.75±363g/day, range 5002000), compared with the SRL group
(1093.9±417g/day, range 500-2000)
(p=.3). All patients in the study continued to take 5mg/day of oral prednisone. Four patients (25%) in the CS
group (p=.039) with a functioning graft
changed their regimen to SRL due to
interstitial fibrosis and tubular atrophy
confirmed by biopsy. We maintained
all patients in the SRL group with a
functioning graft on the SRL/MMF/ST
regimen. After one year of follow-up,
2 patients in the SRL group (11.1%)
and 3 in the CS group (17.7%) had episodes of AR (p=ns).
Graft function calculated by the glomerular filtration rate estimated using the
MDRD (Modification of Diet in Renal
Disease) formula10 and serum creatinine
is displayed in Table 2. We did not find a
statistically significant difference between
the two groups, independently of whether
they were an ITT population or a population OT. Patients in the SRL group had a
higher elimination of proteins in 24h urine
(p=.039) than patients in the CS group in
the ITT population. Serum haemoglobin
was similar in both cases. Cholesterol and
triglycerides were significantly higher in
the SRL group (Table 2).
There were a total of 81 adverse effect events, which were mostly infectious (14 in the SRL group and
16 in the CS group). There was a
similar incidence in new onset diabetes after transplantation (NODAT) (10% in the SRL group versus
9.5% in the CS group). No patient
developed a malignancy during follow-up. Six patients (37.5%) in the
SRL group and 31.3% (n=5) in the
CS group were taking angiotensin-converting-enzyme
inhibitors
and/or angiotensin receptor blockers
after 5 years (p=.7). Similarly, more
patients in the SRL group were taking lipid-lowering drugs than in the
CS group (n=7, 43.8%, versus n=6,
37.5%) (p=.2).
In summary, despite the fact that
our results need to be carefully reviewed due to certain limitations,
such as the sample size, retrospective recording and a population
of low immunological risk, we
concluded that living donor transplantation patients with selective
induction on the SRL/MMF/ST
regimen have similar graft survival and function 5 years after transplantation to those on the CSA/
MMF/ST regimen.
Table 1. Clinical and demographic parameters
Group A
SirolimusCyclosporine
P value
Patients (n)
Recipient’s age (years), mean SD (range)
Sex (male:female)
BSA, mean SD (range)
Dialysis time (months), mean (range)
HLA match, mean SD (range)
Donor’s age (years), mean (range)
Group B
20
21
ns
29,6 7,6 (18-40)
31,2 9,21 (18-52) ns
12:8
12:9
ns
1,73 0,24 (1,31-2,19)
1,63 0,1 (1,43-1,97)
ns
24,25 13,7 (2-62)
26 12,6 (3-60)
ns
2,7 1 (0-5)
2,9 1,1 (0-4)
ns
37,8 (21-56)
37,9 (27-59)
ns
CMV serology
D+/R-
22
D+/R+
1416
D-/R-
22
D-/R+
21
CMV: cytomegalovirus, ns: not significant, SD: standard deviation.
532
Nefrologia 2014;34(4):526-44
Table 2. Graft function based on the analysis of patients on treatment and those who we intended to treat
MDRD eGFR (ml/min/1,73 m2)
ITT population
Mean±SD (range)
Population OT
Mean±SD (range)
Serum creatinine (mg/dl)
ITT population Mean±SD (range)
Population OT
Mean±SD (range)
Protein in 24h urine (mg/day)
ITT population Mean±SD (range)
Population OT Mean±SD (range)
Haemoglobin (g/dl)
ITT population
Mean±SD Population OT Mean±SD Total cholesterol (mg/dl)
ITT population
Mean±SD Population OT Mean±SD Triglycerides in blood (mg/dl)
ITT population
Mean±SD Population OT Mean±SD Group A (SRL)
Group B (CSA)
n = 16
53.8±19 (20-90.9)
n = 16
53.8±19 (20-90.9)
n = 16
54.7±18.7 (29-83.7)
n = 12
54.1±19.1 (29-83.7)
n = 16
1.6±0.6 (1.0-3.7)
n = 16
1.6±0.6 (1.0-3.7)
n = 16
1.49±0.4 (1.0-2.2)
n = 12
1.47±0.5 (1.0-2.2)
n = 16
293.6±280 (50-814)
n = 16
293.6±280 (50-814)
n = 16
110.6±192 (0-620)
n = 12
136.7±205 (0-620)
n = 16
13.1±2.21
n = 16
13.1±2.21 n = 16
12.2±1.68 n = 12
12.6±1.83 n = 16
221.3±43.4 n = 16
221.3±43.4 n = 16
192.5±34.3
n = 12
190.4±41.6
n = 16
208.4±101.8 n = 16
208.4±101.8
n = 16
149.2±36.1 n = 12
147±32.6 P value
0.88 (ns)
0.91 (ns)
0.54 (ns)
0.67 (ns)
0.039 (s)
0.09 (ns)
0.24 (ns)
0.57 (ns)
0.046 (s)
0.063 (ns)
0.041 (s)
0.036 (s)
CS: cyclosporine, eGFR: estimated glomerular filtration rate, ITT: intention-to-treat population, MDRD: modification of diet in renal
disease, ns: not significant, OT: on treatment, SD: standard deviation, SRL: sirolimus.
The authors declare the following
conflicts of interest:
- Dr. Gustavo Martínez Mier receives lecture fees from Pfizer, Roche
and Novartis and consultancy fees
from Novartis and Sanofi.
1. Nankivell BJ, Borrows RJ, Fung CL,
OĆonnel PJ, Allen RD, Chapman
JR. The natural history of chronic alNefrologia 2014;34(4):526-44
lograft nephropathy. N Engl J Med
2003;349:2326-33.
2. Schena FP, Pascoe MD, Alberu J, del
Carmen Rial M, Oberbauer R, Brennan
DC, et al. Conversion from calcineurin
inhibitors to sirolimus: maintenance
therapy in renal allograft recipients:
24 months: efficacy and safety results
from the CONVERT trial. Transplantation
2009;87:233-42.
3. Kreis H, Cisterne JM, Land W. Sirolimus in association with mycophenolate
mofetil induction for the prevention of
acute graft rejection in renal allograft re-
cipients. Transplantation 2000;69:125260.
4. Flechner SM, Goldfarb D, Modlin C,
Feng J, Krishnamurthi V, Mastroianni
B, et al. Kidney transplantation without calcineurin inhibitor drugs: a prospective, randomized trial of sirolimus
versus cyclosporine. Transplantation
2002;74:1070-6.
5. Hamdy AF, El-Agroudy AE, Bakr MA,
Mostafa A, El-Baz M, El-Shahawy el-M,
et al. Comparison of sirolimus with lowdose tacrolimus versus sirolimus based
calcineurin inhibitor-free regimen in live
533
donor renal transplantation. Am J Transplant 2005;5:2531-8.
6. Ekberg H, Tedesco-Silva H, Demirbas A, Vítko
S, Nashan B, Gürkan A, et al. Reduced exposure to calcineurin inhibitors in renal transplantation. N Engl J Med 2007;357:2562-75.
