3 1 - N U M B e R 2 - 2 0 1 1: Official Publication of The Spanish Society of Nephrology

Included in ISI-WOK, MEDLINE, EMBASE, IME, IBECS, SCIELO
V o l u m e
3 1
N u m b e r
2 011
TRENDS RELATED TO IMR PLACES ASSIGNED TO NEPHROLOGY DIAGNOSTIC AND INTERVENTIONAL NEPHROLOGY ADVANCES IN THE DIAGNOSIS OF TUBERCULOSIS INFECTION IN DIALYSIS PATIENTS SURVIVAL FOR PERITONEAL DIALYSIS VS HAEMODILYSIS AND VASCULAR CALCIFICATION MECHANISMS RELATIONSHIP BETWEEN LEPTIN AND CARDIOVASCULAR MORTALITY IN HEMODIALYSIS PATIENTS 25 HYDROXY VITAMIN D LEVELS IN PREDIALYSIS PATIENTS PLEUROPERITONEAL COMMUNICATION IN PATIENTS ON PERITONEAL DIALYSIS
Sociedad Espaola de Nefrologa
Official Publication of the Spanish Society of Nephrology

Full version in English and Spanish at www.revistanefrologia.com
Nefrologa Journal
Editor-in-Chief: Carlos Quereda Rodrguez-Navarro Executive editor: Roberto Alczar Arroyo Deputy editors: Andrs Purroy Unanua, ngel Luis Martn de Francisco, Fernando Garca Lpez Honorary editors: Luis Hernando Avendao, David Kerr, Rafael Matesanz Acedos SUBJECT EDITORS (editors of thematic areas)
Experimental Nephrology A. Ortiz* J. Egido de los Ros S. Lamas J.M. Lpez Novoa D. Rodrguez Puyol J.M. Cruzado CRF-Ca/P Metabolism E. Fernndez* J. Cannata Anda R. Prez Garca M. Rodrguez J.V. Torregrosa Peritoneal Dialysis R. Selgas* M. Prez Fontn C. Remn M.E. Rivera Gorrin G. del Peso Clinical Nephrology M. Praga* J. Ara J. Ballarn G. Fernndez Jurez F. Rivera A. Segarra Arterial Hypertension R. Marn* J.M. Alczar L. Orte R. Santamara A. Rodrguez Jornet Haemodialysis A. Martn Malo* P. Aljama F. Maduell J.A. Herrero J.M. Lpez Gmez J.L. Teruel Diabetic Nephropathy F. de lvaro* J.L. Grriz A. Martnez Castelao J.F. Navarro J.A. Snchez Tornero R. Romero Nephropathy and Cardiovascular Risk J. Dez* A. Cases J. Luo Renal Transplantation J. Pascual* M. Arias J.M. Campistol J.M. Griny M.A. Gentil A. Torres Hereditary Nephropathies R. Torra* X. Lens J.C. Rodrguez Prez M. Navarro E. Coto V. Garca Nieto Quality in Nephrology F. lvarez-Ude* M.D. Arenas E. Parra Moncasi P. Rebollo F. Ortega Paediatric Nephrology I. Zamora* N. Gallego A.M. Snchez Moreno R. Vilalta Chronic Kidney Disease A.L. Martn de Francisco* A. Otero E. Gonzlez Parra I. Martnez J. Portols Prez Acute Renal Failure F. Liao* F.J. Gainza J. Lavilla E. Poch Nephropathology J. Blanco* I.M. Garca E. Vzquez Martul A. Barat Cascante
Evidence-Based Nephrology Vicente Barrio* (Director of Supplements), Fernando Garca Lpez (Methodology assessment), Editors: Mara Auxiliadora Bajo, Jos Conde, Joan M. Daz, Mar Espino, Domingo Hernndez, Ana Fernndez, Milagros Fernndez, Fabin Ortiz, Ana Tato. Continued Training (journal NefroPlus) Andrs Purroy*, R. Marn, J.M. Tabernero, F. Rivera, A. Martn Malo. * Coordinators of thematic area
EDITORIAL BOARD
A. Alonso J. Arrieta F.J. Borrego D. del Castillo P. Gallar M.A. Frutos D. Jarillo V. Lorenzo A. Mazuecos A. Oliet L. Pallardo J.J. Plaza D. Snchez Guisande J. Teixid J. Alsina P. Barcel J. Bustamente A. Darnell P. Garca Cosmes M.T. Gonzlez L. Jimnez del Cerro J. Lloveras B. Miranda J. Olivares V. Prez Baasco L. Revert A. Serra F.A. Valds F. Anaya A. Barrientos A. Caralps P. Errasti F. Garca Martn M. Gonzlez Molina I. Lampreabe B. Maceira J. Mora J. Ortuo S. Prez Garca J.L. Rodicio L. Snchez Sicilia A. Vigil J. Aranzbal G. Barril F. Caravaca C. de Felipe S. Garca de Vinuesa A. Gonzalo R. Lauzurica J.F. Macas E. Martn Escobar J.M. Morales R. Peces J.M. Tabernero A. Vallo G. de Arriba C. Bernis E. Fernndez Girldez F.J. Gmez Campder P. Gmez Fernndez E. Huarte E. Lpez de Novales R. Marcn J. Montenegro A. Palma L. Piera J. Rodrguez Soriano A. Tejedor
INTERNATIONAL COMMITEE BOARD

E. Burdmann (Brazil) B. Canaud (France) J. Chapman (Australia) R. Coppo (Italy) R. Correa-Rotter (Mexico) F. Coso (USA) G. Eknoyan (USA) A. Felsenfeld (USA) J.M. Fernndez Cean (Uruguay) J. Frazao (Portugal) M. Ketteler (Germany) Levin, Adeera (Canada) Li, Philip K.T. (Hong Kong, China) L. Macdougall (United Kingdon) P. Massari (Argentina) S. Mezzano (Chile) B. Rodrguez Iturbe (Venezuela) C. Ronco (Italy) J. Silver (Israel) P. Stevinkel (Sweden) A. Wiecek (Poland) C. Zoccali (Italy)
COUNCIL OF THE SPANISH SOCIETY OF NEPHROLOGY

SUBSCRIPTIONS, ADVERTISING AND PUBLISHING
Information and subscriptions: S.E.N. Secretary: revistanefrologia@senefro.org Tel: 902 929 210 Queries regarding of manuscripts: soporte@revistanefrologia.com Avda. dels Vents 9-13, Esc. B, 2. 1. Edificio Blurbis 08917 Badalona Tel. 902 02 09 07 - Fax. 93 395 09 95 Rambla del Celler 117-119, 08190 Sant Cugat del Valls. Barcelona Tel. 93 589 62 64 - Fax. 93 589 50 77 Distribuido por: E.U.R.O.M.E.D.I.C.E., Ediciones Mdicas, S.L. Copyright 2011. Grupo Editorial Nefrologa. All rights reserved. ISSN: 2013-2514 Sociedad Espaola de Nefrologa 2011. All international rights reserved. No part of this publication may be reproduced, stored in a retrieval system or transmitted in any form or by any means, mechanical, electronic, photocopying, recording or otherwise, without the prior written permission of the publisher. Nefrologa is distributed exclusively among medical professionals.
President: Dr. Alberto Martnez Castelao Vice-president: Dr. Isabel Martnez Secretary: Dr. Jos Luis Grriz Treasurer: Dr. Mara Dolores del Pino Ordinary members: Dr. Gema Fernndez Fresnedo Dr. Elvira Fernndez Girldez Dr. Julio Pascual Dr. Jos Mara Portols
Web Page of Nefrologa: E-mail Editor-in-Chief:
Director of Nefrologa Publishing Group: Dr. Carlos Quereda Rodrguez Chairperson of the Dialysis and Transplantation Registry: Dr. Ramn Saracho Chairpersons of Education and Research: Dr. Juan Francisco Navarro Dr. Josep Maria Cruzado Chairperson for selection of the SEN Congress presentations: Dr. Rosa Snchez Hernndez
Links: www.revistanefrologia.com revistanefrologia@senefro.org cquereda.hrc@salud.madrid.org
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Volume 31 - Number 2 - 2011
RULES OF PUBLICATION IN NEFROLOGIAGA

NEFROLOGA is the official publication from the Spanish Society of Nephrology (SEN) and is a cited reference in the Institute for Scientific Information Web of Knowledge (ISI-WOK). It is included in the bibliographic databases MEDLINE, EMBASE, IME, IBECS and SCIELO. The articles tables of contents are reproduced in Current Contents-Clinical Practice, Current Advances in Biological Sciences and other ISI publications. Full versions of the texts, (including English versions of regular issues) can be accessed from the NEFROLOGA Web site. Some full versions are also included in SciELO (scielo.isciii.es/scielo.php). The abstracts in English are found in Excerpta Medica and PubMed. NEFROLOGA publishes basic or clinical research papers associated with nephrology, arterial hypertension, dialysis and kidney transplantation. All articles undergo a peer revision process, and all original texts are both assessed internally and proof-read externally. NEFROLOGA endorses the publication rules used by the International Committee of Medical Journal Editors (ICMJE). The Journals main language of publication is Spanish, and articles written in English by non-Hispanic authors are accepted. All contents of the regular issues are also available in English, and are easily accessible on the Journal's Web site, along with the original version. NEFROLOGA publishes six issues per year (one every two months). There is also a Continuing Education edition (NEFROPLUS) and a series of special editions about topical subjects, such as EVIDENCE-BASED NEPHROLOGY issues. NEFROLOGA belongs to the Grupo Editorial Nefrologa publisher, which is a SEN member that manages printed and digital issues to publish scientific opinions regarding nephrology and continuing education in this area. All of the contents and additional material published in NEFROLOGA, NEFROPLUS and other editions from Nefrologa or Grupo Editorial Nefrologa are included on the NEFROLOGA Web site (www.revistanefrologia.com) (free access). Information regarding the method for sending papers and the complete rules of publication in the journal can be easily accessed from the site.
NORMAS PARA LA PUBLICACIN DE UN ARTCULO EN NEFROLOGA

NEFROLOGA es la publicacin oficial de la Sociedad Espaola de Nefrologa y est referenciada en la Web of Knowledge del Institute for Scientific Information (ISIWOK). Est incluida en las bases de datos bibliogrficas, MEDLINE, EMBASE, IME, IBECS y SCIELO. Los sumarios se reproducen en Current Contents-Clinical Practice, Current Advances in Biological Sciences y en otras publicaciones del ISI. Desde la propia Web de NEFROLOGA puede accederse a los textos ntegros, incluida la versin inglesa de los nmeros ordinarios; tambin los textos ntegros originales estn incluidos en SciELO (scielo.isciii.es/scielo.php). En Excerpta Medica y en PubMed se encuentran los resmenes en ingls. NEFROLOGA publica artculos de investigacin bsica o clnica relacionados con nefrologa, hipertensin arterial, dilisis y trasplante renal. Se rige por el sistema de revisin por pares, y todos los trabajos originales se someten a evaluacin interna y a revisiones externas. NEFROLOGA suscribe las normas de publicacin del International Committee of Medical Journal Editors (ICMJE). El idioma de la Revista es el espaol, y se admiten artculos en ingls de autores que no son de habla hispana. Todos los contenidos de los nmeros regulares disponen tambin de su versin a texto completo en ingls, de acceso libre en la Web de la Revista, al igual que la versin original. NEFROLOGA publica al ao 6 nmeros regulares, cada dos meses, y dispone de una edicin de Formacin Continuada (NEFROPLUS) y de una serie de suplementos y nmeros extraordinarios sobre temas de actualidad, incluyendo los nmeros de NEFROLOGA BASADA EN LA EVIDENCIA. NEFROLOGA se encuadra en el Grupo Editorial Nefrologa, rgano de la Sociedad Espaola de Nefrologa que coordina la produccin de ediciones impresas o en formato digital para transmisin de pensamiento cientfico nefrolgico y formacin continuada en Nefrologa. Todos los contenidos y material complementario publicados en NEFROLOGA, NEFROPLUS y otras ediciones de NEFROLOGA o del Grupo Editorial Nefrologa, se incluyen en el sitio Web de NEFROLOGA (www.revistanefrologia.com) de acceso libre y gratuito, en el que se especifican el procedimiento de envo y las normas completas requeridas para la publicacin de un artculo en la Revista.
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contents
Volume
31 - Number 2 - 2011
V o l u m e 3 1 N u m b e r 2 2 011
EDITORIALS
TRENDS RELATED TO IMR PLACES ASSIGNED TO NEPHROLOGY DIAGNOSTIC AND INTERVENTIONAL NEPHROLOGY
129 131
How can we make nephrology more appealing to junior doctors?

F. Ortega Surez
ADVANCES IN THE DIAGNOSIS OF TUBERCULOSIS INFECTION IN DIALYSIS PATIENTS SURVIVAL FOR PERITONEAL DIALYSIS VS HAEMODILYSIS AND VASCULAR CALCIFICATION MECHANISMS RELATIONSHIP BETWEEN LEPTIN AND CARDIOVASCULAR MORTALITY IN HEMODIALYSIS PATIENTS 25 HYDROXY VITAMIN D LEVELS IN PREDIALYSIS PATIENTS
Diagnostic and interventional nephrology: an opportunity for Spanish nephrologists

M. Rivera, C. Quereda
PLEUROPERITONEAL COMMUNICATION IN PATIENTS ON PERITONEAL DIALYSIS
rgano Oficial de la Sociedad Espaola de Nefrologa

Full version in English and Spanish at www.revistanefrologia.com
EDITORIAL COMMENTS
134 137 Autosomal dominant polycystic kidney disease and sickle cell trait
R. Peces, C. Peces
Advances in the diagnosis of latent tuberculosis infection in patients receiving renal replacement therapy
M. Arias Guilln, R. Palomar, M. Arias
SHORT REVIEWS
142 148 Vascular calcification: types and mechanisms
J.M. Valdivielso
Front page images. See page 227 of this issue. M. Martn et al. Delayed diagnosis of primary hyperoxaluria in a young patient with advanced chronic renal failure Nefrologa 2011;31(2):227-9. Panels A and B: Multinucleated giant cells with oxalate crystals. Panel C: Birefringent oxalate crystals under polarised light. Panel D: Star or rosette-shaped oxalate crystal deposits. Panel E: Refringent to polarised light. Panel F: Peripheral reaction and destruction of bone trabeculae.
New insights into the pathophysiology of oedema in nephrotic syndrome

H. Rondon-Berrios
SPECIAL ARTICLE
155 Trends in resident positions offered in nephrology (1985-2008)
C. Bernis Carro, Comisin Nacional de la Especialidad de Nefrologa en Espaa
ORIGINALS
162 Co-inheritance of autosomal dominant polycystic kidney disease and sickle cell trait in African Americans
R. Peces, C. Peces, E. Cuesta-Lpez, C. Vega-Cabrera, S. Azorn, V. Prez-Dueas, R. Selgas
169 174
Detection of latent tuberculosis infection in peritoneal dialysis patients: new methods

R. Palomar, M. Arias Guilln, C. Robledo, R. Agero, J. Agero, C. Rodrguez, l. Molinos, E. Rodrigo, F. Ortega, M. Arias
Current peritoneal dialysis compared with haemodialysis: of incident dialysis patients in the Canary Islands in recent years
medium-term
survival
analysis
J.M. Rufino, C. Garca, N. Vega, M. Maca, D. Hernndez, A. Rodrguez, B. Maceira, V. Lorenzo
185
Clinical and biochemical characteristics of predialysis patients in terms of 25 hydroxy vitamin D levels
I. Rodrguez Villarreal, O. Ortega, P. Gallar, M. Snchez, R. Callejas, C. Gracia, C. Garca la Calle, M. Ortiz, J.C. Herrero, C. Mon, A. Oliet, A. Vigil
192
Should a cystography be performed on all breastfeeding infants with mild to moderate dilatation of the urinary tract? Renal function can help to answer this question
V. Garca Nieto, S. Gonzlez Cerrato, V.E. Garca Rodrguez, O. Mesa Medina, M.J. Hernndez Gonzlez, M. Monge Zamorano, M.I. Luis Yanes
contents
Volume
31 - Number 2 - 2011
199 206
Dispositional optimism in patients on chronic haemodialysis and its possible influence on their clinical course
A.I. Morales Garca, M.D. Arenas Jimnez, A. Reig-Ferrer, F. lvarez-Ude, T. Malek, A. Moledous, M.T. Gil, E.M. Cotilla
Relationship between leptin and all-cause and cardiovascular mortality in chronic hemodialysis patients
J.J. Dez, M. Bossola, M.J. Fernndez-Reyes, E. di Stasio, L. Tazza, G. Luciani, R. Codoceo, P. Iglesias, A. Rodrguez, E. Gonzlez, R. Selgas
213
Pleuroperitoneal communication in patients on peritoneal dialysis One hospital's experience and a review of the literature
R. Daz Mancebo, G. del Peso Gilsanz, M. Rodrguez, B. Fernndez, M. Ossorio Gonzlez, M.A. Bajo Rubio, R. Selgas Gutirrez
LETTERS TO THE EDITOR A) Brief papers on basic research and clinical investigation
218 219 Risk factors for abdominal hernias in patients undergoing peritoneal dialysis
M. Gracia Toledo, M. Borrs Sans, A. Gabarrell, J. Durn, E. Fernndez Girldez
Successful pregnancy in a patient with chronic renal failure undergoing haemodialysis

K.R. Furaz Czerpak, A. Puente Garca, E. Corchete Prats, M.A. Moreno, R. Martn Hernndez
B) Brief case reports

221 223 Nephropathy following administration of angiogenesis inhibitors
A. Vello Romn, M. Samprn Rodrguez, B. Pazos Arias, C. Romero Reinoso, A. Peteiro Cancelo
First case of peritoneal infection due to Oerskovia turbata (Cellulosimicrobium funkei)

L. Betancourt Castellanos, E. Ponz Clemente, D. Fontanals Aymerich, C. Blasco Cabaas, D. Marquina Parra, C. Grau Pueyo, M. Garca Garca
225 226 227
A patient with acute renal failure and episcleritis, is there more than meets the eye?
A.P. Bernardo, J.M. Montalbn, E. Rocha
Severe ethanol poisoning treated by haemodialysis

J.O. Quispe Gonzales, B. Gmez Giralda, C. Ruiz-Zorrilla Lpez, M.I. Acosta Ochoa, K. Ampuero Anachuri, A. Molina Miguel
Delayed diagnosis of primary hyperoxaluria in a young patient with advanced chronic renal failure
M. Martn, G. Martn Reyes, A. Torres de Rueda, R. Toledo Rojas, C. Jironda, I. Garca, T. Garca de la Oliva, M.L. Prez Vaca, D. Hernndez
229 231 233 234 236 238
Diagnosis of secondary hypertension causing miscarriage during the first trimester of pregnancy
O. Fikri Benbrahim, R. Garca Agudo, F. Cazalla Cadenas, A. Martnez Calero, J. Gonzlez-Spnola
Flare lupus during induction teraphy with ciclophosphamide in difusse proliferative lupus nephritis
M. Heras, A. Saiz, M.J. Fernndez-Reyes, R. Snchez, P. Zurita, C. Urrego
Multiple myeloma, severe hypercalcaemia, acute renal failure and multiple organ failure due to calcicosis
J.G. Martnez Mateu, G.P. Losada Gonzlez, M.A. Munar Vila, M. Uriol Rivera, G. Gmez Marqus, A.C. Tugores
Rapidly progressive renal failure as the onset of an IgA nephropathy in an elderly patient
M. Heras, A. Saiz, J. Pardo, M.J. Fernndez-Reyes, R. Snchez, F. lvarez-Ude
Cytomegalovirus-associated haemophagocytic syndrome in a kidney transplant patient

S. Bea Granell, I. Beneyto Castello, D. Ramos Escorihuela, J. Snchez Plumed, P. Snchez Prez, J. Hernndez-Jaras, S. Rivas
Partial recovery of kidney function for an autologous transplant in a patient with chronic kidney disease and multiple myeloma
R.M. de Alarcn Jimnez, S. Roca Meroo, G.M. lvarez Fernndez, M.A. Garca Hernndez, M.J. Navarro Parreo, C. Jimeno Gri, E. Zarco Pedrinaci, M. Molina Nez
List of misprints
2011 Revista Nefrologa. Official Publication of the Spanish Nephrology Society
editorials
See the special article on page 155
How can we make nephrology more appealing to junior doctors?

F. Ortega Surez
Chairman of the Spanish Nephrology Commission. Area Manager for Clinical Nephrology, Urology and Bone-Mineral Metabolism. Asturias Central Hospital. Oviedo, Spain
Nefrologia 2011;31(2):129-30
doi:10.3265/Nefrologia.pre2011.Feb.10842
ver the past thirty-odd years, Spanish nephrology has experienced a rollercoaster ride with regards the number of nephrology specialists, with numbers plummeting and rocketing on various occasions. Since the middle of this decade, we are to experience a surplus of specialists again, if we do not correct the problem immediately. The Spanish Nephrology Commission (Comisin Nacional de la Especialidad de Nefrologa) has put forward two options to resolve this situation. Firstly, considering available data, it has considered drastically reducing the number of internal medicine residency (IMR) positions assigned to nephrology, initially from 93 (a number that the Commission itself had deemed appropriate) to 59, to further reduce it to forty-something. On the other hand, it is planning on examining the matter further to have better scientific grounds for decision making. This issue of Nefrologa has published an article on this matter: Trends in resident positions offered in nephrology (1985-2008),1 by Carmen Berns Carro, Spanish Nephrology Commission (President: F. Ortega Surez. Vice president and Secretary: C. Quereda Rodrguez-Navarro. Members: A. Martnez Castelao, J.A. Grriz Teruel, R. Matesanz Acedos, A. Sans Boix, P. Abigar Luquin, A. Snchez Casajs, C. Bernis Carro, I. Auyanet Saavedra, M.J. Prez Sez). The articles main objective was to report the trends related to the importance of nephrology, considering junior doctors
preference towards choosing nephrology for their IMR training. As such, one of the conclusions reached was that graduated doctors are less and less interested in choosing nephrology. This phenomenon, which also occurs in the USA and several other European Union countries, has been caused by many factors: 1. Lack or poor information given at university level. 2. Nephrology is considered as a complicated and demanding training area; however, nephrology training programmes are perceived as excellent training for junior resident doctors in many specialisation areas (although there are some gaps). 3. Nephrology is not well-paid; there are very little possibilities of working for the private sector, and significant work load. 4. In general, junior doctors are not likely to gain the most fulfilling experience in a hospital department as all positions are already filled. Therefore, a vast proportion of young nephrologists are having to work in outpatient haemodialysis centres or on-duty programmes, where in some cases they unfortunately have very little contact with the hospital departments. 5. Dialysis has also been described as not being very rewarding, as it offers very poor quality of life to patients (the opposite of what is said when working with kidney transplantation, glomerulonephritis and kidney physiology problems). 6. Dependence on other departments (e.g. vascular surgery). Financial factors are not deemed of utmost importance for changing this situation, although we must consider the following work styles2-6:
129
Correspondence: Francisco Ortega Surez Presidente de la Comisin Nacional de la Especialidad. Nefrologa. Director del rea de Gestin Clnica de Nefrologa. Urologa y Metabolismo seo y Mineral. Hospital Universitario Central de Asturias, Oviedo, Spain fortega@hca.es
editorials
1. Evidence-based medicine. 2. Clinical and basic research incorporated into daily nephrology departments routines. 3. Greater clinical independence, and recovery of aspects that are often forgotten (acute kidney failure, kidney biopsy, etc.). 4. Reintroduce a greater weighting of transplant patients, primary and secondary nephrology disorders, hydroelectrolyte disorders and acid-base balance, calcium-phosphorus metabolism problems, as well as all types of dialysis patients. 5. Improved coordination with outpatient centres and primary care. 6. Improved education, i.e. showing university medical students (in theoretical and practical classes) what they could learn if they were to choose nephrology. 7. Adjusting the number of quality work positions offered in accordance with demand.
F. Ortega Surez. Making nephrology more appealing to junior doctors
REFERENCES
1. Bernis C por la Comisin Nacional de la Especialidad de Nefrologa en Espaa (F. Ortega Surez, C. Quereda Rodrguez-Navarro, A. Martnez Castelao, JA Grriz Teruel, R. Matesanz Acedos, A. Sans Boix, P. Abigar Luquin, A. Snchez Casajs, I. Auyanet Saavedra, M.J. Prez Sez). Evolucin de las plazas asignadas a nefrologa en la convocatoria MIR (1985-2008). Nefrologia 2011;31(2):155-61. 2. Lane CA, Healy C, Ho MT, et al. How to attract a nephrology trainee: quantitative questionnaire results. Nephrology 2008;13:116-23. 3. Lane CA, Brown MA. Nephrology: a specialty in need of resuscitation? Kidney Int 2009;76:594-6. 4. Thornton J, Esposto F. How important are economic factors in choice of medical specialty? Health Econ 2003;12:67-73 5. De Francisco ALM, Piera C. NEPHROLOGY AROUND EUROPE: Organization models and management strategies: Spain. J Nephrology (in press). 6. Berns JSA. Survey-Based Evaluation of Self-Perceived Competency after Nephrology Fellowship Training. Clin J Am Soc Nephrol 2010;5:490-6.
EDITORS NOTE
The content of that Editorial and the article on page 155 are without a doubt extremely important for the future of Spanish nephrology. The editors therefore invite Spanish nephrologists to send their opinions and observations on the matter, using the Letters to the editor format.
Sent for review: 11 Feb. 2011 | Accepted: 11 Feb. 2011 130 Nefrologia 2011;31(2):129-30
editorials
Diagnostic and interventional nephrology: an opportunity for Spanish nephrologists

M. Rivera, C. Quereda
Nephrology Department. Ramn y Cajal Hospital. IRYCIS. Madrid, Spain
Nefrologia 2011;31(2):131-3
alf-way through the 20th century, nephrologists were responsible for numerous milestones, leading us to modern nephrology as we know it today. Nephrologists have designed and developed instruments that are fundamental for our speciality, such as renal biopsy,1 the first haemodialysis shunt,2 double lumen catheters,3 the first arteriovenous fistula for haemodialysis,4 the first tunnelled catheter for peritoneal dialysis,5 and laparoscopic catheter placing.6 Furthermore, Dr J Holmes, considered the father of diagnostic ultrasound,7 was also a nephrologist. However, as dialysis treatment progressed, nephrologists stopped performing interventions on their patients, to the advantage of other specialities (surgeons and radiologists, mainly) yet to the detriment of overall patient care. A clear example is the significant increase in the number of patients that received dialysis through a permanent catheter or a synthetic bypass, compared with those that have received an arteriovenous fistula, during recent decades.8 Kidney patient care was therefore fragmented, being placed into the hands of other specialists, who did not fully understand the reality of kidney diseases. Furthermore, as reported by ONeill,9 we nephrologists started to spend more time on the telephone, asking for tests, than solving our patients problems. In 2000, a group of American nephrologists, aware of this controversial situation, decided to create the American Society of Diagnostic and Interventional Nephrology (ASDIN)10 so as to defeat the apathy that had developed. Its objective was for nephrologists to regain leadership, promoting the appropriate application of their techniques, that they themselves had developed, and to improve
nephrology patients care. This Society strives to promote interventional nephrology within nephrology services and has presented an annual congress since 2005. It also has a section in the journal Seminars in Dialysis, where its original articles are published. Since 2004, the International Society of Nephrology created the Interventional Nephrology Committee with the aim of promoting and addressing issues related with this new discipline, such as healthcare provision and training.11
INTERVENTIONAL NEPHROLOGY IN THE WORLD Diagnostic and interventional nephrology is expanding in the United States. This discipline is being included more frequently as a permanent feature of courses and congresses, such as the Annual Scientific Meeting of the American Society of Nephrology, which has been taking place since 2000.12 Hospitals offering training under this subspeciality have also increased notably in North America. However, according to a recent survey published on this matter,13 there still are not enough hospitals and even fewer are ASDINaccredited.14-16 Interest is also growing in Latin America. Countries such as Puerto Rico, Peru, Brazil, Mexico, Colombia, Argentina and Venezuela have been incorporating interventional nephrology into their daily healthcare and in scientific meetings.17,18 The Latin American Society of Nephrology and Hypertension considers interventional nephrology as a discipline in itself and has its own interventional nephrology advisory committee.19 Europe, on the other hand, is more interested in diagnosis than intervention, i.e. introducing ultrasound to nephrology. We can assume this fact because ultrasound has featured occasionally in European Dialysis and Transplant Association pre-congress courses. However, very few studies conducted by nephrologists are presented in congresses or published in the Nephrology Dialysis and Transplantation journal.
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Correspondence: Maite Rivera Servicio de Nefrologa. Hospital Ramn y Cajal. IRYCIS. Carretera de Colmenar km 9,100. 28034 Madrid. Spain. mriverag.hrc@salud.madrid.org mriverago@gmail.com
editorials
INTERVENTIONAL NEPHROLOGY IN SPAIN This subspeciality has hardly been developed in Spain. Although we are aware that there are numerous interventional nephrologists in Spain and that several departments boast an ultrasound machine, very few have published their experiences on performing fistula for haemodialysis,20 placing tunnelled catheters,21,22 ultrasoundguided renal biopsy,23 or peritoneal dialysis catheters.24,25 However, there are brilliant, consolidated initiatives for diagnostic ultrasound for vascular access.26 Lastly, in recent years we have learnt that kidney disease is an independent cardiovascular risk factor, and if attended to at early stages, nephrologists may have more treatment variables available, crucially influencing patient survival and quality of life. Therefore, kidney patients diagnosis and follow-up should not only involve examining renal anatomy, but also evaluate the cardiovascular risk, by measuring the carotid intima-media thickness, for example.27-30 This aspect is being actively researched in an important Spanish multicentre study, which is supported by the Spanish Society of Nephrology (S.E.N.).31 We have had a diagnostic and interventional ultrasound unit at the Servicio de Nefrologa (Nephrology Department) of the Ramn y Cajal Hospital since 1991.22-35 From this moment onwards, we have been able to examine our patients (those suffering from kidney diseases and transplant recipients) using conventional ultrasound, later implementing Doppler imaging. Our initial idea was to recover the renal biopsy technique, but, in our experience, incorporating these diagnostic procedures in the nephrology departments daily routine has been extremely useful. It is an important tool for diagnosing and monitoring patients suffering from clinical kidney diseases, high blood pressure, or receiving kidney transplants. Since 1995, we have been surgically implanting catheters for peritoneal dialysis. Since 2010, we have been evaluating the vascular access using ultrasound (pre- and post-surgery) and placing transitory central catheters using real-time ultrasound. Lastly, in our department, we also perform minor surgery, such as removing Schon tunnelled catheters (which was previously performed by vascular surgeons), repairing peritoneal catheters and draining abscesses. Interest with regards diagnostic and interventional nephrology is growing in Spain, something which is reflected in the number of courses taking place.36,37
M. Rivera et al. Diagnostic and interventional nephrology:
not the case, as we are relieving other specialities of numerous examinations and interventions, which may be of the utmost importance to us, but are less of a priority for them. In either case, there should be consensus with regard to interventional nephrology throughout the hospital so that it benefits the patients. Another disadvantage, in our opinion, is that more focus is given to interventional nephrology than other areas. In our hospital there is a nephrologist who organises the Unidad de Nefrologa Diagnstica e Intervencionista (diagnostic and interventional nephrology unit), which is integrated by other nephrologists from the department. Each one is not only responsible for a given nephrology area, but also performs interventions. Given that they are continuously in contact with their patients, techniques are performed more swiftly. We have standardised each and every one of the activities performed in our department to avoid outcome variability. Lastly, excessive workload is one of the main reasons for diagnostic ultrasound and interventional techniques being included as part of our routine. This has therefore improved the situation for other specialities (e.g. cardiology) by increasing staff.
CONCLUSION Diagnostic and interventional nephrologists provide complete, rapid treatment to resolve problems associated with kidney diseases. We are able to recover diagnostic and treatment techniques from other specialists. If nobody is able to imagine a cardiologist living without an ultrasound machine or a cath lab, then maybe it would not be so difficult to envisage a new type of nephrologist, who would be a master of ultrasound, perform renal ultrasounds and vascular mapping of the upper extremity to gain vascular access, perform ultrasound-guided biopsy and provide early diagnosis for vascular access complications. Nephrologists would also be responsible for starting dialysis programmes, as it would be them who place tunnelled catheters for haemodialysis and the peritoneal catheter or perform arteriovenous fistula surgery. Furthermore, they would be capable of evaluating chronic kidney patients cardiovascular risk, adapting treatments to these parameters throughout the diseases development. To achieve these goals, nephrologists must complete training in experienced centres and scientific societies must create training programmes and establish the minimum accreditation requirements. In this respect, we recognise the S.E.N.s interest in promoting this type of programme. In Spain, the national commission for this speciality should assess whether these skills should be included in the nephrologists training programme. This new approach to
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DISADVANTAGES AND OBSTACLES Our first obstacle is that we must overcome the assumption that we are stepping into other specialists fields, which is
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21. Royo P, Garca-Testal A, Soldevila A, Panadero J, Cruz JM. Catteres tunelizados. Complicaciones en su insercin. Nefrologa. 2008;28:543-8. 22. Ibrik O, Samon R, Roca R, Viladoms J, Mora J. Catteres tunelizados para hemodilisis tipo sistema Tesio de catteres gemelos mediante tcnica ecodirigida. Anlisis retrospectivo de 210 catteres. Nefrologa. 2006;26:719-25. 23. Toledo K, Prez MJ, Espinosa M, Gmez J, Lpez M, Redondo D, et al. Complicaciones asociadas a la biopsia renal percutnea. Experiencia en Espaa 50 aos despus. Nefrologa. 2010;30:539-43. 24. Lanuza M, Minguela JI, Rodado R, Muriel J, Ruiz-de-Gauna R. Our nine-year experience with the self-locating catheter: comparison of malfunction rate with other Tenckhoff catheter variants. Int J Artif Organs. 2006;26:138-41. 25. De lvaro F, Selgas R, Bajo MA, Serrano P, Fernndez-Reyes MJ, Del Peso G, et al. Moncriefs technique for peritoneal catheter placement: experience of a CAPD unit. Adv Perit Dial. 1994;10:199-202. 26. Ibeas J, Vallespn J, Rodrguez-Jornet A, Branera J, Fortuo JR, Bermdez P, et al. Portable Doppler-ultrasound used by the nephrologist in the hemodialysis Unit for the immediate detection of fistula pathology and ultrasound guided cannulation: consolidation of a technique incide a protocolized interdisciplinary team with vascular surgeons, interventional radiologists and infirmary. A 4 years experience. J Am Soc Nephrol. 2008;19:254A. 27. Junyent M, Martnez M, Borrs M, Betriu A, Coll B, Craver L, et al. Utilidad de las tcnicas de imagen y biomarcadores en la prediccin del riesgo cardiovascular en pacientes con enfermedad renal crnica en Espaa: Proyecto NEFRONA. Nefrologa. 2010;30:119-26. 28. Sarnak MJ, Levey AS, Schoolwerth AC, Coresh J, Culleton B, Hamm LL, et al. Kidney disease as a risk factor for development of cardiovascular disease: a statement from the American Heart Association Councils on Kidney in Cardiovascular Disease, High Blood Pressure Research, Clinical Cardiology, and Epidemiology and Prevention. Circulation. 2003;108:2154-69. 29. Go A, Chertow GM, Fan D, McCullough CE, Hsu CY. Chronic Kidney disease and the risks of death, cardiovascular events and hospitalization. N Engl J Med. 2004;351:1296-305. 30. Weiner DE, Tighiouart H, Amin MG, Stark PC, McLeod B, Griffith JL, et al. Chronic kidney disease as a risk factor for cardiovascular disease and all-cause mortality: a pooled analysis of community-based studies. J Am Soc Nephrol. 2004;15:1307-15. 31. Fernndez E, Martnez-Castelao A. Proyecto NEFRONA: banco de datos de libre utilizacin. Nefrologa. 2011;31:5-8. 32. Rivera M, Merino JL, Puig-Hooper C, Marcen-Letosa R, Rodrguez JR, Liao F, et al. Interventional Nephrology: A One-Center Experience for 15 Years. J Am Soc Nephrol. 2006;17:754A. 33. Rivera M. Incorporacin de la ecografa a la prctica rutinaria del nefrlogo: nuestra experiencia. Nefrologa. 1995;15:104-7. 34. Rivera M, Ortuo J. Ultrasonography in Nephrology. Am J Kidney Dis. 1998;32:703. 35. Rivera M, Quereda C. La ecografa realizada por el nefrlogo: nuestra experiencia. NefroPlus. 2009;2:9-16. 36. http://www.seacv.es/congresos/V_CURSO_ECO_V8.pdf 37. www.nefrosur.com/index.php?option=com_content&view=category&layout=blog&id=18&
nephrology may make this discipline more attractive to future resident junior doctors.
REFERENCES
1. Iversen P, Brun C. Aspiration biopsy of the kidney. Am J Med. 1951;11:324-30. 2. Quinton WE, Dillard DH, Cole JJ, Scribner BH. Eight months experience with silastic-teflon bypass cannulas. Trans Am Soc Artif Int Organs. 1962;8:236-45. 3. Uldall PR, Dyck RF, Woods F, Merchant N, Martin GS, Cardella CJ, et al. A subclavian cannula for temporary vascular access for haemodialysis and plasmapheresis. Dial Transplant. 1979;8:963-8. 4. Brescia MJ, Cimino JE, Appel K, Hurwich BJ. Chronic hemodialysis using venipuncture and surgically created arteriovenous fistula. N Engl J Med. 1966;275:1089-92. 5. Tenckhoff H, Schechter H. A bacteriologically safe peritoneal access device. Trans Am Soc Artif Int Organs. 1968;14:181-7. 6. Ash SR. Bedside peritoneoscopic peritoneal catheter placement of Tenckhoff and newer peritoneal catheters. Adv Peritoneal Dial. 1998;14:75-9. 7. Holmes JH. Early diagnostic ultrasonography. J Ultrasound Med. 1983;2:33-43. 8. Ethier J, Mendelssohn DC, Elder SJ, Hasegawa T, Akizawa T, Akiba T, et al. Vascular access use and outcomes: an international perspective from the dialysis outcomes and practice patterns study. Nephrol Dial Transplant. 2008;23:3219-26. 9. ONeill C. The new Nephrologist. Am J Kidney Dis. 2000;35:978-9. 10. www.asdin.org 11. http://www.isn-online.org/isn/society/about/isn_20016.html 12. http://www.asn-online.org/education_and_meetings/renal_week/archives/ 13. Berns JS, ONeilL WC. Performance of Procedures by Nephrologists and Nephrology Fellows at U.S. Nephrology Training Programs. Clin J Am Soc Nephrol. 2008;3:941-7. 14. Niyyar VD, Work J. Interventional Nephrology: Core Curriculum 2009. Am J Kidney Dis. 2009;54:169-82. 15. ONeill WC, Ash SR, Work J, Saad TF. Guidelines for Training, Certification, and Accreditation for Hemodialysis Vascular Access and Endovascular Procedures. Semin Dial. 2003;16:173-6. 16. Teitelbaum I, Burkar J. Core Curriculum in Nephrology Peritoneal Dialysis. Am J Kidney Dis. 2003;42:1082-96. 17. Nascimento MM, Chula D, Campos R, Nascimento D, Riella MC. Interventional Nephrology in Brazil: Current and Future Status. Semin Dial 2006;19:172-5. 18. Torre Len F, Rivera Bermdez C, Hernndez V, Silva J, Santiago Delpn E. Interventional Nephrology in Puerto Rico. Semi Dial. 2006;19:176-9. 19. http://www.slanh.org 20. Garca-Tro G, Alonso M, Saavedra J, Cigarrn S, Lamas JM. Gestin integral del acceso vascular por los nefrlogos. Resultados de tres aos de trabajo. Nefrologa. 2007;27:335-9.
Sent for review: 1 Feb. 2011 | Acepted: 4 Feb. 2011 Nefrologia 2011;31(2):131-3 133
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Autosomal dominant polycystic kidney disease and sickle cell trait