7. Flechner SM, Glyda M, Cockfield S,
Grinyó J, Legendre Ch, Russ G, et al.
The ORION study: comparison of two
sirolimus-based regimens versus tacrolimus and mycophenolate mofetil in renal allograft recipients. Am J Transplant
2011;11(8):1633-44.
8. Martínez-Mier G, Mendez-Lopez MT,
Budar-Fernandez LF, Estrada-Oros J,
Franco-Abaroa R, George-Micelli E, et
al. Living related kidney transplantation
without calcineurin inhibitors: initial ex-
perience in a Mexican center. Transplantation 2006;82(11):1533-6.
9. Martinez-Mier
G,
Mendez-Lopez
Marco T, Budar-Fernandez LF, Avila-Pardo SF, Zamudio-Morales C. Living related kidney transplantation
without calcineurin inhibitors: 3-year
results of a randomized prospective
trial in a Mexican center. (Poster presented at American Transplant Congress 2009, Boston, MA, USA). Am J
Transplant 2009;79:s2:500 Abstract
1098.
10. Levey A, Greene T, Kusek J, Beck Gft
MSG. A simplified equation to predict glomerular filtration rate for serum creatinine (Abstract). J Am Soc
Nephrol 2000;11:155A.
Gustavo Martínez-Mier1,
Sandro F. Ávila-Pardo1,
Marco T. Méndez-López2,
Luis F. Budar-Fernández2,
Benjamín Franco-Ahumada1,
Felipe González-Velázquez3
1
Servicio de Trasplantes. IMSS UMAE 189
ARC. Hospital Regional de Alta Especialidad
de Veracruz (Mexico); 2 Servicio de Trasplantes.
IMSS UMAE 189 ARC. Veracruz (México); 3
Servicio de Investigación. IMSS UMAE 189
ARC. Veracruz (Mexico).
Correspondence: Gustavo Martínez Mier
Servicio de Trasplantes. IMSS UMAE 189 ARC,
Hospital Regional de Alta Especialidad de
Veracruz. Alacio Pérez, 928-314.
Zaragoza, 91910. (Mexico).
[email protected]
[email protected]
C) BRIEF CASE REPORT
Hepatitis C virus
infection, interferon
α and lupus; a curious
combination
Nefrologia 2014;34(4):534-6
To the Editor,
Drug-induced lupus is a syndrome that
shares clinical and analytical characteristics with idiopathic systemic lupus
erythematosus and which appears after
exposure to certain drugs that induce
autoantibody formation.
In 1945, Hoffman described the first
case of drug-induced lupus, which involved the antibiotic sulfadiazine as
the agent responsible for the condition.
Eight years later, in 1953, Morrow et
al. published a new case relating to the
use of hydralazine1. Since then, the list
of associated drugs has continued to
increase and in recent years, biological
therapies, such as tumour necrosis factors (TNF) and interferons (IFN), have
joined with classic agents, such as procainamide, the aforementioned hydralazine, isoniazid or minocylcine2,3,4.
534
The mechanism causing this condition
has not been fully defined; immunogenetic (certain HLA alleles) and pharmacogenetic (slow acetylator phenotype) factors appear to play an important role in its aethiopathogeny1,5.
In terms of clinical presentation, the
most common symptoms are fever,
general malaise, muscle pain, joints
pain, arthritis, rash and serositis. Unlike idiopathic lupus, kidney, haematologic and nervous system disorders
are uncommon6. Antihistone antibodies are typical laboratory findings.
Hypocomplementaemia and anti-double-stranded DNA, characteristics of
idiopathic lupus, tend to be absent,
although the latter can test positive in
cases of anti-TNF- or IFN-induced lupus (Table 2).
The interval of time between starting
the drug and the condition appearing is
highly variable, being between 2 weeks
and 7 years in the case of IFN-α; a case
developing two months after the drug’s
suspension has been described7.
This condition’s prognosis is favourable, such that discontinuation of the
responsible drug is followed by recovery in the majority of cases, in a time
frame that can stretch from weeks to
months. Until then, non-steroidal anti-inflammatory drugs (NSAID), hydroxychloroquine and low-dose systemic corticosteroids can be used temporarily to control symptoms.
CASE
We present a 51-year-old male, with
chronic kidney failure secondary to
IgA glomerulonephritis, on a periodic
haemodialysis programme, hypertensive, an ex-user of cocaine by inhalation and with chronic hepatitis C virus
(HCV) disease, for which reason he
was treated with ribavirin and pegylated IFN-α (180μg per week) for
49 weeks, obtaining a sustained viral
response. Two weeks after finishing
this treatment, he sought consultation
due to asthenia and generalised joint
pain of 10-15 days evolution, also experiencing in the last 48 hours 38 ºC
fever and increased right hip pain. In
the physical examination he presented
pain on moving the aforementioned
joint, with neither functional weakNefrologia 2014;34(4):526-44
Table 1. Medicines associated with drug-induced lupus4
Medicines definitively associated with drug-induced lupus
Chlorpromazine
Isoniazid
Hydralazine
Methyldopa
Minocycline
Procainamide
Quinidine
Medicines possibly associated with drug-induced lupus
Acebutolol
Phenylbutazone
Para-aminosalicylic
Acecainide
Phenytoin
Penicillamine
Nalidixic acid
Phenopyrazone
Penicillin
Adalimumab
Fluvastatin
Perazine
Allopurinol
Griseofulvin
Perphenazine
Aminoglutethimide
Guanoxan
Pyrathiazine
Amoproxan
Ibuprofen
Pyridoxine
Anthiomaline
Infliximab
Practolol
Atenolol
Interferon-α
Promethazine
Atorvastatin
Interferon-γ
Propafenone
Benoxaprofen
Interleukin-2
Propylthiouracil
Captopril
Labetalol
Propranolol
Carbamazepine
Leuprolide
Psoralen
Chlorprothixene
Levodopa
Quinidine
Chlorthalidone
Levomepromazine
Reserpine
Cimetidine
Lithium
Simvastatin
Cinnarazine
Lovastatin
Sulindac
Clonidine
Mephyton
Sulfadimethoxine
Danazol
Mesalazine
Sulfamethoxypyridazine
Diclofenac
Methimazole
Sulfasalazine
Diphenylhydantoin
Methysergide
Tetracyclines
Disopyramide
Methylthiouracil
Tetracin
Enalapril
Metoprolol
Thioamide
Spironolactone
Metrizamide
Thioridazine
Streptomycin
Minoxidil
Timolol
Oestrogens
Nitrofurantoin
Tolazamide
Etanercept
Nomifensine
Tolmetin
Ethosuximide
Oxyphenisatin
Trimethadione
Ethylphenacemide
Oxprenolol
Table 2. Characteristics of spontaneous and drug-induced lupus6
Clinical characteristics
Constitutional symptoms
Arthralgia and arthritis
Pleuropericarditis
Hepatomegaly
Rash
Kidney disease
Central nervous system disorder
Haematological abnormalities
Immunological abnormalities
- ANA
- Anti-RNP
- Anti-Sm
- Anti-dsDNA
- Antihistone
- Complement
Nefrologia 2014;34(4):526-44
Spontaneous lupus
Drug-induced
lupus
83%
90%
50%
25%
74%
53%
32%
Common
50%
95%
50%
25%
10-20%
5%
0%
Uncommon
95%
40-50%
20-30%
80%
60-80%
Bajo
95%
20%
Rare
Rare
90-95%
Normal
ness nor inflammatory signs at this
level nor in other joints. The increase
of acute-phase reactants (C reactive
protein was 9, ESR 120 and neutrophilia) stood out in the laboratory
analysis. Blood cultures were taken
(which were sterile) and, in order to
rule out septic arthritis, an ultrasound
of the joint was requested, which did
not show signs of arthritis nor joint
fluid on being drained and analysed.
An echocardiogram ruled out endocarditis. In the study undertaken to
rule out tumours/inflammation (bone
scan, body gallium scan and chest/
abdominal/pelvic CT scan), degenerative changes were only observed
in the scapulohumeral, glenohumeral
and coxofemoral joints, with no other
significant findings. The autoimmunity test was positive for ANA (IIF)
at titres of 1:80 and anti-chromatin
(antihistone), with negative anti-dsDNA and normal complement levels.
Other findings were rheumatoid factor 29 and positive cryoglobulins (but
with only 0.33% cryocrit). It must be
mentioned that one year before, prior
to starting treatment with pegylated
IFN, autoimmunity was negative and
by contrast, cryoglobulins were positive with 4.4% cryocrit. Given these
results suggesting drug-induced lupus
(related to the pegylated IFN-α that
the patient had been receiving until
two weeks before due to his HCV),
treatment with NSAID, low dose corticosteroids and hydroxychloroquine
was started, with significant improvement of symptoms.
Lymphocyte populations were also
counted before and during IFN-α therapy, showing significant lymphopenia,
with a decrease of both T cells (CD4+
and CD8+) and B cells during treatment (Figure 1).
DISCUSSION
Drug-induced lupus is a condition
without established diagnostic criteria. It should be considered in those
patients who have received one of
the implied drugs for longer than one
month and who have compatible symp535
Pilar Auñón-Rubio,
Eduardo Hernández-Martínez,
Ángel Sevillano-Prieto,
Enrique Morales-Ruiz
12 de Octubre. Madrid. (Spain).
Correspondence: Pilar Auñón Rubio
12 de Octubre. Madrid. (Spain).
[email protected]
Cells/ml
1600
1400
1200
1000
800
600
400
200
0
Before starting IFN
Total Lymphocytes CD8+ T cells
During IFN treatment
CD3+ lymphocytes
CD19+ B cells
CD4+ T cells
Figure 1. Evolution of lymphocyte populations following treatment with interferon α.
IFN: interferon.
toms and autoimmunity test. The
growing appearance of new pharmacological therapies, as well as the
important pharmacosurveillance of
their adverse effects, make the list of
agents associated with this condition
increasingly comprehensive. For this
reason, high clinical suspicion is key,
and therefore timing is of great importance.
For our patient, significant lymphocyte depletion induced by IFN-α
should also be noted. Although T
cell lymphopenia is an effect already
described with the use of IFN-α due
to thymus’ function alteration, this
situation, together with the patient’s
significant B lymphopenia, would
mean a dysregulation of the immune
response which could be involved in
autoimmunity.
536
1. Hess E. Drug-related lupus. N Engl J Med
1988;318:1460-2.
2. Mongey AB, Hess EV. Drug insight:
autoimmune effects of medications—
what’s new? Nat Clin Pract Rheumatol
2008;4:136-44.
3. Fritzler MJ. Drugs recently associated with
lupus syndromes. Lupus 1994;3(6):455-9.
4. Aguirre Zamorano MA, López Pedrera
R, Cuadrado Lozano MJ. Lupus
inducido por fármacos. Med Clin (Barc)
2010;135(3):124-9.
5. Adams LE, Mongey AB. Role of genetic
factors in drug-related autoimmunity.
Lupus 1994;3(6):443-7.
6. Schur PH, Massarotti EM. Lupus erythematosus:
clinical evaluation and treatment. New York:
Springer; 2012. pp. 211-21.
7. Wilson LE, Widman D, Dikman SH,
Gorevic
PD.
Autoimmune
disease
complicating antiviral therapy for hepatitis
C virus infection. Semin Arthritis Rheum
2002;32(3):163-73.
8. Beq S, Rozlan S, Pelletier S, Willems B,
Bruneau J, Lelievre JD, et al. Altered
thymic function during interferon therapy
in HCV-infected patients. PLoS One
2012;7(4):e34326.
Baclofen neurotoxicity
in a patient with
end-stage chronic renal
failure
Nefrologia 2014;34(4):536-8
To the Editor,
Baclofen
(4-beta-chlorophenyl-gamma-aminobutyric acid) is
a muscle relaxant, used as an antispasmodic in diseases such as multiple sclerosis, medullary trauma
and hiccups 1,2 .
It is mainly excreted through the
kidneys (69%-85%) and has a 2 to
6 hr. half life in healthy people.
There is a high risk of neurotoxicity in patients with renal failure,
especially if administered with
<30ml/min glomerular filtration
rate, causing episodes of unconsciousness 3,4 .
Baclofen intoxication in dialysis
patients is rare, with very diverse
forms of clinical presentation 5-9 .
We present the clinical case of a
patient with baclofen-induced encephalopathy, with atypical clinical evolution; symptoms did not
improve with haemodialysis and
the patient went into complete remission following the drug’s discontinuation.
Nefrologia 2014;34(4):526-44
CASE DESCRIPTION
We present a 31-year-old patient with
traumatic spinal injury at 20 and a
history of repeated urinary infections
related to neurogenic bladder (selfcatheterisation) and episodes of urinary obstruction. In 2009 he was referred to the nephrology department
due to stage 2 chronic kidney disease, with nephrotic-range proteinuria (1.3mg/dl creatinine, 20g/24h
proteinuria). The patient refused renal biopsy and in the same year, he
stopped attending nephrology consultations.
In January 2012 he started experiencing episodes of deteriorating levels
of consciousness. Cranial computerised tomography and lumbar puncture were performed, both with normal results. Electroencephalogram
showed diffuse slowing. At that time,
creatinine was 3.3mg/dl. The clinical
profile was suggested as secondary to
urinary infection.
The same symptoms repeated in
April 2012, accompanied by spatial and time disorientation. He presented a new episode in the same
month, but this time with behavioural change (infantilism, nervousness, aggressiveness). Cerebral MRI
was unremarkable. Following this
episode, treatment with clonazepam
was started.
In May 2012, due to end-stage renal
failure analysis results and symptoms, haemodialysis was started using a temporary catheter in the right
jugular vein.
Approximately once a month, in the
first two hours after starting dialysis,
the patient experienced episodes of
reduced levels of consciousness and,
at times, psychomotor agitation.