R. Peces1, C. Peces2
1 2
Nephrology Department. La Paz University Hospital. IdiPAZ. Madrid, Spain Information Technology Division. SESCAM. Toledo, Spain
Nefrologia 2011;31(2):134-6
doi:10.3265/Nefrologia.pre2011.Jan.10773
acroscopic haematuria due to the rupture of renal cysts is a common manifestation of autosomal dominant polycystic kidney disease (ADPKD). Many patients with ADPKD have frequent episodes of haematuria or evidence of intracystic haemorrhage throughout the progression of the disease. 1 The presence of sickle cell trait (Hb AS) is also accompanied by manifestations in the kidney, particularly haematuria, and papillary necrosis is the most frequent cause of macroscopic haematuria in heterozygous carriers of this haemoglobinopathy. 2-6 In one study, macroscopic haematuria was the cause for 4% of all hospital admissions of Afro-Americans with sickle cell trait. 7 As such, it is not surprising that the simultaneous inheritance of both genetic diseases can create a synergy with regard to the appearance of these haemorrhagic complications. Despite the fact that the association of these two hereditary diseases, ADPKD and sickle cell trait, was first recorded in the 1990s, when a study suggested that Afro-American patients with ADPKD and sickle cell trait could develop chronic renal failure (CRF) early in life, 8,9 only recently was it pointed out that sickle cell trait is a risk factor for the development of chronic kidney disease in a population of Afro-Americans with CRF.10,11 Haemoglobin S is the result of glutamic acid being replaced by valine as the sixth amino acid in the beta globin chain, which produces a haemoglobin tetramer (alpha2/beta S2) that is poorly soluble when
Correspondence: Ramn Peces Servicio de Nefrologa. Hospital Universitario La Paz. IdiPAZ. Madrid. Spain cpeces@varnetmail.com 134
deoxygenated. 4 Polymerisation of this type of deoxyhaemoglobin (HB S) is essential to vaso-occlusive phenomena. 4,7,12,13 The polymer assumes the form of an elongated fibre that becomes aligned with other fibres, resulting in the distortion of the erythrocyte into the classic crescent-moon or sickle shape, and a drastic reduction in the flexibility of the cell. The common renal manifestations of this disease in homozygous individuals (Hb SS) include defects in urine concentrations (altered counter current mechanism), distal renal tubular acidosis, abnormal proximal tubular function, and in early stages, increased glomerular filtration rate. 14,15 The primary cause of these symptoms appears to be the deformation of erythrocytes (which adopt the sickle shape) in the vasa recta capillaries of the renal medulla. It is well established that dehydration, acidosis, decreased oxygen pressure, and high osmolarity are the primary triggers for erythrocytes to adopt the sickle shape. The normal medullary medium plays an important role in this process, as it has a low oxygen pressure and high osmolarity. Furthermore, blood flow in vasa recta capillaries is much slower than in cortical vessels, leading to a longer transit time. Congestion and stasis in vasa recta capillaries can cause focal haemorrhage and necrosis. Finally, these processes can lead to interstitial inflammation and fibrosis, tubular atrophy, and papillary infarctions due to vascular lesions. These lesions are more severe in patients with Hb SS genotypes than in Hb AS carriers. In very early stages, the physiopathology of hyperfiltration is believed to be attributed to the vasculopathy associated with haemolysis more than vaso-occlusive processes related to viscosity. 14,15 In order to control haematuria resulting from papillary necrosis, several different medical treatments have been used, such as administering vasopressin, tranexamic acid, and oral urea, or direct haemostasis over the affected papillae, which includes the use of laser treatment.4,16-19
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infarction, and sudden death. 4,7,12,13,20 Some of these events can occur during conditions of extreme physical stress, and are occasionally attributed to vaso-occlusive crises, suggesting that, although sickle cell trait is usually quiescent, it is not always benign. Sickle cell trait is associated with health deterioration in terms of urine concentration, haematuria, and renal papillary necrosis. 21 A less common cause of haematuria in these cases is renal medullary carcinoma, which is a tumour that is almost exclusively found in Hb AS patients. 22 Although sickle cell trait alone may not be sufficient for the development of chronic kidney disease, it could contribute to the progression of CRF in the presence of additional factors such as ADPKD, diabetes, and hypertension. Since patients with sickle cell trait and diabetes mellitus are prone to suffering from papillary necrosis and episodes of haematuria, 23,24 it is possible that the pathophysiological factors induced by sickle cell trait could exacerbate the microvascular complications that arise from diabetes mellitus. Meanwhile, it is unknown if sickle cell trait patients have an increased risk of developing microvascular complications associated with diabetes mellitus. Recently, association with sickle cell trait has been recognised as an indicator of poor prognosis in diabetic patients, and patients with African heritage develop renal failure on average 10 years earlier than Caucasian patients.
Sickle cell disease (Hb SS) affects approximately 300 000 live births per year. 4,7 The prevalence of sickle cell trait is approximately 8%-10% in Afro-Americans, 4 and can be as high as 25%-30% in certain areas of western Africa. 4,7 Roughly 2.5 million people in the USA and 30 million people in the world are heterozygous for the gene that causes sickle cell disease. The presence of sickle cell trait (Hb AS), the most common haemoglobinopathy in the United States, is estimated to be 40 to 50 times more common than sickle cell anaemia (Hb SS), and is particularly prevalent among individuals that descend from Sub-Saharan Africa, India, Saudi Arabia and Mediterranean countries. 4,7 With the current patterns of global migration, the number of carriers of the sickle cell haemoglobin gene is increasing in Europe, and is estimated to be around 1% of the total population. As such, many European countries have introduced early detection programmes for haemoglobinopathies in newborn infants. Sickle cell trait is a benign disorder with no haematological manifestations in the heterozygous carrier, since the morphology of the erythrocytes, red blood cell indices, reticulocyte count, and peripheral blood smears are normal. In spite of the generally benign nature of Hb AS, several different potentially severe complications have been described. For instance, Hb AS carriers can develop rhabdomyolysis, heat stroke, acute renal failure, papillary necrosis, splenic
KEY CONCEPTS
1. Sickle cell trait (Hb AS) is a benign disorder carried by heterozygous individuals, with no haematological manifestations. The morphology of erythrocytes, red blood cell indices, reticulocyte counts, and peripheral blood smears are all normal. 2. Dehydration, acidosis, reduced O2 pressure, and high osmolarity are the primary triggers for the sickle shape taken by erythrocytes in the vasa recta capillaries. 3. Hb AS is associated with deteriorating urine concentrations, haematuria, and renal papillary necrosis. 4. Simultaneous inheritance of sickle cell trait and ADPKD can create a synergy, causing recurrent haematuria. 5. In Afro-American patients with ADPKD, sickle cell trait must be ruled out. 6. Although the existence of sickle cell trait alone may not be enough for developing chronic kidney disease, it could contribute to the progression of CRF in the presence of other factors such as ADPKD, diabetes, and arterial hypertension.
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REFERENCES
1. Masoumi A, Reed-Gitomer B, Kelleher C, Bekheirnia MR, Schrier RW. Developments in the management of autosomal dominant polycystic kidney disease. Ther Clin Risk Manag 2008;4:393-407. 2. De Jong PE, Statius Van Eps LW. Sickle cell nephropathy: new insights into its pathophysiology. Kidney Int 1985;27:711-7. 3. Allon M. Renal abnormalities in sickle cell disease. Arch Intern Med 1990;150:501-4. 4. Kiryluk K, Jadoon A, Gupta M, Radhakrishnan J. Sickle cell trait and gross hematuria. Kideny Int 2007;1:706-10. 5. Niang A, Diouf B, Ndiaye/Sene FS, Fall S, Moreira/Diop T. Sickle cell disease and the kidney. Saudi J Kidney Dis Transpl 2004;15:180-4. 6. WHO. Sickle-cell Anaemia. Report by the Secretariat. Fifty-ninth World Health Assembly. 2 April, 2006. 7. Shaw C, Sharpe CC. Could sickle cell trait be a predisposing risk factor for CKD? Nephrol Dial Transplant 2010;25:2403-5. 8. Yium J, Gabow P, Johnson A, Kimberling W, Martnez-Maldonado M. Autosomal dominant polycystic kidney disease in blacks: clinical course and effects of sickle-cell hemoglobin. J Am Soc Nephrol 1994;4:1670-4. 9. Kimberling WJ, Yium JJ, Johnson AM, Gabow PA, Martnez-Maldonado M. Genetic studies in a black family with autosomal dominant polycystic kidney disease and sickle-cell trait. Nephron 1996;72:595-8. 10. Derebail VK, Nachman PH, Key NS, Ansede H, Falk RJ, Kshirsagar AV. High prevalence of sickle cell trait in african americans with ESRD. J Am Soc Nephrol 2010;21:413-7. 11. Cavanaugh KL, Lanzkron S. Time to recognize an overlooked trait. J Am Soc Nephrol 2010;21:385-6. 12. Tsaras G, Owusu-Ansah A, Boateng FO, Amoateng-Adjepong Y. Complications associated with sickle cell trait: a brief narrative review. Am J Med 2009;122:507-12. 13. Funakoshi H, Takada T, Miyahara M, Tsukamoto T, Noda K, Ohira Y,
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14.
15. 16.
17.
18. 19.
20. 21.
22.
23.
24.
et al. Sickle cell trait as a cause of splenic infarction climbing mt. Fuji. Intern Med 2010;49:1827-9. Haymann JP, Stankovic K, Levy P, et al. Glomerular hyperfiltration in adult sickle cellanemia: a frequent hemolysis associated feature. Clin J Am Soc Nephrol 2010;5:756-61. Hirschberg R. Glomerular hyperfiltration in sickle cell disease. Clin J Am Soc Nephrol 2010;5:748-9. Baldree LA, Ault BH, Chesney CM, Stapleton FB. Intravenous desmopressin acetate in children with sickle trait and persistent macroscopic hematuria. Pediatrics 1990;86:238-43. Moudgil A, Kamil ES. Protracted, gross hematuria in sickle cell trait: response to multiple doses of 1-desamino-8-D-arginine vasopressin. Pediatr Nephrol 1996;10:210-2. Pariser S, Katz A. Treatment of sickle cell trait hematuria with oral urea. J Urol 1994;151:401-3. Herard A, Colin J, Youinou Y, et al. Massive gross hematuria in a sickle cell trait patient with renal papillary necrosis. Conservative approach using a balloon ureteral catheter to tamponade the papilla bleeding. Eur Urol 1998;34:161-2. Scheinman JI. Sickle cell disease and the kidney. Nat Clin Pract Nephrol 2009;5:78-88. Connes P, Hardy-Dessources MD, Hue O. Counterpoint: sickle cell trait should not be considered asymptomatic and as a benign condition during physical activity. J Appl Physiol 2007;103:2138-40. Dimashkieh H, Choe J, Mutema G. Renal medullary carcinoma: a report of 2 cases and review of the literature. Arch Pathol Lab Med 2003;127:e135e138. Ajayi AA, Kolawole BA. Sickle cell trait and gender influence type 2 diabetic complications in African patients. Eur J Intern Med 2004;15:312-5. Bleyer AJ, Reddy SV, Sujata L, et al. Sickle cell trait and development of microvascular complications in diabetes mellitus. Clin J Am Soc Nephrol 2010;5:1015-20.
Sent for review 11 Dec. 2010| Accepted 17 Jan. 2011 136 Nefrologia 2011;31(2):134-6
editorial comments
See original article on page 169
Advances in the diagnosis of latent tuberculosis infection in patients receiving renal replacement therapy
M. Arias Guilln1, R. Palomar2, M. Arias2
Servicio de Neumologa. Hospital Universitario Central de Asturias-INS. Oviedo, Asturias, Spain Servicio de Nefrologa. Hospital Marqus de Valdecilla. Universidad de Cantabria. ISCIII (REDINREN 06/16). Fundacin Marqus de Valdecilla-IFIMAV. Santander, Spain
1 2
Nefrologia 2011;31(2):137-41
fter many years without any new developments in this field, new diagnostic tools have recently been incorporated in both the latent phase and in the active infection phase. New methods were required in the study of the general population to improve the existing arsenal, and in the case of the renal patient, especially in advanced stages and in replacement therapy, the need for improvement was evident. As a result of the publication in this issue of the Journal on a study analysing the results of a comparison between the tuberculin skin test (TST) and new in vitro diagnostic methods for the detection of latent tuberculosis infection (LTBI), we will summarise the potential impact of these methods on the treatment of renal disease patients in these Editorial Comments.
because even though TB is a notifiable disease, it is estimated that at least one-third of the cases go unreported. According to the Registry of the Spanish Society of Nephrology (S.E.N.), the incidence of patients receiving renal replacement therapy (RRT) in 2009 was 129 patients per million population (pmp), with the majority (85%) in haemodialysis (HD), 12% in peritoneal dialysis (PD) and 2.8% with pre-dialysis kidney transplant (KT). The prevalence was 1039.4 patients pmp, with 47.67% in HD, 4.8% in PD and 47.51% with functioning grafts. Although the incidence of patients receiving RRT has remained stable over the last ten years in Spain, there are differences between the different regions of the country. In Europe, the incidence varies from 94.6 to 263 patients pmp, and the prevalence between 64.9 and 1115.1 patients pmp, so we are in the average range compared to surrounding countries.3 It is clear that transplant patients, who are immunocompromised, as well as those undergoing dialysis, which causes uraemiarelated alterations in the immune system, present a state of immunodeficiency that makes them more susceptible to infection. These alterations primarily affect cellular immunity,4 including the decreased proliferative response of the lymphocytes, Interleukin-2 deficit, peripheral Blymphocyte deficiency and the increase in cellular apoptosis.5-7 As LTBI is characterised by a significant cellular immune response (in the absence of detectable mycobacteria), the alteration of this response could lead to an increase in the reactivation of TB in uraemic patients and a hyporesponse in the tests based on delayed hypersensitivity.
TUBERCULOSIS DISEASE TODAY According to data from the World Health Organization (WHO),1 one third of the world population currently has LTBI. In 2006, there were more than 9200 000 new cases of tuberculosis (TB) worldwide, with a prevalence of more than 14 million people and nearly 1.7 million deaths, which represents a mortality rate of 18%. The WHO believes that the global incidence rate reached its peak in 2002, with variations related to population changes. According to the latest data published by the Red de Vigilancia Epidemiolgica de Espaa (Spanish epidemiological surveillance network),2 6070 cases of TB were recorded in 2009. However, these figures should be viewed with caution
Correspondence: Miguel Arias Guilln Servicio de Neumologa. Hospital Universitario Central de Asturias-INS. Doctor Bellmunt, s/n. 33006 Oviedo. Asturias. Spain. miguelariasguillen@gmail.com nefpfm@humv.es
DIAGNOSIS OF TUBERCULOSIS INFECTION The usual method to diagnose tuberculosis infection is the TST, which clearly shows, after injecting a purified protein derivative (PPD), a state of prior hypersensitivity in the body
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when confronted with this substance. The tuberculin used in Europe is the RT-23 PPD. In recent years, new diagnostic methods have been investigated and approved based on in vitro quantification of the cellular immune response. These methods, generically called by the acronym IGRA (Interferon-Gamma-Release Assays), detect the release of interferon gamma in response to specific TB antigens.8 Interferon-gamma is an indispensable molecule in the protective immune response against this microorganism. This cytokine, produced by CD4+ T lymphocytes, CD8+ T lymphocytes and NK cells, activates infected macrophages, with the consequent release of IL-1 and TNF-alpha which limit the growth and multiplication of the mycobacteria. Individuals with a deficit in the receptors or in genes that encode the synthesis of this molecule are likely to present mycobacterial infections more often and with greater severity. The same can be said for patients undergoing immunosuppressive treatment which interferes with these signalling pathways of the immune response.
M. Arias Guilln et al. Tuberculosis and renal disease
longitudinal studies that allow us to conclude the ability of IGRA to predict the risk of developing active TB. A study was conducted in Germany on 601 close contacts of people who had an acid-fast bacilli smear and were culturepositive for M. tuberculosis. The QFT-GIT yielded better performance in predicting active TB13 than the TST, using a cut-off point of 5mm. Five (2.3%) out of the 219 close contacts with an induration of >5mm developed TB, whereas six (14.6%) of the 41 close contacts with positive results from the QFT-GIT developed the disease. However, 59% of the close contacts had an induration (TST) of 59mm. The percentage of those considered TST-positive with a cut-off point of 10mm and developed active TB (5 out of 90 [5.6%]) was similar to the percentage who were QFTGIT-positive (6 out of 41 [14.6%]). Furthermore, only 2 out of 6 close contacts that were QFT-GIT-positive and developed active TB were microbiologically confirmed. In another study, sensitivity to predict subsequent active TB did not show any difference between the two tests.14 The outcome of another study on 339 immigrants in the Netherlands demonstrated that the TST and the QFT-GIT had similar validity in predicting active TB. 15 Follow-up was carried out for 2 years on those close contacts with a TST>5 between 0 and 3 months after the diagnosis of the index patient. Nine (3.1%) out of 288 close contacts with a TST>10mm developed active TB, and seven (3.8%) out of 184 with a TST>15mm, five (2.8%) out of 178 with a positive QFT-GIT, and six (3.3%) out of 181 with a positive T-SPOT.TB also developed the disease. Sensitivity to detect the development of active TB in the follow-up period was 100% for the TST with a cut-off point of 10mm, 88% for a TST with a cut-off of 15mm, 63% for the QFT-GIT and 75% for the T-SPOT.TB. Although the TST with a cut-off point of 10mm detected the greatest number of close contacts who developed active TB (100%) and the QFT-GIT identified the least number of close contacts who developed active TB (5/[63%]), the sensitivity of both tests were not any different. In view of everything published, IGRA do not seem to bring any added advantage in predicting the development of tuberculosis disease compared to the TST.
IN VITRO TRIALS BASED ON INTERFERON PRODUCTION (IGRA) There are two techniques on the market for in vitro diagnosis of TB infection: QuantiFERON-TB-Gold In Tube (Cellestis, Victoria, Australia)9 and T-SPOT.TB (Oxford Immunotec, Oxford, United Kingdom)10. First generation QuantiFERON TB, approved by the Food and Drug Administration (FDA) of the United States in 2001, detected the release of interferon-gamma in response to the TST. In 2004, the FDA approved the second generation of this diagnostic test called QuantiFERON-TB Gold, which unlike the first generation, does not use the mycobacterial antigens of the TST, but rather synthetic peptides which simulate more specific antigens such as the Early Secreted Antigenic Target-6 (ESAT-6) and the Culture Filtrate Protein-10 (CFP-10). These two molecules are encoded by the RD-1 region of the Mycobacterium tuberculosis genome and significantly increase the specificity compared to the TST. These antigens are absent in M. bovis and in the majority of non-tuberculous mycobacteria (with the exception of M. kansasii, M. marinum or M. szulgai). At present, the third generation of this test, called QuantiFERON-TB Gold In Tube (QFT-GIT), is already on the market and includes a third mycobacterial antigen: the TB 7.7 and tubes specifically designed to collect blood samples for this test.
USE OF QTF-GIT AND T.SPOT.TB IN CONTACT TRACING So far, there have been numerous studies carried out based on TB contact tracing. It was initially based on the TST, but since the introduction of IGRA, the latter have often been the subject of research in this group.16, 7 In two papers, it was observed that more recent exposure (longer exposure or a greater number of alcohol-resistant bacilli in the sputum) is associated with more positive IGRA than positive TST,
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VALIDITY OF QTF-GIT AND T.SPOT.TB IN PREDICTING THE DEVELOPMENT OF TUBERCULOSIS DISEASE The risk of developing active TB in a person with a positive TST is estimated at 5%-10%.11,12 However, there are few
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Inconclusive results in immunocompromised patients In cases where the QTF-GIT increases up to 4.42% and in cases where the T.SPOT.TB is up to 6.12%.
which suggests that IGRA could be more effective in the detection of recent infection.
SENSITIVITY OF SCREENING TESTS There are two meta-analyses18, 9 that summarise the results obtained so far on IGRA (Table 1).
ADVANTAGES OF TECHNIQUES FOR IGRA TESTING VERSUS TUBERCULIN SKIN TEST IGRA techniques offer important advantages over the TST: 1) They do not interfere with the BCG vaccine; 2) They avoid subjectivity in interpreting and the reading visits, and 3) They include a positive control that provides valuable information when interpreting a presumably false negative test as a true negative or inconclusive (technical errors or immunosuppression).
INVALID RESULTS FOR BOTH TESTS Inconclusive results for QTF-GIT Out of a total of 21 922 patients, 469 (2.14%) presented inconclusive results (CI 95%, 0.02-0.023).
Inconclusive results for T-SPOT.TB Experience with dialysis patients Out of a total of 12 165 patients, 462 (3.80%) had inconclusive results (CI 95%, 0.035-0.042). If 80 cases were added in which there was not a sufficient number of cells available for testing, the number of inconclusive results would rise to 4.46 (CI 95%, 0.0410.048). The difference in the percentage of inconclusive results between the two IGRA is greater for the QTF-GIT. Due to the alterations in the immune system, dialysis patients are particularly likely to develop active TB, which could reach a TB incidence of up to eight times greater than in the general population.20 Moreover, it is associated with a higher mortality, which is why the detection of LTBI is an important issue in this population. For decades, the TST has yielded poor results in detecting latent tuberculosis in these patients and an anergy rate that could reach 44%.21-24
Table 1. Results of the study comparing different diagnostic methods for detecting confirmed tuberculosis
Objective Sensitivity No. Studies No. Patients Sensitivity Heterogeneity TST >10 1238 69.9% (0.67-0.72) 81.3% QFT-GIT 19 988 81% (0.78-0.83) 77.5% T-SPOT.TB 17 837 87.5% (0.85-0.90) 75.6%
Objective Specificity No. Studies No. Patients Sensitivity TST 6 847 (No BCG) 97% QFT-GIT 5 513 99.2% (0.98-1.00, 95% CI) T-SPOT.TB 3 255 86.3% (0.81-0.90, 95% CI)
Objective Inconclusive No. Patients Inconclusive IC: immunocompromissed Nefrologia 2011;31(2):137-41 QFT-GIT 21 922 2.14% (0.02-0.02) IC* 1.42% T-SPOT.TB 12 165 3.80% (0.03-0.04) IC 6,12% 139
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Although they are beginning to publish studies on the validity of IGRA in the detection of LTBI, comparing them occasionally with tuberculin, we have little data on sensitivity and the rate of inconclusive results in patients with renal disease in general, and specifically on treatment with replacement techniques. To date, there are no similar studies available on the PD population. In the study published in this issue, the validity of IGRA versus TST was analysed for the detection of LTBI in 54 PD patients, and it revealed promising results. As in the study carried out on HD patients, there is a substantial percentage of inconclusive results. Therefore, it is vital to accumulate new series to strengthen and clarify the results. In that study, an assessment by an expert pulmonologist is used as the gold standard to detect LTBI and the authors concluded that IGRA could complement the tuberculin skin test, but there is still not sufficient evidence.
endemic. Anti-tuberculosis treatment is complicated, particularly due to the anti-TB drugs that induce cytochrome P-450 (rifampicin)27 and liver dysfunction caused by Isoniazid.28 The results on IGRA in solid-organ transplant are controversial, while in some studies the sensitivity is similar to the TST, in others, it is higher.25,29
Utility of IGRA in the future With current knowledge, the question is whether or not IGRA could replace TST to rule out tuberculosis infection in immunocompromised patients. Pending further studies about this subject, we can state that: 1) Currently, there is not enough data available on the long-term development of TB that enables us to make the decision whether or not to treat based solely on the results of IGRA in patients receiving RRT; 2) The theoretical basis of IGRA indicates that these techniques measure a different type of immune response than that which occurs in the delayed hypersensitivity to the TST; 3) Unlike what occurs in the contact tracing study, in immunocompromised patients, both recent and remote tuberculosis infections are just as important; 4) There seems to be no sufficient evidence as of yet that shows that IGRA can replace the TST, and 5) We can conclude that IGRA are supplemental assays to the TST as performing both tests simultaneously increases the likelihood of diagnosing TB. In any event, IGRA represent a significant advancement in the diagnosis of tuberculosis infection.
Kidney transplant patients The prevalence of TB among kidney transplant recipients has been widely published. The incidence of LTBI among these patients is estimated at 20-70 times higher than in the general population.25 In these patients, TB contributes to graft dysfunction through direct effects on the graft as well as drug interactions. Furthermore, it increases mortality.26 Reducing the risk of TB is an important priority in organ transplants, especially in countries where the disease is
KEY CONCEPTS
1. The risk of tuberculosis is increasing in patients with chronic renal failure, dialysis and kidney transplants. 2. The tuberculin skin test presents a high number of false positives and false negatives in these types of patients. 3. IGRA improve the diagnosis of latent tuberculosis infection as they are not affected by the vaccine or the type of mycobacteria. 4. At present, IGRA are supplemental assays and they are not an alternative to the tuberculin skin test. Using both techniques combined increase the detection rate of latent tuberculosis infection in the general and the peritoneal dialysis population.
REFERENCES
1. World Health Organization (2008) Global Tuberculosis ControlSurveillance, Planning, Financing. Geneva. www.who.int 2. Red Nacional de Vigilancia Epidemiolgica, Instituto de Salud Carlos III. Enfermedades de declaracin obligatoria. Casos 140 notificados por comunidades autnomas. Informe anual Espaa 2009. www.isciii.es 3. http://www.senefro.com. 4. Winthrop KL, Daley CL. A novel assay for screening patients for Nefrologia 2011;31(2):137-41
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18. Menzies D, Pai M, Comstock G. Meta-analysis: New test for the diagnosis of latent tuberculosis infection: areas of uncertainty and recommendations for research. Ann Intern Med 2007;146:340-54. 19. Pai M, Zwerling A, Menzies D. Systematic review: T-cell-based assays for the diagnosis of latent tuberculosis infection: an update. Ann Intern Med 2008;149(3):177-84. 20. Simon TA, Paul S, Wartenberg D, et al. Tuberculosis in hemodialysis patients in New Jersey: a statewide study. Infect Control Hosp Epidemiol 1999;20:607-9. 21. Cengiz K, Seker A. Boosted tuberculin skin testing in hemodialysis patients. Am J Infect Control 2006;34:383-7. 22. Ravi Shankar MS, Aravindan AN, Sohal PM, et al. The prevalence of tuberculin sensitivity and anergy in chronic renal failure in an endemic area: tuberculin test and the risk of post-transplant tuberculosis. Nephrol Dial Transplant 2005;20:2720-4. 23. SmirnoffM, Patt C, Seckler B, et al. Tuberculin and anergy skin testing of patients receiving long-term hemodialysis. Chest 1998;113:25-7. 24. Girndt M, Heisel O, Kohler H. Influence of dialysis with polyamide vs haemophan haemodialysers on monokines and complement activation during a 4-month long-term study. Nephrol Dial Transplant 1999;14:676-82. 25. Muoz P, Rodrguez C, Bouza E. Mycobacterium tuberculosis infection in recipients of solid organ transplants. Clin Infect Dis 2005;40:5817. 26. Cavusoglu C, Cicek-Saydam C, Karasu Z, et al. Mycobacterium tuberculosis infection and laboratory diagnosis in solid-organ transplant recipients. Clin Transplant 2002;16:257-61. 27. Ram R, Swarnalatha G, Prasad N, et al. Tuberculosis in renal transplant recipients. Transpl Infect Dis 2007;9:97-101. 28. Krance MB, Fisher MA. Prophylaxis of mycobacterial infections in immunocompromised patients. Am Fam Physician 1996;54:1981-8. 29. Manuel O, Humar A, Preiksaitis J, et al. Comparison of Quantiferon-TB gold with tuberculin skin test for detecting latent tuberculosis infection prior to liver transplantation. Am J Transplant 2007;7:2797-801.
5.
6. 7.
8. 9. 10. 11. 12. 13.
14. 15.
16.
17.
latent tuberculosis infection prior to anti-THF therapy. Nature Clin Prac 2008;4(9):456-7. Wauters A, Peetermans WE, Van der Brande P, et al. The value of tuberculin skin testing in hemodialysis patients. Nephrol Dial Transplant 2004;19:433-8. Descamps-Latscha B, Chatenoud L. T cells and B cells in chronic renal failure. Semin Nephrol 1996;16:183-91. Gonzlez-Gutirrez M, De Francisco ALM, Sanz S, et al. Interleukin2 deficit in hemodialysis patients. Role of prostaglandins. Renal Failure 1992;14(4):563-9. Domnguez J, Ruiz-Manzano J. Prueba de la tuberculina: es la hora del cambio? Arch Bronconeumol 2006;42:47-8. http://www.vidrl.org.au/labsandunits /mrl/tbgold.pdf. http://www.oxfordimmunotec.com/ Horsburgh CR, Jr. Priorities for the treatment of latent tuberculosis infection in the United States. N Engl J Med 2004;350:2060-7. Vynnycky E, Fine PE. Lifetime risks, incubation period, and serial interval of tuberculosis. Am J Epidemiol 2000;152:247-63. Diel R, Loddenkemper R, Meywald-Walter K, Niemann S, Nienhaus A. Predictive value of a whole blood IFN-gamma assay for the development of active tuberculosis disease after recent infection with Mycobacterium tuberculosis. Am J Respir Crit Care Med 2008;177:1164-70. Stout JE, Menzies D. Predicting tuberculosis: does the IGRA tell the tale? Am J Respir Crit Care Med 2008;177:1055-7. Kik SV, Franken WP, Mensen M, et al. Predictive value for progression to tuberculosis by IGRA and TST in immigrant contacts. Eur Respir J 2009 2006;28:24-30. Adetifa IM, Lugos MD, Hammond A, et al. Comparison of two interferon gamma release assays in the diagnosis of Mycobacterium tuberculosis infection and disease in The Gambia. BMC Infect Dis 2007;7:122. Dominguez J, Ruiz-Manzano J, De Souza-Galvao M, et al. Comparison of two commercially available gamma interferon blood tests for immunodiagnosis of tuberculosis. Clin Vaccine Immunol 2008;15:168-71.
Sent for review: 1 Feb. 2011 | Accepted: 4 Feb. 2011 Nefrologia 2011;31(2):137-41 141
short reviews
Vascular calcification: types and mechanisms