The patient was evaluated in November 2012 by the Neurology and Psychiatry department, with no relevant
findings. They diagnosed the condition as secondary to hypoxic metabolic encephalopathy.
Nefrologia 2014;34(4):526-44
Despite presenting correct KT and
Kt/V, we increased the number of
dialysis sessions to 4/week, without
clinical improvement.
the drug’s excretion, baclofen’s half
life went from 15.5h in patients with
stage 5 chronic renal failure not on dialysis to 2.06h in dialysis patients11-13.
In January 2013, we decided to suspend treatment with baclofen (Lioresal®), replacing it with tizanidine and
diazepam. After two weeks of tizanidine treatment, the patient stopped
the drug because of drowsiness and
spasticity was controlled only with
diazepam.
We suspect that this patient’s clinical
symptoms can be attributed to a sudden suppression of baclofen levels in
blood. It is worth noting that similar
cases have been described in sudden
withdrawals of this drug in patients
with intrathecal perfusions.14,15
10 months after the drug’s discontinuation, the patient had not re-experienced neurological symptoms.
DISCUSSION
Spasticity is a classic symptom in
spinal injury patients. Baclofen is
widely used in these patients, despite
their high risk of neurotoxicity, as a
result of having reduced renal function due to neurogenic bladder. We
also have to bear in mind that, on assessing serum creatinine levels, we
overestimated the renal function due
to a decrease in muscular mass10.
Psychomotor agitation is a rare
symptom of baclofen-induced encephalopathy. This encephalopathy
usually manifests itself as a reduced
level of consciousness. Our patient
initially presented this symptom,
since the same baclofen dose was
used as in a patient with normal renal
function. Following deterioration in
renal function and the start of haemodialysis, the patient experienced the
atypical symptom of psychomotor
agitation.
In reviewing the literature, we observe that the pharmaco-dynamics
of baclofen in dialysis patients is
expressed as C = C0 + eKet, where
Ke is dependent on the drug’s renal
(Kr) and non-renal (Knr) metabolism. In dialysis patients, renal clearance is restricted to clearance during dialysis; thus Kr = Kd, where
Kd = 0.291/h and Knr 0.045/h, therefore Ke = Kd + Knr = 0.336/h. Given
Despite no clear indications about
baclofen in pharmacological guides,
we do not recommend the use of this
drug in dialysis patients.
1. Peces R, Navascués RA, Baltar J,
Laurés AS, Alvarez-Grande J. Baclofen
neurotoxicity in chronic haemodialysis
patients with hiccups. Nephrol Dial
Transplant 1998;13(7):1896-7.
2. Chou CL, Chen CA, Lin SH, Huang
HH. Baclofen-induced neurotoxicity
in chronic renal failure patients with
intractable hiccups. South Med J
2006;99(11):1308-9.
3. Su W, Yegappan C, Carlisle EJ, Clase
CM. Reduced level of consciousness
from baclofen in people with low kidney
function. BMJ 2009;339:b4559.
4. Chen KS, Bullard MJ, Chien YY, Lee
SY. Baclofen toxicity in patients with
severely impaired renal function. Ann
Pharmacother 1997;31(11):1315-20.
5. Hsieh MJ, Chen SC, Weng TI, Fang
CC, Tsai TJ. Treating baclofen overdose
by hemodialysis. Am J Emerg Med
2012;30(8):1654.e5-7.
6. Dias LS, Vivek G, Manthappa M, Acharya
RV. Role of hemodialysis in baclofen
overdose with normal renal function.
Indian J Pharmacol 2011;43(6):722-3.
7. Bassilios N, Launay-Vacher V, Mercadal
L, Deray G. Baclofen neurotoxicity
[correction of unerotoxicity] in a chronic
haemodialysis patient. Nephrol Dial
Transplant 2000;15(5):715-6.
8. Himmelsbach FA, Köhler E, Zanker
537
B, Wandel E, Krämer G, Poralla
T, et al. [Baclofen intoxication in
chronic
hemodialysis
and
kidney
transplantation]. Dtsch Med Wochenschr
1992;117(19):733-7.
9. Seyfert S, Kraft D, Wagner K. [Baclofen
toxicity during intermittent renal
dialysis (author’s transl)]. Nervenarzt
1981;52(10):616-7.
10.El-Husseini A, Sabucedo A, Lamarche J,
Courville C, Peguero A. Baclofen toxicity
in patients with advanced nephropathy:
proposal for new labeling. Am J Nephrol
2011;34(6):491-5.
11.Chen YC, Chang CT, Fang JT, Huang
CC. Baclofen neurotoxicity in uremic
patients: is continuous ambulatory
peritoneal dialysis less effective than
intermittent hemodialysis? Ren Fail
2003;25(2):297-305.
12.Brvar M, Vrtovec M, Kovac D, Kozelj
G, Pezdir T, Bunc M. Haemodialysis
clearance of baclofen. Eur J Clin
Pharmacol 2007;63(12):1143-6.
13. Wu VC, Lin SL, Lin SM, Fang CC.
Treatment of baclofen overdose by
haemodialysis: a pharmacokinetic study.
Nephrol Dial Transplant 2005;20(2):4413.
14.Karol DE, Muzyk AJ, Preud’homme XA.
A case of delirium, motor disturbances,
and autonomic dysfunction due to
baclofen and tizanidine withdrawal:
a review of the literature. Gen Hosp
Psychiatry 2011;33(1):84.e1-2.
15. Salazar ML, Eiland LS. Intrathecal
baclofen
withdrawal
resembling
serotonin syndrome in an adolescent
boy with cerebral palsy. Pediatr Emerg
Care 2008;24(10):691-3.
Pablo Justo-Ávila,
Luciemne Fernández-Antuña,
M. Teresa Compte-Jove,
Cristina Gállego-Gil
Sección de Nefrología. Hospital de la Santa
Creu. Tortosa, Tarragona. (Spain).
Correspondence: Pablo Justo Ávila
Sección de Nefrología. Hospital de la Santa
Creu. Avda. Mossèn Valls, 1.
43590. Tortosa, Tarragona.
(Spain).
[email protected]
[email protected]
538
Achromobacter
xylosoxidans in two
haemodialysis patients
Nefrologia 2014;34(4):538-9
To the Editor,
Achromobacter (alcaligenes) xylosoxidans (AX) is a gram-negative, aerobic
bacillus, carried by animals (rabbits,
ferrets), although it is also present in
normal human flora, especially of the
skin and gastrointestinal tract1.
It is an opportunistic bacterium with
low virulence, except in immunocompromised patients, in whom it can cause
serious infections such as meningitis,
endocarditis and, most commonly, bacteraemia2.
Patients with a catheter are more likely
to develop AX and it is more frequent
in peritoneal dialysis (PD) than haemodialysis (HD) patients, where there are
few published cases; all cases are associated with a central venous catheter
(CVC)3-5. Contamination of the catheter, the heparin multi-dose vials, the
antiseptic solutions and the dialysate
itself have been described as possible
sources of infection, and the clothes or
hands of the health staff as methods of
transmission5.
new catheterisations due to infections
of the catheter entry site).
The patient was admitted due to fever
and shivers following dialysis, symptoms compatible with bacteraemia, with
positive blood cultures of Staphylococcus (St.) aureus. There was associated
infection in the catheter entry site, for
which reason the catheter, which was
cultured and resulted positive for AX,
St. aureus and Enterococcus faecalis,
was removed. The clinical and bacteriological infectious condition disappeared
with combined treatment of the three
bacteria.
CASE 2
A 46-year-old male patient, hypertensive, with hyperuricemia and CKD possibly secondary to chronic glomerulonephritis (GN), on HD since 1995. He
received two cadaveric kidney transplants, with possible early recurrence
of membranous GN and restarted HD
in 2004.
CASE 1
The patient was a 67-year-old female,
from Bulgaria, hypertensive, diabetic,
obese, with dyslipidaemia and chronic
kidney disease (CKD) possibly secondary to diabetes and/or nephroangiosclerosis, on HD since January 2008. Low
socioeconomic status, living with animals and bad personal hygiene.
The patient had multiple vascular accesses, the last being left humero-axillary prosthetic AVF (polytetrafluoroethylene), which resulted in ulceration
on the skin close to the anastomosis
with serous secretion, leaving the
prosthesis exposed. A temporary CVC
was implanted and a culture, growing
AX, was taken from the ulcer. The patient did not show increase of acute
phase reactants nor systemic infection
data. He received intravenous antibiotics according to the antibiogram,
after which the culture was repeated,
with development of AX continuing.
He received new courses of antibiotics, without managing to eradicate
the bacterium (three AX positive cultures). Thus, surgical removal of the
prothesis was decided upon and the
implanting of a new vascular access
(femoral saphenous AVF). The culture
after the surgical wound tested negative for AX.
Left humeral-cephalic arteriovenous
fistula (AVF) was performed, with slow
recovery, carrying out HD using a temporary CVC (multiple removals and
CONCLUSIONS
Although AX is not a common bacterium, it can be seen in HD patients.
We present two cases of AX that occurred in our department on the same
date in patients undergoing the same
HD session.
Nefrologia 2014;34(4):526-44
In case 1, the patient had multiple factors for developing AX infection: contact with animals, poor socioeconomic
conditions, poor personal hygiene and
having a CVC. For these reasons, we
think that it was the primary focus of
the infection. The removal of the catheter and specific antibiotic treatment resolved the bacteraemia.
In case 2, colonisation of the prothesis could be due to transmission by
the clothes or hands of the healthcare
staff, since multi-dose vials were not
used, nor were there other infections in
the unit that could be associated with
contamination of the dialysate. In this
instance, as expected, the bacterium
was not eradicated until removing the
prosthetic material, despite receiving
various courses of antibiotics according
to the antibiogram. In addition, it is the
first case described in the literature on
fistula contamination by AX.
1. Ahmed MS, Nistal C, Jayan R, Kuduvalli M,
Anijeet HK. Achromobacter xylosoxidans,
an emerging pathogen in catheter-related
infection in dialysis population causing
prosthetic valve endocarditis: a case report
and review of literature. Clin Nephrol
2009;71(3):350-4.
2. Al-Jasser AM, Al-Anazi KA. Complicated
septic shock caused by Achromobacter
xylosoxidans bacteraemia in a patient with
acute lymphoblastic leukaemia. Libyan J
Med 2007;2(4):218-9.
3. Turgutalp K, Kiykim A, Ersoz G, Kaya A.
Fatal catheter-related bacteraemia due to
Alcaligenes (Achromobacter) Xylosoxidans
in a haemodialysis patient. Int Urol Nephrol
2012;44(4):1281-3.
4. Nalek-Marín T, Arenas MD, Perdiguero
M, Salavert-Lleti M, Moledous A, Cotilla
E, et al. A case of endocarditis of difficult
diagnosis in dialysis: could “pest” friends be
involved? Clin Nephrol 2009;72(5):405-9.
5. T ena D, Carranza R, Barberá JR,
Valdezate S, Garrancho JM, Arranz M, et al.
Outbreak of long-term intravascular catheterNefrologia 2014;34(4):526-44
related bacteraemia due to Achromobacter
xylosoxidans subspecies xylosoxidans in
a haemodialysis unit. Eur J Clin Microbiol
Infect Dis 2005;24(11):727-32.
M. Eugenia Palacios-Gómez, Adoración
Martín-Gómez, Sergio García-Marcos
Unidad de Nefrología. Hospital de Poniente.
El Ejido, Almería. (Spain).
Correspondence: M. Eugenia Palacios Gómez
Unidad de Nefrología. Hospital de Poniente.
Carretera de Almerimar, S/N.
04700, El Ejido, Almería. (Spain).
[email protected]
[email protected]
Methylmalonic
acidemia with
homocystinuria.
A very rare cause of
kidney failure in the
neonatal period
Nefrologia 2014;34(4):539-40
To the Editor,
Methylmalonic acidemia with homocystinuria (MMAH) is a rare congenital metabolic and heterogeneous
disorder affecting vitamin B12 or cobalamin (cbl) metabolism. The disorder causes a reduction in the levels
of adenosyl and methylcobalamin
coenzymes, in turn reducing the activity of their respective enzymes,
methylmalonyl-CoA mutase and methionine synthase. This results in the
accumulation of methylmalonic acid
and homocysteine in the blood and
tissues, with an increase in the urinary excretion of both compounds1.
Various forms of the disease have
been described: cblC, cblD and cblF.
Neonatal presentation of this condition includes failure to thrive, encephalopathy, psychomotor retardation, haematological abnormalities
of the three series and renal damage1.
We present two cases diagnosed in
our department, who died from atyp-
ical haemolytic uraemic syndrome
(HUS) associated with severe kidney
failure.
The first case was a 25-day-old
male, admitted due to bilious vomiting and liquid bowel movements
which had started four days earlier. He was the second son of
first-cousin parents. On admission
he presented mild malnutrition, hypotonia and hypoactivity. He had
normochloraemic metabolic acidosis. Following slight improvement
on being subjected to complete
fasting, feeding was started; poor
tolerance, neurological deterioration, pancytopenia and liver and renal failure were observed.
Subsequently, on initiating parenteral
nutrition, microangiopathic anaemia
was reported together with increased
thrombocytopenia
(haemoglobin
6.7 g/l, platelets 10,000/mm3) and
worsening of renal failure. Atypical
HUS was diagnosed. In addition, he
experienced various convulsive episodes, with encephalopathic findings in the electro-encephalogram.
He died 20 days after admission with
severe kidney failure (creatinine
1.3mg/dl, urea 193mg/dl, potassium
6.6mEq/l).