J.M. Valdivielso
Nephrology Department. Arnau de Vilanova University Hospital. IRBLLEIDA, Lleida, Spain
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doi:10.3265/Nefrologia.pre2010.Nov.10754
ABSTRACT Vascular calcification has traditionally been considered to be a passive process that was associated with advanced age, atherosclerosis, uncommon genetic diseases and some metabolic alterations such as diabetes mellitus and end-stage kidney failure. However, in the last years, vascular calcification has been proven to be an active and regulated process, similar to bone mineralisation, in which different bone-related proteins are involved. Recent results question the classic classification of vascular calcification into intimal and medial calcification, at least in capacitance arteries. Pro and anti-calcifying mechanisms play an active role in calcium deposition in vascular cells, making this area an active focus of research. The identification of therapeutic targets which can slow down the progression or even reverse vascular calcification could be an important step forward in the treatment of patients with chronic kidney disease. Keywords: Medial calcification. Intimal calcification. End stage renal disease. Vascular calcification.
Calcificacin vascular: tipos y mecanismos RESUMEN Clsicamente se consideraba que la calcificacin vascular era un proceso pasivo y degenerativo que frecuentemente ocurra con la edad avanzada, aterosclerosis, varias alteraciones metablicas (como diabetes mellitus y estadios finales de enfermedad renal) y en raras enfermedades genticas. Sin embargo, desde hace algunos aos, la calcificacin vascular es considerada como un proceso activo y regulado de manera semejante a la mineralizacin y metabolismo del hueso, en el que se encuentran implicadas diversas protenas seas. Resultados recientes cuestionan la clsica separacin de la calcificacin vascular en calcificacin de la ntima y calcificacin de la media, al menos en arterias de capacitancia. Mecanismos procalcificantes y anticalcificantes desempean un papel activo en la deposicin de calcio en las clulas vasculares, por lo que su estudio se ha convertido en un rea muy activa de investigacin. La identificacin de dianas teraputicas que puedan enlentecer o incluso revertir la calcificacin vascular podra suponer un avance muy importante en las estrategias teraputicas para los pacientes afectados de enfermedades renales. Palabras clave: Calcificacin de la media. Calcificacin de la ntima. Enfermedad renal crnica. Calcificacin vascular.
INTRODUCTION Calcium phosphate may be deposited as bioapatite crystals (similar to bone) in blood vessels and heart valves in vascular calcification.1 Traditionally, calcification has been classified depending on where the calcium was deposited. In
Correspondence: Jos Manuel Valdivielso Servicio de Nefrologa. Hospital Universitari Arnau de Vilanova. IRBLLEIDA. Rovira Roure, 80. 25198 Lleida. Spain. valdivielso@medicina.udl.es 142
this way, arterial calcification has been divided into intimal calcification (associated with atheromatous plaques2) and medial calcification (known as Mnckebergs sclerosis) linked to vascular stiffness due to the mineralisation of elastic fibres and atherosclerosis seen with age, diabetes and chronic kidney disease (CKD).3 The first one would be linked to an increased deposit of lipids and inflammatory cell infiltrate, while the phenotypic transformation of vascular smooth muscle cells towards osteoblast-like cells would be more important in the second one. A mixture of both
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short reviews
in patients with CKD and significantly associated with death due to cardiovascular disease [CVD] in these patients15) cause clusters of bioapatite crystals to form and grow.16 Bioapatite is the main mineral component of bones, fish bones and shells. In vitro studies found that when VSMC were incubated with high concentrations of calcium or phosphorus, bioapatites accumulated in the extracellular matrix. When they were incubated with both elements at the same time, a synergistic effect of calcification was observed.17 However, this process is not just a passive precipitation of divalent ions, but rather a phenotypic change of VSMC and the up-regulation of genes commonly associated with bone differentiation.18 The effects of hyperphosphataemia are mediated by a sodium-dependent phosphate cotransporter (NPC). Type III NPC, Pit-1, has been found in VSMC. High phosphorus levels stimulate the load while elevated calcium levels increases the Pit-1 mRNA expression. This transporter allows phosphorus to accumulate within cells, which acts as a signal for the expression of osteogenic genes. This causes mineral molecules to be secreted (matrix vesicles, calcium-binding proteins, alkaline phosphatase and collagen-rich extracellular matrix). The combination of these factors induces the cell to change and become susceptible to calcification (Figure 1).
calcifications is seen in patients with CKD.4,5 However, recent results seem to suggest that this classification is not very clear and that both would be manifestations of the atherosclerotic process,6 at least in great arteries. Mnckeberg first described this in 1903.7 He described in his article the presence of calcification in the middle layer of 18 patients arteries with no evidence of plaque. However, the description was made without the help of modern-day techniques to measure lipid deposit, extracellular matrix, etc. It would not be too far fetched to think that what he was actually describing was different stages in the evolution of atherosclerotic plaque. However, several studies have described patients with Mnckebergs sclerosis in the last few years.8-12 If we analyse these studies in detail, we can come to the conclusion that there are characteristics of atherosclerotic lesions in nearly all of them: increased intima-media thickness, disruption of the internal elastic lamina or even lipid deposits. Furthermore, the great arteries have a middle layer with a low number of vascular smooth muscle cells. They are, therefore, more sensitive to the atherosclerotic process than to phenotypic transformation towards osteoblast-like cells. A recent study by our group using ultrasound, the only noninvasive method to determine the exact location of vascular calcifications, shows that vascular calcification of capacitance arteries is associated with the presence of atherosclerosis.13 In this paper, we have studied the presence of vascular calcifications and atheromatous plaques in carotid, femoral and brachial arteries in 232 patients and 208 control patients. The most common type of vascular calcification was linear calcification of the intima, followed by atheromatous plaque calcification. What seemed to be a new type of vascular calcification is not, in fact, since calcification of the internal elastic lamina had histologically already been described in coronary arteries.11 Another important result was that linear calcification of the intima was intimately associated with the presence of plaques, as it was not found in radial arteries (which do not develop atherosclerosis). The study also concluded that absence of carotid plaque was a protective factor. Therefore, our results seem to indicate that the predominant type of vascular calcification of great arteries in patients on dialysis is associated with the presence of atherosclerosis.
Cell death and apoptosis Vascular calcification is linked to the appearance of matrix vesicles with cytoplasmic content and intact cell membrane (as happens in bone development). These vesicles are formed from cells where mineralisation starts or they are the result of the cell apoptosis process (apoptotic bodies). The wall of uraemic patients is damaged by inflammation processes and oxidative stress and one may therefore think
Elevated phosphorus Elevated calcium
VASCULAR CALCIFICATION MECHANISMS Vascular calcification is an active and regulated process that involves different mechanisms that are not mutually exclusive.14
Phenotypic modulation of the VSMC Osteogenic markers
Matrix vesicles loaded with Ca/P
Mineral Matrix vesicles Collagen
Matrix mineralisation
Calcium and phosphorus Some authors refer to them as passive mechanisms of calcification. Elevated levels of Ca, P and CaxP (prevalent
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Adapted from Giachelli et al.1.
Figure 1. Model of the effects of calcium and phosphorus on the mineralisation of VSMC.
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that there is cell apoptosis. Proudfoot et al.19 showed that apoptosis regulates vascular calcification in vitro. According to these authors, matrix vesicles are capable of concentrating calcium inside and bioapatite crystals originate in them.
in MGP (MGP-/- OPN+/+). These studies, therefore, indicate that OPN is an inducible inhibitor of vascular calcification in vivo.
Osteoprotegerin Calcification inhibitors Under normal conditions blood vessel cells express mineralisation-inhibiting molecules. The loss of their expression, as happens in CKD, causes what is known as loss of natural inhibition, giving rise to spontaneous calcification and increased mortality. A list with these calcification-inhibiting molecules has been drawn up after mutation analysis on mice, including among others: Osteoprotegerin (OPG) is a member of the tumour necrosis factor receptor family that has been identified as a regulator of bone resorption. 31 OPG is produced by many tissues, including the cardiovascular system, lungs, kidney and immune system.32 In advanced calcified lesions, OPG is found around the calcified area. It has been seen that OPG-deficient mice develop severe osteoporosis and medial calcification. 33 Therefore, OPG is obviously an inhibitor of vascular calcification. The potential of OPG as a marker of cardiovascular disease has been studied. As the severity of vascular calcification increases so does the serum OPG level. 34 OPG functions as a soluble decoy receptor for the receptor activator of NF-kB (RANK) ligand (RANKL). 32 RANKL is produced by activated T cells and stimulates RANK. This activation enables, among others, an increased expression of inflammation mediators. In addition, OPG is a receptor for tumour necrosis factor-related apoptosis-inducing ligand (TRAIL), which is a powerful apoptosis inducer. TRAIL is found in many different tissues, including VSMC and endothelial cells. In human atherosclerotic lesions, TRAIL has been located around calcified areas.9
Matrix Gla Protein Matrix Gla Protein (MGP) was the first calcification inhibitor to be identified. It is a vitamin K-dependant protein that is constitutively expressed in VSMC and endothelial cells of normal blood vessels, but its expression is greatly reduced in calcified arteries.20 It has also been observed that its expression is reduced in in vitro calcification models.21 Serum MGP levels are lower in patients with calcifications than in those without it.22 Furthermore, MGP knockout mice develop severe medial calcifications and die of a ruptured aorta.23
Fetuin A Fetuin A is a serum glycoprotein that inhibits ectopic vascular calcification. It is a powerful inhibitor of hydroxyapatite formation, reducing the formation of crystals in in vitro solutions containing calcium and phosphorus without affecting those that are already formed.24 Mice that are deficient in this protein develop extensive calcifications in soft tissue such as the myocardium, kidneys, tongue and skin.25
Calcification activators There are studies that speculate that, as well as hyperphosphataemia and hypercalcaemia, there are substances present in the blood serum of patients with CKD capable of stimulating calcification.35 Bovine VSMC in the presence of uraemic serum increases the expression of calcification-related proteins. A large number of uraemic factors have been identified that are capable of inducing osteogenic genes, transforming osteoblasts and secreting some bone matrix proteins in the walls of blood vessels and soft tissue. Some of these factors are: tumour necrosis factor (TNF),36 inflammatory cytokines,37 fibronectin,38 type-I collagen38 and 25-hydroxycholesterol.39 These uraemic serum substances stimulate the expression of molecules essential to vesicular calcification.
Osteopontin Osteopontin (OPN) is a phosphoprotein that is usually found in mineralised tissue such as bones and teeth, and is involved in regulating mineralisation as it inhibits apatite crystal growth.26 Although it is not found in normal arteries, some authors have detected its expression in atherosclerotic plaques and calcified aortic valves.27-29 Giachelli et al.30 crossed OPN-/- mutant mice (that had no vascular symptoms) with MGP-/- mutant mice (that had developed vascular calcifications) to examine the role of OPN in vascular calcification. OPN-/- MGP-/- mice showed a more accelerated calcification than those that were only deficient
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Alkaline phosphatase Alkaline phosphatase (ALP) is one of the osteoblastic phenotype markers and is considered essential in the vascular calcification process. It has been detected in vascular and heart valve calcifications. ALP expressed on the surface of cells can act on phosphate liberators,
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osteoclast formation, fusion, differentiation, activation and survival, leading to increased bone resorption and bone loss.51 RANKL stimulates its specific receptor RANK, which is expressed in fewer cells such as progenitor cells and mature osteoclasts, activated T cells and dendritic cells.52-54 The activation of RANK by RANKL triggers the NF-B intracellular signalling cascade. The final stage of RANK activation is the NK-B translocation into the nucleus, which can take place by the classical or alternative pathway. Both pathways are regulated by their kinases which are, respectively, IKK and IKK. The NK-B translocation to the nucleus modulates the expression of different genes, e.g. BMP4 (Figure 2).55 The biological effects of OPG are the opposite of RANKL-mediated effects, due to the fact that OPG acts as a soluble inhibitor that prevents RANKL interaction and the subsequent stimulation of its RANK receptor. 56 The first signs that this system was involved in vascular calcification came out of a study on OPG-knockout mice, which had osteoporosis and calcifications of the aorta and kidney arteries. 33 OPG expression can be found in the media of great arteries 31 and in many different types of blood vessel cells, such as VSMC and endothelial cells. 57,58 It has been proven that it acts as an autocrine survival factor in endothelial cells. 58 In contrast, RANKL and RANK have only been found in calcified areas of transgenic mice, in the arteries of wild mice. 59 Other studies have demonstrated that OPG inhibits vascular calcification in in vivo rats caused by both vitamin D and warfarin. 60 The definitive proof that RANKL directly promotes vascular calcification came in 2009, when one of the studies from our laboratory proved that RANKL directly increases calcification of VSMC by increasing BMP4 expression. This increased expression is due to the activation of the alternative NFkB signalling pathway.
releasing inorganic phosphate. 40 Inflammatory cytokines and vitamin D induce its up-regulation and mineralization.40,41
Core-binding factor alpha 1 Core-binding factor alpha 1 (Cbfa1) is the main regulator of bone cell differentiation. Cbfa1-deficient mice have problems with cartilage formation and bone mineralisation. 42 It acts as a transcription factor that accelerates the expression of important osteoblast lineage genes such as osteocalcin, osteopontin, ALP or type-I collagen. 20 Its expression is up-regulated by phosphate 43 and uraemic toxins.35
Bone morphogenic proteins Bone morphogenic proteins (BMP) are a group of, at least, 30 proteins that receive their name from their osteoinductive properties. BMP belong to the transforming growth factor-beta (TGF-) superfamily. They act by binding to a heterodimeric system of transmembrane receptors (BMP-1 and BMP-2 receptor) that trimerises upon binding. The binding of a BMP to its specific type II receptor results in the type 1 receptor being activated. This causes phosphorylation and nuclear translocation of the Smad transcription factors thus modifying the transcription rate of target genes. 44 They then induce ectopic bone formation.45 BMP2 is a powerful bone morphogenic protein and its expression triggers osteogenic transcriptional regulatory programs in the arterial tree. BMP2 induces Msx2 as well as Cbfa1 in VSMC.46 Msx2 is needed for the formation of intramembranous bones and it is critical for osteoblast differentiation, endochondral bone formation and neovascularisation. They were recognised as mediators of vascular calcification long ago: BMP2 and BMP4 are involved in mineralisation and induction of local inflammation, while BMP7 slows down vascular calcification. BMPs are expressed in different cells in atherosclerotic lesions as well as in endothelial lesions and VSMC.47,48 The effect of BMP2 on vascular calcification is inhibited by MGP.49
Classical pathway
Alternative pathway
Immature form
It is ubiquitinised and becomes susceptible to degradation by proteasome 26. After being released, IkB is translocated into the nucleus and activates the transcription rate of different genes.
Mature form It may be translocated into the nucleus and activate the transcription rate of different genes.
RANKL RANKL (also known as OPGL) is a protein consisting of 316 amino acids with a molecular weight of 38kD. Its expression is also modulated by several cytokines, glucocorticoids and PTH.50 RANKL is produced by osteoblast lineage cells and activated T cells. It promotes
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Binding of RANKL to its RANK receptor causes NFB to translocate into the nucleus. The translocation can take place via two pathways: the classic and the alternative. In the classical pathway: ikk, ikk and ikk.
Figure 2. Diagram of the activation of RANK by RANKL.

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KEY CONCEPTS
1. Recent results seem to indicate that vascular calcification is always associated with the presence of atheromatous plaques in great arteries, more than with mineral metabolism disorders. This does not rule out that mineral metabolism disorders might intensify vascular calcification.
2. Pro-calcifying and anti-calcifying mechanisms play an important role in the pathophysiology of vascular calcification. Therapies that aim to reduce vascular calcification in patients on dialysis should be directed at trying to reduce atherosclerosis as well as restoring anti-calcifying mechanisms or inhibiting pro-calcifying mechanisms.
REFERENCES
1. Giachelli CM. Vascular calcification mechanisms. J Am Soc Nephrol 2004;15:2959-64. 2. Burke AP, Taylor A, Farb A, et al. Coronary calcification: insights from sudden coronary death victims. Z Kardiol 2000;89(Suppl 2):49-53. 3. Edmonds ME, Morrison N, Laws JW, Watkins PJ. Medial arterial calcification and diabetic neuropathy. Br Med J (Clin Res Ed) 1982;284:928-30. 4. Schwarz U, Buzello M, Ritz E, et al. Morphology of coronary atherosclerotic lesions in patients with end-stage renal failure. Nephrol Dial Transplant 2000;15:218-23. 5. Ibels LS, Alfrey AC, Huffer WE, et al. Arterial calcification and pathology in uremic patients undergoing dialysis. Am J Med 1979;66:790-6. 6. McCullough PA, Chinnaiyan KM, Agrawal V, et al. Amplification of atherosclerotic calcification and Monckebergs sclerosis: a spectrum of the same disease process. Adv Chronic Kidney Dis 2008;15:396-412. 7. Mnckeberg JG. Ueber die reine Mediaverlakalkung der Extremitaetenarterien und ihr Verhalten zur Arteriosklerose. Virchows Arch A Pathol Anat Histol 1903;171:141-67. 8. Shanahan CM, Cary NR, Salisbury JR, et al. Medial localization of mineralization-regulating proteins in association with Monckebergs sclerosis: evidence for smooth muscle cell-mediated vascular calcification. Circulation 1999;100:2168-76. 9. Schoppet M, Al Fakhri N, Franke FE, et al. Localization of osteoprotegerin, tumor necrosis factor-related apoptosis-inducing ligand, and receptor activator of nuclear factor-kappa B ligand in Monckebergs sclerosis and atherosclerosis. J Clin Endocrinol Metab 2004;89:4104-12. 10. Castillo BV, Jr., Torczynski E, Edward DP. Monckebergs sclerosis in temporal artery biopsy specimens. Br J Ophthalmol 1999;83:1091-2. 11. Micheletti RG, Fishbein GA, Currier JS, et al. Calcification of the internal elastic lamina of coronary arteries. Mod Pathol 2008;21:1019-28. 12. Goebel FD, Fuessl HS. Monckebergs sclerosis after sympathetic denervation in diabetic and non-diabetic subjects. Diabetologia 1983;24:347-50. 13. Coll B, Betriu A, Martnez-Alonso M, et al. Large Artery Calcification on Dialysis Patients Is Located in the Intima and Related to 146 Atherosclerosis. Clin J Am Soc Nephrol 2010. In press. doi:10.2215/CJN.04290510 Speer MY, Giachelli CM. Regulation of cardiovascular calcification. Cardiovascular Pathology 2004;13:63-70. Block GA, Hulbert-Shearon TE, Levin NW, Port FK. Association of serum phosphorus and calcium x phosphate product with mortality risk in chronic hemodialysis patients: A national study. Am J Kidney Dis 1998;31:607-17. Block GA, Port FK. Re-evaluation of risks associated with hyperphosphatemia and hyperparathyroidism in dialysis patients: Recommendations for a change in management. Am J Kidney Dis 2000;35:1226-37. Reynolds JL, Joannides AJ, Skepper JN, et al. Human vascular smooth muscle cells undergo vesicle-mediated calcification in response to changes in extracellular calcium and phosphate concentrations: A potential mechanism for accelerated vascular calcification in ESRD. J Am Soc Nephrol 2004;15:2857-67. Steitz SA, Speer MY, Curinga G, et al. Smooth muscle cell phenotypic transition associated with calcification: upregulation of Cbfa1 and downregulation of smooth muscle lineage markers. Circ Res 2001;89:1147-54. Proudfoot D, Skepper JN, Hegyi L, et al. Apoptosis regulates human vascular calcification in vitro - Evidence for initiation of vascular calcification by apoptotic bodies. Circ Res 2000;87:1055-62. Tyson KL, Reynolds JL, McNair R, et al. Osteo/chondrocytic transcription factors and their target genes exhibit distinct patterns of expression in human arterial calcification. Arterioscler Thromb Vasc Biol 2003;23:489-94. Mori K, Shioi A, Jono S, et al. Expression of matrix Gla protein (MGP) in an in vitro model of vascular calcification. FEBS Lett 1998;433:19-22. Jono S, Ikari Y, Vermeer C, et al. Matrix Gla protein is associated with coronary artery calcification as assessed by electron-beam computed tomography. Thromb Haemost 2004;91:790-4. Luo G, Ducy P, Mckee MD, et al. Spontaneous calcification of arteries and cartilage in mice lacking matrix GLA protein. Nature 1997;386:78-81. Heiss A, DuChesne A, Denecke B, et al. Structural basis of calcification inhibition by alpha 2-HS glycoprotein/fetuin-A. Formation of colloidal calciprotein particles. J Biol Chem 2003;278:13333-41. Nefrologia 2011;31(2):142-7
14. 15.
16.
17.
18.
19.
20.
21. 22.
23. 24.
short reviews
necrosis factor-alpha and oncostatin M derived from macrophages. Circ Res 2002;91:9-16. Jono S, Nishizawa Y, Shioi A, Morii H. 1,25-dihydroxyvitamin D-3 increases in vitro vascular calcification by modulating secretion of endogenous parathyroid hormone-related peptide. Circulation 1998;98:1302-6. Ducy P, Zhang R, Geoffroy V, et al. Osf2/Cbfa1: a transcriptional activator of osteoblast differentiation. Cell 1997;89:747-54. Jono S, Mckee MD, Murry CE, et al. Phosphate regulation of vascular smooth muscle cell calcification. Circ Res 2000;87:E10-E17. Chen D, Zhao M, Mundy GR. Bone morphogenetic proteins. Growth Factors 2004;22:233-41. Wang EA, Rosen V, DAlessandro JS, et al. Recombinant human bone morphogenetic protein induces bone formation. Proc Natl Acad Sci USA 1990;87:2220-4. Hruska KA, Mathew S, Saab G. Bone morphogenetic proteins in vascular calcification. Circ Res 2005;97:105-14. Bostrom K, Watson KE, Horn S, et al. Bone morphogenetic protein expression in human atherosclerotic lesions. J Clin Invest 1993;91:1800-9. Shin V, Zebboudj AF, Bostrom K. Endothelial cells modulate osteogenesis in calcifying vascular cells. J Vasc Res 2004;41:193-201. Zebboudj AF, Imura M, Bostrom K. Matrix GLA protein, a regulatory protein for bone morphogenetic protein-2. J Biol Chem 2002;277:4388-94. Kong YY, Boyle WJ, Penninger JM. Osteoprotegerin ligand: a regulator of immune responses and bone physiology. Immunol Today 2000;21:495-502. Kong YY, Feige U, Sarosi I, et al. Activated T cells regulate bone loss and joint destruction in adjuvant arthritis through osteoprotegerin ligand. Nature 1999;402:304-9. Anderson DM, Maraskovsky E, Billingsley WL, et al. A homologue of the TNF receptor and its ligand enhance T-cell growth and dendritic-cell function. Nature 1997;390:175-9. Myers DE, Collier FM, Minkin C, et al. Expression of functional RANK on mature rat and human osteoclasts. FEBS Lett 1999;463:295-300. Green EA, Flavell RA. TRANCE-RANK, a new signal pathway involved in lymphocyte development and T cell activation. J Exp Med 1999;189:1017-20. Kanegae Y, Tavares AT, Izpisua Belmonte JC, Verma IM. Role of Rel/NF-kappaB transcription factors during the outgrowth of the vertebrate limb. Nature 1998;392:611-4. Yasuda H, Shima N, Nakagawa N, et al. Osteoclast differentiation factor is a ligand for osteoprotegerin/osteoclastogenesis-inhibitory factor and is identical to TRANCE/RANKL. Proc Natl Acad Sci USA 1998;95:3597-602.
25. Schafer C, Heiss A, Schwarz A, et al. The serum protein alpha 2-Heremans-Schmid glycoprotein/fetuin-A is a systemically acting inhibitor of ectopic calcification. J Clin Invest 2003;112:357-66. 26. Giachelli CM, Steitz S. Osteopontin: a versatile regulator of inflammation and biomineralization. Matrix Biol 2000;19:615-22. 27. Ikeda T, Shirasawa T, Esaki Y, et al. Osteopontin mRNA is expressed by smooth muscle-derived foam cells in human atherosclerotic lesions of the aorta. J Clin Invest 1993;92:2814-20. 28. Fitzpatrick LA, Severson A, Edwards WD, Ingram RT. Diffuse calcification in human coronary arteries. Association of osteopontin with atherosclerosis. J Clin Invest 1994;94:1597-604. 29. Hirota S, Imakita M, Kohri K, et al. Expression of osteopontin messenger RNA by macrophages in atherosclerotic plaques. A possible association with calcification. Am J Pathol 1993;143:1003-8. 30. Speer MY, Mckee MD, Guldberg RE, et al. Inactivation of the osteopontin gene enhances vascular calcification of matrix Gla proteindeficient mice: evidence for osteopontin as an inducible inhibitor of vascular calcification in vivo. J Exp Med 2002;196:1047-55. 31. Simonet WS, Lacey DL, Dunstan CR, et al. Osteoprotegerin: A novel secreted protein involved in the regulation of bone density. Cell 1997;89:309-19. 32. Collin-Osdoby P. Regulation of vascular calcification by osteoclast regulatory factors RANKL and osteoprotegerin. Circ Res 2004;95:1046-57. 33. Bucay N, Sarosi I, Dunstan CR, et al. osteoprotegerin-deficient mice develop early onset osteoporosis and arterial calcification. Genes & Development 1998;12:1260-8. 34. Jono S, Ikari Y, Shioi A, et al. Serum osteoprotegerin levels are associated with the presence and severity of coronary artery disease. Circulation 2002;106:1192-4. 35. Moe SM, Duan D, Doehle BP, et al. Uremia induces the osteoblast differentiation factor Cbfa1 in human blood vessels. Kidney Int 2003;63:1003-11. 36. Tintut Y, Patel J, Parhami F, Demer LL. Tumor necrosis factor-alpha promotes in vitro calcification of vascular cells via the cAMP pathway. Circulation 2000;102:2636-42. 37. Stenvinkel P, Ketteler M, Johnson RJ, et al. IL-10, IL-6, and TNF-alpha: central factors in the altered cytokine network of uremia-the good, the bad, and the ugly. Kidney Int 2005;67:1216-33. 38. Watson KE, Parhami F, Shin V, Demer LL. Fibronectin and collagen I matrixes promote calcification of vascular cells in vitro, whereas collagen IV matrix is inhibitory. Arterioscler Thromb Vasc Biol 1998;18:1964-71. 39. Watson KE, Bostrom K, Ravindranath R, et al. TGF-beta 1 and 25hydroxycholesterol stimulate osteoblast-like vascular cells to calcify. J Clin Invest 1994;93:2106-13. 40. Shioi A, Katagi M, Okuno Y, et al. Induction of bone-type alkaline phosphatase in human vascular smooth muscle cells: roles of tumor
41.
42. 43. 44. 45.
46. 47.
48. 49.
50.
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Sent for review: 29 Nov. 2010 | Accepted: 30 Nov. 2010 Nefrologia 2011;31(2):142-7 147
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New insights into the pathophysiology of oedema in nephrotic syndrome

H. Rondon-Berrios
Division of Nephrology. Department of Internal Medicine. University of New Mexico School of Medicine. Albuquerque, New Mexico (USA)
Nefrologia 2011;31(2):148-54
ABSTRACT Oedema is a common clinical manifestation of nephrotic syndrome. However, the pathophysiological mechanism of sodium retention in nephrotic syndrome has been intensely debated for decades. Several clinical and experimental observations argue against the classic or "underfill" hypothesis of oedema formation in nephrotic syndrome. In many patients, oedema formation in nephrotic syndrome is due to the kidney being intrinsically unable to excrete salt and is unrelated to systemic factors (i.e. hypoalbuminaemia, decreased effective arterial blood volume, and secondary hyperaldosteronism). The cortical collecting duct is the nephron site of sodium retention in nephrotic syndrome. Activation of the epithelial sodium channel in the cortical collecting duct is responsible for sodium retention in nephrotic syndrome. In nephrotic syndrome, a defective glomerular filtration barrier allows the passage of proteolytic enzymes or their precursors, which have the ability to activate the epithelial sodium channel, thereby causing the the subsequent sodium retention and oedema. Keywords: Oedema. Nephrotic syndrome. Hypoalbuminemia. Epithelial sodium channel. Plasmin
Avances en la fisiopatologa del edema en el sndrome nefrtico RESUMEN El edema es una manifestacin clnica frecuente del sndrome nefrtico (SN); sin embargo, el mecanismo fisiopatolgico responsable de la retencin de sodio ha sido un tema de intenso debate durante dcadas. Muchas observaciones clnicas y experimentales no apoyan a la hiptesis clsica o del underfill en la formacin del edema nefrtico. En numerosos pacientes, el edema propio del SN se produce por un defecto renal intrnseco en la excrecin de sodio y es independiente de factores sistmicos (p. ej., hipoalbuminemia, disminucin del volumen arterial efectivo o hiperaldosteronismo secundario). El punto de la nefrona donde se produce la retencin de sodio en el SN es el tbulo colector cortical. La activacin del canal de sodio epitelial a ese nivel es responsable de la retencin de sodio en la patologa que nos ocupa. Una barrera glomerular defectuosa propia del SN permitira el paso de enzimas proteolticas o sus precursores que a su vez activaran el canal de sodio epitelial causando de esa manera su retencin y consiguiente edema. Palabras clave: Edema. Sndrome nefrtico. Hipoalbuminemia. Canal epitelial de sodio. Plasmina.
INTRODUCTION Oedema is defined as the accumulation of fluid in the interstitial space and is a frequent clinical manifestation of nephrotic syndrome (NS). However, its pathophysiology has been under considerable debate for decades. The classic hypothesis, also called the underfill hypothesis, postulates that sodium retention in NS is secondary to decreased effective arterial blood volume, hence the term underfill. The hypothesis suggests the following sequence of events (Figure 1): urinary loss of proteins in NS, especially albumin, causing hypoalbuminaemia, which in turn causes a decrease in plasma oncotic pressure. This decrease in plasma oncotic pressure would then cause an imbalance in Starling forces, resulting in the
Correspondence: Helbert Rondon-Berrios Division of Nephrology. Department of Internal Medicine. University of New Mexico School of Medicine, ACC 5. MSC10 5550. 1 University of New Mexico, 87131-0001. Albuquerque, New Mexico, USA. HRondon@salud.unm.edu 148
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retention in the kidneys, with subsequent oedema. However, several experimental and clinical observations made over the years do not support this hypothesis.
Nephrotic syndrome
Albuminuria
EXPERIMENTAL AND CLINICAL OBSERVATIONS AGAINST THE UNDERFILL HYPOTHESIS 1,2 (Table 1) Patients and laboratory rats with low serum albumin levels do not develop oedema or sodium retention Joles et al3 measured the plasma and interstitial oncotic pressure of Nagase rats, which are mutant rats characterised by analbuminaemia. The researchers found no signs of sodium retention in those animals. Furthermore, Lecomte et al 4 carried out observations on patients with congenital analbuminaemia and found that most had no oedema. Many other published series of patients with congenital analbuminaemia do not report the appearance of oedema as the main symptom. 5 Steyl et al 6 studied 50 patients hospitalised in a general medical ward in South Africa and noted that 24 patients had a serum albumin level lower than 3.5g/dl, mostly associated with chronic inflammation (tuberculosis). Of these 24 patients,
Hypoalbuminaemia
Reduction in plasma oncotic pressure
Translocation of fluid from the intravascular space to the interstitial space
Decrease in effective arterial blood volume
Renin-angiotensin-aldosterone system Sympathetic nervous system Arginine-vasopressin Atrial natriuretic peptide Table 1. Arguments against the underfill hypothesis ofoedema formation in nephrotic syndrome 1. Patients and laboratory rats with low serum albumin levels do not develop oedema or sodium retention. 2. Natriuresis in the recovery phase of nephrotic syndrome Oedema begins when proteinuria disappears but before serum albumin returns to normal levels. 3. The absolute decrease in plasma oncotic pressure does not Figure 1. Classic or underfill hypothesis of oedema formation in nephrotic syndrome. affect the volume of the intravascular space in nephrotic syndrome. 4. Plasma and blood volumes are normal or increased in nephrotic syndrome. 5. Intravascular space expansion with albumin does not
Sodium and water retention by the kidney
movement of fluid from the intravascular space to the interstitial space, causing a decrease in effective arterial blood volume and consequently, relative hypovolaemia. This would then result in activation of the reninangiotensin-aldosterone and sympathetic nervous systems, increased antidiuretic hormone release and inhibition of atrial natriuretic peptide release. Activation of these systems would cause sodium and water
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increase natriuresis in patients with nephrotic syndrome. 6. The activation of the renin-angiotensin-aldosterone system is not involved in the development of oedema in nephrotic syndrome. 7. Bilateral adrenalectomy does not prevent sodium retention in nephrotic syndrome in laboratory rats.
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only six had oedema. These six patients with oedema had an alternative diagnosis that clearly explained the presence of oedema (cor pulmonale). During the study, they found some patients with serum albumin levels below 1.5g/dl, but none of them had oedema.
The activation of the renin-angiotensin-aldosterone system is not involved in the development of oedema in nephrotic syndrome Brown et al12, administered captopril to a group of NS patients and observed no change in sodium excretion despite suppressing serum aldosterone concentrations. In another study, Usberti et al13 reported similar findings when using spironolactone.
Natriuresis in the recovery phase of nephrotic syndrome begins when proteinuria disappears but before serum albumin returns to normal levels7 The absolute decrease in plasma oncotic pressure does not affect the volume of the intravascular space in nephrotic syndrome Studies performed on dogs suggest that the absolute decrease in plasma oncotic pressure would not affect plasma or blood volume. 8 Patients with NS caused by glomerulonephritis were studied by measuring their plasma and interstitial oncotic pressure: 12 patients in the active phase, 3 in complete remission and 3 in partial remission. 9 The researchers found that plasma and interstitial oncotic pressure were decreased in the active phase of NS but slowly returned to normal values during remission. During this time, the oncotic pressure gradient between plasma and interstitium was constant. 9 These studies show that it is the change in the oncotic pressure gradient between plasma and interstitium and not just the absolute decrease in plasma oncotic pressure that causes the movement of fluid from the intravascular to the interstitial space.
Adrenalectomy does not prevent sodium retention and the development of ascites in nephrotic syndrome in laboratory rats De Seigneux et al studied a group of rats from which they had removed both adrenal glands. The rats were administered dexamethasone to prevent adrenal failure.14 The researchers induced NS in the rats by administering puromycin. The rats developed oedema and sodium retention despite having been adrenalectomised. These findings suggest that aldosterone does not play a major role in sodium retention that is characteristic of NS.
ALTERNATIVE HYPOTHESIS OR OVERFILL HYPOTHESIS OF OEDEMA FORMATION IN NEPHROTIC SYNDROME Contrary to the classic hypothesis, the alternative hypothesis (also called the overfill hypothesis) postulates that sodium retention in many NS patients is a primary renal phenomenon and may be caused by an intrinsic renal defect in sodium excretion, which in turn causes an expansion in plasma volume (hence the term overfill). Although the molecular mechanism of sodium retention in the kidneys has not been clearly explained, there are a number of studies on this topic, which we describe below.
Plasma and blood volumes are normal or increased in nephrotic syndrome Geers et al10 measured plasma volumes in 88 patients with NS and in 51 controls. Plasma volume was measured by administration of radioactive albumin I. 131 Blood volume was calculated based on plasma volume and haematocrit. The plasma and blood volume of NS patients was found to be high in 14%, normal in 84% and low in only 2% of cases.
Molecular mechanisms of sodium retention in nephrotic syndrome The first observations supporting the overfill hypothesis were made by Chandra15 and Ichikawa.16 Most of our understanding of the molecular mechanisms of sodium retention in NS has come from the use of animal models that induced NS by puromycin aminonucleoside (PAN). When PAN is administered to rats, it causes massive proteinuria and sodium retention. The renal histopathology induced by PAN resembles minimal change disease.17-19 Using the technique of selective unilateral perfusion through the left renal artery with PAN first described by Bricker in dogs20 and later by Hoyer in rats,21 Chandra15 and Ichikawa16 showed that proteinuria and sodium retention were confined to the kidney perfused with PAN. The unilateral NS model allows
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Intravascular space expansion with albumin does not increase natriuresis in patients with nephrotic syndrome The effect of an intravenous infusion of hyperoncotic albumin (75g) was observed in patients with NS. 11 After the infusion, blood volume increased up to 120% of baseline. Plasma renin activity and serum aldosterone concentration decreased to the point of being suppressed. Urinary sodium excretion did not change significantly.
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pump. Deschenes et al24 found that the activity of this pump was increased in rats treated with PAN when compared to control rats. These authors also observed that the increase in pump activity was confined to the cortical collecting tubule.24 However, many subsequent studies have shown that, in rats treated with PAN, the activity of this pump and other sodium transporters (such as NHE3) is decreased when compared to control rats.25
the study of a proteinuric kidney and a control kidney in the same animal. It must be emphasised that the sodium retention by the kidney perfused with PAN occurred without a reduction in plasma protein concentration, suggesting that the sodium retention observed in NS was due to an intrinsic renal defect in sodium excretion rather than due to extrinsic or systemic factors such as hypoalbuminaemia.
The cortical collecting tubule is the reabsorption point for sodium in nephrotic syndrome Ichikawa16 also performed micropuncture studies of superficial nephron tubular segments in the unilateral NS model in rats, and showed that the amount of sodium at the end of the distal convoluted tubule is the same in the proteinuric kidney as in the normal kidney. The final urine of the nephrotic kidney, however, contained three times less sodium than the urine from the normal kidney, suggesting that stimulation of sodium reabsorption in the NS occurs in the cortical collecting tubule.
The role of ENaC in sodium retention in nephrotic syndrome Another sodium transporter that has been reported to be strongly involved in sodium retention in NS is the epithelial sodium channel or amiloride-sensitive sodium channel (ENaC). ENaC is composed of three subunits: , , and . The first studies conducted on the role of ENaC in sodium retention in NS showed that there was no increase in protein expression (nor mRNA) of any of the three subunits of ENaC in rats treated with PAN when compared to control rats.26 However, subsequent studies have shown an increase in protein expression of the three subunits of ENaC,14,25 as well as an increase in the movement of these subunits from the cytosol to the apical plasma membrane. ENaC is regulated by several factors, one of which is the enzyme 11--hydroxysteroid dehydrogenase type 2 (11HSD2). Mineralocorticoid receptor activation causes an increase in ENaC activity by increasing expression of the gene that encodes the ENaC subunit and a decrease in its intracellular recycling system mediated by the ubiquitin ligase Nedd4-2.27 Cortisol has the same affinity as aldosterone to the mineralocorticoid receptor. However, aldosterone acts as the sole agonist of this receptor even though the concentration of cortisol in plasma is 100 times the concentration of aldosterone. The 11HSD2 enzyme usually protects the mineralocorticoid receptor from cortisol activation by locally transforming it into cortisone, which is inactive on this receptor. Nevertheless, in pathological states such as in the syndrome of apparent mineralocorticoid excess, the activity of the 11HSD2 enzyme is reduced, allowing the cortisol to activate the mineralocorticoid receptor and cause sodium retention.28 A study by Kim et al29 showed that the activity of the 11HSD2 enzyme is reduced in rats with NS caused by mercuric chloride-induced membranous nephropathy when compared to control rats, which may explain the sodium retention in these animals. However, other studies have not confirmed these findings.14,30 Another important factor in the regulation of ENaC is the group of serine proteases. These are a group of proteolytic enzymes that cleave the and ENaC subunits in specific sites and thereby increase sodium conductance through the channel.31,32 Under experimental conditions, sodium conductance is low in ENaC that has not been exposed to
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The role of NHE3 in sodium retention in the NS Despite the findings of Ichikawa et al, other studies have postulated that sodium retention in NS may occur in other nephron segments. Sixty-six percent of sodium filtered by the glomerulus is reabsorbed in the proximal tubule by the action of the Na-H cotransporter (NHE3). It would be reasonable then to assume that this segment would, at least in part, contribute to the sodium retention observed in NS. Besse-Eschmann et al22 found that NHE3 activity (normalised to the amount of protein) was increased by 88% in rats treated with PAN, compared to control rats. NHE3 is present at two locations of the proximal tubular brush border, forming oligomers: 1) in the intervillous space, where it is associated with the megalin receptor (a protein responsible for the reabsorption of albumin and other substances filtered by the glomerulus), representing the inactive form of NHE3, and 2) in the microvillous space, where it is free and represents the active form of the transporter.23 The researchers also found that in rats treated with PAN there was NHE3 movement from the intervillous space to the microvillus space.22 They suggested that albumin filtered by the NSs defective glomerular barrier could dissociate NHE3 from megalin and increase movement of NHE3 to the microvilli so that it might perform its sodium retention function from there.22
The role of the Na+/K+-ATPase pump in sodium retention in nephrotic syndrome Another sodium transporter that has been reported to be involved in sodium retention in NS is the Na+/K+-ATPase
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proteolysis by serine proteases. The first step in ENaC activation by serine proteases occurs in the Golgi complex, where a protease called furin cleaves the subunit at the R205 and R231 sites (thus releasing an inhibitory peptide of 26 amino acids) and the subunit at the R143 site.33 If this ENaC conductance were measured under experimental conditions, it would be intermediate. After this enzymatic process, the channel is assembled in the apical plasma membrane. For ENaC to be completely active and have high sodium conductance, it must be activated by a second protease (such as prostasin, neutrophil elastase or pancreatic elastase).34 The first observations on ENaC activation by serine proteases in proteinuric states were made by Kastner et al.35 Passero et al36 found that ENaC currents increased when ENaC was exposed to plasmin, suggesting that plasmin acts as a second protease and is capable of activating ENaC. Passero36 also discovered that plasmin activates ENaC by cleaving the subunit at the K194 site. Perhaps the most convincing evidence to date about the role of serine proteases in ENaC activation in NS is the recently published report by Svenningsen et al.37 They found that urine in nephrotic rats treated with PAN increased the ENaC currents and that amiloride abolished them. Svenningsen et al investigated why the urine of these nephrotic rats activated ENaC and found that the ENaC currents were abolished when ENaC was exposed to aprotinin, a known inhibitor of serine proteases. Another important observation was that the urine of nephrotic rats did not increase ENaC currents when subjected to heat. When serine protease activity in this urine was measured, it was found to be high. All these findings suggest that the urine of nephrotic rats contains a serine protease capable of activating ENaC.37 Several previous studies performed on NS patients have documented the presence of plasminogen in the urine of these patients.38,39 After several purification steps and mass spectrometry (MALDI-TOF), Svenningsen et al found that plasminogen and/or plasmin were the serine proteases responsible for ENaC activation in the urine of nephrotic rats. The urine of nephrotic rats contained both substances, but the plasma from these animals only contained plasminogen, suggesting that plasmin was formed in the urine in situ and was not filtered out of the plasma.37 Plasmin is known to come from the activation of plasminogen through the enzymatic action of urokinase, which is normally present in the collecting tubule.40 Svenningsen et al37 observed that the cortical collecting tubule cells of nephrotic rats had urokinase activity. They also observed that while the combination of plasminogen and urokinase increased ENaC currents in oocytes, plasminogen and urokinase were incapable of doing so in isolation.37 Another important finding was that amiloride not only blocks ENaC but also blocks the urokinase enzyme responsible for converting plasminogen into plasmin.37 Significantly, Svenningsen et al37 were able to reproduce all of the
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previously described results with urine from NS patients. To summarise, the plasminogen present in plasma is probably filtered through NSs own defective glomerular barrier and is then converted into plasmin by the action of urokinase present in the collecting tubule. Plasmin would then activate ENaC, resulting in sodium retention with the subsequent appearance of oedema (Figure 2).
The use of amiloride to treat nephrotic oedema Treatment of oedema in NS is traditionally based on a low sodium diet (2.3g of sodium a day or 6g of sodium chloride a day) and the use of loop diuretics. Amiloride is a potassium-sparing diuretic and its use has traditionally been restricted to the prevention of hypopotassaemia associated with the use of loop diuretics. However, according to the findings described above, the use of amiloride may play an important role in the treatment of oedema in NS. In our clinical experience, the use of amiloride enhances diuresis caused by loop diuretics. This has been reproduced experimentally41 and has also been reported in other clinical studies.42 We usually start treatment of nephrotic oedema with a 1mg dose of bumetanide orally twice a day and a 5mg dose of amiloride orally once a day. Amiloride should not be used in isolation but rather in combination with loop diuretics, given that although the collecting tubule plays a key role in sodium retention in NS, in absolute terms it only contributes 4% of total filtered sodium reabsorption.
Plasminogen
Defective glomerular barrier
Principal cell Collecting tubule Plasminogen