The second case was a 24-day-old
male, who was taken to hospital due
to 7% weight loss following birth,
hypotonia and general malaise. The
parents were also first cousins. He
was admitted with a diagnosis of suspected sepsis (increase of acute-phase
reactants and positive haemoculture
for coagulase-positive staphylococcus). He also had normochloraemic
metabolic acidosis. Antibiotics were
prescribed and the patient continued
with complete fasting, with good
clinical response. Poor tolerance,
respiratory difficulty, neurological
deterioration, pancytopenia and liver failure were observed on beginning nutrition. At that time, he was
diagnosed with dilated myocardiopathy with reduced ejection fraction,
which normalised after suspending
539
nutrition. Parenteral nutrition was subsequently started, when kidney failure
occurred (oligoanuria, creatinine 1mg/
dl, urea 90mg/dl), accompanied by
anaemia and thrombopenia (haemoglobin 7.7g/l, platelets 21,000/mm3).
Therefore, continuous venovenous
haemofiltration was started. Although
the presence of schistocytes was unknown, we suspected that he suffered
from atypical HUS. Cerebral echography showed severe cortical atrophy. 30
days after admission the diagnosis of
methylmalonic acidemia with homocystinuria was confirmed. Given the
unfavourable prognosis, we decided
upon a limitation of therapeutic effort.
The most noteworthy data from the
metabolic and genetic study of both
patients, required for diagnosis, are
shown in Table 1. Our patients were
suffering from the most common
variant of the disease (cblC), which
is caused by homozygous or compound heterozygous mutations in the
MMACHC gene [methylmalonic aciduria (cobalamin deficiency) cblC
type, with homocystinuria], which is
located on the 1p34 chromosome.
A symptom-free period is typical in
methylmalonic acidemia with homocystinuria, since for clinical symptoms to appear, protein intake is required, with the consequential accumulation of methylmalonic acid and
homocysteine. This explains why, in
our patients, deterioration was observed on restarting feeding, whether
enteral or parenteral. At times, there
was a larvate clinical sign which
was precipitated by intercurrent disease, often an infection, as occurred
in case 2. Dilated myocardiopathy
(case 2) is also described as a complication, of which a case diagnosed
prenatally was reported2, as well as
other cardiac disturbances in relation
to thromboembolisms.
The pathogenesis of thrombotic microangiopathy is related to the increase of plasma methylmalonic acid
and homocysteine levels. The latter
modifies the vascular endothelial’s
antithrombatic properties by interfering in the inhibition of platelet aggregation mediated by nitric oxide,
which favours the union of the tissue
plasminogen activator with the endothelial. This results in an increase of
the endothelial expression of procoagulants. In addition, homocysteine
thiolactone, homocysteine metabolite, can cause cell damage by inducing intracellular accumulation of free
radicals and methylmalonic acid can
interfere in the mitochondrial metabolism of renal cells. Association
with HUS is uncommon, although
described, above all, in newborns3,4,
as was confirmed in case 1 and suspected in case 2. At birth, many patients already have kidney failure,
which could be reversible with early treatment (hydroxocobalamin,
trimethylglycine, folate and protein
restriction), which did not occur in
our cases given the late diagnosis4,5.
Consequently, early clinical suspicion is fundamental for trying to
improve renal function as much as
possible.
Homozygous mutation in
MMACHC gene (type cblC)
540
Orlando Mesa-Medina, Mónica Ruiz-Pons,
Víctor García-Nieto, José León-González,
Santiago López-Mendoza,
Carlos Solís-Reyes
Hospital Universitario Nuestra Señora de
Candelaria. Santa Cruz de Tenerife. (Spain).
Correspondence: Orlando Mesa Medina
Hospital Universitario Nuestra Señora
de Candelaria. Santa Cruz de Tenerife. (Spain).
[email protected]
Table 1. Biochemical and genetic data
Case 1
Methylmalonic acid (urine)
124mmol/mol Cr
Normal: 0.8-8.5mmol/mol Cr
Homocysteine (serum)
Normal: 3.7-7.5mcmol/l
1. Deodato F, Boenzi S, Rizzo C, Dionosi-Vici
C. The clinical picture of early-onset cobalamin C defect (methylmalonic aciduria
and homocystinuria). Pediatr Child Health
2008;18:S57-60.
2. De Bie I, Nizard SD, Mitchell GA. Fetal
dilated cardiomyopathy: an unsuspected presentation of methylmalonic aciduria and hyperhomocystinuria, cblC type.
Prenat Diagn 2009;29:266-70.
3. Rogé Canales M, Rodrigo Gonzalo de
Liria C, Prats Viñas LJ, Vaquero Pérez M,
Ribes Rubió A, Rodés Monegal M, et al.
Síndrome hemolítico-urémico neonatal
asociado a aciduria metilmalónica y homocistinuria. An Esp Pediatr 1996;45:97-8.
4. Menni F, Testa S, Guez S, Chiarelli G, Alberti L, Esposito S. Neonatal atypical hemolytic uremic syndrome due to methylmalonic aciduria and homocystinuria. Pediatr
Nephrol 2012;27:1401-5.
5. Huemer M, Simma B, Fowler B, Suormala
T, Bodamer OA, Sass JO. Prenatal and postnatal treatment in cobalamin C defect. J
Pediatr 2005;147:469-72.
Case 2
2150mmol/mol Cr
85mcmol/l
109mcmol/l
c.271dupA/c.271dupA
c.271dupA/c.271dupA
An uncommon cause
of linfadenopathy
in a kidney transplant
patient: Cat-scratch
disease
Nefrologia 2014;34(4):540-2
Dear Editor,
Cat scratch disease (CSD) is an
infectious disease that usually presents
Nefrologia 2014;34(4):526-44
as a self-limiting illness characterized
by regional lymphadenopathy, fever and
constitutional symptoms in association
with a cat scratch or bite.1-4 In most cases,
Bartonella henselae is the etiologic agent
and cats are important reservoirs.2-5
We report a case of CSD in a 38-yearold Caucasian female recipient of
a deceased kidney transplant since
2006 due to chronic renal failure of
unknown etiology. Her maintenance
immunosuppressive treatment was
mycophenolate mofetil and cyclosporine.
She was also medicated with calcium
carbonate, vitamin D, atenolol, folic
acid, fluoxetine, omeprazole, ferrous
sulfate.
Six years post transplantation the
patient was admitted to the hospital
with a 4-week history of asthenia,
low fever, loss of weight and multiple
painful cervical ganglions. There was
no previous history of tuberculosis.
She had close contact at home with
cats. On physical examination, the
patient had a temperature of 37,3ºC,
pulse rate of 84/min, blood pressure of
134/88mmHg, respiratory rate of 16/
min and pulse oximetry of 100% in
ambient air. She had multiple bilateral
painful ganglions only in cervical
region (node size ≤4cm). There was no
rash. Examination of the lungs, heart
and abdomen revealed no abnormalities
including hepatosplenomegaly. The
graft was painless. Laboratory tests
revealed a white blood cell count
11,81×10^3/L (neutrophils
65,8%,
lymphocytes 23,6%, monocytes 10%,
eosinophils 0,1%), normochromicnormocytic anemia (Hgb 9,6g/dL);
creatinine 1,2mg/dL (basal value),
blood urea nitrogen 39mg/dL; protein C
reactive 143mg/L; LDH, SGOT, SGPT,
total bilirubin and alkaline phosphate
without alterations. Ultrasound cervical
ecography demonstrated multiple
ganglion formations.