uPA
Plasmin
Principal cell
inactive ENaC
Plasmin Na+
Active ENaC
uPa: urokinase Figure 2. Plasmin in the cortical collecting duct activates ENaC.
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KEY CONCEPTS
1. In a large number of NS patients, the pathophysiology of oedema is not related to the presence of hypoalbuminaemia, decreased intravascular space volume or secondary hyperaldosteronism. 2. NS oedema is caused by an intrinsic renal defect in sodium excretion. 3. Sodium retention in NS occurs in the cortical collecting tubule. 4. ENaC, one of the sodium transporters present in the cortical collecting tubule, is involved in sodium retention in NS. 5. The defective glomerular barrier in NS allows the passage of many proteins, among them plasminogen. 6. Urokinase, an enzyme naturally present in the cortical collecting tubule epithelium, is responsible for converting plasminogen into plasmin. 7. Plasmin, formed in situ in the cortical collecting tubule, activates ENaC causing sodium retention and oedema. 8. Amiloride enhances diuresis caused by loop diuretics in NS.
REFERENCES
1. Deschenes G, Guigonis V, Doucet A. Molecular mechanism of edema formation in nephrotic syndrome. Arch Pediatr 2004;11:108494. 2. Doucet A, Favre G, Deschenes G. Molecular mechanism of edema formation in nephrotic syndrome: therapeutic implications. Pediatr Nephrol 2007;22:1983-90. 3. Joles JA, Willekes-Koolschijn N, Braam B, et al. Colloid osmotic pressure in young analbuminemic rats. Am J Physiol 1989;257:F23-28. 4. Lecomte J, Juchmes J. So-called absence of edema in analbuminemia. Rev Med Liege 1978;33:766-70. 5. Koot BG, Houwen R, Pot DJ, et al. Congenital analbuminaemia: biochemical and clinical implications. A case report and literature review. Eur J Pediatr 2004;163:664-70. 6. Steyl C, Van Zyl-Smit R. Mechanisms of oedema formation: the minor role of hypoalbuminaemia. S Afr Med J 2009;99:57-9. 7. Oliver WJ. Physiologic Responses Associated with Steroid-Induced Diuresis in the Nephrotic Syndrome. J Lab Clin Med 1963;62:44964. 8. Manning RD, Jr., Guyton AC. Effects of hypoproteinemia on fluid volumes and arterial pressure. Am J Physiol 1983;245:H284-93. 9. Koomans HA, Kortlandt W, Geers AB, et al. Lowered protein content of tissue fluid in patients with the nephrotic syndrome: observations during disease and recovery. Nephron 1985;40:391-5. 10. Geers AB, Koomans HA, Boer P, et al. Plasma and blood volumes in patients with the nephrotic syndrome. Nephron 1984;38:170-3. 11. Koomans HA, Geers AB, vd Meiracker AH, et al. Effects of plasma volume expansion on renal salt handling in patients with the nephrotic syndrome. Am J Nephrol 1984;4:227-34. 12. Brown EA, Markandu ND, Sagnella GA, et al. Lack of effect of captopril on the sodium retention of the nephrotic syndrome. Nephron 1984;37:43-8. 13. Usberti M, Gazzotti RM. Hyporeninemic hypoaldosteronism in patients with nephrotic syndrome. Am J Nephrol 1998;18:251-5. Nefrologia 2011;31(2):148-54
14. De Seigneux S, Kim SW, Hemmingsen SC, et al. Increased expression but not targeting of ENaC in adrenalectomized rats with PANinduced nephrotic syndrome. Am J Physiol Renal Physiol 2006;291:F208-17. 15. Chandra M, Hoyer JR, Lewy JE. Renal function in rats with unilateral proteinuria produced by renal perfusion with aminonucleoside. Pediatr Res 1981;15:340-4. 16. Ichikawa I, Rennke HG, Hoyer JR, et al. Role for intrarenal mechanisms in the impaired salt excretion of experimental nephrotic syndrome. J Clin Invest 1983;71:91-103. 17. Caulfield JP, Reid JJ, Farquhar MG. Alterations of the glomerular epithelium in acute aminonucleoside nephrosis. Evidence for formation of occluding junctions and epithelial cell detachment. Lab Invest 1976;34:43-59. 18. Fiegelson EB, Drake JW, Recant L. Experimental aminonucleoside nephrosis in rats. J Lab Clin Med 1957;50:437-46. 19. Ryan GB, Karnovsky MJ. An ultrastructural study of the mechanisms of proteinuria in aminonucleoside nephrosis. Kidney Int 1975;8:21932. 20. Bricker NS, Stokes JM, Lubowitz H, et al. Experimentally induced permanent unilateral renal disease in dogs. J Lab Clin Med 1958;52:571-9. 21. Hoyer JR, Mauer SM, Michael AF. Unilateral renal disease in the rat. I. Clinical, morphologic, and glomerular mesangial functional features of the experimental model produced by renal perfusion with aminonucleoside. J Lab Clin Med 1975;85:756-68. 22. Besse-Eschmann V, Klisic J, Nief V, et al. Regulation of the proximal tubular sodium/proton exchanger NHE3 in rats with puromycin aminonucleoside (PAN)-induced nephrotic syndrome. J Am Soc Nephrol 2002;13:2199-206. 23. Biemesderfer D, DeGray B, Aronson PS. Active (9.6 s) and inactive (21 s) oligomers of NHE3 in microdomains of the renal brush border. J Biol Chem 2001;276:10161-7. 24. Deschenes G, Gonin S, Zolty E, et al. Increased synthesis and avp unresponsiveness of Na,K-ATPase in collecting duct from nephrotic 153
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rats. J Am Soc Nephrol 2001;12:2241-52. 25. Kim SW, Wang W, Nielsen J, et al. Increased expression and apical targeting of renal ENaC subunits in puromycin aminonucleoside-induced nephrotic syndrome in rats. Am J Physiol Renal Physiol 2004;286:F922-35. 26. Audige A, Yu ZR, Frey BM, et al. Epithelial sodium channel (ENaC) subunit mRNA and protein expression in rats with puromycin aminonucleoside-induced nephrotic syndrome. Clin Sci (Lond) 2003;104:389-95. 27. Loffing J, Korbmacher C. Regulated sodium transport in the renal connecting tubule (CNT) via the epithelial sodium channel (ENaC). Pflugers Arch 2009;458:111-35. 28. Hammer F, Stewart PM. Cortisol metabolism in hypertension. Best Pract Res Clin Endocrinol Metab 2006;20:337-53. 29. Kim SW, De Seigneux S, Sassen MC, et al. Increased apical targeting of renal ENaC subunits and decreased expression of 11betaHSD2 in HgCl2-induced nephrotic syndrome in rats. Am J Physiol Renal Physiol 2006;290:F674-87. 30. Bistrup C, Thiesson HC, Jensen BL, et al. Reduced activity of 11betahydroxysteroid dehydrogenase type 2 is not responsible for sodium retention in nephrotic rats. Acta Physiol Scand 2005;184:161-9. 31. Hamm LL, Feng Z, Hering-Smith KS. Regulation of sodium transport by ENaC in the kidney. Curr Opin Nephrol Hypertens; 19:98-105. 32. Kleyman TR, Carattino MD, Hughey RP. ENaC at the cutting edge: regulation of epithelial sodium channels by proteases. J Biol Chem 2009;284:20447-51. 33. Hughey RP, Bruns JB, Kinlough CL, et al. Epithelial sodium channels are activated by furin-dependent proteolysis. J Biol Chem 2004;279:18111-4.
34. Passero CJ, Hughey RP, Kleyman TR. New role for plasmin in sodium homeostasis. Curr Opin Nephrol Hypertens;19:13-9. 35. Kastner C, Pohl M, Sendeski M, et al. Effects of receptor-mediated endocytosis and tubular protein composition on volume retention in experimental glomerulonephritis. Am J Physiol Renal Physiol 2009;296:F902-11. 36. Passero CJ, Mueller GM, Rondon-Berrios H, et al. Plasmin activates epithelial Na channels by cleaving the gamma subunit. J Biol Chem 2008;283:36586-91. 37. Svenningsen P, Bistrup C, Friis UG, et al. Plasmin in nephrotic urine activates the epithelial sodium channel. J Am Soc Nephrol 2009;20:299-310. 38. Lau SO, Tkachuck JY, Hasegawa DK, et al. Plasminogen and antithrombin III deficiencies in the childhood nephrotic syndrome associated with plasminogenuria and antithrombinuria. J Pediatr 1980;96:390-2. 39. Vaziri ND, Gonzales EC, Shayestehfar B, et al. Plasma levels and urinary excretion of fibrinolytic and protease inhibitory proteins in nephrotic syndrome. J Lab Clin Med 1994;124:118-24. 40. Piedagnel R, Tiger Y, Lelongt B, et al. Urokinase (u-PA) is produced by collecting duct principal cells and is post-transcriptionally regulated by SV40 large-T, arginine vasopressin, and epidermal growth factor. J Cell Physiol 2006;206:394-401. 41. Deschenes G, Wittner M, Stefano A, et al. Collecting duct is a site of sodium retention in PAN nephrosis: a rationale for amiloride therapy. J Am Soc Nephrol 2001;12:598-601. 42. Guigonis V, Nathanson S, Doucet A, Deschenes G. Amiloride potentiates edema removal by furosemide in nephrotic children. J Am Soc Nephrol 2001;12: 135A.
Sent for reiew: 8 Nov. 2010 | Accepted el: 16 Nov. 2010 154 Nefrologia 2011;31(2):148-54
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Trends in resident positions offered in nephrology (1985-2008)

C. Bernis Carro, Spanish Nephrology Comission*
Nephrology Department. La Princesa University Hospital. Madrid, Spain
Nefrologia 2011;31(2):155-61
ABSTRACT This article reviews the trends in positions of internal medicine resident (IMR) assigned to nephrology in Spain from 1985 to 2008. We analyse the number of positions, the changes of average points received (435 to 377), and the average position for nephrology (253 to 3457). We also observed the distribution by sex for the candidates (from 42% to 72% feminisation) over the 24 years examined. Nephrology is positioned 29th of the 47 specialities offered on Spanish IMR training programmes. These data should be an indication to all nephrologists that change is needed. We must examine which factors are involved in the lessening interest in Nephrology as a career among medical graduates and then strive to resolve the problems. Keywords: Teaching. Fellowship. Nephrology. Education. Feminisation.
Evolucin de las plazas asignadas a nefrologa en las convocatorias MIR (1985-2008) RESUMEN Analizamos la evolucin de las plazas asignadas a nefrologa en la convocatoria MIR desde 1985 a 2008. Se recoge el nmero de plazas y se calculan la calificacin media anual y el nmero de orden promedio. El nmero de plazas adjudicadas ha aumentado un 464% (de 17 a 96), con una progresiva feminizacin que llega al 72,5% en los ltimos aos. La calificacin media anual de los candidatos ha disminuido de 435 a 377 puntos y el puesto medio de eleccin se ha ido retrasando del 253 al 3.457. Los datos sugieren una prdida de atractivo de la especialidad que debe llevar a examinar y corregir los factores implicados. Palabras clave: Docencia. Especializacin. Nefrologa. Educacin. Feminizacin.
INTRODUCTION The future for nephrology greatly depends on developing programmes that appeal to potential candidates.1 Recently, access and training in the field of nephrology has aroused reflection both in Spain 2,3 and overseas. 4-6 In this study, we hope to contribute to the debate by providing concrete data concerning the number of internal medical residency (IMR) positions 1 assigned for nephrology in Spain during the past 24 years.
Correspondence: Carmen Bernis Carro Servicio de Nefrologa. Hospital Universitario La Princesa. Diego de Len, 62. 28002 Madrid. Spain. cbernis@senefro.org
* Group members: President: F. Ortega Surez. Vicepresident and Secretary: C. Quereda Rodrguez-Navarro. Board member: A. Martnez Castelao, J.L. Grritz Teruel, R. Matesanz Acedos, A. Sanz Boix, P. Abigar Luquin, A. Snchez Casajs, C. Bernis Carro, I. Auyanet Saavedra, M.J. Prez Sez.
Medicine graduates wishing to take part in an IMR training programme must sit an official exam. The mark of the exam is worth 75% of the final score, with an academic transcript taking up the remaining 25%. Candidates are then put on a ranking list and those with the most points have first choice of IMR speciality and the hospital where they will complete the programme. Medical graduates must complete IMR training to work in the public sector. 155
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MATERIAL AND METHOD Data concerning the openings awarded from 1895 to 2008 was provided by the Spanish Ministry of Health. Based on the broken down data, we calculated the average number of points for each year (including the average exam points and academic transcript) and the average position for nephrology. We collected data on the average position for the first and last junior doctor that chose nephrology each year, as well as the number of openings assigned to nephrology and distribution by sex.
C. Bernis Carro et al. Trends in resident positions in nephrology
first 5 years, this percentage was 42.2% compared with 72.4% over the past 10 years, which seems to have stabilised. The average annual number of points for positions awarded to nephrology has decreased from 435 to 377 points (Figure 3). The average position has a clear trend to be delayed, being 253 at the beginning of the period and 3457 at the end (Figure 4). The ranking position of the first junior doctor to choose nephrology has changed significantly (Figure 5). The ranking position of the last junior doctor has moved backwards, going from 937 position to 5485 position (Figure 6). Table 2 shows the list of hospitals that have been requested by the top 5 IMR nephrology trainees during the study period.
RESULTS Table 1 shows a summary of the data. The number of positions assigned to nephrology has increased from 17 to 96, representing a 464% increase throughout the study period (Figure 1). There is a significant variation between sexes (Figure 2). Throughout this period, 65% of nephrology junior doctors were women. During the
DISCUSSION The number of nephrology IMR openings awarded throughout this period has markedly increased until 2009. This 464% increase is in line with the general
Table 1. Trends related to IMR nephrology places assigned (1985-2008)

No. 1985 1986 1987 1988 1989 1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 156 17 21 44 36 43 46 48 57 69 59 36 31 29 35 32 52 50 65 84 83 87 90 94 96 M 9 15 28 19 22 25 24 21 24 23 12 8 10 12 7 16 16 9 15 20 26 30 33 30 F 8 6 16 17 21 21 24 36 45 36 24 23 19 23 25 36 34 56 69 63 61 60 61 66 Ratio M/F 1.8 2.5 1.7 1.1 1.07 1.1 1 0.56 0.53 0.63 0.5 0.3 0.52 0.52 0.28 0.44 0.47 0.17 0.21 0.31 0.42 0.5 0.54 0.45 Average points 434.5 421.6 456.2 434.8 403.7 400.6 433.8 415.5 410.8 443.7 489.3 394.1 482.4 446 442.3 433.8 405.1 376.7 367.4 356.3 347.1 367.8 360.1 377.1 Average position 252.5 502.2 714.5 880.1 857.9 1199 887.8 1708 1938.4 1956.4 1591 1748.7 1607.4 1819.5 1702.6 2007.3 2108.7 2352 3072 2927.9 3196.4 3117.9 3834.1 3457.3 First trainee 16 2 2 63 47 139 41 114 222 625 87 136 870 551 731 304 440 241 463 381 608 197 1.429 149 Last trainee 937 854 1512 1666 2175 3243 1876 3027 3303 2956 2399 2830 3140 2759 2372 2762 2851 3463 4194 4210 5027 5630 5330 5485
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100 90 80 70 60 50 40 30 20 10 0 1985 1986 1987 1988
NO. IMR PLACES ASSIGNED TO NEPHROLOGY PER YEAR
1989
1990
1991
1992
1993
1994
1995
1996
1997
1998
1999
2000
2001
2002
2003
2004
2005
2006
2007
Figure 1. Trends related to IMR places assigned to nephrology (1985-2008)
80 70 60 50 40 30 20 10 0 Men Women Men Women
Figure 2. Distribution by sex of IMR nephrology places assigned (1985-2008)
context of the specialist positions awarded within the Ministry of Health policy 7 and the National Clinical Speciality Commissions. 2 This increase has remarkably made this speciality one of three medical specialities that have increased the most. 8 Recently, there has been a lack of nephrologists to cover the estimated needs 2 and
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increasing demand was forecast in view of an ageing population. 2,3 However, this specialist growth rate could continue, bringing with it a surplus of nephrologists, as described in Gonzlez Lpez Valcrcel and Patricia Barbers latest 2009 report on the supply and demand of specialist doctors in Spain: 2008-2025. 8 In this respect,
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IMR NEFROLOGY TRAINEES: AVERAGE POINTS
1985
1986
1987
1988
1989
1990
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1992
1993
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1995
1996
1997
1998
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2000
2001
2002
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2007 2007 2008
Figure 3. Average number of points for IMR nephrology trainees (1985-2008)
IMR NEFROLOGY TRAINEES: AVERAGE POSITION 4000 3500 3000 2500 2000 1500 1000 500 0 1985 1986 1987 1988 1989 1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006
Figure 4. Average position for IMR nephrology trainees (1985-2008).
the Speciality Commission has approved that the number of openings awarded be reduced. Calculating future needs is always a difficult task, resulting as an estimate, 2,7,9 given that it is partly dependent on the
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number of active nephrologists and their age. 2,7,8 However, it also depends on the ageing population and health priorities, meaning that there are several possible scenarios.
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2008
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FIRST IMR TRAINEE TO CHOOSE NEPHROLOGY 1400 1200 1000 800 600 400 200 0 1985 1986 1987 1988 1989 1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2007 2008 2008
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Figure 5. Nephrology IMR: trends related to first trainee to choose this speciality (1985-2008).
6000
LAST IMR TRAINEE TO CHOOSE NEPHROLOGY
5000
4000
3000
2000
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0 1985 1986 1987 1988 1989 1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006
Figure 6. Nephrology IMR: trends related to last trainee to choose this speciality (1985-2008).
Regarding distribution by sex, there was a significant increase in the number of women choosing nephrology. Feminisation of the medical profession is a well recognised process that has grown stronger throughout the world over
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the past 30 years.9-11 Throughout the study period, 65% of IMR trainees were women. During the first 5 years, this percentage was 42.2% compared with 72.4% over the past 10 years, which seems to have stabilised. When considering
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Table 2. Summary of centres requested by the top five nephrology IMR trainees (1985-2008).
rea Especializada de Albacete Ciutat Sanitria i Universitria de Bellvitge C.H. Ourense Fundacin Jimnez Daz Fundacin Puigvert Hospital Carlos Haya Hospital Clnic de Barcelona Hospital Clnico San Carlos Hospital Clnico Universitario Nalencia Hospital de Cruces Hospital del Mar Hospital Doctor Peset Hospital Universitario Central Asturias Hospital General Universitario Gregorio Maran Hospitalgeneral Universitario de Alicante Hospital Universitario A Corua Hospital Universitario la Fe Hospital Universitario La Paz Hospital Universitario 12 de Octubre Hospital Universitario Germans Trias i Pujol Hospital Universitario Marqus de Valdecilla Hospital Universitario Miguel Servet Hospital Universitario Reina Sofa Hospital Universitario Ramn y Cajal Hospital Universitario Virgen de la Macarena Hospital Universitario Virgen del Roco Hospital Universitario Virgen de las Nieves Hospital Universitario Virgen de la Arrixaca Hospital Vall dHebron Albacete Barcelona Orense Madrid Barcelona Mlaga Barcelona Madrid Valencia Barakaldo Barcelona Valencia Oviedo Madrid Alicante La Corua Valencia Madrid Madrid Badalona Santander Zaragoza Crdoba Madrid Sevilla Sevilla Granada Murcia Barcelona 3 7 1 1 2 6 16 1 1 2 1 5 2 10 4 3 11 2 12 3 3 4 5 9 3 1 1 5 2
the whole IMR population (i.e. all specialities), 80% of trainees are women.8 Nephrology training data for the USA show that 30% are women.5 European nephrology training data are considered within overall internal medicine data, showing a similar phenomenon.14 The total of active female nephrologists in Spain is 42.8%,8 being one of the highest ranking specialities, only coming after haematology (52%), general practice (49.2%) and paediatrics (60.1%).8 There are even more female nephrologists in France.13 A recent study has been published in the Spanish journal Nefrologa on female integration and participation within nephrology in Spain.15 The average annual number of points for positions awarded to nephrology has decreased from 435 to 377 points (Figure 3). The ranking position of the first junior doctor to choose nephrology has changed significantly (Figure 5); and that of the last junior doctor has moved backwards, going from 937 position to 5485 position (Figure 6). All of these data show us that our speciality is becoming less and less attractive to young professionals. Nephrology is positioned 29th of the 47
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specialities offered on the IMR training programme.8 It is astonishing to see that in the USA there is a difficulty to fill all of the nephrology training openings with American juniors, meaning that this speciality has the most foreign professionals (41%).5 In recent years, some specialities have had high drop out rates. In this respect, it seems that the drop out rate for nephrology programmes is low, being around 6%, which is similar to that of internal medicine (5.8%), lower than biochemical medicine (40%) and higher than cardiology (1.4%).8 Data concerning the ranking of the first junior doctor to choose nephrology (Figure 5) and most requested hospitals for the top 5 trainees are interesting, but they are quite incidental (Table 2.) Personal choice for these few positions could be influenced by multiple aspects, from the size of the centres population, whether there is a university with school of medicine, or the number of positions offered, amongst others.
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de Gran Canaria Oferta y necesidad de mdicos especialistas en Espaa 2006-2030, marzo 2007. Available at: http://www.mspsi.es/profesionales/formacion/docs/necesidadesEspecialistas06_30.pdf Gonzlez Lpez Valcarcel B, Barber P, del Grupo de Investigacin de Economa de la Salud de la Universidad de Las Palmas de Gran Canaria Oferta y necesidad de mdicos especialistas en Espaa 20082025, marzo 2009. Available at: http://www.mspsi.es/profesionales/formacion/docs/necesidadesEspecialistas2008_2025.pdf Matesanz R. Las necesidades de especialistas: el hilo de Ariadna. Nefrologia 2005;25:589-90 Bernis Carro C, Cmara Gonzlez C. Liberacin y utopa. En: Durn MA (ed.). La mujer y la medicina. Akal, 1982. Levinson W, Lurie N. When most doctors are women: What lies ahead? Ann Intern Med 2004;141:471-4. Arrizabalaga P, Bruguera M. Feminizacin y ejercicio de la medicina. Med Clin (Barc) 2009;133(5):184-6. Arrizabalaga P. Feminizacin y ejercicio de la nefrologa. Nefrologia 2010;30:1010-3. Palsson R, Kellett J, Lindgren S, Merino J, Semple C, Sereni D; For the EFIM/UEMS Working Group on Competencies in Internal Medicine in Europe. Core competencies of the European internist: A discussion paper. Eur J Intern Med 2007;18(2):104-8. Legmann M, Kahn Bensaude I, Romestaing P. Atlas de la dmographie mdicale en France. Situation au Javier 2009. Conseil National de l Ordre des Mdicins. Available at: http:www.web.ordre.medecin.fr/demographie/atlas2009.pdf Kohan DE, Rosenberg ME. Nephrology training programs and applicants: a very good match. Clin J Am Soc Nephrol 2009;4(1):242-7. Barrio Lucia V, Garca Lpez F, Quereda Rodrguez-Navarro C. Los suplementos de Nefrologa basada en la evidencia como instrumento para la formacin continuada. Nefrologia 2008;28(Suppl 2):1. Niyyar VD, Work J. Interventional nephrology: core curriculum 2009. Am J Kidney Dis 2009;54(1):169-82. Goh BL, Ganeshadeva Yudisthra M, Lim TO. Establishing learning curve for Tenckhoff catheter insertion by interventional nephrologist using CUSUM analysis: how many procedures and in which situation? Semin Dial 2009;22(2):199-203. Haq NU, Sayeed S, Ali SA. Impact of training in interventional nephrology on hemodialysis vascular access types. Semin Dial 2009;22(1):90-2. Vachharajani TJ, Moossavi S, Salman L, Wu S, Maya ID, Yevzlin AS, et al. Successful models of interventional nephrology at academic medical centers. Clin J Am Soc Nephrol 2010;5(11):2130-6.
In brief, our study suggests that this speciality is becoming less attractive in Spain, which is a common concern in other countries, as described in various studies.4-6,16 There are doubtlessly many factors involved, from the job market perspectives to the training programmes content and methodology. Understanding the situation and the opinions of those involved is an important step forward.3,6 As nephrologists, we need to actively develop interesting programmes that appeal to motivated individuals, introducing innovation, enthusiasm, intensity and integrity.16 The way that we conceive medical training has changed, being based on assessing skills, new simulation techniques, and introducing evidence as a teaching tool.1,3,4,18 Although there are still very few publications about nephrology, there are opportunities for developing new teaching techniques. However, we must highlight that interventional nephrology has contributed interesting studies that link the learning process with outcome.19-21
8.
9. 10. 11. 12. 13. 14.
REFERENCES
1. Perazella MA. Nephrology fellowship training in the 21st century: where do we stand? Clin J Am Soc Nephrol 2010;5(3):387-9. 2. Ortega Surez F. Situacin de la especialidad de Nefrologa en relacin a las necesidades de nefrlogos y a su formacin. Nefrologia 2008;28(3):241-4. 3. Quereda C, por la Comisin Nacional de la Especialidad de Nefrologia en Espaa (Presidente: F. Ortega Surez. Vicepresidente y Secretario: C. Quereda Rodrguez-Navarro. Vocales: A.L. Martn de Francisco Hernndez, R. Matesanz Acedos, R. Alczar Arroyo, A. Sanz Boix, C. Bernis Carro, P. Abaigar Luquin, A. Snchez Casajs, E. Mrida Herrero, M.A. Garca Prez). Algunos aspectos de la situacin de la formacin de especialistas en Espaa. Nefrologia 2008;28(3):263-71. 4. Parker MG. Nephrology training in the 21st century: toward outcomes-based education. Am J Kidney Dis 2010;56(1):132-42. 5. Rosenberg ME. Adult nephrology fellowship training in the United States: trends and issues. J Am Soc Nephrol 2007;18(4):1027-33. Epub 2007 Feb 28. 6. Berns JS. A survey-based evaluation of self-perceived competency after nephrology fellowship training. Clin J Am Soc Nephrol 2010;5(3):490-6. 7. Gonzlez Lpez Valcrcel B, Barber P, del Grupo de Investigacin de Economa de la Salud de la Universidad de Las Palmas
15.
16. 17.
18. 19.
20.
21.
EDITORS NOTE
The content of this article and the Editorial on page 129 are without a doubt extremely important for the future of Spanish nephrology. The editors therefore invite Spanish nephrologists to send their opinions and observations on the matter, using the Letters to the editor format.
Sent for review 3 Feb. 2011 | Accepted 4 Feb. 2011 Nefrologia 2011;31(2):155-61 161
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See editorial comment on page 134
Co-inheritance of autosomal dominant polycystic kidney disease and sickle cell trait in African Americans
R. Peces1, C. Peces2, E. Cuesta-Lpez3, C. Vega-Cabrera1, S. Azorn1, V. Prez-Dueas3, R. Selgas1
Nephrology Department. La Paz University Hospital. IdiPAZ. Madrid, Spain Information Technology Area. SESCAM. Toledo, Spain 3 Radiology Department. Hospital Universitario La Paz. IdiPAZ. Madrid, Spain
1 2
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doi:10.3265/Nefrologia.pre2010.Dec.10660
ABSTRACT Background: Macroscopic haematuria secondary to renal cyst rupture is a frequent complication in autosomal dominant polycystic kidney disease (ADPKD). Sickle-cell disease is an autosomal recessive haemoglobinopathy that involves a qualitative anomaly of haemoglobin due to substitution of valine for the glutamic acid in the sixth position of 3-globin gene on the short arm of chromosome 11. For the full disease to be manifested, this mutation must be present on both inherited alleles. The severity of the disease is proportional to the quantity of haemoglobin S (Hb S) in the red cells; sickle-cell trait (Hb S <50%) and homozygous sickle-cell disease (Hb S >75%). In sickle-cell disease, the abnormal Hb S loses its rheological characteristics and is responsible of the various systemic manifestations including those of the kidney, such as macroscopic haematuria secondary to papilar necrosis. Despite the generally benign nature of the sickle-cell trait, several potentially serious complications have been described. Metabolic or environmental changes such as hypoxia, acidosis, dehydration, hyperosmolality or hyperthermia may transform silent sickle-cell trait into a syndrome resembling sickle-cell disease with vaso-occlusive crisis due to an accumulation of low deformable red blood cells in the microcirculation originating haematuria from papilar necrosis. On the other hand, it has been demonstrated an earlier onset of end-stage renal disease (ESRD), in blacks with ADPKD and sickle-cell trait when compared with blacks with ADPKD without the trait. Patients and methods: We studied 2 African American families (4 patients) which presented with both ADPKD and sickle-cell trait (Hb S <50%). The diagnosis of sickle-cell trait was confirmed by haemoglobin electrophoresis. The renal volume was measured by magnetic resonance (MRI). Results: The proband subject in family 1 presented frequent haematuria episodes, associated to increase of renal volume, developed very early ESRD and was dialysed at the age of 39 years. The other 3 patients in family 2 presented different degree of renal function. Conclusions: The presence of sickle haemoglobin should be determined in African American and west African patients with ADPKD because it is an important prognostic factor. Co-herence of sickle-cell trait may have influence on ADPKD evolution to ESRD and other complications, such as cystic haemorrhages. MRI can identify intracystic haemorrhage and permit renal volume measure. Keywords: Co-inheritance. Sickle-cell haemoglobin. Haemoglobin S. Heterozygous. Autosomal dominant polycystic kidney disease. Chronic renal failure.
Co-herencia de poliquistosis renal autosmica dominante y hemoglobina con rasgo falciforme en afroamericanos RESUMEN Antecedentes: La hematuria macroscpica derivada de la rotura de quistes renales es una manifestacin habi-
Correspondence: Ramn Peces Servicio de Nefrologa. Hospital Universitario La Paz. IdiPAZ. Paseo de la Castellana, 261. 28046 Madrid. Spain. cpeces@varnetmail.com 162
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presence of renal cysts that gradually increase in number and size, leading to end-stage chronic renal failure at an average age of 50-60 years. In autosomal dominant polycystic kidney disease (ADPKD), macroscopic haematuria resulting from the rupture of renal cysts is a common manifestation.1 Drepanocytosis, or sickle cell disease, is inherited as an autosomal recessive haemoglobin abnormality caused by the substitution of valine for glutamic acid at position 6 in the 3-globin gene on the short arm of chromosome 11. The severity of the disease is proportional to the amount of haemoglobin S (HbS) in red blood cells: sickle cell trait (HbS<50%) and homozygous sickle cell disease (HbS>75%). In sickle cell disease, abnormal haemoglobin S loses its rheological properties and is responsible for several systemic manifestations, including those of the kidney, such as papillary infarcts due to vascular lesions. In sickle cell disease, chronic renal failure (CRF) may be a complication in up to 4%20% of cases. The presence of sickle cell trait (HbAS) may also be associated with renal manifestations, especially haematuria. Papillary necrosis is the most common cause of macroscopic haematuria in heterozygous patients with sickle cell trait.2-6 The association of these two hereditary diseases, ADPKD and sickle cell trait, has been rarely reported in the literature. In the 1990s, it was reported that African American patients with ADPKD, who also had sickle cell trait, could develop ESRD earlier. 7,8 Since then, there have been no references to families or series with this genetic association, despite the relative frequency of both hereditary diseases. Four patients belonging to 2 African American families, with co-inheritance of ADPKD and sickle cell trait (heterozygous) are described. In one case, the patient developed ESRD at 39 years of age after numerous recurrent episodes of macroscopic haematuria. The other 3 patients had varying degrees of renal function.
tual en la poliquistosis renal autosmica dominante (PQRAD). La enfermedad por clulas falciformes es una anomala de la hemoglobina, que se hereda con carcter autosmico recesivo, consistente en la sustitucin de la valina por el cido glutmico en la posicin 6 del gen de la 3-globina en el brazo corto del cromosoma 11. La gravedad de la enfermedad es proporcional a la cantidad de hemoglobina S (Hb S) en los hemates: los heterocigotos con hemoglobina con rasgo falciforme (Hb S <50%) y los homocigotos con enfermedad por clulas falciformes (Hb S >75%). La presencia de hemoglobina con rasgo falciforme (Hb AS) se acompaa de manifestaciones renales, especialmente hematuria, y la necrosis papilar es la causa ms frecuente de hematuria macroscpica en los pacientes heterocigotos portadores de esta hemoglobinopata. La asociacin de estas dos enfermedades hereditarias, PQRAD y hemoglobina con rasgo falciforme, se ha comunicado raramente. Se ha sugerido que los pacientes con PQRAD y hemoglobina con rasgo falciforme podan desarrollar precozmente insuficiencia renal crnica (IRC). Recientemente, se ha comunicado que la hemoglobina con rasgo falciforme es un factor de riesgo predisponente para el desarrollo de enfermedad renal crnica en afroamericanos. Pacientes y mtodos: Se estudiaron 2 familias de origen afroamericano (4 pacientes) que co-heredaron la PQRAD y la hemoglobina con rasgo falciforme (heterocigotos). El diagnstico de hemoglobina falciforme (Hb S) se realiz por electroforesis de la hemoglobina. El volumen renal se midi mediante resonancia magntica (RM). Resultados: La paciente ndice, perteneciente a una de las familias, present episodios de hematuria macroscpica recidivantes, asociados con incremento del volumen renal y desarrollo precoz de IRC avanzada, precisando tratamiento con dilisis a los 39 aos de edad. Las 3 pacientes pertenecientes a la otra familia, de tres generaciones diferentes, presentaron distintos grados de funcin renal. Conclusiones: En los pacientes afroamericanos y del frica subsahariana con PQRAD, debe determinarse la presencia de hemoglobina falciforme, porque sta puede ser un importante factor pronstico. La co-herencia de PQRAD y hemoglobina con rasgo falciforme puede influir en la evolucin hacia la IRC y en el desarrollo de complicaciones, como el sangrado qustico. La imagen de RM es una herramienta de utilidad para identificar las hemorragias qusticas y para medir el volumen renal. Palabras clave: Co-herencia. Hemoglobina falciforme. Hemoglobina S. Heterocigoto. Poliquistosis renal autosmica dominante. Insuficiencia renal crnica.
PATIENTS AND METHODS The diagnosis of ADPKD was made from the family history and related imaging tests that included ultrasound, magnetic resonance imaging (MRI) and in some cases, computed tomography (CT) also. Although there were no DNA genetic studies, the ADPKD was in all probability PKD1 (chromosome 16), taking into account the form of presentation, clinical features and time of diagnosis in these families. The first family consisted of two generations and the second of three. The diagnosis of sickle cell trait (HbS) was performed by electrophoresis of haemoglobin in acid and alkaline media. The total renal volume was determined by non163
INTRODUCTION Polycystic kidney disease is an inherited, autosomal dominant disease caused by mutations in two genes, PKD1 (the short arm of chromosome 16) and PKD2 (the long arm of chromosome 4). It is characterised by the
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Index Case (Case 1)
ADPKD Sickle cell
The number is year born Figure 1. Family tree for family 1.
enhanced MRI in T1 and T2 weighted sequences, and by manual segmentation technique, adding the volume of both kidneys. In all patients with recurrent haematuria, the presence of renal medullary carcinoma was ruled out. Figures 1 and 2 show both family trees. Figures 3, 4 and 5 show representative images of the polycystic kidneys. Tables 1 and 2 summarise the clinical characteristics and evolution data of the patients.
An African American woman born in 1968 (a native of Santo Domingo) who was diagnosed with ADPKD at 35 years old after renal ultrasound, which was performed due to an episode of renal colic with passage of several blood clots. Her family history showed that her father ha been diagnosed with ADPKD, and had undergone haemodialysis treatment since 55 years old. A younger sister was also diagnosed with ADPKD, although her degree of renal function was unknown. Her mother, the younger sister and the patient herself were carriers of sickle cell trait (HbAS). She was studying in Germany in April 2005 when she began with right flank pain and dark haematuria with clots. She had to be hospitalised and was diagnosed with a complicated renal cyst. At that time she had a serum Cr of 2mg/dl and Hb of 5.2g/dl, transfusion of 4 units of packed red blood cells was required. A week later, she was re-admitted for recurrent pain in the right flank, requiring strong analgesia. Following the completion of cystoscopy, a bladder mass compatible with clots was discovered which required 2 more transfusions. She received antibiotics and symptomatic treatment, and her anaemia improved to Hb 13.6g/dl and serum Cr 1.9mg/dl. An analytical control in October 2006 revealed serum Cr 2.4mg/dl and Cr clearance of 29ml/min. By MRI, the volume of the kidneys was RK 1392ml and LK 1485ml (total renal volume of 2877ml), and several cysts with signs of intracystic bleeding. Haemoglobin electrophoresis showed the following distribution: HbS
ADPKD Sickle cell
The number is year born
Figure 2. Family tree for family 2.