She was observed on admission by an
otorhinolaryngologist who prescribed
metronidazole plus amoxicillin and
clavulanate for a nasopharynx´s
infection. Serologies for Epstein-Barr
Nefrologia 2014;34(4):526-44
internment (without improvement of
complains) and began azithromycin
500mg on day one, followed by 250mg
for four days. There has been a good
clinic improvement with involution
of ganglion swelling and resolution of
the pain and fever. One month later the
patient was asymptomatic, without any
signs of recurrence.
Figure 1. Ganglion biopsy – Focus of necrosis,
some surrounded by granulomatous
inflammation in cortical region (H&E,
original magnification x40).
virus, herpes virus, cytomegalovirus,
toxoplasmosis, brucella, leishmania,
and HIV infection were negative.
Blood culture was sterile. Chest and
abdominal CT scan without changes.
Quantiferon test for tuberculosis
was indeterminate. Peripheral blood
cytometry and cytometry of ganglion
did not showed immunophenotypic
alterations compatible with lymphoma.
An ganglion biopsy was performed
and histological examination revealed
reactive lymphadenitis with central
necrosis (Ziehl neelsen was negative)
alterations compatible with CSD
(Figures 1 and 2). She stopped the
initial antibiotherapy on the 6th of
Figure 2. Ganglion biopsy – Focus of
stellate aspect necrosis with epithelioid
macrophages in the periphery (H&E,
original magnification x100).
This
case
report
intends
to
illustrate that the investigation of
an
immunocompromised
kidney
transplant patient presenting with
lymphadenopathy may constitute a
challenge given the wide differential
diagnosis possible. The presence
of enlarged lymph nodes in those
patients should lead to post-transplant
lymphoproliferative disorders (PTLD)
as a first hypothesis; however more
benign and unsuspected causes must be
the cause.
The risk of PTLD is associated with
the degree of immunosupression, time
post transplant and the presence of
Epstein-Barr virus.6-9 Their incidence
is approximately 30 to 50 times greater
than in the general population and
comprises a wide histological spectrum
from hyperplastic appearing lesions,
non-Hodgkin lymphoma or multiple
myeloma histology.6,8
Regional lymphadenopathy is the
hallmark of CSD in association with
mild constitutional symptoms and a
previous history of cat scratch or bite.1-3
In our case the investigation was wide
and extensive once this disease can
mimic the more common PTLD disease
or others infectious causes.2-4 In addition
to serological tests a lymph node biopsy
was performed to exclude lymphoma
or other malignant causes. It has been
proposed that at least three of four
criteria must be present to establish the
diagnosis of CSD: a) cat or flea contact;
b) negative serology for other causes
of adenopathy or sterile pus aspirated
from a node or a positive Bartonella
PCR assay or liver or spleen lesions
on CT scan; c) positive serology for
Bartonella henselae (EIA or IFA≥1:64);
d) biopsy showing granulomatous
541
inflammation consistent with CSD
or a positive Warthin-Starry silver
stain.2,3,10 The diagnosis of CSD in our
patient was based on the presence of a
cat contact history, negative serology
for other causes and a ganglion biopsy
compatible with CSD (Figures 1 and
2). Serologic methods for detection of
Bartonella henselae were not available
in our hospital and it was not possible
to isolate this agent by culture. The
treatment of this entity is recommended
in immunocompromised patients due to
high risk for disseminated and recurrent
CSD.2,3
Although CSD had rarely been reported
in kidney transplant patients it should be
considered in the differential diagnosis
of patients with lymphadenopathy and a
history of cat exposure.5 The absence of
easy complementary tests, the difficulty
in isolating the bacteria and the need
of tissue biopsy makes a difficult
diagnosis.
1. Spach D, Kaplan S. Treatment of cat
scratch disease. Available at: www.uptodate.com (accessed in 01/10/2013).
2. Spach D, Kaplan S. Microbiology, epidemiology, clinical manifestations, and
diagnosis of cat scratch disease. Available at: www.uptodate.com (accessed in
01/10/2013).
3. Lamps L, Scott M. Cat-scratch disease. Historic, clinical, and pathologic perspectives.
Am J Clin Pathol 2004;121 Suppl:S71-80.
4. Goral S, Scott M, Dummer S, Miller G, Antony S, Helderman J. Cat-scratch disease
in a patient undergoing haemodialysis.
5. Rheault MN, van Burik, Mauer M, Ingulli
E, Ferrieri P, Jessurun J, et al. Cat-scratch
disease relapse in a kidney transplant recipient. Pediatr Transplant 2007;11(1):105-9.
6. Newstead C. Lymphoproliferative disease
post-renal transplantation. Nephrol Dial
Transplant 2000;15:1913-6.
7. Quinlan S, Pleiffer R, Morton L, Engels E.
Risk factors for early-onset and late-onset
542
post-transplant lymphoproliferative disorder in U.S. kidney recipients. Am J Hematol
2011;86(2):206-9.
8. Friedberg J, Aster J. Epidemiology, clinical manifestations, and diagnosis of
post-transplant lymphoproliferative disorders. Available at: www.uptodate.com
(acceded in 01/10/2013).
9. Caillard S, Dharnidharka V, Agodoa L,
Bohen E, Abbott K. Posttransplant lymphoproliferative disorders after renal transplantation in the United States in era of
modern immunosuppression. Transplantation 2005;80:1233-43.
10. Souza G. Cat scratch disease: case report.
Rev Med Minas Gerais 2011;21(1):75-8.
Cláudia Bento1, La Salete Martins2,
André Coelho3, Manuela Almeida2,
Sofia Pedroso2, Leonídeo Dias2, Ramon
Vizcaíno3, António Castro-Henriques2,
António Cabrita2
1
Department of Nephrology. Centro
Hospitalar de Trás-os-Montes e Alto Douro.
Vila Real (Portugal); 2 Department of
Nephrology. Hospital Geral de Santo António.
Porto (Portugal); 3 Department of Clinical
Pathology. Hospital Geral de Santo António.
Porto (Portugal).
Correspondence: Claudia Bento
Department of Nephrology.
Centro Hospitalar de Trás-os-Montes e Alto
Douro. Vila Real (Portugal)
[email protected]
Extreme hypocalcaemia
and hyperparathyroidism
following denosumab.
Is this drug safe
in chronic kidney
disease?
Nefrologia 2014;34(4):542-4
doi:10.3265/Nefrologia.pre2014.Mar.12383
To the Editor,
Nefrología has recently published
a case of post-denosumab hypocalcaemia and we would like to
contribute to this subject 1. Denos-
umab is an anti-RANKL (receptor
activator of nuclear factor-κ B ligand) monoclonal antibody used in
osteoporosis treatment as an antiresorptive agent. Unlike bisphosphonates, denosumab does not appear
to be nephrotoxic 2, nor does it require dosage adjustments in kidney
failure due to its favourable pharmacokinetic and pharmacodynamic profile 1,3. However, the qualitative bone changes in osteoporosis
patients are not comparable with
the wide spectrum of alterations
in bone turnover that accompanies
chronic kidney disease (CKD) 4.