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Figure 3. MRI of case 3 where the kidneys retain their shape, with multiple small cysts (TRV=603ml). A) Coronal view B) Axial view.
Figure 4. MRI of Case 2 showing enlarged kidneys, with multiple large cysts, a number of which show signs of intracystic haemorrhage (TRV=1322ml). A) Coronal view B) Axial view.
40%, HbA 57% and HbA2 3% (Table 1). Between 2006 and 2008 she had several episodes of recurrent haematuria with clots, accompanied by anaemia, which required multiple transfusions. In June 2008, her analytical results were serum Cr 4.4mg/dl and Cr clearance 15ml/min. By MRI, the volume of the kidneys was RK 2748ml and LK 2076ml (total renal volume of 4824ml). After repeated episodes of haematuria (some spontaneous and one after an accidental fall) and anaemia not responding to medical treatment, including tranexamic acid, an embolisation was proposed, which
was not accepted by the patient. In September 2008 a left nephrectomy was performed. Haemodialysis via a permanent jugular catheter was then required. Attempts (on two occasions) to conduct an arteriovenous fistula for haemodialysis were unsuccessful due to thrombosis. After two years on haemodialysis and having suffered persistent haematuria, an embolisation and right nephrectomy had to be performed in September 2010. Neither of the two surgical samples from the nephrectomies showed changes consistent with renal medullary carcinoma.
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Figure 5. Axial view of CT in case 1 showing extremely enlarged kidneys, with multiple cysts with intracystic signs of haemorrhage-haematoma (TRV=2877ml).
haematuria is a symptom of presentation in 35% of cases, and microscopic or macroscopic haematuria is observed in 50%. 1 The risk of haematuria appears to be associated with the presence of hypertension and with an increase in the size of the cysts. Although most patients report trauma and violent exercise as possible precipitating causes, no association has been unequivocally demonstrated. Currently, with the widespread use of imaging techniques, and specifically MRI, intracystic bleeding can be observed which had previously gone unnoticed in many cases. These facts are very important, as it is known that ADPKD patients who have frequent episodes of haematuria or evidence of intracystic haemorrhage have a more rapid progression to CRF. Moreover, the presence of sickle cell trait (HbAS) is characterised by renal manifestations, especially haematuria, with papillary necrosis being the most common cause of macroscopic haematuria in heterozygous carriers of this haemoglobinopathy. 9-12 It is therefore not surprising that the co-inheritance of both genetic diseases causes a synergy in terms of the occurrence of these bleeding complications and in the development of CRF. In family 1, one of the diseases, the autosomal dominant ADPKD, was transmitted in the paternal line while the maternal line carried the other recessive, sickle cell trait (Fig. 1). In this family, the index case was a woman with two genetic diseases who developed rapidly progressing CRF and had to start haemodialysis at 39 years of age.
DISCUSSION In ADPKD, macroscopic haematuria resulting from the rupture of renal cysts is a common manifestation. Thus,
Table 1. Clinical and haematological characteristics of the 4 patients with ADPKD and HbAS
Case Year born/sex Electrophoresis (acid pH) Hb F 1 2 3 4 1968/woman 1944/woman 1971/woman 1998/woman 0.7% 0.4% 0.1% 0.8% Hb A2 4.0% 3.8% 3.6% 4.1% Hb S 40% 44% 44% 42% Electrophoresis (alkaline pH) Hb A 57% 57% 63% 57% HbS 40% 42% 37% 41% Hb A2 3% 1% 2% + + + + Sickling
Table 2. Renal evolution data for the 4 patients with ADPKD and HbAS
Case Patient age/sex SCr mg/dl 1 2 3 4 38/woman 65/woman 38/woman 11/woman 2.40 1.68 0.85 0.44 CCr ml/min/1.73 m2 29 56 131 145 Proteinuria g/day 0.28 0.15 0.23 0.12 TRV ml 2.877 1322 603 4 cysts
TRV = Total renal volume. 166 Nefrologia 2011;31(2):xx
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disease. 16 It may be that the production of proangiogenic factor stimulants, present in both diseases and acting synergistically, are responsible for cystic bleeding and rapid progression to CRF in some cases of ADPKD. The presence of sickle cell trait (HbAS) may also affect the course and care of patients with ESRD, as it may be an independent risk factor for venous thromboembolism among African Americans. 13 This predisposition towards thrombosis may affect the arteriovenous fistula failure and loss of vascular access, as occurred in our index case. In conclusion, the existence of sickle cell trait should be determined in African American patients and those from West Africa with ADPKD, as its presence may be an important prognostic factor. The co-inheritance of sickle cell trait may influence complications in patients with ADPKD and the evolution of CRF. This is probably also applicable to other highly prevalent renal pathologies, such as hypertension and diabetes mellitus.
In this patient, renal cysts formed and developed very early, and the association of sickle cell trait (HbAS) very probably favoured recurrent episodes of macroscopic haematuria, intracystic haemorrhage and early development of advanced CRF. It is worth noting that, in this case, the episodes of haematuria were sometimes preceded by an airplane ride lasting several hours (obviously in a position of relative hypoxia) or by minimal trauma. Moreover, sequential MRI measuring renal volume showed a significant increase in a relatively short time (68% in 2 years). This was no doubt due to intracystic bleeding and the intrarenal haematomas detected in the later stages of the disease. They were confirmed by CT and finally pathologically. This development contrasted with that of the father, who was not a sickle cell trait carrier and required haemodialysis treatment at 55 years old. In family 2, both diseases, ADPKD and sickle cell trait were inherited by the same (maternal) line (Fig. 2). In this family, ADPKD was diagnosed early in one of the members, at 11 years old (case 4). This patient and the mother (case 3) showed glomerular hyperfiltration. The grandmother (case 2), who had some episodes of macroscopic haematuria, developed CRF, with MRI of intracystic bleeding and a moderately elevated total renal volume. To our knowledge, this is the first study that has evaluated families with this genetic association in Europe. Surprisingly, only two papers regarding this matter were found in the literature, both from the same group, which described the association of two genetic diseases, ADPKD and sickle cell trait in African Americans. 7,8 In one of them, the African American patients with ADPKD and HbAS showed a faster progression towards ESRD than those without the sickle cell trait. 7 Moreover, there are few data in the literature examining the relationship between sickle cell trait and chronic kidney disease. Only recently, a US study reported a 50% higher prevalence of sickle cell trait in a population of African Americans with ESRD, compared with that inferred from the haemoglobinopathy newborn screening programme, meaning that it may represent a risk factor for the development of chronic kidney disease.13,14 The mechanism by which sickle cell trait contributes to the progression of chronic kidney disease in ADPKD may be multifactorial. 15 The repeated occurrence of localised areas of sickling and vein occlusion, leading to chronic microvascular damage, may cause chronic hypoxia and tubulointerstitial fibrosis. It is possible that sickle cell trait, coexisting with other conditions affecting the renal microvasculature, like ADPKD, could act synergistically to accelerate renal damage. It must be borne in mind that serum levels of angiogenic factors reveal a proangiogenic state in adults with sickle cell
Acknowledgements
This study was partially funded by a grant from the Instituto de Salud Carlos III, the Spanish Ministry of Health an Innovation (EC08/00236) and the Research Activity Intensification Programme (Programa Intensificacin Actividad Investigadora, LanEntralgo/CM) to RP.
REFERENCES
1. Masoumi A, Reed-Gitomer B, Kelleher C, Bekheirnia MR, Schrier RW. Developments in the management of autosomal dominant polycystic kidney disease. Ther Clin Risk Manag. 2008;4:393-407. 2. De Jong PE, Statius Van Eps LW. Sickle cell nephropathy: new insights into its pathophysiology. Kidney Int. 1985;27:711-7. 3. Allon M. Renal abnormalities in sickle cell disease. Arch Intern Med. 1990;150:501-4. 4. Kiryluk K, Jadoon A, Gupta M, Radhakrishnan J. Sickle cell trait and gross hematuria. Kidney Int. 2007;1:706-10. 5. Niang A, Diouf B, Ndiaye/Sene FS, Fall S, Moreira/Diop T. Sickle cell disease and the kidney. Saudi J Kidney Dis Transpl. 2004;15:180-4. 6. WHO. Sickle-cell Anaemia. Report by the Secretariat. Fifty-ninth World Health Assembly. 2 April, 2006. 7. Yium J, Gabow P, Johnson A, Kimberling W, Martnez-Maldonado M. Autosomal dominant polycystic kidney disease in blacks: clinical course and effects of sickle-cell hemoglobin. J Am Soc Nephrol. 1994;4:1670-4. 8. Kimberling WJ, Yium JJ, Johnson AM, Gabow PA, Martnez167
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Maldonado M. Genetic studies in a black family with autosomal dominant polycystic kidney disease and sickle-cell trait. Nephron. 1996;72:595-8. Zadeii G, Lohr JW. Renal papillary necrosis in a patient with sickle cell trait. J Am Soc Nephrol. 1997;8:1034-9. Hedayati B, Anson KM, Patel U. Focal renal infarction: an unusual cause of haematuria in a patient with sickle cell trait. Br J Radiol. 2007;80:e105-106. Tsaras G, Owusu-Ansah A, Boateng FO, Amoateng-Adjepong Y. Complications associated with sickle cell trait: a brief narrative review. Am J Med. 2009;122:507-12. Scheinman JI. Sickle cell disease and the kidney. Nat Clin Pract
9. 10.
11.
12.
Nephrol. 2009;5:78-88. 13. Derebail VK, Nachman PH, Key NS, Ansede H, Falk RJ, Kshirsagar AV. High prevalence of sickle cell trait in african americans with ESRD. J Am Soc Nephrol. 2010;21:413-7. 14. Cavanaugh KL, Lanzkron S. Time to recognize an overlooked trait. J Am Soc Nephrol. 2010;21:385-6. 15. Shaw C, Sharpe CC. Could sickle cell trait be a predisposing risk factor for CKD? Nephrol Dial Transplant. 2010;25:2403-5. 16. Duits AJ, Rodriguez T, Schnog JJ; CURAMA Study Group. Serum levels of angiogenic factors indicate a pro-angiogenic state in adults with sickle cell disease. Br J Haematol. 2006;134:116-9.
Sent for review: 13 Oct. 2010 | Accepted: 9 Dic. 2010 168 Nefrologia 2011;31(2):xx
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See editorial comment on page 137
Detection of latent tuberculosis infection in peritoneal dialysis patients: new methods

R. Palomar1, M. Arias Guilln2, C. Robledo1, R. Agero3, J. Agero4, C. Rodrguez5, L. Molinos2, E. Rodrigo1, F. Ortega5, M. Arias1
1 Nephrology Department. Marqus de Valdecilla Hospital. Cantabria University. ISCIII (REDINREN 06/16). Fundacin Marqus de Valdecilla-IFIMAV. Santander, Spain 2 Pulmonology Department. INS- Asturias Central University Hospital Oviedo, Spain 3 Pulmonology Department. Marqus de Valdecilla University Hospital. Santander, Spain 4 Microbiology Department. Marqus de Valdecilla University Hospital. Santander, Spain 5 Nephrology Department. Asturias Central University Hospital. Oviedo, Spain
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ABSTRACT Objective: The risk for tuberculosis (TB) is increased in patients with chronic renal failure and dialysis. Tuberculin skin test (TST) is the classical diagnostic method for screening despite its low sensitivity. New methods based on interferon-gamma have been developed. The aim of this study was to evaluate if Quantiferon TB-gold In Tube (QFTGIT) could be useful in the diagnosis of TB infection in patients on peritoneal dialysis (PD). Patients and methods: Fifty-four patients on PD were included in the study. They were evaluated for latent tuberculosis with QFT-GIT, TST and an assessment by an expert pulmonologist using patients medical history and x-rays. Agreement between test results was determined. Results: The prevalence of a positive TST was 29.6% for the first test and 31.5% for the second (booster effect). A positive chest x-ray increased the rate of detection of patients with latent TB infection up to 42.6% and the expert physicians evaluation to 44.4%. The correlation between QFT-GIT and TST was fair (=0.36; P=.006), as it was between TST and expert physicians evaluation (=0.257; P=.06). Conclusions: According to our experience QFT-GIT represents an important advantage in the diagnosis of latent TB infection in chronic renal failure patients on PD. It may complement but not replace TST. Keywords: Chronic renal failure. Peritoneal dialisis. QuantiferonTB-gold In Tube. Tuberculin Skin Test. Tuberculosis.
Deteccin de la infeccin tuberculosa latente en pacientes en dilisis peritoneal: nuevos mtodos RESUMEN Introduccin: El riesgo de tuberculosis (TB) est aumentado en pacientes con insuficiencia renal crnica y en dilisis. La prueba de la tuberculina (PT) es el test de cribado clsico en estos pacientes, a pesar de su baja sensibilidad. En los ltimos aos se han desarrollado nuevos mtodos diagnsticos que se basan en la produccin de interfern gamma tras la estimulacin con antgenos de M. tuberculosis. El objetivo de este estudio fue evaluar si el Quantiferon TB-gold In Tube (QFT-GIT) puede contribuir en el diagnstico de la infeccin tuberculosa en pacientes en dilisis peritoneal (DP). Pacientes y mtodos: Se incluyeron 54 pacientes en DP. Se valor la posibilidad de infeccin tuberculosa latente mediante el QFT-GIT, la PT y la valoracin clinicorradiolgica por parte de un neumlogo experto. Se estudiaron las concordancias entre los tests. Resultados: La prevalencia de un resultado positivo para el test de la tuberculina fue del 29,6% para el primer test y del 31,5% para el segundo (valorando el efecto booster). Una radiografa de trax positiva aumentaba la deteccin de infeccin tuberculosa latente hasta un 42,6% y la del neumlogo hasta un 44,4%. El nivel de correlacin entre el QFT-GIT y la PT fue moderado (kappa = 0,36; p = 0,006), al igual que entre la PT y la valoracin del neumlogo (kappa = 0,257, p = 0,06). Conclusiones: El QFT-GIT aporta algunas ventajas en el diagnstico de la infeccin tuberculosa en pacientes con insuficiencia renal crnica en DP, y puede complementar a la prueba de la tuberculina. Palabras clave: Insuficiencia renal crnica. Dilisis peritoneal. QuantiferonTB-gold In Tube. Prueba de la Tuberculina. Tuberculosis.
INTRODUCTION
Correspondence: Rosa Palomar Fontanet Servicio de Nefrologa. Hospital Marqus de Valdecilla. Universidad de Cantabria. ISCIII (REDINREN 06/16). Fundacin Marqus de Valdecilla-IFIMAV. Avda. Valdecilla, s/n. 39008 Santander. Spain. nefpfm@humv.es
The prevalence of tuberculosis (TB) in Spain varies depending on the region. The incidence of tuberculosis has dropped in Spain over the last decade; however, it is important to know that, even in areas of low prevalence, the
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occurrence of TB in immunocompromised patients is an important cause of morbidity and mortality.1 Uraemia is known to be associated with a large number of immune system disorders, most of them linked to impaired cellular immunity.2 Latent tuberculosis is characterised by a strong cellular immune response in the absence of detectable mycobacteria. As this infection is controlled by the cellular immune response, impairment in cellular immunity may lead to the reactivation of latent tuberculosis infection.1 At present the skin sensitivity to the tuberculin is the method used to detect latent tuberculosis infection. The response to this antigen depends on the infectious load and the condition of the individuals cellular immunity. It has low sensitivity and specificity. Furthermore, in uraemic patients the delayed immune response to skin tests is reduced3 as well as the macrophage function.2 This may cause cutaneous anergy and alter the response to the tuberculin skin test (TST). For this reason, TST is not routinely performed on dialysis patients. Given the fact that there is no gold standard test to diagnose TB, some groups have studied tests that use InterferonGamma Release Assays (IGRA). They have compared these with TST in order to determine their sensitivity and specificity in different subgroups of the population.1,4-6 The different regulations concerning the use of IGRA depend on each country. For example, the CDC (Center for Disease Control) in the USA recommends replacing TST with IGRA in all cases; while in the United Kingdom, the National Institute of Health and Clinical Excellence (NICE) recommends the use of IGRA in combination with TST only when the tuberculin skin test was positive. Other countries such as France or Canada have adopted these recommendations. However, they are based on costeffectiveness studies which compare TST with one of the IGRA (QFT-GIT or T-SPOT.TB) available on the market. In a recently published study, Pooran et al7 compared the two types of IGRA. They reached the conclusion that it was cheaper to use a regimen combining TST/IGRA rather than using T-SPOT.TB or QFT-GIT or TST on their own for contact tracing. While T-SPOT.TB and QFT-GIT on their own prevent more cases of active TB, they do not better the lower cost of the combined use of TST/IGRA. However, these conclusions depend largely on the population studied. The aim of our study was to compare QFT-GIT with the TST as a screening method to detect latent tuberculosis in patients on peritoneal dialysis (PD).
R. Palomar et al. Detection of latent TB in peritoneal dialysis
and Asturias Central Hospital in Oviedo. They had no signs or symptoms of active or extrapulmonary tuberculosis (between December 2007 and July 2008). They also had to accept to take part in the study. The TST and the QFT-GIT were performed on all patients included in the study. Patients with a high risk of latent tuberculosis were taken to be any patient living in a TB endemic area, any patient that claimed to have been in contact with people infected with TB or any patient with previous history of TB and any patient who had a chest x-ray that was compatible with a previous TB infection.
Tuberculin skin test The TST was performed by TB specialist nurses. All patients were administered 2 IU Rt-23 PPD on the inside of their forearm. The results were assessed after 72 hours in accordance with the established regulations. The test was considered positive with an induration of _5mm. In patients > that had been previously vaccinated with BCG, the TST was considered to be positive with an induration of >10mm _ (except in patients with previous contact with tuberculosis, chest x-ray suggestive of TB, infected by the human immunodeficiency virus [HIV] or diagnosed with silicosis). The test was repeated 10 days later in patients that had no induration on the first test to rule out a possible booster effect.
Quantiferon - TB Gold In Tube The QFT-GIT test (Cellestis, Carnegie, Victoria, Australia) was performed according to the manufacturers instructions. The blood samples were processed 6 to 8 hours after being extracted. The blood was put into 3 different tubes: one did not contain antigens (control), the second tube contained TB antigens and the third contained phytohaemagglutinin (mitogen or positive control). The incubation time was 1824h at 37C. The results were considered positive, negative or inconclusive according to the criteria established in the manufacturers software. TST and QFT-GIT were performed on the same day.
Pulmonologists assessment Two pulmonologists who are experts in TB (one in each hospital) assessed the risk factors for latent tuberculosis, including medical history of active TB or contact with an active case, vaccination, or born in a TB endemic area. The results of TST and chest x-ray were also assessed. All the data was assessed to determine whether the patient had been previously infected with M. tuberculosis.
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PATIENTS AND METHODS Patients The study included patients with chronic renal failure (CRF) on PD from the Marqus de Valdecilla Hospital in Santander
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There were 10 positive cases (18.5%), 34 negative (62.96%) and 10 inconclusive results in the QFT-GIT. Nine (26%) of the negatives had a medical history of TB, a chest x-ray or a positive pulmonologists assessment. Five of the inconclusive cases were re-evaluated (1 stayed negative and the other 4 inconclusive). Of the 9 inconclusive results, 1 patient had a positive TST and the others had an induration of 0mm. Three of the patients had a low risk for TB and 6 had a high risk. The factors associated with an inconclusive QFT-GIT are shown in Table 2.
Statistical analysis The data analysis was performed with the statistical software SPSS (SPSS version 12.0, Chicago, IL) and P values less than 0.05 were considered significant. Cohens kappa coefficient was used to calculate the level of agreement between the two tests (TST and QFT-GIT). The following criteria were used to interpret the results (according to Landis and Koch): kappa below 0.00 poor, 0.00-0.20 slight, 0.21-0.40 fair, 0.41-0.60 moderate, 0.61-0.80 substantial and 0.81-1.00 almost perfect.
High-risk patients compared with low-risk patients RESULTS Characteristics of the population studied (Table 1) A total of 54 patients were included between December 2007 and July 2008. All the patients were negative for HIV. Eight had serum albumin levels below 3.20mg/dl. The majority (31; 57.4%) had not had the BCG vaccine. Ten of the patients had a medical history of TB, two of them had not been treated correctly and one suffered a relapse of tuberculosis. No cases of primary infection or reactivation of tuberculosis were detected during the follow-up. A total of 32 patients (59%) were at high risk and the other 22 (41%) were at low risk of latent tuberculosis. Neither of the two tests (TST/QIT-GIT) was able to distinguish between the high-risk and low-risk patients.
Agreement between the TST, QFT-GIT and the pulmonologists assessment The agreement between the three diagnosis methods is shown in Table 3. A posterior analysis between the conflicting tests showed that QFT-GIT was positive in 3 patients that were negative for tuberculin and was negative in 9 patients that were positive for tuberculin. The TST was positive in 10 patients who were found to be positive by the pulmonologist and negative in 7 patients considered positive for TB by the pulmonologist.
TST, QFT-GIT and pulmonologists assessment TST had a 29.6% prevalence of positives (16 patients) for the first test and 31.5% (17 patients) for the second one. TST had 5.8% of false positives and three false negatives (8.1%). A positive chest x-ray detected 6 additional cases of latent TB (42.6%) and the pulmonologists assessment detected 7 additional cases (44.4%). The pulmonologist found evidence of previous tuberculosis infection in 14 cases (26.5%).
DISCUSSION As there is no gold standard diagnosis technique for latent tuberculosis, several authors have compared the use of IGRA with TST in different groups of patients (general population, children, hospitalised patients at-risk and immunocompromised patients).1,4-5 TST has been used routinely despite its low specificity, high number of false positives (previous vaccination with BCG or infection by non-tuberculosis mycobacteria), and low sensitivity (high number of false negatives in immunocompromised patients and patients with cutaneous anergy). Woeltje et al studied 307 patients on HD, 32% had cutaneous anergy to three different allergens and 9% of the patients without anergy tested positive for TST.8 In our study, the positive response to TST was similar to that described for patients on HD.2 The finding of 6 TST-negative patients with positive chest xray can be explained by the rate of cutaneous anergy described above in HD patients. Immune system impairment has been described in uraemic patients leading to a high rate of infections and mortality.9 This delayed immune response leads to interleukin-2 deficit, B-cell lymphopenia, increased cell apoptosis, impaired T-lymphocyte activation and more
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Table 1. Patients characteristics

Characteristics Age (meanSD) Sex (M/W) Cause of renal failure: - Chronic glomerulonephritis - Adult polycystic disease - Interstitial Nephritis - Diabetic neuropathy - Ischaemic neuropathy - Others - Unknown Time on PD (months) No previous TB Immunosuppression PD: peritoneal dialysis; TB: tuberculosis. Nefrologia 2011;31(2):169-73 no.=54 57.216.1 34/20 10 (18.5%) 2 (3.7%) 9 (16.7%) 14 (25.9%) 7 (13%) 2 (3.7%) 10 (18.5%) 26.418.5 9 (18%) 7 (14.3%)
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Table 2. Univariate analysis of the risk factors for inconclusive results of Quantiferon-TB gold (QTF-G)
Variable Inconclusive QFT-G (no.=9) Age (years) Time on PD (months) Albumin (g/dl) Leukocytes (cells/ml) Lymphocytes (%) High risk for TB (%) Negative TST %) BCG vaccination (%) 50.2 33.9 3.4 7211 15 6 (66.6%) 8 (90%) 3 (33.3%) Conclusive QFT-G (no.=45) 58.6 24.8 3.6 7494 21 26 (57.8%) 29 (64.4%) 20 (44.4%) 0.15 0.18 0.17 0.80 0.04 0.62 0.15 0.54 P
antigen-presenting cells.10-15 All these changes in the hosts responses may explain the negative results for TST, regardless of whether they had cutaneous anergy or not. The use of IGRA in HD patients has been researched with similar results to ours. One of these studies was specifically
designed to compare TST with QFT-GIT in 203 patients on HD and found a reasonable correlation between them. Therefore, TST for TB screening without a physicians assessment was not recommended for this population, but rather using a combination of IGRA with a physicians assessment.16 More recently, Torres et al found a moderate
Table 3. Agreement between the tuberculin skin test, Quantiferon-TB Gold and assessment by a pulmonologist, excluding patients with inconclusive results for QFT-GIT*
* Positive QFT-GIT Negative QFT-GIT Total Agreement % coefficient P * Positive QFT-GIT Negative QFT-GIT Total Agreement % coefficient P * Positive pulmonologist Negative pulmonologist Total Agreement % coefficient P TST: tuberculin skin test; QFT-GIT: Quantiferon-TB Gold 172 Nefrologia 2011;31(2):169-73 Positive TST 7 (13%) 9 (16.6%) 16 (35.5%) 73.3 0.36 0.006 Pos. Pulmonologist 4 (7.4%) 8 (14.8%) 12 (26.7%) 68 0.15 0.330 Positive TST 7 (13%) 10 (16.6%) 17 (31.5%) 70 0.257 0.060 Negative TST 7 (13%) 30 (55.5%) 37 (68.5%) Total 14 (26%) 40 (72.2%) 54 (100%) Neg. Pulmonologist 6 (11.1%) 27 (48.1%) 33 (73.3%) Total 10 (18.5%) 35 (63%) 45 (100%) Negative TST 3 (5.5%) 26 (48.2%) 29 (64.5%) Total 10 (18.5%) 35 (64.8%) 45 (100%)
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3. Sester M, Sester U, Clauer P, et al. Tuberculin skin testing underestimates a high prevalence of latent tuberculosis infection in hemodialysis patients. Kidney Int 2004;65:1826-34. 4. Torres HE, Zapico M, Vivas S, et al. Aplicacin clnica de una prueba de produccin de interfern gamma para el diagnstico de tuberculosis latente en poblaciones hospitalarias de riesgo. Med Clin (Barc) 2008;130(20):761-6. 5. Manuel O, Humar A, Preiksaitis J, et al. Comparison of QuantiferonTB gold with tuberculin skin test for detecting latent tuberculosis infection prior to liver transplantation. Am J Transplant 2007;7:2797801. 6. Winthrop KL, Daley CL. A novel assay for screening patients for latent tuberculosis infection prior to anti-THF therapy. Nature Clin Prac 2008;4(9):456-7. 7. Pooran A, Booth H, Miller RF, et al. Different screening strategies (single or dual) for the diagnosis of suspected latent tuberculosis: a cost effectiveness analysis. BMC Pulm Med 2010;10:7. 8. Woeltje KF, Mathew A, Rothstein M, Seiler S and Fraser VJ. Tuberculosis infection and anergy in hemodialysis patients. Am J Kidney Dis 1998; 31: 848-52. 9. U.S. Renal Data System. 1999 Annual Data Report. Am J Kidney Dis 1999;34:S9-S19. 10. Descamps-Latscha B, Chatenoud L. T cells and B cells in chronic renal failure. Semin Nephrol 1996;16:183-91. 11. Gonzlez-Gutirrez M, De Francisco ALM, Sanz S, et al. Interleukin2 deficit in hemodialysis patients. Role of prostaglandins. Renal Failure 1992;14(4):563-9. 12. Fernndez-Fresnedo G, Ramos MA, Gonzlez-Pardo MC, et al. B lymphopenia in uraemia is related to an accelerated in vitro apoptosis and dysregulation of Bcl-2. Nephrol Dial Transplant 2000;15:502-10. 13. Smirnoff M, Patt C, Seckler B, et al. Tuberculin and anergy skin testing of patients receiving long-term hemodialysis. Chest 1998;113:257. 14. Grindt M, Sester U, Sester M, et al. Impaired cellular immune function in patients with end-stage renal failure. Nephrol Dial Transplant 1999;14:2807-10. 15. Meuer SC, Hauer M, Kurz P, et al. Selective blockade of the antigen-receptor-mediated pathway of T cell activation in patients with impaired primary immune responses. J Clin Invest 1987;80:743-9. 16. Passalent L, Khan K, Richardson R, et al. Detecting latent tuberculosis infection in Hemodialysis patients: a head-to head comparison of the T-SPOT.TB test, tuberculin skin test, and an expert physician panel. J Am Soc Nephrol 2007;2:68-73. 17. http://www. senefro.org
level of agreement between both tests with a similar sample size to ours. This study included hospitalised patients with a high risk of suffering from TB (some on HD). They recommended using QFT-GIT routinely in this type of patients, at least in cases on HD, to try and establish when to treat the tuberculosis.4 These results in PD patients can be explained by cutaneous anergy as well as the low production of QFT-GIT and other cytokines. In this study, 16% of patients were inconclusive for QFTGIT. Our results coincide with those of Manuel et al, although these authors studied a different group of immunocompromised patients (with chronic liver disease).5 By analysing all these data, we could come to the conclusion that the inconclusive results are probably related to immunodeficiency. This study investigated for the first time the contribution of QFT-GIT to improving the diagnosis of tuberculosis in PD patients. Its main weakness is the number of patients who had a positive skin test and/or QTF-GIT. Our results correlate well with the percentage of positive results found in the few publications there are, and the number of patients studied is relatively high given the low incidence and prevalence of PD patients in Spain.17 To conclude, we believe that IGRA represent an important advance in the diagnosis of tuberculosis, and at this moment they can complement the TST but not replace it. The role of IGRA in the screening of at-risk people, including PD patients diagnosed with CRF, still has to be defined; therefore, longitudinal studies that provide solid evidence on their prognostic value in the long-term development of TB are needed.
REFERENCES
1. Sester U, Junker H, Hodapp T, et al. Improved efficiency in detecting cellular immunity towards M. tuberculosis in patients receiving immunosuppressive drug therapy. Nephrol Dial Transplant 2006;21:3258-62. 2. Wauters A, Peetermans WE, Van der Brande P, et al. The value of tuberculin skin testing in hemodialysis patients. Nephrol Dial Transplant 2004;19:433-8.
Sent for review: 6 Dic. 2010 | Accepted: 5 Ene. 2011 Nefrologia 2011;31(2):169-73 173
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Current peritoneal dialysis compared with haemodialysis: medium-term survival analysis of incident dialysis patients in the Canary Islands in recent years
J.M. Rufino1, C. Garca2, N. Vega3, M. Maca4, D. Hernndez5, A. Rodrguez6, B. Maceira1, V. Lorenzo1
Nephrology Department. University Hospital of Canarias. La Laguna, Santa Cruz de Tenerife, Spain Nephrology Department. Gran Canaria Island University Hospital. Las Palmas de Gran Canaria. Las Palmas, Spain 3 Nephrology Department. Dr. Negrn University Hospital, Gran Canaria. Las Palmas de Gran Canaria, Las Palmas, Spain 4 Nephrology Department. Nuestra Seora de Candelaria University Hospital. Santa Cruz de Tenerife, Santa Cruz de Tenerife, Spain 5 Nephrology Department. Carlos Haya University Hospital. Mlaga, Mlaga, Spain 6 General Directorate of Healthcare Programmes. Regional Organ and Tissue Transplant Coordination Unit. Santa Cruz de Tenerife, Santa Cruz de Tenerife, Spain
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ABSTRACT Introduction: Important differences in patient survival exist between peritoneal dialysis (PD) and haemodialysis (HD). Several different studies have shown that PD yields a better survival rate than HD in the first and second years of treatment, especially in younger patients and non-diabetic patients with low comorbidity, whereas HD produces better results in diabetic patients, elderly patients, and in patients with greater comorbidity. In recent years, interesting changes have occurred in PD units in the Canary Islands, such as the introduction of peritoneal dialysis solutions with bicarbonate dialysate and low content of glucose degradation products, extended use of automated dialysis, and continuity of physicians and nurses in PD units, in addition to enhancing visits for advanced chronic kidney disease (ACKD). Objective: This situation led us to perform our study with the primary objective of comparing medium-term survival among incident dialysis patients on HD versus PD in recent years in the Canary Islands, and as a secondary objective, to compare survival between these two types of dialysis by subgroups as defined by age, sex and diabetes. Material and methods: This was a retrospective cohort study comparing survival between HD and PD patients starting dialysis in the Canary Islands between 01/01/2006 and 31/12/2009, with adjustment based on the propensity score analysis. We analysed data from the RERCAN database, which collects data on demographic variables, changes in type of dialysis, province and hospital of the patient, and mortality and its causes. We calculated Kaplan-Meier estimates of survival based on the overall population and stratified by age, sex and diabetes. We applied a Cox proportional hazards model for survival to estimate the relative mortality risk of PD compared with HD, using as independent variables: age, sex, quartiles of propensity score, the province of the patient, and diabetes. Finally, we applied a Cox model with time-dependent effects, using as a fixed risk factor the initial type of dialysis in order to assess the effect of PD versus HD on short and medium-term survival. Results: The cohort included 1469 patients (173 PD and 1296 HD), with a mean age of 62.5 years, 65% male. Mean follow-up was 16.212.4 months. Factors associated with greater probability of choosing PD were younger age and living in the province of Las Palmas. The cumulative mortality in the intention to treat (ITT) analysis was 27.1% in the HD group and 8.7% in the PD group, P<.0001. The cumulative probability of survival by ITT using PD vs HD was 96.6% versus 89% at 6 months (P<.001), 96% versus 80% at 12 months (P<.001), 90% versus 65% at 24 months (P<.001), 82% versus 58% at 36 months (P<.001) and 73% versus 45% at 46 months (P<.001). In the subgroup analysis, survival was also higher in PD patients compared to HD patients both over and under 65 years old, in both diabetic and non-diabetic patients, and in both genders. The same analysis
Correspondence: Juana Margarita Rufino Hernndez Servicio de Nefrologa. Hospital Universitario de Canarias. Ofra, s/n. La Cuesta. 38320 La Laguna. Santa Cruz de Tenerife. Spain. margaritarufino@hotmail.com 174
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los datos de la base de datos RERCAN (Registro de Enfermos Renales de Canarias) que recoge variables demogrficas, cambios de modalidad de dilisis, provincia y hospital de procedencia del paciente, mortalidad y causas de mortalidad. Se calcularon las estimaciones de Kaplan-Meier de supervivencia comparada en la cohorte global y por estratos definidos por la edad, sexo y diabetes. Aplicamos el modelo de riesgos proporcionales de Cox de supervivencia para estimar los riesgos relativos de mortalidad de la DP en comparacin con la HD, utilizando como variables independientes de ajuste la edad, el sexo, el score de propensin por cuartiles, la provincia de procedencia del paciente y la diabetes. Finalmente, se aplic un modelo de Cox estratificado en el tiempo (Cox time-dependent effects) usando como factor de riesgo fijo la modalidad inicial de dilisis, para valorar el efecto en la supervivencia, a corto y medio plazo, de la DP comparada con la HD. Resultados: La cohorte incluy a 1.469 pacientes (173 en DP y 1.296 en HD), con una edad media de 62,5 aos, el 65% hombres. El seguimiento medio fue de 16,2 12,4 meses. Los factores asociados con una mayor probabilidad de elegir DP fueron la menor edad y la provincia de Las Palmas. La mortalidad acumulada, en el anlisis por intencin de tratar, fue en el grupo de HD del 27,1% y en el grupo de DP de 8,7 % (p <0,0001). La probabilidad acumulada de supervivencia por intencin de tratar para DP y HD fue del 96,6 frente al 89% a los 6 meses (p <0,001), del 96 frente al 80% a los 12 meses (p <0,001), del 90 frente al 65% a los 24 meses (p <0,001), del 82 frente al 58% a los 36 meses (p <0,001) y del 73 frente al 45% a los 46 meses (p <0,001). En el anlisis por subgrupos, la supervivencia fue tambin mayor en los pacientes en DP con respecto a los de HD tanto en los mayores de 65 aos como en los menores, en los diabticos y en los no diabticos, y tanto en hombres como en mujeres. El mismo anlisis a partir de los 90 das mostr resultados muy similares. En el anlisis por intencin de tratar, el riesgo de mortalidad ajustado por el modelo de Cox para la DP en comparacin con la HD fue un 61% menor que para HD (RR: 0,398; IC 95%: 0,237-0,669; p = 0,001), ajustado para edad, diabetes, sexo, provincia y score de propensin. Desglosado por aos de supervivencia en tcnica, el riesgo relativo de mortalidad para la DP en comparacin con la HD en el primer ao fue tambin significativamente inferior (RR: 0,509; IC 95%: 0,259-0,999; p = 0,049). A partir del segundo ao, slo la edad se mostr como factor de riesgo de mortalidad (RR: 2,785; IC 95%: 1,525-5,086; p = 0,001) y no hubo diferencias entre las dos tcnicas de dilisis. Conclusin: En Canarias, la DP ha demostrado ventajas de supervivencia a corto y medio plazo respecto a la HD. Resulta notable que este beneficio se ha constatado en pacientes jvenes y de edad avanzada, diabticos y no diabticos, hombres y mujeres, as como que esta ventaja se mantenga incluso tras aos despus de aplicar la tcnica. Palabras clave: Supervivencia en dilisis. Soluciones biocompatibles. Dilisis peritoneal. Hemodilisis
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from the 90th day onward produced similar results. In the ITT analysis, the Cox-adjusted mortality risk for PD was 61% lower than for HD (RR: 0.398, 95% CI 0.237-0.669, P=.001), adjusted for age, diabetes, sex, patients province and propensity score. Broken down by years of survival on the technique used, the relative risk of death for PD compared with HD in the first year was also significantly lower (RR 0.509, 95% CI: 0.259-0.999, P=.049). From year 2 onwards, only age was a risk factor for mortality (RR: 2.785, 95% CI: 1.525-5.086, P=.001) and no differences were shown between the two dialysis techniques. Conclusion: In the Canary Islands, PD has demonstrated survival advantages over HD in the short and medium term. It is remarkable that this benefit was found in young and old patients, men and women, and diabetic and non-diabetic patients, and that this advantage was maintained even after years of being on dialysis. Keywords: Survival on dialysis. Biocompatible peritoneal solutions. Peritoneal dialysis. Haemodialysis .
Dilisis peritoneal actual comparada con hemodilisis: anlisis de supervivencia a medio plazo en pacientes incidentes en dilisis en la Comunidad Canaria en los ltimos aos RESUMEN Introduccin: Existen importantes diferencias en los resultados de supervivencia de paciente y tcnica entre dilisis peritoneal (DP) y hemodilisis (HD) en las distintas series publicadas. Varios estudios han demostrado que la DP tiene mejor supervivencia que la HD en el primer y segundo ao de tratamiento, sobre todo en los pacientes ms jvenes, no diabticos y con menor comorbilidad, mientras que la HD parece mejor en los pacientes diabticos, de ms edad y mayor comorbilidad. En la Comunidad Canaria, en los ltimos aos se han ido realizando cambios asistenciales interesantes en las unidades de DP, como son la introduccin de las soluciones de DP con bao de dilisis con bicarbonato y con bajo contenido en productos de degradacin de la glucosa, la extensin del uso de la dilisis automatizada y la continuidad del mdico y de la enfermera en las unidades de DP, adems de la potenciacin de las consultas de enfermedad renal crnica avanzada (ERCA). Objetivo: Esta situacin nos condujo a realizar nuestro estudio con el objetivo principal de comparar la supervivencia a medio plazo entre pacientes incidentes en HD frente a DP en los ltimos aos en Canarias y como objetivos secundarios comparar la supervivencia entre dichas modalidades por subgrupos definidos por edad, sexo y diabetes. Material y mtodos: Se trata de un trabajo de cohorte retrospectivo que compara la supervivencia entre HD y DP de pacientes que inician dilisis en la Comunidad Canaria entre el 1-1-2006 y 31-12-2009, con ajuste basado en el anlisis de propensin. Se analizaron
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INTRODUCTION In spite of the technological innovations in renal replacement therapy for chronic kidney disease (CKD), important differences still exist in terms of survival results between peritoneal dialysis (PD) and haemodialysis (HD). Possible justification for this controversy may be found in initial patient comorbidity, the experience at the dialysis centre, and confounding factors for the clinical indications of each technique within the context of retrospective observational studies.1-7 Consequently, methodological differences, such as the absence of prospective study designs, small sample sizes, and the absence of statistical methods based on propensity scores in the majority of published studies could bias survival results.1,8-10 Propensity scores can be a very useful tool in this type of observational study, in which the distribution of clinical variables such as age, sex, and comorbidity can be very different between study groups, and are defined as the probability that a patient will be assigned to a given treatment group, in this case, type of dialysis, based on the clinical characteristics of the patient at that time. In any case, several studies have shown that treatment with PD leads to better survival rates than with HD in the first and second years of treatment, above all in younger, non-diabetic patients with lower comorbidity, whereas HD appears to produce better results in diabetic, older patients with greater comorbidity.11-22 However, in recent years, interesting changes in health care have been introduced into PD units, such as PD solutions with bicarbonate dialysate and low content of glucose degradation products, extended use of automated dialysis and continuity of physicians and nurses in PD units, in addition to enhancing consultations for advanced chronic kidney disease (ACKD). This changing situation has led us to carry out this study with the primary objective of comparing medium-term survival of incident dialysis patients on HD versus PD in recent years in the Canary Islands. As a secondary objective
we will compare survival between these two different types of dialysis by patient subgroups as defined by age, sex, and diabetes.
MATERIAL AND METHOD This is a retrospective cohort study comparing survival between adult HD and PD patients starting dialysis in the Canary Islands between 1 January 2006 and 31 December 2009. It was adjusted based on the propensity score analysis in order to mitigate the influence of the differences in baseline characteristics of the patients that chose one type of dialysis or the other. We analysed data from the RERCAN database (kidney patient registry of the Canary Islands), which collects demographic variables such as age, sex, underlying disease, changes in type of dialysis, province and hospital of the patient, and mortality and its causes. Patients that were already on haemodialysis or had received transplants were excluded from the study.
Statistical Method We compared the different parameters collected during the study between HD and PD patients. Continuous variables were first compared using Students t-tests, and differences between proportions were estimated using chi-square tests. In order to account for the differences in baseline characteristics between patients, and thus reduce any possible bias in favour of one type of dialysis, we performed a propensity analysis, which was subsequently used as an adjustment variable in the Cox analysis. We estimated the propensity score for choosing PD at the start of dialysis using a logistical regression model that included all covariables that resulted predictive in the comparison of standardised differences in the baseline characteristics of patients based on the type of dialysis (Table 1 and Table 2).
Table 1. Comparison of baseline characteristics of patients starting PD and those starting HD

Incident dialysis patients on PD (No. = 173) Age Male Diabetes mellitus Province TFE/LP 56.6 (15.1) 68.2% 62.4% 65/108 Incident dialysis patients on HD (No. = 1296) 63.4 (15.1) 64.5% 44% 688/608 0.0001 0.338 0.106 0.0001 P value
PD patients were significantly younger and primarily came from the province of Las Palmas. TFE: Santa Cruz de Tenerife province; LP: Las Palmas province; PD: peritoneal dialysis; HD: haemodialysis. 176 Nefrologia 2011;31(2):174-84
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Table 2. Logistical regression. Factors associated with choosing PD as the technique of first choice
B Age >65 years Province LP 0.940 0.550 95% CI 0.278-0.550 1.246-2.413 Exp (B) 0.391 1.734 P value 0.0001 0.001
The factors associated with choosing PD as the first option for dialysis treatment were age <65 years and home province of Las Palmas. TFE: Santa Cruz de Tenerife province; LP: Las Palmas province. Values have been adjusted for sex and diabetes.
The causes for halting follow-up were: patient death, kidney transplantation, loss of follow-up, patient transfer to another type of treatment, or the final date of the study, which was 31 December 2009. The primary analysis focused on patient survival compared by dialysis type, according to intention to treat (ITT) analysis (starting at day 0). Secondary analyses included survival compared by dialysis type starting at the 90th day of treatment, and a stratified analysis based on age (using the median age of the sample, 65 years, as the cut-off point), sex, and diabetes. We calculated Kaplan-Meier survival estimates based on the global sample and on the previously defined categories. We then developed a Cox proportional regression model for survival in order to estimate the relative mortality risks of PD compared with HD, using as independent variables for adjustment: age, sex, quartiles of propensity score, the province of the patient, diabetes, and underlying disease. Finally, we applied a Cox model with time-dependent effects, using the initial method of dialysis as a fixed risk factor in order to assess the short and medium-term effects of dialysis (PD vs HD) on patient survival.18 We considered values to be statistically significant when P<.05. We used SPSS version 13.0 software for all statistical analyses (SPSS Inc., Chicago, USA).
kidney disease (7.5%), systemic disease (2.6%), and other. The distribution of underlying conditions was similar in both treatment groups. Table 1 shows the comparison of patient characteristics based on the type of dialysis started on day 0. PD patients were significantly younger, and were primarily from the province of Las Palmas. These factors associated with a greater probability of choosing PD (Table 2) were used to develop the propensity score using the beta values from the significant variables produced by the logistical regression. We distributed the propensity score values into quartiles: 26% of patients (n=380) had a score of +0.55 (score 4), 22% (n=323) had a score of 0 (score 3), 23% (n=336) had a score of -0.39 (score 2), and 29% (n=430) had a score of -0.94 (score 1). Higher scores (score 4 being the highest) indicated a greater probability that the patient would choose PD. The cumulative mortality rate from the ITT analysis was 27.1% in the HD group and 8.7% in the PD group (P<.0001). Similarly, in the analysis based on survival after the 90th day of dialysis treatment, the cumulative mortality rate was 13.5% in the HD group and 5% in the PD group (P<.0001). Figure 1 displays the comparative Kaplan-Meier survival curves for the global sample from day 0 (Figure 1A), and from day 90 (Figure 1B). In greater detail, the cumulative probability of survival by ITT for PD and HD was 96.6% vs 89% at 6 months (P<.001), 96% vs 80% at 12 months (P<.001), 90% vs 65% at 24 months (P<.001), 82% vs 58% at 36 months (P<.001), and 73% vs 45% at 46 months (P<.001). The same analysis starting at day 90 yielded very similar results. With regards to the analysis by subgroups, survival was surprisingly higher in patients on PD than those on HD, both in patients older and younger than 65 years, in both diabetics and non-diabetics, and in both women and men (Figure 2, Figure 3, and Figure 4). In the score 1 group (the group with the highest probability of choosing HD, n=430), patient mortality was 40% for patients on HD (168/412), and 22.2% for those on PD (4/18) (P=.08). For the score 4 group (the group with the highest probability of choosing PD, n=380), mortality was 12.3% for HD patients (38/308), and 5.6% for PD patients (4/72) (P=.06).
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RESULTS The patient cohort included 1469 adults and 1235 of them (84%) survived more than 90 days after the start of dialysis. The mean age of patients was 62.515.3 years (range: 7-94, median: 65), and 65% were men. 11.8% of patients received PD at the start of dialysis (n=173 out of 1469). The mean follow-up period was 16.212.4 months (range: 1-47, median: 13, 75th percentile: 24 months). The underlying conditions were: chronic glomerulonephritis (7%), interstitial nephropathy (4.3%), diabetic nephropathy (44.3%), familial nephropathy (0.7%), ischaemic nephropathy (11.1%), unknown origin (15.3%), polycystic
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A
P=0.0001
B
P=0.0001
% Survival
Time PD HD PD HD
% Survival
Time
Figure 1. A) Comparative survival of incident patients between DP (- -) and HD (- -), by intention to treat from day 0. B) Comparative survival of incident patients between DP (- -) and HD (- -) from day 90. Time: months from the start technique. PD: peritoneal dialysis. HD: haemodialysis.
A
P=0.006 % Survival
B
P=0.01 % Survival Time
Time
Figure 2. A) Comparative survival of indicent patients over 65 between DP (- -) and HD (- -), by intention to treat from day 0. B) Compartive survival of incident patients aged 65 or younger between DP (- -) and HD (- -), intention to treat from day 0. Time: months since the start of the technique. PD: peritoneal dialysis. HD: haemodialysis.
The primary causes of death were: cardiovascular (41%), infectious (19%), neoplastic (7.7%), and gastrointestinal or hepatic (3%). We observed no differences with regard to the distribution of causes of death between the two patient groups. 26.6% of the patients on PD received transplants, and 14% were transferred to HD. Of these, mortality was not different from those that did not switch treatments (8.8% vs 8.7%). In the HD group, 10.2% of patients received transplants, and only 1.7% of patients (n=22) were transferred to PD, with somewhat lower mortality observed in these patients than in those that did not switch (9.1% vs 27.4%, P=.055). In the ITT analysis, the mortality risk adjusted by model 1 for age, sex, patients province of origin, and diabetes was
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61% lower for the PD group than for HD (0.398; 95% CI: 0.237-0.669; P=.001; Table 3). Age also stood out as a significant risk factor for mortality. In model 2 (Table 3), we adjusted the model using the following independent variables: sex, diabetes, and propensity score. In this model, the Cox-adjusted mortality risk was also 61% lower for PD patients than for those on HD (RR: 0.398; 95% CI: 0.2370.669; P=.0001), and the mortality risk for patients in the propensity score 4 group (those with the highest probability of choosing PD) was 63% lower than for those in group 1 (the highest probability of choosing HD) (RR: 0.278; 95% CI: 0.198-0.390; P=.0001). Broken up into the first 3 years of follow-up, the relative risk of mortality for patients on PD compared to HD in the first
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B
P=0.008 P=0.0001
% Survival
Time
% Survival
Time
Figure 3. A) Comparative survival of incident patients with diabetes between DP (- -) and HD (- -), intention to treat from day 0. B) Comparative survival of incident patients without diabetes between DP (- -) and HD (- -), intention to treat from day 0. Time: months from the start of the technique. PD: peritoneal dialysis. HD: haemodialysis.
A
P=0.0001
P=0.0001
% Survival
% Survival
Time
Time
Figure 4. A) Comparative survival of incident patients between women DP (- -) and HD (- -), intention to treat from day 0. B) Comparative survival of incident patients between males DP (- -) and HD (- -), intention to treat from day 0. Time: months from the start of the technique. PD: peritoneal dialysis. HD: haemodialysis.
year was 0.334 (95% CI: 0.136-0.818; P=.016). After the first year of survival on dialysis, the predictors for mortality were age, diabetes, and dialysis technique (Table 4). After the second year, only age remained a risk factor for mortality (2.785; 95% CI: 1.525-5.086; P=.001), and no differences were observed between the two different dialysis techniques.
DISCUSSION Our study has shown that PD holds significant advantages in terms of medium-term survival over HD in the Canary Islands. Several studies have reviewed comparative survival between patients on PD and HD, with varying and sometimes contradictory results, probably due to the heterogeneity of confounding factors that may affect the prognosis of these patients,3,10-22,33-41 such as: initial comorbidity, the experience
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at the dialysis centre, a programmed or urgent start to dialysis, complications in peritoneal and vascular access points, the length of time on dialysis, and the different study designs, samples, and statistical methodologies used for analysing the results. In theory, prospective cohort studies are the best type of study design for studying the relationship between two variables (treatment type and prognosis) through time. However, few studies of this type have been published that analyse comparative survival between patients on HD and PD, since they require large sample sizes in order to achieve adequate stratification and adjustment of the study population, which generally requires a multi-centre study design.1,7 As such, observational studies covering a large sample of patients are the most useful in comparative studies that assess the differences in results between the two different dialysis techniques. In our case, we have added a propensity analysis in order to make our analysis more robust.8,10
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Table 3. Cox proportional regression model for survival to estimate the relative risks of mortality while on PD compared to HD
RR (95% CI) Model 1 Age >65 years Technique: PD vs HD Diabetes Sex Province LP/TFE Modelo 2 Propensity Score (with respect to 1) Score 2 Score 3 Score 4 Technique: PD vs HD Sex Diabetes 0.827 (0.650-1.053) 0.333 (0.239-0.466) 0.278 (0.198-0.390) 0.398 (0.237-0.669) 0.991 (0.802-1.226) 1.155 (0.939-1.420) 0.123 0.0001 0.0001 0.0001 0.173 0.937 2.989 (2.342-3.816) 0.398 (0.237-0.669) 1.155 (0.939-1.420) 0.991 (0.802-1.226) 0.829 (0.672-1.023) 0.0001 0.001 0.173 0.936 0.080 P value
The independent adjustment variables in model 1 are: age, sex, province of origin of the patient, and diabetes. In this model, the Coxadjusted mortality risk was 61% lower for PD than for HD (0.398; 95% CI: 0.237-0.669; P=.001). Age also stood out as a significant mortality risk factor. In model 2, we used the following independent adjustment variables: sex, diabetes, and propensity score. In this model, the Coxadjusted mortality risk was also 61% lower for PD than for HD (RR: 0.398; 95% CI: 0.237-0.669; P=.0001), and the mortality risk for patients in the propensity score group 4 (those with the highest probability of choosing PD) was 63% lower than for group 1 (those with the highest probability of choosing HD) (RR: 0.278; 95% CI: 0.198-0.390; P=.0001). PD: peritoneal dialysis; HD: haemodialysis; LP: Las Palmas province; TFE: Santa Cruz de Tenerife province.
Several different studies have demonstrated that PD yields better survival rates than HD in the first and second years of treatment, above all in younger, nondiabetic patients with lower comorbidity, whereas HD appears to produce better results in older, diabetic patients with greater comorbidity. 3,10,21,40,42,54 However, these studies all refer to incident dialysis patients from almost 10 years ago, specifically in the 90s and early 2000s, when PD was still underdeveloped and recent technical improvements had yet to be introduced. Indeed, a recent study published in the United States by Mehrotra et al, with almost 700 000 incident dialysis patients, compared long-term mortality between HD and PD and reported that survival was similar between both techniques, both in the global sample and when adjusted by group according to age, diabetes, and comorbidity. 5 They also observed that the survival of patients on PD has improved spectacularly in recent years, specifically in the cohort of patients from 2002 to 2004 with respect to previous years. When researching comparative survival between dialysis techniques, it is also important to perform an analysis of survival in different time periods. Several different large-scale observational studies 2,42 report that the
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relative mortality risk of PD as compared to HD is unstable through time, such that the survival advantage of PD decreases through time on dialysis, with advanced age, and with the presence of diabetes. However, in our study, only age turned out to be a risk factor for mortality in our patients between the second and third or fourth year of treatment, while before 2 years, HD (and not PD), along with diabetes mellitus and age were significant risk factors for mortality. This observation was supported by the Yeates study 35 in 2008 (abstract), which concluded that the initial advantages of PD were maintained for a longer period of time, and even showed that no statistically significant differences existed in favour of HD even at the end of the follow-up period. 1,35 Recently, a publication from the EDTA records with data from the United Kingdom, Austria, Spain, Italy, and Norway, and adjusted for comorbidity (age, primary kidney disease, sex, and nationality) showed that no significant differences existed between the two different types of dialysis treatment.9,38 One could reasonably argue that pre-dialysis education, which was widely extended throughout the Canary Islands in recent years, could have influenced these improved survival results for PD, but it would be logical
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account the variable type of peritoneal dialysis solution (standard or biocompatible) for PD patients. However, since early 2006, approximately 70% of patients that started PD in the Canary Islands received treatment with biocompatible solutions, i.e., solutions with physiological pH and a bicarbonate buffer, low concentrations of glucose degradation products, amino acids, and glucose polymers. This may have influenced the positive results observed in diabetic patients. A specifically designed study could uncover the precise role of these new solutions in improving survival of patients on PD. There are limitations to this study. In the first place, since dialysis type was not randomly assigned to each patient, direct causality cannot be inferred, and although the propensity analysis is a useful statistical tool, it is no substitute for randomisation. Secondly, the study was performed retrospectively, using the database compiled by the Canary Islands registry of renal patients, and the prognostic biomarkers and covariables were only measured at the start of dialysis treatment. Additionally, important variables were not present in the registry, the most important being comorbidity. These gaps will require further studies to research the potential benefits of different treatment components, such as biocompatible solutions in patients with high cardiovascular risk. Nevertheless, older patients and diabetic patients tend to have high associated comorbidity. In our study, even these patients had better survival rates when on PD. Thirdly, we were also unable to analyse data on the dialysis dosage, type of HD (online or standard), manual or automated PD, residual diuresis, and the start of dialysis with a central venous catheter. With respect to the latter, dependence on a central venous catheter remains high in HD patients during the first months of treatment, and its use is associated with higher rates of morbidity and mortality. Indeed, mortality of patients on HD was higher in the first 3 months of our study, and dropped from 27.1% at the start of treatment to 13.5% after three months. This could be related to the start of HD with a venous catheter instead of an arteriovenous fistula (AVF). In PD, mortality from day 0 was 8.7%, and dropped to 5% after 90 days, thus always lower than HD. In spite of these limitations, our study analysed survival based on all data compiled from study patients, using a good Cox analysis and a propensity analysis in order to make the statistical methodology more robust. In summary, we have observed that survival was greater for patients that started renal replacement therapy with PD as compared to HD, even in older and diabetic patients, in which we expected to observe a lower life expectancy and greater level of comorbidity. Until now,
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Tabla 4. Cox proportional regression model for survival to estimate the relative risks of mortality while on PD as opposed to HD after the first year of survival
RR (95% CI) Age >65 years Diabetes Technique: PD vs HD Sex Province LP/TFE 2.250 (1.572-3.220) 1.590 (1.145-2.208) 0.509 (0.259-0.999) 0.920 (0.664-1.273) 0.941 (0.681-1.300) P value 0.0001 0.006 0.049 0.613 0.712
As independent adjustment variables, we used age, sex, diabetes, and province of origin of the patient. Adjusted mortality risk was 49% lower for PD than for HD (RR: 0.509; 95% CI: 0.259-0.999; P=.049). Age and diabetes also stood out as significant factors for mortality risk after the first year on dialysis. PD: peritoneal dialysis; HD: haemodialysis; LP: Las Palmas province; TFE: Santa Cruz de Tenerife province
then that the positive impact on survival rates due to the advanced chronic kidney disease (ACKD) education would benefit both techniques, not just PD. Furthermore, improved survival in HD patients is known to be one of the greatest impacts of ACKD education, since it notably improves the number of patients that starts treatment with a developed vascular access point. 48 However, ACKD education could influence the patients choice of PD over HD in a greater number of cases. 49 Another hypothesis that could explain the results observed in favour of PD could be the development in the last decade of new PD solutions that attempt to reduce bio-incompatability and improve clinical results in PD patients. In animal models, long-term exposure to biocompatible solutions causes reduced expression of vascular endothelial growth factor, an increase in mesothelial cell mass, and a reduction in proinflammatory markers, microvascular proliferation and sub-mesothelial fibrosis compared to conventional glucose solutions. 23-32,43-47 The clinical benefits related to the greater biocompatibility of these solutions have been pointed out on several occasions, and include reduced pain and abdominal discomfort during infusion, reduced incidence and duration of peritonitis, reduced formation of final products from advanced glycosylation, and increased patient survival when compared to conventional solutions. 23-27,43-47 However, to our knowledge we currently still lack medium-term mortality studies comparing incident dialysis patients on HD and those on PD, using the new, more biocompatible solutions for the PD patients. Our study did not take into
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the majority of the studies indicated that, in these patients, HD technique was superior to PD. Although this study may have clinically relevant implications for healthcare in the Canary Islands, our results must be verified by studies in other populations and with a greater sample size, as factors such as geography, race, and health systems can influence the results of a study with a similar design. Finally, with regard to the economic costs of treatment, PD again offers advantages over HD. In a cost-effectiveness review of different types of dialysis, Arrieta indicated that the cost of HD is approximately 47 000 euros per patient per year, whereas PD is around 32 000.50 These differences in cost are substantial, and must be taken into account when deciding which technique to prescribe or when designing a dialysis centre.52-54 The study by Berger et al,53 started in January 2004, also researched this aspect of dialysis care, comparing costs of PD versus HD in incident dialysis patients with a minimum follow-up period of 1 year, and using propensity score matching between patients on PD and HD. HD patients were hospitalised more than double the number of times that PD patients, and the mean healthcare cost incurred over the 12-month follow-up period was 43 510 dollars more in HD than in PD. The study by Mendelsson et al22 assessed a far-reaching survey performed among nephrologists with regard to their patients. They observed that 78% of patients that started dialysis had no contraindications for PD, which would indicate that an optimal and affordable distribution of dialysis methods is necessary among patients that start renal replacement therapy. REFERENCES
CONCLUSIONS To conclude, in this analysis we verified that PD provides advantages in terms of survival over HD, and especially, that these results continue to stand out even when the data is stratified by age, diabetes, and sex. Given that both methodologies continue to be improved year after year, periodic reviews of comparative survival rates can help inform patients regarding their decision as to which type of dialysis to receive.
Acknowledgements
The authors would like to thank the entire nephrological community that has provided data for the RERCAN. We would also like to thank Marcos Getino Melin, technician at the Direccin General de Programas Asistenciales (General Directorate of Healthcare Programmes), Canary Island Health Services, for supervising the registry data collection.
1. Remn Rodrguez C, Quirs Ganga PL, Portols J, Marrn B. Anlisis crtico de los estudios de supervivencia en dilisis. Nefrologia 2010;1(Supl Ext 1):8-14. 2. McDonald SP, Marshall MR, Johnson DW, et al. Relationship between dialysis modality and mortality. J Am Soc Nephrol 2009;20:155-63. 3. Vonesh EF, Snyder JJ, Foley RN, Collins AJ. Mortality studies comparing peritoneal dialysis and hemodialysis: What do they tell us? Kidney Int 2006;70:S3-S11. 4. Bloembergen WE, Port FK, Mauger EA, Wolfe RA. A comparison of mortality between patients treated with hemodialysis and peritoneal dialysis. J Am Soc Nephrol 1995;6(2):177-83. 5. Mehrotra R, Chiu YW, Kalantar-Zadeh K, Bargman J. Similar Outcomes With Hemodialysis and Peritoneal Dialysis in Patients With End-Stage Renal Disease. Arch Intern Med 2010;Sep 27. 6. Vonesh EF, Moran J. Mortality in end-stage renal disease: A reassessment of differences between patients treated with hemodialysis and peritoneal dialysis. J Am Soc Nephrol 1999;10:354-65. 7. Korevaar RT, Feith GW. Dekker FW, et al. Effect of starting with hemodialysis compared with peritoneal dialysis in patients new on dialysis treatment: A randomized controlled trial. Kidney Int 2003;64:2222-8. 8. Weinhandl ED, Foley RN, Gilbertson DT, Arneson TJ, Snyder JJ, Collins AJ. Propensity-matched mortality comparison of incident hemodialysis and peritoneal dialysis patients. J Am Soc Nephrol 2010;21:499-506. 9. Van Manen JF, Van Dijk PC, Stel V, et al. Confoundign effect of comorbidity in survival studies in patients on renal replacement therapy. Nephrol Dial Transplant 2007;22:187-95. 10. Winkelmayer WC, Glynn RJ, Mittleman MA, Levin R, Pliskin JS, Avorn J. Comparing mortality of elderly patients on hemodialysis versus peritoneal dialysis: a propensity score approach. J Am Soc Nephrol 2002;13:2353-62. 11. Liem YS, Wong JB, Hunink MGM, et al. Comparison of hemodialysis and peritoneal dialysis survival in The Netherlands. Kidney Int 2007;71:153-8. 12. Miskulin DC, Meyer KB, Athienites NV, et al. Comorbidity and other factors associated with modality selection in incident dialysis patients: The CHOICE study. Am J Kidney Dis 2002;39:324-36. 13. Huisman RM, Martin GM, et al. Patients-related and centre-related factors influencing technique survival of peritoneal dialysis in The Netherlands. Nephrol Dial Transplant 2002;17:165560. 14. Keshaviah P, Collins AJ, Ma JZ, et al. Survival comparison between hemodialysis and peritoneal dialysis based on matched doses of delivered therapy. J Am Soc Nephrol 2002;13:S48-S52. 15. Korevaar RT, Feith GW, Dekker FW, et al. Effect of starting with hemodialysis compared with peritoneal dialysis in patients new on dialysis treatment: A randomized controlled trial. Kidney Int 2003;64:2222-8. 16. Termorshuizen F, Korevaar JC, Dekker FW, Van Manen JG, Boeschoten EW, Krediet RT. Hemodialysis and peritoneal dialysis: Nefrologia 2011;31(2):174-84
182
originals
mnguez-Jimnez C, Jimnez-Heffernan JA, et al. Peritoneal dialysis and epithelial-to-mesenchymal transition of mesothelial cells. N Engl J Med 2003;348(5):403-13. Bajo MA, Prez-Lozano ML, Albar-Vizcano P, Del Peso G, Castro MJ, Gonzlez-Mateo G, et al. Low-GDP peritoneal dialysis fluid (balance) has less impact in vitro and ex vivo on epithelial-to-mesenchymal transition (EMT) of mesothelial cells than a standard fluid. Nephrol Dial Transplant 2010. Jun 22, [Epub ahead of print]. Locatelli F, Marcelli D, Conte F, DAmico M, Del Vecchio L, Limido A, et al. Survival and development of cardiovascular disease by modality of treatment in patients with end-stage renal disease. J Am Soc Nephrol 2001;12:2411-7. Canada-USA (CANUSA) Peritoneal dialysis Study Group. Adequacy of dialysis and nutrition in continuous peritoneal dialysis: association with clinical outcomes. J Am Soc Nephrol 1996;7:198-207. Yeates KE, Zhu N, Vonesh E, et al. Survival of patients receiving hemodialysis versis peritoneal dialysis in Canada: 1991-2000 with follov-up to 2005. J Am Soc Nephrol 2008;19:abstract 279A. Locatelli F, Marcelli D, Conte F. Dialysis patient outcomes in Europe vs the USA. Nephrol Dial Transplant 1997;12:1816-9. Foley RN, Parfrey PS, Harnett JD, et al. Mode of dialysis therapy and mortality in end-stage renal disease. J Am Soc Nephrol 1998;9:267-76. Kramer A, Stel V, Zoccali C, Heaf J, Ansell D, Grnhagen-Riska C, et al., ERA-EDTA Registry. An update on renal replacement therapy in Europe: ERA-EDTA Registry data from 1997 to 2006. Nephrol Dial Transplant 2009;24(12):3557-66. Mehrotra R, Chiu YW, Kalantar-Zadeh K, Vonesh E. The outcomes of continuous ambulatory and automated peritoneal dialysis are similar. Kidney Int 2009;76(1):97-107. Ganesh SK, Hulbert-Shearon T, Port FK, Eagle K, Stack AG. Mortality differences by dialysis modality among incident ESRD patients with and without coronary artery disease. J Am Soc Nephrol 2003;14(2):415-24. De Jonge H, Bammens B, Lemahieu W, Maes BD, Vanrenterghem Y. Comparison of peritoneal dialysis and haemodialysis after renal transplant failure. Nephrol Dial Transplant 2006;21(6):1669-74. Vonesh EF, Snyder JJ, Foley RN, Collins AJ. The differential impact of risk factors on mortality in hemodialysis and peritoneal dialysis. Kidney Int 2004;66(6):2389-401. Lee HY, Park HC, Seo BJ, Do JY, Yun SR, Song HY, et al. Superior patient survival for continuous ambulatory peritoneal dialysis patients treated with a peritoneal dialysis fluid with neutral pH and low glucose degradation product concentration (Balance). Perit Dial Int 2005;25(3):248-55. McIntyre CW. Update on peritoneal dialysis solutions. Kidney Int 2007;71(6):486-90. Fan SL, Pile T, Punzalan S, Raftery MJ, Yaqoob MM. Randomized controlled study of biocompatible peritoneal dialysis solutions: effect on residual renal function. Kidney Int 2008;73(2):200-6. Choi HY, Kim DK, Lee TH, Moon SJ, Han SH, Lee JE, et al. The 183
17.
18.
19.
20.
21.
22.
23.
24.
25.
26.
27.
28.
29.
30.
31.
comparison of adjusted mortality rates according to the duration of dialysis: analysis of the Netherlands Cooperative Study on the Adequacy of Dialysis 2. J Am Soc Nephrol 2003;14:2851-60. Van Biesen W, Vanholder R, Debacquer D, et al. Comparison of survival on CAPD and haemodialysis: statistical pitfalls. Nephrol Dial Transplant 2000;15:307-11. Dekker FW, De Mutsert R, Van Dijk PC, Zoccali C, Jager KJ. Survival analysis: time-dependent effects and time-varying risk factors. Kidney Int 2008;74:994-7. Murphy SW, Foley RN, Barrett BJ, et al. Comparative mortality of hemodialysis and peritoneal dialysis in Canada. Kidney Int 2000;57:1720-6. Ross S, Dong E, Gordon M, Connelly J et al. Meta-analysis of outcome studies in edn-stage renal disease. Kidney Int 2000;57(Suppl 74):S28-38. Jaar BG, Coresh J, Plantinga LC, Fink NE, Klag MJ, Levey AS, et al. Comparing the risk for death with peritoneal dialysis and hemodialysis in a national cohort of patients with chronic kidney disease. Ann Intern Med 2005;143(3):174-83. Mendelssohn DC, Mujais SK, Soroka SD, Brouillette J, Takano T, Barre PE, et al. A prospective evaluation of renal replacement therapy modality eligibility. Nephrol Dial Transplant 2009;24(2):555-61. Han SH, Ahn SV, Yun JY, Tranaeus A, Han DS. Mortality and technique failure in peritoneal dialysis patients using advanced peritoneal dialysis solutions. Am J Kidney Dis 2009;54(4):71120. Feriani M, Kirchgessner J, La Greca G, Passlick-Deetjen J. Randomized long-term evaluation of bicarbonate-buffered CAPD solution. Kidney Int 1998;54(5):1731-8. Montenegro J, Saracho R, Gallardo I, Martnez I, Muoz R, Quintanilla N. Use of pure bicarbonate-buffered peritoneal dialysis fluid reduces the incidence of CAPD peritonitis. Nephrol Dial Transplant 2007;22(6):1703-8. Ahmad S, Sehmi JS, Ahmad-Zakhi KH, Clemenger M, Levy JB, Brown EA. Impact of new dialysis solutions on peritonitis rates. Kidney Int Suppl 2006; 103:S63-6. Mortier S, Faict D, Lameire NH, De Vriese AS. Benefits of switching from a conventional to a low-GDP bicarbonate/lactatebuffered dialysis solution in a rat model. Kidney Int 2005;67(4):1559-65. Williams JD, Topley N, Craig KJ, Mackenzie RK, Pischetsrieder M, Lage C, et al., Euro Balance Trial Group. The Euro-Balance Trial: the effect of a new biocompatible peritoneal dialysis fluid (balance) on the peritoneal membrane. Kidney Int 2004;66(1):408-18. Bajo MA, Del Peso G, Snchez-Villanueva R, Castro MJ, Aroeira L, Selgas R. New peritoneal dialysis solutions and their combinations. Nefrologia 2008;28 (Suppl 6):59-66. Witowski J, Korybalska K, Ksiazek K, Wisniewska-Elnur J, Jrres A, Lage C, et al. Peritoneal dialysis with solutions low in glucose degradation products is associated with improved biocompatibility profile towards peritoneal mesothelial cells. Nephrol Dial Transplant 2004;19(4):917-24. Yez-M M, Lara-Pezzi E, Selgas R, Ramrez-Huesca M, Do-
32.
33.
34.
35.
36. 37.
38.
39.
40.
41.
42.
43.
44. 45.
46.
Nefrologia 2011;31(2):174-84
originals
clinical usefulness of peritoneal dialysis fluids with neutral pH and low glucose degradation product concentration: an open randomized prospective trial. Perit Dial Int 2008;28(2):174-82. 47. Grzegorzewska AE. Biocompatible peritoneal dialysis solutions: do they indeed affect the outcome? Pol Arch Med Wewn 2009;119(4):242-7. 48. Lorenzo V, Martn M, Rufino M, Hernndez D, Torres A, Ayus JC. Predialysis nephrologic care and a functioning arteriovenous fistula at entry are associated with better survival in incident hemodialysis patients: an observational cohort study. Am J Kidney Dis 2004;43(6):999-1007. 49. Marrn B, Ortiz A, De Sequera P, Martn-Reyes G, De Arriba G, Lamas JM, et al., Spanish Group for CKD. Impact of end-stage renal disease care in planned dialysis start and type of renal replacement therapy-a Spanish multicentre experience. Nephrol
Dial Transplant 2006;21(Suppl 2):ii51-5. 50. Arrieta J. Evaluacin econmica del tratamiento sustitutivo renal (hemodilisis, dilisis peritoneal y trasplante) en Espaa. Nefrologia 2010;1(Supl. Ext.):37-47. 51. Selgas R. Calidad y sostenibilidad del tratamiento sustitutivo renal. Editor especial. Nefrologa 2010;1(Supl. Ext.):1. 52. Portols J, Remn C. En busca de la eficiencia y la sostenibilidad del tratamiento renal sustitutivo integrado. Nefrologia 2010;1(Supl. Ext.):2-7. 53. Berger A, Edelsberg J, Inglese GW, Bhattacharyya SK, Oster G. Cost comparison of peritoneal dialysis versus hemodialysis in end-stage renal disease. Am J Manag Care 2009;15(8):509-18. 54. Coronel F, Cigarrn S, Herrero JA. Morbimortalidad en pacientes diabticos en dilisis peritoneal. Experiencia de 25 aos en un solo centro. Nefrologia 2010. In press.
Sent for review: 21 Nov. 2010 | Accepted: 17 Jan. 2011 184 Nefrologia 2011;31(2):174-84
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Clinical and biochemical characteristics of predialysis patients in terms of 25 hydroxy vitamin D levels
I. Rodrguez Villarreal1, O. Ortega1, P. Gallar1, M. Snchez1, R. Callejas1, C. Gracia1, C. Garca la Calle2, M. Ortiz1, J.C. Herrero1, C. Mon1, A. Oliet1, A. Vigil1
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Nephrology Department. Severo Ochoa Hospital. Legans, Madrid, Spain Biochemistry Department. Severo Ochoa Hospital. Legans, Madrid, Spain
Nefrologia 2011;31(2):185-91
ABSTRACT Introduction: Decreased levels of 25 hydroxyvitamin D (25[OH]D) have been reported in patients with chronic kidney disease (CKD). The pleiotropic effects of vitamin D are known to go beyond mineral metabolism. Objetives: The aims of this study were to: 1) Determine the 25(OH)D levels in predialysis outpatients. 2) Find out the clinical and biochemical characteristics of patients with 25(OH)D deficiency, and predictive factors for the deficiency. Patients and methods: An observational study in 79 predialysis outpatients was performed. Clinical and biochemical parameters were analysed in terms of nutrition, inflammation and mineral metabolism in relation to serum levels of 25(OH)D. Levels of 25(OH)D lower than 15ng/ml were considered to be deficient. Results: Serum levels of 25(OH)D were deficient in 41 patients (52%). The comparative study regarding levels of vitamin 25(OH)D showed the group of patients with a deficiency, i.e. those with less than 15ng/ml, were older (70 11.97 vs 61 14.5; p = 0.005), had a greater body mass index, BMI, (30 4.06 vs 27.1 5.08; p = 0.003) and increased proteinuria (1.42g/24h (0.532.96) vs 0.51 (0.20-1.48), p = 0.009). This group included a greater number of diabetic patients: 20 (76.9%) vs 6 (23%), p = 0.002. They had a higher level of parathyroid hormone (PTH): 359 (239-658) vs 233 (129-323), p = 0.000; and more patients were under treatment with Calcitriol: 28 (62.2%) vs 17 (37.8%), p = 0.024. In the multivariate analysis, high levels of PTH (OR 13.38; CI 95% [2.94-60.89]; p=0.001), increased proteinuria (OR 4.41; CI 95% [1.1217.25]; p = 0.033); and being diabetic (OR 5.713; CI 95% [1.43-22.77]; p = 0.014) were independent predictor factors for patients with 25(OH)D deficiency. Conclusions: In our study, we observed a high prevalence of 25(OH)D deficiency among patients with CKD. The increased levels of PTH, the increase of proteinuria and the presence of diabetes were independent predictors for 25(OH)D deficiency. Keywords: Chronic kidney disease. Predialysis. 25 hydroxy vitamin D levels.
Caractersticas clnicas y bioqumicas de pacientes en predilisis con respecto a los niveles de 25 hidroxivitamina D RESUMEN Introduccin: Se ha descrito una disminucin de los niveles de 25 hidroxivitamina D (25[OH]D), en los pacientes con enfermedad renal crnica (ERC). Conocemos que el efecto pleiotrpico de la vitamina D va ms all del metabolismo mineral. Objetivos: Los objetivos del estudio fueron: 1) determinar los niveles de 25(OH) D en pacientes con ERC seguidos en consulta de predilisis. 2) Analizar caractersticas clnicas y bioqumicas de los pacientes con respecto a los niveles de 25(OH)D y los posibles factores predictivos de la deficiencia en 25(OH)D. Pacientes y mtodos: Realizamos un estudio obsevacional en 79 pacientes con ERC. Analizamos datos clnicos y parmetros bioqumicos en cuanto a nutricin, inflamacin y metabolismo mineral en relacin con los niveles de 25(OH)D. Se consider deficiencia de 25(OH)D si los niveles eran inferiores a 15 ng/ml. Resultados: Cuarenta y un pacientes (52%) presentaron deficiencia de 25(OH)D. Comparando los datos analizados segn los niveles de vitamina
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Correspondence: Isabel Rodrguez Villarreal Seccin de Nefrologa. Hospital Severo Ochoa. Avda de Orellana, s/n. 28911 Legans. Madrid. Spain. irodriguez.hsvo@salud.madrid.org
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25(OH)D mayores o menores de 15 ng/ml, el grupo de pacientes con deficiencia en 25(OH)D tenan: ms edad (70 11,97 frente a 61 14,5; p = 0,005), mayor ndice de masa corporal (IMC) (30 4,06 frente a 27,1 5,08; p = 0,017), y mayor proteinuria (1,42 g/24 h [0,53-2,96] frente a 0,51 [0,20-1,48]; p = 0,009). La hormona paratiroidea (PTH) se encontraba ms elevada (359 [239-658] frente a 233 [129-323]; p = 0,000), y ms pacientes recibieron tratamiento con calcitriol oral (28 [62%] frente a 17 [37,8%]; p = 0,024). El porcentaje de diabticos fue mayor en este grupo (20 [76,9%] frente a 6 [23%]; p = 0,002). En el anlisis multivariante, la presencia de diabetes (OR: 5,713; IC95% [1,43-22,77]; p = 0,014), el aumento de PTH (OR: 13,38; IC95% [2,94-60,89]; p = 0,001), y la proteinuria ms elevada (OR: 4,41; IC95% [1,12-17,25]; p = 0,033) fueron factores predictivos independientes de la deficiencia en 25(OH)D. Conclusiones: Los pacientes con ERC tienen alta prevalencia de deficiencia de 25(OH)D. El aumento de PTH, la elevacin de la proteinuria, y la presencia de diabetes fueron factores predictivos independientes de la deficiencia en 25(OH)D. Palabras clave: Enfermedad renal crnica. Predilisis. Niveles de 25 hidroxivitamina D.
I. Rodrguez Villarreal et al. 25 hydroxy vitamin D in CKD
health of the general population is becoming increasingly understood.5,6 A deficiency in 25(OH)D has been linked to cardiovascular disease, diabetes, the progression of chronic kidney disease (CKD) and immune system disorders.7 CKD patients have a deficiency of the substrate 25(OH)D and the active form 1,25-(OH)2D. A deficiency in the substrate 25(OH)D, both for those with CKD 8-11 and the general population, 12 has been associated with age, loss of appetite and factors affecting cutaneous synthesis, such as low sun exposure13 and skin pigmentation.14 A deficiency in the active form 1,25-(OH)2D would be produced by a reduction in the substrate 25(OH)D and decreased activity of the enzyme 1-alphahydroxylase, due to reduced renal mass. 15 Currently, the discovery of fibroblast growth factor (FGF)-23 has opened up other avenues for understanding mineral metabolism disorders from the early stages of CKD. FGF-23 is a protein produced in the bone, which acts on the kidneys producing phosphaturia and suppressing the expression of the enzyme 1-alphahydroxylase, which decreases production of 1,25-(OH)2D. 16,17 FGF-23 increases in parallel with a decrease in renal function: the increase of phosphorus in the diet would stimulate FGF-23 resulting in a decrease of 1,25-(OH)2D from the early stages of CKD. Moreover, activity of the enzyme 1-alphahydroxylase in other tissues leads us to believe in the importance of maintaining optimal levels of 25(OH)D. The study objectives were as follows:
INTRODUCTION The skin and certain foods are sources of vitamin D. The action of UV rays on the skin produces provitamin D (cholecalciferol D3). This process involves factors such as age and skin pigmentation.1 Dietary vitamin D depends on the consumption of dairy products, fish and fortified cereals, producing ergocalciferol D2.2 Subsequently, vitamin D binds to proteins and is transported in the blood to the liver where hydroxylation of carbon 25 occurs, forming calcidiol (25[OH]D). This process is not regulated by hormones, as levels depend only on the availability of the substrate. Calcidiol (25[OH]D) is an indicator of vitamin D deficiency. There is then a second hydroxylation in the kidney via the enzyme 1-alpha-hydroxylase, resulting in the formation of calcitriol (1,25-[OH]2D), the active form of vitamin D.3 Both calcidiol and calcitriol can activate the vitamin D receptors which are widely spread throughout the body. These receptors pro-differentiation, antiproliferative and immunomodulatory activities have many physiological effects.4 This uses 80% of vitamin D, although the best known action of vitamin D is the regulation of mineral metabolism. Knowledge of vitamin D, the substrate 25(OH)D and the active form 1,25-(OH)2D is of most interest because of their pleiotropic actions. The involvement of vitamin D in the
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1. Determine the 25(OH)D levels in predialysis outpatients. 2. Compare clinical and laboratory data regarding nutrition, inflammation and mineral metabolism with levels of 25(OH)D. 3. Analyse potential predictors for a deficiency in 25(OH)D.
MATERIAL AND METHOD Study population An observational study was conducted on 79 stable CKD predialysis outpatients between March and September 2008. Patients with an infection or a vascular disease during that period were excluded. The 25(OH)D level was measured between February and March 2008, due to its seasonal nature.
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insufficiency if the levels were between 15 and 30ng/ml, and normal values were above 30ng/ml, according to the KDOQI guidelines.18
The mean follow-up period for predialysis consultation was 33 months, with a range of 12-196 months. Twenty-six patients (33%) were diabetic, 76 (97.4%) were hypertensive, 32 (40.5%) had a cardiovascular event, and 23 (29%) had cardiac events only. Included in the latter were: angina (10 patients), acute myocardial infarction (3), episodes of heart failure (4), tachyarrhythmias (5) and pericarditis (1). A number of patients were treated with phosphorus binders: 23 (29%) with aluminium hydroxide, 10 (13%) with sevelamer and 20 (25%) with calcium carbonate. While 45 patients (57%) received oral calcitriol as the only form of vitamin D.
Statistical analysis The normality of the variables distribution was determined using the Kolmogorov-Smirnov test. Those variables with a normal distribution were expressed as meanSD, while those that did not have a normal distribution were expressed as median and 25-75 percentiles. Categorical variables were expressed as number and percentage. The comparison between continuous variables was performed using the Mann-Whitney U test. For more than two groups, the Kruskal-Wallis test was used. Categorical variables were compared using the chi square test. The Spearmans bivariate correlation was used to determine the association of the analysed data with 25(OH)D levels. Statistically significant variables were selected as potential independent 25(OH)D deficiency predictors for the multivariate binary logistic regression analysis, with the dependent variable being a deficiency or not of 25(OH)D. The independent variables introduced with the following cutoff points were: PTH median of 291pg/ml, proteinuria median of 0.98g/24h, age over 65 years, BMI greater than 30kg/m2, women and the presence of diabetes. The statistical analysis was performed using the statistical program SPSS version 15 (SPSS). Values of P<.05 were considered significant.
Parameters analysed The following were measured: Mineral metabolism analysis 25(OH)D, including D2 and D3, calcium (Ca), phosphorus (P), alkaline phosphatase (ALP) and parathyroid hormone (PTH).
Renal function parameters Serum creatinine (CRP), creatinine clearance (CCr) and proteinuria at 24 hours were measured.
Nutritional parameters The weight and height of all patients were measured to calculate their body mass index (BMI). The levels of albumin, prealbumin and transferrin (TF) were also determined. The inflammatory state was determined by C-reactive protein (CRP) by immunoturbidimetry. The reference values were 010mg/l. Comorbidity was analysed using the Charlson comorbidity index. A fasting blood test was performed on all patients after collecting their urine 24 hours before. Biochemical data were analysed in the hospitals central laboratory. PTH was measured by chemiluminescence with reference values of 16-87pg/ml. Vitamin 25(OH)D levels were measured by chemiluminescent radioimmunoassay (CLIA), Dia-Sorin LIAISON. Its concentration was nanomolar, only 3% was free, and it mostly circulates in the serum bound to lipophilic proteins. The reference values were 8-60ng/ml. A deficiency in 25(OH)D levels was considered as below 15ng/ml,
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RESULTS The CKD stage distribution of the 79 patients was as follows: stage 3: 6 patients (8%); stage 4: 50 patients (63%); and stage 5: 23 patients (29%). The clinical and biochemical data of the 79 patients are shown in Table 1. Levels of 25(OH)D in the 79 patients were distributed as follows: 41 (52%) were deficient (less than 15ng/ml), 33 (42%) were insufficient (between 15 and 30ng/ml), and only 5 patients (6%) had normal levels (greater than 30ng/ml), see Figure 1. Levels of 25(OH)D in CKD stages 3, 4 and 5 expressed as median and interquartile range were: stage 3: 19.8ng/ml (12.3-33.7); stage 4: 15ng/ml (4-34.6); and stage 5: 12.5ng/ml (4-23.8). Decreased levels were observed in all CKD stages, with a tendency to decrease as the CKD stage increased (P=.097), see Figure 2.
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Table 1. Clinical and biochemical characteristics of patients
Variables Age (years), mean (range) Predialysis follow-up time (months) Men (%) BMI (kg/m2) Diabetes (%) Cardiac events (%) Comorbidity (Charlson index) Calcium (mg/dl) 25(OH)D (ng/ml) Phosphorus (mg/dl) Alkaline phosphatase (U/l) PTH (pg/ml) Prealbumin (mg/dl) Albumin (g/dl) Transferrin (mg/dl) CRP (mg/l) Creatinine (mg/dl) CCr (ml/min) Proteinuria (g/day) Treatment with calcitriol Treatment with aluminium hydroxide Treatment with calcium carbonate Treatment with sevelamer No. = 79 66 14 (33-92) 33 (12-196) 50 (63.3%) 28.47 4.8 26 (33%) 23 (29%) 3 (2-4) 9.3 0.66 14.3 (9,7-21.7) 4.6 1.09 92.14 37.66 291 (193-454) 32.8 8.2 3.9 0.3 209 35.30 4.3 (2-9.6) 3,6 0.96 18 7,3 0.98 (0.30-2.07) 45 (57%) 23 (29%) 20 (25%) 10 (13%) 25(OH)D vitamin
No. = 5 (6%)
No. = 41 (52%)
25(OH)D levels (ng/mL) Deficient <15ng/mL Insufficient 15-30ng/mL Normal >30ng/mL
No. = 33 (42%)
No.: number of patients in each group.
Figure 1. Distribution of patients according to 25(OH)D levels.
CKD stages Results expressed as median and interquartile range.
Data are expressed as meanSD or range, median (interquartile range) or percentage. BMI = body mass index, PTH = parathyroid hormone, CCr = creatinine clearance.
Figure 2. 25(OH)D levels in CKD, stages 3,4 and 5.
Table 2 compares the data analysed with respect to 25(OH)D levels higher or lower than the cut-off point of 15ng/ml. The 25(OH)D deficient group was older (7011.97 vs 6114.5 years, P=.005) had a higher BMI (304.06 vs 275.08, P=.017), and had more diabetic patients (20 [76.9%] vs 6 [23%] P=.002). No differences were found in the number of cardiac events: 10 (43.5%) vs 13 (56.5%), P=.598. There were no differences in renal function, as measured by serum creatinine and creatinine clearance. Proteinuria in g/24h was higher in this group, 1.42 (0.53-2.96) vs 0.51 (0.20-1.48), P=.009. Regarding mineral metabolism, PTH figures were higher, 359 (239-658) vs 234 (129-323), P=.000. There were no differences in the levels of calcium, phosphorus or alkaline phosphatase. Most patients were treated with calcitriol, 28
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(62.2%) vs 17 (37.8%), P=.024, with no difference in the dose received. For nutritional parameters: albumin (3.90.34 vs 40.3), P=.086; prealbumin (328.4 vs 348), P=.087; and transferrin (20533 vs 21238), P=.477 showed no differences with respect to 25(OH)D levels. The inflammatory state as measured by CRP also showed no differences with respect to the 25(OH)D levels: 4 (2-9) vs 5.75 (2-10), P=.790. In the univariate analysis (Table 3), the 25(OH)D levels correlated inversely with PTH (r=-0.355, P=.0001), age (r=0.297, P=.008), BMI (r=-0.327, P=.004) and proteinuria (r=0.291, P=.009). In the multivariate analysis (Table 4), the presence of diabetes (OR: 5.713, 95% CI [1.43-22.77], P=.014); increased PTH
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Table 2. Comparison of clinical and biochemical data regarding 25(OH)D levels