For this reason and in relation to
the changes in mineral metabolism
caused by denosumab, its safety
in this population could be questioned. We describe a patient with
advanced CKD with extreme hypocalcaemia and hyperparathyroidism
following continuous administration of denosumab.
The patient is a 75-year-old female
who sought treatment for tremors,
muscle spasms and paraesthesia in
the limbs. Stage 5 CKD, probably
secondary to nephroangiosclerosis
and diabetes mellitus, stands out in
her medical history. She is allergic
to penicillin and is treated with insulin, doxazosin, nifedipine GITS,
torsemide, acetylsalicyclic acid, oral
iron, erythropoietin, paricalcitol and
calcifediol. She was treated, until 7
months before, with 70mg alendronic
acid, which was suspended on starting six-monthly subcutaneous 60mg
denosumab. Her nephrologist was
unaware of the prescription of this
drug. She presented the following
analysis: creatinine 3.6mg/dl, total
corrected calcium 10.06mg/dl, ionic
calcium 5.1mg/dl, phosphate 5.1mg/
dl, alkaline phosphatase 157U/l, bicarbonate 27.6mmol/l, parathyroid
hormone (PTH) 436pg/ml, 25-vitamin D 30.2ng/ml. The evolution of
the biochemical parameters until the
last analysis 14 days after denosumab is shown in Figure 1. The patient
did not attend this last evaluation due
to not feeling well. Six days later,
Nefrologia 2014;34(4):526-44
20
18
16
14
12
10
8
6
4
Parenteral
post-correction
2
0
Denosumab 60
May
Corrected calcium
August
Denosumab 60
October
Phosphorus
November
PTH (X 100)
December
Alkaline phosphatase (X 10)
Figure 1. Evolution of biochemical parameters.
PTH: parathyroid hormone
she was examined in the Emergency
Department: urea 154mg/dl, 6mg/dl
creatinine, 4.36mg/dl total corrected calcium, 2.4mg/dl ionic calcium,
6.7mg/dl phosphate, 1.3mg/dl magnesium, 59U/l alkaline phosphatase,
18.6mmol/l bicarbonate, 1900pg/
ml PTH. Electrocardiogram (ECG):
440ms corrected QT (QTc). Oral and
intravenous calcium replacement and
intravenous calcitriol were started,
with the disappearance of symptoms.
After 15 days of parenteral replacement, the analytical parameters had
normalised (Figure 1): ECG: QTc
402ms. PTH remained 1858pg/ml.
The recommendations for the use
of denosumab in kidney failure are
based on a clinical trial involving
very few patients, over a 16 week
follow-up period and following only
one dose of the drug 3. In addition,
the authors excluded, in part of the
study, those subjects with 1.25-dihydroxyvitamin D levels <30pg/
ml, severe renal failure and PTH
≥110pg/ml or kidney failure and
PTH ≥300pg/ml. Even so, 22%-25%
of the cases with moderate-severe
Nefrologia 2014;34(4):526-44
renal failure or patients on dialysis
presented hypocalcaemia. The authors recommend calcium and vitamin D supplements for its prevention. In another clinical trial carried
out over 36 months in post-menopausal women with CKD and estimated glomerular filtration rate
>15ml/min, cases of hypoparathyroidism, hyperparathyroidism, hypercalcaemia and hypovitaminosis
D were excluded; PTH levels were
not monitored in the study 2.
In recent months, cases of hypocalcaemia in chronic nephropathies
have continued to be reported 1,5-8.
Non previous biphosphonate use
and kidney failure are risk factors
for developing hipocalcaemia 8.
Consequently, our patient may only
have developed hypocalcaemia following the second dose, since she
had previously been treated with
alendronate.
Denosumab reduces the number of
osteoclasts and bone formation rate.
Hypocalcaemia would be related to
the rapid mineral deposit of calci-
um in the new bone matrix, which
would behave similarly to a hungry
bone following parathyroidectomy3.
However, as occurred in this case,
PTH was not suppressed, but hyperstimulated. In addition to sudden
hypocalcaemia following the second
denosumab dose, PTH levels were
progressively increasing to very
high levels following the first dose,
despite vitamin D supplements; we
also observed a reduction of alkaline phosphatase. For some experts,
this inhibition of osteoclastogenesis
could favour adynamic bone disease
in CKD 4,5.
The monitoring of calcium levels 8-14 days after treatment has
been advised 7. However, this does
not guarantee its prevention, since
it is not known when the nadir is
reached 7.
Denosumab can cause potentially
fatal short-term adverse effects, as
well as other unknown long-term effects, on the bone of CKD patients.
For these reasons, some authors
recommend not using denosumab
in CKD patients or only using it if
a bone biopsy has previously been
carried out 4,6.
1.Martín-Baez IM, Blanco-García R,
Alonso-Suárez M, Cossio-Aranibar
C, Beato-Coo LV, Fernández-Fleming
F.
Severe
hypocalcaemia
postdenosumab. Nefrologia 2013;33:6145.
2. Jamal SA, Ljunggren O, StehmanBreen C, Cummings SR, McClung MR,
Goemaere S, et al. Effects of denosumab
on fracture and bone mineral density
by level of kidney function. J Bone
Miner Res 2011;26:1829-35.
3. Block GA, Bone HG, Fang L, Lee
E, Padhi D. A single-dose study of
denosumab in patients with various
degrees of renal impairment. J Bone
Miner Res 2012;27:1471-9.
543
4. Ott SM. Therapy for patients with CKD
and low bone mineral density. Nat Rev
Nephrol 2013;9:681-92.
5. Torregrosa JV. Dramatic increase in
parathyroid hormone and hypocalcemia
after denosumab in a kidney transplant
patient. Clin Kidney J 2013;6:122.
6. McCormick BB, Davis J, Burns KD. Severe
hypocalcemia following denosumab
injection in a hemodialysis patient. Am
J Kidney Dis 2012;60:626-8.
544
7. Farinola N, Kanjanapan Y. Denosumabinduced hypocalcaemia in high bone
turnover states of malignancy and
secondary hyperparathyroidism from
renal failure. Intern Med J 2013;43:12436.
8. Okada N, Kawazoe K, Teraoka K, Kujime
T, Abe M, Shinohara Y, et al. Identification
of the risk factors associated with
hypocalcemia induced by denosumab.
Biol Pharm Bull 2013;36:1622-6.
Ana E. Sirvent, Ricardo Enríquez, María
Sánchez, César González, Isabel Millán,
Francisco Amorós
Universitario de Elche. Alicante. (Spain).
Correspondence: Ana E. Sirvent
Universitario de Elche. Camí de l’ Almàssera 11.
03203 Alicante. (Spain).
[email protected]
[email protected]
Nefrologia 2014;34(4):526-44

originals - Revista Nefrologia

Transcripción

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