Clinical and analytical data 25(OH)D >15ng/ml No.=38 (48%) Predialysis follow-up time (months) Age (years), mean Sex (men/women) BMI (kg/m2) Diabetes (%) Cardiac events (%) Charlson comorbidity Creatinine (mg/dl) CCr (ml/min) Proteinuria (g/da) PTH (pg/ml) Calcium (mg/dl) Phosphorus (mg/dl) Alkaline phosphatase (U/l) Treatment with calcitriol (%) Calcitriol dose (g/week) Albumin (g/dl) Prealbumin (g/dl) Transferrin (mg/dl) C-reactive protein (mg/l) 15 (12-42) 61 14.5 25/13 27 5.08 6 (23.1%) 10 (43.5%) 2.5 (2-4) 3.6 1.08 19.76 8.04 0.51 (0.20-1.48) 233 (129-323) 9.3 0.7 4.6 1.1 85.45 33.06 17 (37.8%) 1.34 0.46 4 0.3 34 8 212 38 4.2 (2-9) 25(OH)D <15ng /ml No.=41(52%) 24 (12-48) 70 11.97 25/17 30 4.06 20 (76.9%) 13 (56.5%) 4 (2-4) 3.6 1.08 18.38 6.83 1.42 (0.53-2.96) 359 (239-658) 9.3 0.6 4.6 1.02 97.85 40.71 28 (62%) 1.32 0.40 3.9 0.34 32 8.4 205 33 5.7 (2-10) 0.181 0.005 0.657 0.017 0.002 0.598 0.047 0.821 0.387 0.009 0.000 0.885 0.866 0.223 0.024 0.902 0.086 0.087 0.477 0.790 P
Data are expressed as meanSD, median (interquartile range) or percentage. BMI= body mass index, PTH= parathyroid hormone, CCr= creatinine clearance.
(OR: 13.38, 95% CI [2.94-60.89], P=.001); and higher proteinuria (OR: 4.41, 95% CI [1.12-17.25], P=.033) were independent predictors for 25(OH)D deficiency.
DISCUSSION A high prevalence of 25(OH)D insufficiency was confirmed in CKD patients,7,10,11 with only 6% of the 79 patients having levels considered normal. In CKD patients, there is an association of 25(OH)D deficiency with age, as there is in the general population.12 This could be explained by a combination of factors, such as poor nutrition, gastrointestinal disorders or a lack of skin synthesis due to low sun exposure.1 In CKD patients, dietary restriction and loss of appetite due to uraemia may be stronger determining factors for 25(OH)D deficiency. The nutritional parameters analysed did not differ with respect to 25(OH)D levels, so they cannot be considered as a global malnutrition marker.
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The BMI was higher in patients with decreased 25(OH)D levels, and obesity has been associated with decreased 25(OH)D,19 although the cause is not well known. Vitamin D is fat soluble and could be metabolically active within stores of fat (adipocytes). Therefore, an increased BMI could be accompanied by lower vitamin 25(OH)D plasma levels. However, a study in obese and overweight patients20 found an inverse relationship between vitamin D3 levels and weight and BMI, but not with body fat measured by bioimpedance.
Table 3. Bivariate correlation (Spearman) between 25(OH)D levels and variables studied
Variables PTH (pg/ml) BMI (kg/m2) Age (years) Proteinuria (g/day) Rho 0.355 0.327 0.297 0.291 P 0.001 0.004 0.008 0.009 189
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Table 4. Logistic regression multivariate analysis: potential predictors of vitamin 25(OH)D deficiency
Independent variables Sex (women) Age >65 years PTH>291pg/ml Diabetes mellitus Proteinuria (g/day) >0.98 BMI (kg/m2) >30 Odds ratio (CI 95%) 0.766 (0.165-3.54) 3.44 (0.919-12.89) 13.38 (2.94-60.89) 5.713 (1.43-22.77) 4.41 (1.12-17.25) 3.34 (0.929-12.029) P 0.733 0.066 0.001 0.014 0.033 0.065
PTH was higher and more patients had been treated with oral calcitriol. An increased level of PTH was another independent predictor of deficiency. It has been shown that 25(OH)D deficiency leads to changes in bone mineralisation, independent of PTH levels and the active form 1,25-(OH)2D.31 Additionally, 25(OH)D levels directly regulate the PTH, regardless of the active form, 1,25(OH)2D.32 From the results, it can be concluded that there is a high prevalence of 25(OH)D deficiency and insufficiency in CKD patients, and that increased PTH and proteinuria and the presence of diabetes are independent predictors for 25(OH)D deficiency. A deficiency in 25(OH)D should be corrected at different stages of CKD,33,34 with special attention paid to patients with diabetes and increased proteinuria. If the 25(OH)D deficiency continues, the pleiotropic activity is being neglected and the development of secondary hyperparathyroidism is enhanced. Long-term studies are needed to evaluate the impact of maintaining adequate 25(OH)D levels at different stages of CKD.
Model adjusted r2=0.54. Dependent variable: 25(OH)D deficiency <15 ng/ml
The number of diabetic patients in the 25(OH)D deficient group was higher, and diabetes, among others, was a predictor of 25(OH)D deficiency. Vitamin D receptors have been found in the endocrine pancreatic beta cells; therefore, vitamin D deficiency has been associated with cellular changes in the endocrine pancreas, which would lead to obesity and insulin resistance, thereby favouring a diabetic state.21-23 Proteinuria was higher in the 25(OH)D deficient patient group and was also a predictor for vitamin D deficiency. We know that vitamin D circulates mostly bound to proteins; hence, the higher the proteinuria, the lower the 25(OH)D level.24 A deficiency in 25(OH)D has been documented in other protein loss states, such as nephrotic syndrome25 and treatment with peritoneal dialysis.26,27 For diabetic patients with diabetic nephropathy, proteinuria should be a factor to be considered in the 25(OH)D deficiency found. Over the last 10 years, cardiovascular disease has been associated with 25(OH)D deficiency.28 The inhibitory effect of vitamin D receptors on the expression of the reninangiotensin-aldosterone system protects against cardiac hypertrophy, increasing left ventricular contractility.29,30 No difference was found in the number of cardiac events according to the level of 25(OH)D in this study. The study design features and the number of patients may condition these results. A 25(OH)D deficiency had no influence on the inflammatory status of patients measured by the CRP. Regarding mineral metabolism, calcium and phosphorus figures were controlled. In the 25(OH)D deficient group, the
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REFERENCES
1. Sherman SS, Hollis BW, Tobin JD. Vitamin D status and related parameters in a healthy population: the effects of age, sex, and season. J Clin Endocrinol Metabol 1990;71:405-13. 2. Van Dam RM, Snijder MB, Dekker JM, et al. Potentially modifiable determinants of vitamin D status in an older population in the Netherlands: The Hoorn Study. Am J Clin Nutr 2007;85:755-61. 3. Jones G. Expanding role for vitamin D in chronic Kidney disease importance of blood levels and extrarenal 1 alpha hydroxylase in the classical and non classical actions of 1 alpha 25,dihydroxy vitamin D. Semin Dial 2007;20(4):316-24. 4. Szeto CC, Kam-Tao Li P. The use of vitamin D analogues in chronic kidney diseases: possible mechanisms beyond bone and mineral metabolism. Nephrol Dial Transplant 2009;2:205-12. 5. Heaney RP. Vitamin D in health and disease. Clin J Am Soc Nephrol 2008;3(5):1535-41. 6. Zittermann A. Vitamin D in preventive medicine: Are we ignoring the evidence? Br J Nutr 2003;89(5):552-72. 7. Holick MF. Vitamin D Deficiency. N Engl Med 2007;357:266-81. 8. Mehrotra R, Kermah D, Budoff M, Salusky IB, et al. Hypovitaminosis D in chronic kidney disease. Clin J Am Soc Nephrol 2008;3:1144-51. 9. Canata-Andia JB, Gmez Alonso C. Vitamin D deficiency: a neglected aspect of disturbed calcium metabolism in renal failure. Nephrol Dial Transplant 2002;17:1875-8. 10. Cuppari L, Garcia-Lopes MG. Hypovitaminosis D in chronic kidney disease patients: prevalence and treatment. J Ren Nutr 2009;19:38-43. Nefrologia 2011;31(2):185-91
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Survey. Diabetes Care 2004;27:2813-8. 24. Saha H. Calcium and vitamin D homeostasis in patients with heavy proteinuria. Clin Nephrol 1994;41(5):290-6. 25. Schmidt-Gayk H, Grawunder C, Tschope W, Schmitt W, et al. 25 hydroxy-vitamin D in nephrotic syndrome. Lancet 1977;16(2):1058. 26. Taskapan H, Ersoy FF, Passadakis PS, Tam P, et al. Severe vitamin D deficiency in chronic renal failure patients on peritoneal dialysis. Clin Nephrol 2006;66:247-55. 27. Shah N, Bernardini J, Piraino B. Prevalence and correction of 25(OH) vitamin D deficiency in peritoneal dialysis patients. Perit Dial Int 2005;25:362-6. 28. Wang TJ, Pencina MJ, Booth SL, et al. Vitamin D deficiency and risk of cardiovascular disease. Circulation 2008;117:503-11. 29. Martins D, Wolf M, Pan D, et al. Prevalence of cardiovascular risk factors and the serum levels of 25 Hidroxyvitamin D in the United States. Arch Intern Med 2007;167:1159-65. 30. Michos ED, Melamed ML. Vitamin D and cardiovascular disease risk. Curr Opin Clin Nutr Metabol Care 2008;11:7-12. 31. Ghazali A, Fardellone P, Pruna A, Atika, et al. Is low plasma 25-OHD vitamin D a major risk factor for hyperparathyroidism and Looser zones independent of calcitriol? Kidney Int 1999;55:2169-77. 32. Stavroulopoulos A, Porter CJ, Roe SD, Hosking DJ, Cassidy MJ. Relationship between vitamin D status, parathyroid hormone levels and bone mineral density in patients with chronic kidney disease stages 3 and 4. Nephrology 2008;13(1):63-7. 33. Al-Aly Z, Qazi RA, Gonzalez EA, Zeringue A, Martin KJ. Changes in serum 25-hydroxy vitamin D and plasma intact PTH levels following treatment with ergocalciferol in patients with CKD. Am J Kidney Dis 2007;50(1):59-68. 34. Kooienga L, Fried L, Scragg R, Kendrick J Smits G, Chonchol M. The effect of combined calcium and vitamin-D3 supplementation on serum intact parathyroid hormone in moderate CKD. Am J Kidney Dis 2009;53(3):408-16.
11. Levin A, Bakris GL, Molitch M, Smulders M, et al. Prevalence of abnormal serum vitamin D, PTH, calcium, and phosphorus in patients with chronic Kidney disease. Kidney Int 2007;71:31-8. 12. Zuberi LM, Habib A, Haque N, Jabbar A. Vitamin D deficiency in ambulatory patients. J Pak Med Assoc 2008;58(9):482-4. 13. Saraiva GL, Cendoroglo MS, Ramos LR, Araujo LM, et al. Influence of ultraviolet radiation on the production of 25 hydroxyvitamin D in the elderly population in the city of Sao Paulo (23 degrees 34S), Brazil. Osteoporos Int 2005;16:1649-54. 14. Matsuoka LY, Wortsman J, Haddad JG, Kolm P, et al. Racial pigmentation and the cutaneous synthesis of vitamin D. Archives of dermatology 1991;127:536-8. 15. Wesseling K, Salusky I. Is replacement therapy with nutritional and active forms of vitamin D required in chronic Kidney disease mineral and bone disorder? Curr Opin Nephrol Hypertens 2009;18:308-14. 16. Danzige J. The bone-renal axis in early chronic kidney disease: an emerging paradigm. Nephrol Dial Transplant 2008;23:2733-7. 17. Seiler S, Heine GH, Fliser D. Clinical relevance of FGF-23 in chronic Kidney disease. Kidney Int 2009;76(Suppl14);534-42. 18. K/DOQI clinical practice guidelines for bone metabolism and disease in chronic kidney disease. Am J Kidney Dis 2003;42 (Suppl. 3):S1-202. 19. Sneve M, Figenschau Y, Jorde R. Supplementation with cholecalciferol does not result in weight reduction in overweight and obese subjects. Eur J Endocrinol 2008;159(6):675-84. 20. Thea McGill A, Stewart JM, Lithander FE, et al. Relationships of low serum vitamin D3 with anthropometry and markers of the metabolic syndrome and diabetes in overweight and obesity. Nutr J 2008;7:4. 21. Chiu Kc, Chu A, Go VI, Saad MF. Hypovitaminosis D is associated with insulin resistance and beta cell dysfunction. Am J Clin Nutr 2004;79:820-5. 22. Micho S (ed.). Vitamin D deficiency and the risk of incident Type 2 diabetes. Epidemiology 2008;19(5):666-71. 23. Scragg R, Sowers MF, Bell C. Serum 25-Hidroxyvitamin D, Diabetes, and Ethnicity in the Third National Health and Nutrition Examination
Sent for review: 30 Jul. 2010 | Accepted: 31 Jan. 2011 Nefrologia 2011;31(2):185-91 191
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Should a cystography be performed on all breastfeeding infants with mild to moderate dilatation of the urinary tract? Renal function tests can help to answer this question
V. Garca Nieto1, S. Gonzlez Cerrato1, V.E. Garca Rodrguez2, O. Mesa Medina1, M.J. Hernndez Gonzlez1, M. Monge Zamorano1, M.I. Luis Yanes1
1 2
Paediatric Nephrology Department. Nuestra Seora de Candelaria University Hospital. Santa Cruz de Tenerife, Spain Paediatric Department. Nuestra Seora de Candelaria University Hospital. Santa Cruz de Tenerife, Spain
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ABSTRACT Introduction: Pyelectasis could be defined as mild to moderate dilatation of the urinary tract and is diagnosed by means of an ultrasound (0.5-2cm transverse diameter in the initial ultrasound performed after birth). There is some disagreement about whether cystography should be indicated as standard practice. The aim of this study was to establish if renal function tests are useful in determining which cases of mild to moderate dilatation of the urinary tract do not require an initial cystography. Patients and Methods: The study was conducted on 79 infants (57 males, 22 females) with pyelectasis. Seventy-three were diagnosed in utero and 6 after birth. All infants underwent, at least, one cystography and one desmopressin urine concentration test before one year of age. Results: Compared to infants without vesicoureteral reflux (VUR) (n=68), infants with VUR (n=11; two with Grade I, three with Grade II, five with Grade III, two with Grade IV) showed a significantly lower (P=.006) maximum urine osmolality and a significantly higher microalbumin/creatinine ratio(P<.001) and NAG/creatinine ratio (P=.003). The negative predictive value of the first two tests was 93%. Sensitivity of the maximum urine osmolality to detect VUR was 72.7% (specificity 63.2%). Sensitivity of the microalbumin/creatinine ratio to detect VUR was 62.5% (specificity 75%). The positive probability ratio (PR) was 1.29 for the NAG/creatinine ratio, 2.03 for the maximum urine osmolality and 2.5 for the microalbumin/creatinine ratio. The negative PR was 0.95 for the NAG/creatinine ratio, 0.43 for the maximum urine osmolality and 0.5 for the microalbumin/creatinine ratio. Conclusions: Pyelectasis is a benign condition. Only 2 patients required pharmacological intervention (prophylatic treatment for VUR Grade IV patients). Cystography should not be indicated initially, at least, in cases of microalbuminuria and/or normal urine concentrations. Keywords: Micturating cystography. Microalbuminuria. Concentrating capacity defect. Renal pyelectasis.
Debe realizarse una cistografa a todos los lactantes con dilatacin leve y moderada de las vas urinarias? Las pruebas de funcin renal pueden ayudar a responder esta pregunta
RESUMEN Introduccin: La ectasia pilica puede definirse como la dilatacin leve-moderada de las vas urinarias diagnosticada mediante ecografa (0,5-2 cm de dimetro transversal en la primera ecografa realizada despus de nacer). Existe una cierta divergencia sobre si la cistografa se debe indicar de forma universal. El objetivo del estudio fue conocer si las pruebas de funcin renal son tiles para decidir, en los casos de dilatacin leve y moderada de las vas urinarias, aquellos en los que no se debe solicitar la cistografa inicialmente. Pacientes y mtodos: Se estudiaron 79 nios (57 nios, 22 nias) con ectasia pilica (73, diagnosticadas intratero y seis despus de nacer). A todos se les realizaron, al menos, una cistografa y una prueba de concentracin con estmulo de desmopresina antes del ao de edad. Resultados: En relacin con los ni-
Correspondence: Vctor Garca Nieto Servicio de Nefrologa Peditrica. Hospital Nuestra Seora de Candelaria. Carretera del Rosario, 145. 38010 Santa Cruz de Tenerife. Spain. vgarcianieto@gmail.com 192
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should initially be distinguished from those who can wait for a decision on its indication. Thereby preventing, as much as possible, an unnecessary, uncomfortable procedure and an associated risk of secondary urinary tract infection.16-19 This study shows our concept of sensitive renal function tests (maximum urine osmolality, microalbumin/creatinine ratio and NAG/creatinine ratio), which are useful for initially deciding against cystography in cases of mild and moderate dilatation.
os sin reflujo vesicoureteral (RVU) (n = 68), los nios con RVU (n = 11; dos de grado I, tres de grado II, cinco de grado III, dos de grado IV) mostraron una osmolalidad urinaria mxima significativamente inferior (p = 0,006) y un cociente microalbmina/creatinina (p <0,001) y un cociente NAG/creatinina (p = 0,003) significativamente superiores. El valor predictivo negativo de las dos primeras pruebas fue del 93%. La sensibilidad de la osmolalidad urinaria mxima para detectar RVU fue del 72,7% (especificidad 63,2%). La sensibilidad del cociente microalbmina/creatinina para detectar RVU fue del 62,5% (especificidad 75%). El cociente de probabilidad (CP) positivo para el cociente NAG/creatinina fue 1,29, para la osmolalidad urinaria mxima 2,03 y para el cociente microalbmina/creatinina 2,5. El CP negativo para el cociente NAG/creatinina fue 0,95, para la osmolalidad urinaria mxima 0,43 y para el cociente microalbmina/creatinina 0,5. Conclusiones: La ectasia pilica es una condicin benigna. Slo 2 pacientes requirieron una intervencin mdica de ndole farmacolgica (tratamiento profilctico al ser portadores de RVU grado IV). Al menos, la cistografa no se debe indicar inicialmente en los casos de microalbuminuria y/o concentracin urinaria normales. Palabras clave: Cistografa. Microalbuminuria. Defecto de la capacidad de concentracin. Pielectasia renal.
PATIENTS AND METHODS This is a cross-sectional prospective study of 79 breastfeeding infants (57 boys, 22 girls) diagnosed with mild and moderate pyelectasis. The diagnosis was made in utero for 73 of them, and after birth for the other six. The foetal diagnosis was confirmed when the first ultrasound was performed after birth, with the anteroposterior diameter of the renal pelvis being between 0.5cm14 and 2cm.9,10 The same criterion was applied to infants diagnosed after birth. Patients with an anteroposterior diameter greater than 2cm were excluded. The first ultrasound was carried out at the age of 32.656.1 days (range: 1-240). The ectasia was located on the left side in 32.9% of cases (n=26), and on the right side in 17.7% of cases (n=14), with 49.3% of cases (n=39) being bilateral. The mean and SD of the longitudinal diameter of the pelvis on the left side was 1.010.57cm and 0.750.64cm on the right side. Besides the above ultrasound, the inclusion criteria were a cystography and at least one desmopressin urine concentration test within the first year of life. When the VUR was bilateral, the higher grade value was taken. The microalbumin/creatinine ratio was measured from an isolated urine sample in 64 patients. In addition, the corresponding NAG/creatinine ratio was estimated for 53 infants from an isolated sample. Also, 26 out of the 76 patients (32.9%) were referred for a furosemide renogram during follow-up to rule out urinary tract obstruction. In all cases this was normal.
INTRODUCTION Dilatation of the urinary tract is diagnosed by ultrasound in 1%-5% of pregnancies.1,2 In some cases, it may be the expression of urinary tract abnormalities, such as those causing obstruction or vesicoureteral reflux (VUR).3,4 In the current literature, two terms are used for dilatation of the urinary tract, leading to some confusion: pyelectasis5,6 (from the Latin ectasis, dilatation) and the more traditional term of hydronephrosis.7,8 Some groups prefer to use the term ectasia for mild to moderate dilatation and hydronephrosis for serious cases, i.e. when the anteroposterior diameter of the renal pelvis is at least 2cm, given that most infants who need surgical treatment comply with this latter requirement.9,10 For the majority of cases, where the dilatation is not secondary to abnormalities, we have coined the term simple renal ectasia (ectasia renal simple11), and have suggested that this could indicate a genetic predisposition to suffer from kidney stones in adulthood.12 The risk of any grade of VUR is 4.4% in mild prenatal hydronephrosis and 14% in moderate.13 Some authors suggest cystography in all patients with dilatation of the urinary tract.14,15 However, given its low frequency of association with severe VUR, we believe that patients who would benefit from its diagnosis in the first months of life
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Desmopressin (DDAVP) concentration test Every morning, 10g of intranasal desmopressin were administered.20,21 The 3 following urine samples were then collected. If only two samples were available, the test was discontinued 8 hours later. The highest osmolality value obtained was taken as the test result. Because they were being bottle fed, the babies were restricted to half the bottle contents from the first bottle in the morning until 18.00h to reduce the risk of water intoxication.22
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Laboratory techniques Urine creatinine was measured by the creatininase method, using a Modular Analytics autoanalyser (Roche/Hitachi, Mannheim, Germany). Urine osmolality was measured by determining the freezing point depression with an Osmo Station OM-6050 osmometer (Menarini Diagnostics, Florence, Italy). Microalbumin was measured by a nephelometric technique (Array). N-acetylglucosaminidase (NAG) was determined by an enzymatic colorimetric method based on the hydrolysis of NAG-dichlorophenol sulfonephthalein (Boehringer Mannheim).
Table 1. Normal values of the maximum urine osmolality in the first year of life obtained after desmopressin stimulation23
Age 0-7 days 8-21 days 22-51 days 52-165 days 166-266 days 267-359 days Lower limit of normal 443mOsm/kg 457mOsm/kg 549mOsm/kg 562mOsm/kg 635mOsm/kg 740mOsm/kg
Normal values The normal values used with respect to the maximum urine osmolality,23 microalbumin/creatinine ratio24 and the NAG/creatinine25 appear in Table 1, 2 and 3, respectively. parameters were significantly different in both groups (Table 4). The maximum urine osmolality of the 3 infants with VUR and the normal concentration test was 529mOsm/kg (grade I), 599mOsm/kg (grade II) and 665mOsm/kg (grade III). The two infants with VUR grade IV had both a concentrating capacity defect and increased urinary excretion of microalbumin (254mOsm/kg, microalbumin/creatinine 21.9g/mol and 382mOsm/kg, microalbumin/creatinine 8.7g/mol, respectively). No differences were found in renal function after dividing the sample into two subgroups according to the
Statistical methods Quantitative variables were expressed as the median and interquartile ranges. Bivariate techniques were used for the initial evaluation of contrasts. Thus, Fishers exact test was used to compare the frequencies between the qualitative variables and the Mann-Whitney U test for comparison of the means between two quantitative variables. The sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) were calculated for the three functional parameters studied to detect VUR. Furthermore, the positive and negative likelihood ratios (LRs) were calculated for the same parameters. A probability of less than 0.05 was considered statistically significant. These tests were performed using SPSS statistical software (SPSS V 17.0, SPSS Inc., USA).
Table 2. Normal values of the microalbumin/creatinine ratio in the first year of life24
Age Newborns Upper limit of normal 14.95g/mol 17.16g/mol 10.98g/mol 4.14g/mol
RESULTS Sixty-eight out of the 79 cystograms were normal. VUR was observed in 11 of them (13.9%): 1 of grade I, 3 of grade II, 5 of grade III and 2 of grade IV. The longitudinal diameters of the pelvis for the two patients with the highest VUR grade were 1.2cm and 1.34cm, respectively, and both received prophylactic treatment. The VUR was found on the left side in 4 infants, 2 had it on the right side and in 5 it was bilateral. There was a renal concentrating capacity defect in 33/79 cases (41.7%). Urinary excretion of microalbumin was high in 19/64 cases (29.7%) and the NAG/creatinine ratio was high in 10/53 (18.8%). Patients were distributed according to the presence or absence of VUR, the values of the three functional
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1-3 months 4-6 months 7-23 months
Table 3. Normal values of the NAG/creatinine ratio in the first year of life25
Age 0-3 months 3-6 months 6-12 months Upper limit of normal 46U/g 20U/g 11U/g Nefrologia 2011;31(2):192-8
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Table 5. Comparison between the results for the concentration test and cystography (Fisher exact test P=.02)
Vesicoureteral reflux Normal maximum urine osmolality Reduced maximum urine osmolality 3 8 Absence of vesicoureteral reflux 43 25
longitudinal diameter of the pelvis (greater and smaller than 1cm). Table 5 shows the comparison of the frequencies between the absence and presence of VUR in the urine concentration test. 36.7% of infants with simple renal ectasia (without VUR) had a concentrating capacity defect. Table 6 shows the comparison of the frequencies between the absence and presence of VUR in the urinary excretion of microalbumin. 25% of infants with simple renal ectasia had increased urinary excretion of microalbumin. Table 7 shows the comparison of the frequencies between the absence and presence of VUR in the urinary excretion of NAG. 18.2% of infants with simple renal ectasia had increased urinary excretion of NAG. Table 8 shows values for sensitivity, specificity, positive and negative predictive values and positive and negative likelihood ratios for the three functional parameters studied to detect VUR.
Table 6. Comparison between the results for urinary microalbumin excretion and cystography (Fisher exact test P=.001)
Vesicoureteral reflux Normal Microalbumin/creatinine High Microalbumin/creatinine 5 14 3 42 Absence of vesicoureteral reflux
DISCUSSION Most pyelectasis study protocols recommend an initial cystography14,15,26 or renogram27 in addition to an ultrasound scan. It is surprising that none of the existing protocols mention a renal function study, including those recommended by paediatric nephrologists. In the initial protocol used in our hospital, we performed both a morphological (ultrasound) and renal function study.28 This study is therefore an attempt to confirm that renal function should be examined when selecting which infants diagnosed with mild-moderate urinary tract dilatation should undergo a cystography. In the initial functional study, we did not include parameters for measuring glomerular renal function such as creatinine or cystatin C levels. They are very specific for kidney damage but not sensitive, as renal
parenchymal damage is already considerable when changes are detected. Continuously high microalbumin is an early sign of glomerular damage in hyperfiltration processes, such as diabetic nephropathy. It is also a suitable marker for hyperfiltration in the healthy renal parenchyma, as it increases in cases with a significant absence of the rest of the parenchyma. In addition, microalbuminuria is recognised as a marker of endothelial damage, as occurs in hypertension, for example.29-31 One interesting but not well accepted issue is whether it can also increase in response to situations where there is excess pressure in the urinary tract, as in cases of VUR.32,33 Our results seem to confirm this third utility for
Table 4. Values of maximum urine osmolality, microalbumin/creatinine ratio and NAG/creatinine ratio after separating the sample between those with and without vesicoureteral reflux
Vesicoureteral reflux Maximum urine osmolality (mOsm/kg) 427.2 133.7 (n = 11) Microalbumin/ creatinine (g/mol) NAG/creatinine (U/g) Nefrologia 2011;31(2):192-8 52.1 49.5 (n = 8) 41.2 23.1 (n = 9) Absence of vesicoureteral reflux 560.2 140.5 (n = 68) 9.3 16.3 (n = 56) 21.9 18.9 (n = 44) 195 0.003 <0.001 P 0.006
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Table 7. Comparison between the urinary NAG excretion results and cystography (Fisher exact test P=.32)
Vesicoureteral reflux Normal NAG/ creatinine High NAG/creatinine 2 8 7 36 Absence of vesicoureteral reflux
due to functional damage produced by overpressure on the urinary tract to renal parenchyma. In our results, the NAG/creatinine ratio can be seen as the least sensitive, but most specific of the three parameters studied, similar to that mentioned for the plasma creatinine levels.27 Conversely, the maximum urine osmolality is the most sensitive parameter for detecting VUR (72.7%), but the least specific. The microalbumin/creatinine ratio had a sensitivity and specificity between the above two parameters. The three parameters studied performed very well in calculating the likelihood ratios (LR). They summarise information on the sensitivity and specificity and indicate the tests ability to increase or decrease the likelihood of a particular diagnosis. The higher the LR is above 1, the more likely the diagnosis is to be correct. Thus, the LR for each of these parameters is on the rise, 1.29 for the NAG/creatinine ratio, 2.03 for the maximum urine osmolality and 2.5 for the microalbumin/creatinine ratio. The reported results show the validity of functional tests when considering a cystography. At least two of the functional tests are useful in deciding who should not undergo this procedure. It seems that no functional parameter has a 100% guarantee for the absence of VUR. However, our results suggest that if the patient has a normal concentrating capacity and/or the microalbumin/creatinine ratio is not high, there is a high probability (93%) that it is a simple pyelectasis. Only 3 infants with VUR had a normal renal concentrating capacity and, according to current criteria, their degree of VUR did not require antibiotic prophylaxis42,43 or surgery. In addition, only 1 out of the 3 infants with VUR and a normal microalbumin/creatinine ratio was a grade IV patient, and he or she would have been diagnosed due to clearly impaired urinary concentrating capacity. Furthermore, our study has detected a hitherto unrecognised fact. Some infants with simple renal ectasia had a defect in renal concentrating capacity and/or increased microalbuminuria. Thus, 25% of infants showed a slight increase in urinary excretion of microalbumin and 36.7% had a slight defect in the concentrating capacity.
determining microalbuminuria. Moreover, we confirmed that once VUR is cured, urinary excretion of microalbumin is reduced, compared to initial values.34 NAG is a characteristic enzyme of the renal proximal tubule cells that travels through the tubular lumen, and therefore into urine, in high quantities when there is a cellular aggression. Its levels may be elevated in cases of urinary tract obstruction and in VUR, especially when there is scarring from nephropathy.32,35 The renal concentration test is based on the maximum urine osmolality reached by the effect of argininevasopressin in the renal collecting tubules, stimulating the activity of aquaporins. When any of the various components of this mechanism is disturbed, there is a defect in the concentrating capacity, which is accompanied by polyuria. However, minor defects may go unnoticed. Many kidney disorders that occur with normal glomerular filtration rate, especially many tubulopathies, obstructive uropathies36-38 and VUR,34,39-41 are related to a reduced maximum urine osmolality and, therefore, to a concentrating capacity defect. Table 3 shows how infants with VUR, compared to those with simple renal ectasia, showed significantly reduced maximum urine osmolality values and significantly high NAG/creatinine and microalbumin/creatinine ratios. This is
Table 8. Results for the quality and diagnostic efficiency indices of the three parameters studied to detect VUR
S Maximum urine osmolality Microalbumin/creatinine ratio NAG/ Creatinine ratio 72.7% 62.5% Sp 63.2% 75% PPV 24.2% 26.3% NPV 93.4% 93.3% PPR 2.03 2.5 NPR 0.43 0.5
22.2%
81.8%
20%
83.7%
1.29
0.95
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8. Sidhu G, Beyene J, Rosenblum ND. Outcome of isolated antenatal hydronephrosis: a systematic review and meta-analysis. Pediatr Nephrol 2006;21:218-24. 9. Elder JS. Antenatal hydronephrosis. Fetal and neonatal management. Pediatr Clin North Am 1997;44:1299-321. 10. Gotoh H, Masuzaki H, Fukuda H, Yoshimura S, Ishimaru T. Detection and assessment of pyelectasis in the fetus: Relationship to postnatal renal function. Obstet Gynecol 1998; 92:226-31. 11. Garca Nieto V, Marrero Prez CL, Montesdeoca Melin A. Ectasia de la pelvis renal en la infancia. Sabemos ya lo que significa y cmo debe estudiarse? An Pediatr (Barc) 2004;61:489-92. 12. Garca-Nieto V, Gonzlez-Hernndez MJ, Luis-Yanes MI, Garca-Rodrguez VE, Armas-Rodrguez A, Abreu-Yanes I. Does neonatal renal ectasia is a sign of genetic predisposition to suffer from kidney stones in adults? Pediatr Nephrol 2009;24:1852. 13. Lee RS, Cendron M, Kinnamon DD, Nguyen HT. Antenatal hydronephrosis as a predictor of postnatal outcome: a meta-analysis. Pediatrics 2006; 118:586-93. 14. Jaswon MS, Dibble L, Puri S, Davis J, Young J, Dave R, Morgan H. Prospective study of outcome in antenatally diagnosed renal pelvis dilatation. Arch Dis Child Fetal Neonatal Ed. 1999;80:F135-8. 15. Pea Carrin A, Espinosa Romn L, Fernndez Maseda MA, Garca Meseguer C, Alonso Melgar A, Melgosa Hijosa M, et al. Ectasia pilica neonatal: evolucin a largo plazo y asociacin a anomalas vesicoureterales. An Pediatr (Barc) 2004;61:493-8. 16. Martin CM. Iatrogenic infectious disease problems, with particular reference to pyelonephritis. Md State Med J 1967;16:65-71. 17. Ditscherlein G. Iatrogenic pyelonephritis from the morphologic viewpoint. II. Hazards of pyelonephritis and systemic infection caused by urologic intervention in man. Z Urol Nephrol 1972;65:271-83. 18. Guignard JP, Fawer CL, Kroener A, Queloz J, Landry M. Urinary infections following bladder catheterization. Schweiz Med Wochenschr 1975;105:1354-6. 19. Maskell R, Pead L, Vinnicombe J. Urinary infection after micturating cystography. Lancet 1978;2:1191-2. 20. Aronson AS, Svenningsen NW. DDAVP test for estimation of renal concentrating capacity in infants and children. Arch Dis Child 1974;49:654-9. 21. Monnens L, Smulders Y, Van Lier H, De Boo T. DDAVP test for assessment of renal concentrating capacity in infants and children. Nephron 1981;29:151-4. 22. Garca Nieto V, Hernndez de la Torre M, Hernndez Marrero D, Torres A. Convulsiones como complicacin del empleo de DDAVP para determinar la capacidad de concentracin urinaria. Nefrologia 1987;7:413-4. 23. Garca Nieto V, Duque Hernndez J, Oliva C, Ruiz Pons M, Martn Fumero L, Gmez Sirvent J, et al. Determinacin mediante DDAVP de los valores normales de osmolalidad urinaria mxima en el primer ao de la vida. Nefrologia 1988;8(Suppl 4):37. 24. Yap C, Yap HK, Chio LF. Urine microalbumin/creatinine ratios in Singapore children. The Singapore Paediatr Soc 1991;33:101-6. 25. Caballo Roig N, Yep Chullen G, De la Torre E, Ruiz Jarabo C, Asensio Antn J, Snchez Bayle M. Variacin de la excrecin de N-acetilglucosaminidasa en el primer ao de vida. An Esp Pediatr 1991;34:142-4. 26. Ismaili K, Avni FE, Wissing KM, Hall M; Brussels Free University Peri197
This finding was unknown as it is a minor defect. Nevertheless, in a longitudinal study, our group has demonstrated that both functional defects progressively normalise with age.44 To summarise, because there is a high probability of a mild abnormality, we believe that in cases of urinary tract dilatation, morphological (ultrasound) and functional studies need not always be performed immediately after birth. In particular, when the longitudinal diameter of the renal pelvis is less than 1cm, it could even be done between the third and sixth month of life, as there is a very low risk of detecting severe reflux. A cystography can then be requested, depending on the function test results. We believe that it is acceptable to request this initial radiological test only if both parameters, maximum osmolality and microalbumin, are abnormal. This initial recommendation may be reversed if the pyelic diameter gradually increases, or if children have acute pyelonephritis or if subsequent renal function tests are abnormal, and they would be re-assessed for new morphological studies (cystography and/or furosemide renogram). In short, we believe that the most important issue is to adequately monitor these infants so that no potentially serious clinical condition goes unnoticed, while ensuring a medical approach leading to less discomfort and lower side effects at all times.
REFERENCES
1. Gunn TR, Mora JD, Pease P. Antenatal diagnosis of urinary tract abnormalities by ultrasonography after 28 weeks gestation: incidence and outcome. Am J Obstet Gynecol 1995;172:479-86. 2. Livera LN, Brookfield DS, Egginton JA, Hawnaur JM. Antenatal ultrasonography to detect fetal renal abnormalities: a prospective screening programme. BMJ 1989;298:1421-3. 3. Marra G, Barbieri G, Moioli C, Assael BM, Grumieri G, Caccamo ML. Mild fetal hydronephrosis indicating vesicoureteric reflux. Arch Dis Child Fetal Neonatal Ed 1994;70:F147-9. 4. Kapadia H, Lidefelt KJ, Erasmie U, Pilo C. Antenatal renal pelvis dilatation emphasizing vesicoureteric reflux: two-year follow-up of minor postnatal dilatation. Acta Paediatr 2004;93:336-9. 5. Dremsek PA, Gindl K, Voitl P, Strobl R, Hafner E, Geissler W, Hruby W, Sacher M. Renal pyelectasis in fetuses and neonates: diagnostic value of renal pelvis diameter in pre- and postnatal sonographic screening. AJR Am J Roentgenol 1997;168:1017-9. 6. May Llanas ME, Moreira Echeverra A, Garca Boente CV, Comesas Gonzlez MJ, Filloy Lava AC, Hernndez JL. Ectasia pilica de diagnstico prenatal. Incidencia, protocolo de estudio y diagnsticos finales durante el ao 2003. An Pediatr (Barc) 2004;61:499-501. 7. Fernbach SK, Maizels M, Conway JJ. Ultrasound grading of hydronephrosis: introduction to the system used by the Society for Fetal Urology. Pediatr Radiol 1993;23:478-80. Nefrologia 2011;31(2):192-8
originals
natal Nephrology Study Group. Long-term clinical outcome of infants with mild and moderate fetal pyelectasis: validation of neonatal ultrasound as a screening tool to detect significant nephrouropathies. J Pediatr 2004;144:759-65. Garca Chapull A, Matesanz Prez JL, Lpez Secadas A, Meana Moris AR, Daz Daz E, Sols Snchez G. Evolucin postnatal de las ectasias plvicas renales no obstructivas detectadas por ecografa intrauterina. Rev Esp Pediatr 1995;51:545-8. Garca-Nieto V, Luis-Yanes MI, Hernndez-Gonzlez MJ, Marrero Prez CL, Montesdeoca Melin A. Sensitivity and specificity of four procedures for estimating the renal function to detect morphological anomalies in paediatric patients. Pediatr Nephrol 2005;20:C104. Dahlquist G, Stattin EL, Rudberg S. Urinary albumina excretion rate and glomerular filtration rate in the prediction of diabetic nephropathy; a long term follow-up study of childhood onset type-1 diabetic patients. Nephrol Dial Transplant 2001;16:1382-6. Rademacher ER, Sinaiko AR. Albuminuria in children. Curr Opin Nephrol Hypertens 2009;18:246-51. Vergouwe Y, Soedamah-Muthu SS, Zgibor J, Chaturvedi N, Forsblom C, Snell-Bergeon JK, et al. Progression to microalbuminuria in type 1 diabetes: development and validation of a prediction rule. Diabetologia 2010;53:254-62. Tomlinson PA, Smellie JM, Prescod N, Dalton RN, Chantler C. Differential excretion of urinary proteins in children with vesicoureteric reflux and reflux nephropathy. Pediatr Nephrol 1994;8:21-5. Konda R, Kakizaki H, Nakai H, Hayashi Y, Hosokawa S, Kawaguchi S, et al, Reflux Nephrology Forum, Japanese Prospective Study Group. Urinary concentrations of alpha-1-microglobulin and albumin in patients with reflux nephropathy before and after puberty. Nephron 2002;92:812-6. Ibez Alonso A, Luis Yanes MI, Carmona Cedrs N, Antn Hernndez L, Garca Nieto V. Determinacin de la funcin renal al final del periodo de seguimiento en nios diagnosticados de reflujo vesicoureteral. Arch Esp Urol 2008;61:167-72. Sherman RL, Drayer DE, Leyland-Jones BR, Reidenberg MM. Nacetyl-beta-glucosaminidase and beta 2-microglobulin. Their urinary
27.
28.
29.
30. 31.
32.
33.
34.
35.
excretion in patients with renal parenchymal disease. Arch Intern Med 1983;143:1183-5. 36. Eknoyan G, Suki WN, Martnez-Maldonado M, Anhalt MA. Chronic hydronephrosis: observations on the mechanism of the defect in urine concentration. Proc Soc Exp Biol Med 1970;134:634-9. 37. Kekomaki M, Reunanen M, Vilkki P. Desaminocysteine-D-arginine vasopressin test in the evaluation and postoperative followup of obstructed kidneys in infancy and childhood. J Urol 1982;128:981-3. 38. Chandar J, Abitbol C, Zilleruelo G, Gosalbez R, Montane B, Strauss J. Renal tubular abnormalities in infants with hydronephrosis. J Urol 1996;155:660-3. 39. Walker RD 3rd, Richard GA, Fennell RS, Iravani A, Garin E. Renal growth and scarring in kidneys with reflux and a concentrating defect. J Urol 1983;129:784-6. 40. Kekomaki M, Walker RD. Fractional excretion of magnesium and renal concentrating capacity in refluxing renal units. J Urol 1988;140:1095-6. 41. Gobet R, Cisek LJ, Chang B, Barnewolt CE, Retik AB, Peters CA. Experimental fetal vesicoureteral reflux induces renal tubular and glomerular damage, and is associated with persistent bladder instability. J Urol 1999;162:1090-5. 42. Garin EH, Olavarra F, Garca Nieto V, Valenciano B, Campos A, Young L. Clinical significance of primary vesicoureteral reflux and urinary antibiotic prophylaxis after acute pyelonephritis: A multicenter, randomized, controlled study. Pediatrics 2006;117:626-32. 43. Pennesi M, Travan L, Peratoner L, Bordugo A, Cattaneo A, Ronfani L, et al, North East Italy Prophylaxis in VUR study group. Is antibiotic prophylaxis in children with vesicoureteral reflux effective in preventing pyelonephritis and renal scars? A randomized, controlled trial. Pediatrics 2008;121:e1489-94. 44. Gonzlez-Hernndez MJ, Luis-Yanes MI, Monge M, Gonzlez-Cerrato S, Claverie-Martn FM, Garca-Nieto VM. Longitudinal study of renal function in children diagnosed with simple renal pyelectasis. Pediatr Nephrol 2010;25:1966.
Sent for review: 7 Dec. 2010 | Accepted: 1 Feb. 2011 198 Nefrologia 2011;31(2):192-8
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Dispositional optimism in patients on chronic haemodialysis and its possible influence on their clinical course
A.I. Morales Garca1, M.D. Arenas Jimnez2, A. Reig-Ferrer3, F. lvarez-Ude4, T. Malek2, A. Moledous2, M.T. Gil2, E.M. Cotilla2
Nephrology Department. Nevada Haemodialysis Centre. Granada, Spain Nephrology Department. Perpetuo Socorro Hospital. Alicante, Spain 3 Department of Health Psychology. University of Alicante, Spain 4 Nephrology Department. General Hospital of Segovia, Spain
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ABSTRACT Introduction: Dispositional optimism is a personality trait significantly associated with the use of positive adaptive coping strategies as well as with perceived psychological and physical well-being, and it appears to be an important predictor of illness. Objectives: To analyse if dispositional optimism is significantly associated with the number of hospital admissions of our chronic haemodialysis patients, as well as its relationship with perceived state of health. Methods: We studied 239 patients on chronic haemodialysis. Patients were categorised into two groups according to the variables: hospital admissions/no. of admissions in the last year and dispositional optimism (DO). We used the following variables and questionnaires: 1) Dispositional O/P using the Spanish-validated cross-cultural adaptation of the revised version of the Life Orientation Test (LOT-R) (Scheier, 1994): higher scores mean a higher degree of dispositional optimism. 2) Health-related quality of life (HRQoL) using the different aspects of the COOP/WONCA (CW) charts and its total score. In this case higher scores mean lower HRQoL. 3) Modified Charlson Comorbidity Index (mCCI). 4) Age, gender, and time on dialysis. Results: Mean age was 64.814.3 years; median time on dialysis 2.9 years (range: 0-32); and median LOT-R 21 (range 6-30). Patients considered DO had a lower risk of hospital admissions than pessimists (DP) (OR: 0.55; IC 95%: 0.320.94; P<.05). PD Patients that were admitted in the last year showed a significantly lower score on LOT-R (they were more pessimistic) than those that had no hospital admissions (19.45.7 vs 22.34.6; P=.001). We found no significant differences between admitted and not admitted patients in age, gender, time on haemodialysis and comorbidity. Admitted patients showed worse HRQoL (higher scores in total CW) than those that were not (Total CW: 22.37 vs 19.42; P<.001). PD patients had significantly higher scores than OD patients in all COOPWONCA aspects except in aspect 1 (physical fitness) and 5 (change in health). Conclusions: Pessimistic personality trait is significantly associated with hospital admissions in chronic haemodialysis patients, regardless of age, gender and comorbidity. Optimistic patients perceived a better state of health. Keywords: Dispositional optimism. Haemodialysis. Hospital admissions. Prognostic mediator.
Optimismo disposicional en pacientes en hemodilisis y su influencia en el curso de la enfermedad RESUMEN Introduccin: El optimismo disposicional es un rasgo de personalidad que se relaciona significativamente con el empleo de estrategias positivas de afrontamiento y con el grado de bienestar psicolgico y fsico percibidos por el paciente, y que parece ser, tambin, un importante predictor de enfermedad. Objetivo: Analizar si el optimismo disposicional guarda relacin con el nmero de ingresos hospitalarios que han presentado en el ltimo ao los enfermos renales crnicos estadio Vd en nuestros centros. Material y
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Correspondence: Ana Isabel Morales Garca Servicio de Nefrologa. Centro de Hemodilisis Nevada. Granada. Spain. amoralesg@senefro.org agarmo123@yahoo.es
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mtodos: Se estudiaron 239 pacientes en hemodilisis que fueron categorizados en dos grupos respecto a las variables ingresos /no ingresos hospitalarios en el ltimo ao y optimismo/pesimismo disposicional. Se utilizaron los siguientes cuestionarios y variables: 1) O/P disposicional mediante el LOT-R de Scheier (1994) en su versin espaola: a mayor puntuacin, mayor grado de optimismo disposicional. 2) Calidad de vida relacionada con la salud (CVRS) mediante las lminas COOP/WONCA: a mayor puntuacin peor calidad de vida referida. 3) ndice de comorbilidad de Charlson (ICM). 4) Edad, tiempo en HD y sexo. Resultados: La edad media fue de 64,8 14,3 aos; la mediana de tiempo en hemodilisis de 2,9 aos (rango: 0-32), y la mediana en el LOT-R 21 (rango: 6-30). Los pacientes optimistas (OD) presentaban un menor riesgo de ser ingresados que los pesimistas (PD) (OR: 0,55; IC 95%: 0,32-0,94; p <0,05) y los pacientes con ingresos hospitalarios mostraron una puntuacin en el LOT-R significativamente menor que los que no ingresaron (19,4 5,7 frente a 22,3 4,6; p = 0,001). No se encontraron diferencias significativas en cuanto a edad, tiempo en hemodilisis, e ndice de comorbilidad de Charlson entre los pacientes que ingresaron y los que no ingresaron. Los pacientes que ingresaron mostraban peor calidad de vida relacionada con la salud que los pacientes que no ingresaron (CW total: 22,37 frente a 19,42; p <0,001). Los pacientes PD puntuaban significativamente ms alto que los pacientes OD en las lminas COOP/WONCA en todas las dimensiones exploradas, excepto en las dimensiones 1 (estado fsico) y 5 (cambios en el estado de salud). Conclusiones: El rasgo de personalidad pesimista se asocia con los ingresos hospitalarios independientemente de la edad, el tiempo en dilisis y el grado de comorbilidad del paciente. Por otra parte los pacientes con un rasgo de personalidad optimista tienen una mejor salud percibida. Palabras clave: Optimismo disposicional. Hemodilisis. Ingreso hospitalario. Mediador pronstico.
A.I. Morales Garca et al. Dispositional optimism
negative events to internal factors (it is my fault), stability factors (Im this way, it is how I am, and I cant change), and global factors. They are, therefore, more likely to see stress as a problem that can be changed, that is specific to that moment and that essentially comes from external sources that can be potentially modified or ignored. This personality trait has been identified in several studies as a good predictor of prognosis or recovery in cardiac3-5 and cancer6-8 patients. It appears to be related with the use of positive strategies for coping with stress, i.e., more adaptive coping strategies. Patients with this optimistic personality trait tackle stressful situations and adapt to disease and, as a result, consequent treatments better. Advanced kidney failure requiring kidney replacement therapy affects the patients physical and emotional health. Subjects have to make some important changes to their lifestyle when starting haemodialysis (HD) and this has an effect on their quality of life and probably on their later progress on dialysis. The ability of the subject to control their own behaviour by using adaptive coping strategies is essential during the whole process of adapting to dialysis. This model of behavioural self-control assumes that when difficulties arise, positive expectations increase peoples efforts to be able to meet their objectives, while negative expectations reduce these efforts, sometimes to the point of completely giving up on the task. In this model, optimism and pessimism would be considered as general expectations (favourable or unfavourable, respectively) on events that happen to you during your life. Furthermore, these expectations are considered as stable dispositions (i.e. individual personality traits). That is why it is called dispositional optimism.9 Positive thinking or optimism seem to play an important role in the use of these adaptive coping strategies,10,11 as well as on psychological and physical well-being.12 They also seem to be significant predictors for psychological and physical diseases.13,14 The main aim of this study was to analyse the association between dispositional optimistic personality traits and the number of hospital admissions in one year in our HD population on kidney replacement therapy. The relationship between dispositional optimism and health-related quality of life (HRQoL) was also studied.
INTRODUCTION Several studies have highlighted that certain personality traits are related with the prognosis of a disease, and it seems that some of them might be predictors of illness.1 Dispositional optimism, one of the traits that is capturing the most interest, refers to general positive expectations. This trait was initially proposed and investigated by Scheier et al in their articles in 1986 and 1992. Dispositional optimism is one of the personal resources to protect well-being and is assessed using the Life Orientation Test (LOT-R).2 There is a Spanish-validated cross-cultural adaptation of this test available. This trait consists in having a general positive outlook and expecting positive results; in other words, the tendency to expect positive outcomes in the future. People with dispositional optimism are less likely to attribute
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MATERIAL AND METHOD Patients This was a cross-sectional, observational and retrospective study on 239 HD patients on kidney replacement therapy belonging to three hospitals.
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nephrologists from the units. The other variables were collected from patients medical history. These data were collected cross-sectionally over a period of one month. The number of hospital admissions was recorded for each patient during the following year.
Inclusion and exclusion criteria Of a total of 249 patients on HD in our units, 239 accepted to participate after being informed on the nature and objectives of the study and were included in the study. The exclusion criteria were: patients that had been previously diagnosed with a psychotic or neurological disorder or mental retardation; patients that could not answer the questionnaire due to difficulties with comprehension; and those whose state of health had deteriorated leading to hospital admission or had had a stressful event 30 days before the study (death of a family member/friend, personal illness, their own accident or of someone close to them, change in financial situation, change of job/house, divorce/separated, marriage, loss of job). Of the 10 patients excluded from the study, three were foreigners and did not speak Spanish; therefore, they were not able to answer the test properly. The other seven had been admitted to hospital recently.
Measuring instruments Dispositional optimism: life orientation test-revised The dispositional optimism variable was obtained using Scheiers revised version of the life orientation test (LOT-R)2 published in 1994 in the form of Otero-Lpezs Spanish version (1998).15 This questionnaire is made up of 10 items, 4 of which are filler questions (items 2, 5, 6, 8), i.e. they make the content of the test less obvious and they are not to be used in the analysis. The 6 remaining items measure the level of dispositional optimism: three are positively worded (optimistic direction) and three are negatively worded (pessimistic direction). The subjects are asked to state their level of agreement or disagreement with statements such as in uncertain times, I usually expect the best using a 5-point scale where 1 is disagree a lot and 5 agree a lot. Of the 6 content items, the negatively worded items are inverted and a total score focussed on optimism is obtained. The adaptation of the LOT-R used in this study is included in
Data collection procedure All the patients were informed on the nature and objectives of the study and signed an informed consent form. The Life Orientation Test-Revised (LOT-R) as well as the healthrelated quality of life charts (COOP-WONCA) were filled in during the HD sessions as the patient was in a stable clinical situation. Both tests were administered by trained
Table 1. LOT-Revised (cross-cultural adaptation)

Muy en desacuerdo 1. Cuando no se sabe qu va a suceder, normalmente espero lo mejor. 2. Me resulta fcil relajarme. 3. Cuando algo malo puede ocurrirme, termina sucedindome. 4. Siempre soy optimista sobre mi futuro. 5. Disfruto mucho con los amigos. 6. Para m es importante mantenerme ocupado/a. 7. Casi nunca espero que las cosas vayan a ir como yo deseo. 8. No me enfado demasiado fcilmente. Algo en desacuerdo Indiferente Algo de acuerdo Muy de acuerdo
1 1 1 1 1 1 1 1
2 2 2 2 2 2 2 2 2 2
3 3 3 3 3 3 3 3 3 3
4 4 4 4 4 4 4 4 4 4
5 5 5 5 5 5 5 5 5 5
9. Pocas veces cuento con que vayan a sucederme cosas buenas. 1 10. En general, espero que me ocurran ms cosas buenas que malas. 1
Translated and adapted into Spanish by Carmelo Vzquez and Motserrat Gimnez (School of Psychology, Complutense University of Madrid). Adapted into Spanish by Otero JM et al in 1998.
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Table 1. This test measures stable personality traits and the general predisposition of the individual towards positive or negative results for the future. The higher the score obtained in the LOT-R, the higher the level of dispositional optimism is and vice-versa. As there are no standard scores for the questionnaire, we decided to use the median as a cut-off point to differentiate between dispositional optimism and pessimism. The patients that had a score equal to or lower than the median of the distribution were classified as dispositional pessimists (DP) and those with a score above the median as dispositional optimists (DO).
The COOP-WONCA charts are short, easy to understand and have good criteria for measuring quality. When compared with the SF-36 (widely used in the dialysis population), they show a convergent validity of 0.57, a discriminant validity of 0.22 and Cronbachs alpha of 0.76.18 There are nine charts and each one explores an aspect of the patients quality of life completely. Each aspect has a title and answers the question relating to what has happened in the last two weeks: 1) Physical fitness, 2) Feelings. 3) Daily activities. 4) Social activities. 5) Change in health. 6) Overall health. 7) Pain. 8) Social support. 9) General quality of life. The patients have five possible answers that are accompanied by a drawing or a sign for each answer. The possible answers follow an ordinal scale from 1 to 5, and a higher score means a worse HRQoL. Although it has not been used much in the literature as it does not provide much information if individual scores for each chart are not shown in the results, the possibility of using an index has been accepted (overall COOP-WONCA). This is the total of all the charts, except for number 5 (Change in health), which is read in a different way due to the fact that it has a bipolar structure.
Health-related quality of life (HRQoL): COOP-WONCA (CW) charts The HRQoL was estimated using the Spanish version of the COOP-WONCA charts (CW)16,17(Figure 1). These charts were chosen instead of other questionnaires such as the NHP (Nottingham Health Profile), SIP (Sickness Impact Profile), Kidney Disease Quality of Life (KDQOLTM) or SF-36 based on the fact that they are all similarly valid,18 but these are easier to answer and have been used previously on dialysis patients.18-20
W1 FORMA FSICA Durante las 2 ltimas semanas Cul ha sido la mxima actividad que pudo realizar durante al menos 2 minutos?
W4 ACTIVIDADES SOCIALES Durante las 2 ltimas semanas Su salud fsica y estado emocional han limitado sus actividades sociales con la familia, amigos, vecinos o grupos?
Muy intensa (por ejemplo, correr deprisa)
No, nada en absoluto
Intensa (por ejemplo, correr con suavidad)
Ligeramente
Moderada (por ejemplo, caminar a paso rpido)
Moderadamente
Ligera (por ejemplo, caminar despacio)
Bastante
Muy ligera (por ejemplo, caminar lento o no poder caminar)
Muchsimo
Figure 1. COOP-WONCA charts for measuring quality of life

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RESULTS Mean age was 64.814.3 years and 62.5% of patients were men. The distribution of men and women was similar in both groups of patients (63% men and 37% women vs 60% men and 40% women; P=.45). The median time on HD was 2.9 years (range: 0-32), the mean score on the LOT-R was 21.15.3 and the median 21 (range: 6-30). Of a total of 239 HD patients studied, 65 had been admitted during the previous year. There were no significant differences between the patients considered DP (score equal to/lower than the median of the distribution) and DO (score higher than the median of the distribution) for age (64.116.1 compared to 61.117.0; P=.42), time on HD (15.332.1 compared to 15.530.3; P=.97) and comorbidity according to the CCI (6.762.4 compared to 7.332.88; P=.32). The patients considered DO had a lower risk of being admitted to hospital than pessimists (OR: 0.5; 95% CI, 0.3-0.9; P<.05). The patients admitted to hospital showed a significantly lower score on the LOT-R (pessimist) than those not admitted to hospital (19.45.7 compared to 22.34.6; P=.001). There were no significant differences with regard to age, time on haemodialysis and CCI between patients admitted and those not admitted to hospital (Table 2). Patients admitted to hospital had a worse HRQoL (higher scores in the total CW) than patients not admitted (total CW: 22.37 compared to 19.42; P<.001) (Table 2). Figure 2 shows how the patients considered DP, according to the LOT-R score, had a significantly higher score than DO patients on the COOP-WONCA charts in all the aspects studied, except for aspect 1 (physical fitness) and 5 (change in health). Therefore, pessimistic patients perceived their health state to be worse. There was a -0.47 correlation (P<.001) between the LOT-R scores and the HRQoL scores (overall COOP-WONCA).
Comorbidity: Charlsons comorbidity index Comorbidity was obtained using Charlsons original comorbidity index21 modified in accordance with the proposal of Beddhu et al.22 It included the patients age as another item, the score increasing by one point for every 10 years over the age of 40.
Variables analysed The results obtained in the LOT-R were analysed in accordance with the following variables: 1. Age 2. Sex 3. Average time on HD 4. Charlsons comorbidity index (CCI) 5. HRQoL according to the COOP-WONCA charts 6. Hospital admissions per patient in the last year
Statistical analysis The statistical analysis was carried out using SPSS 12.1 software. Students t-test was used to compare independent samples when the data followed a normal distribution and Wilcoxon test when the samples did not follow it. The chisquare test was used to compare qualitative variables and the strength of association was measured by calculating the odds ratio and the 95% confidence interval. The strength of association between the results obtained using the LOT-R and the HRQoL questionnaire (COOP-WONCA) was evaluated using Pearsons linear correlation coefficient. The results were taken to be statistically significant at P<.05.
Table 2. Relation of the different variables analysed with hospital admission
Admitted to hospital N=65 LOT-R Age (years) mCCI Charlson Time on HD (years) Overall CW 19.4 5.7 66.1 12.1 7.3 2.9 5.2 6.3 23.4 6.9 Not admitted to hospital N=75 22.3 4.6 63.4 16.3 7.40 2.6 5.8 7.1 19.36 5.0 P
DISCUSSION This study evaluated dispositional optimism (DO) in HD patients. This is a personality trait that is currently being studied extensively in other areas of medicine. However, its influence on patients with kidney diseases is still unknown. Our results highlight that HD patients with a pessimistic personality trait have a higher risk of being admitted to hospital than optimistic patients. Furthermore, these admissions do not depend on age, sex, time on HD, or associated pathology. Authors such as Hudetz,23 King and Karensen, among others, have identified DO as a good predictor of prognosis and recovery in patients undergoing cardiovascular surgery as well as cardiac and cancer patients. It has been suggested that this relationship between DO and a more favourable course of the disease lies in the patients
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0.001 0.27 0.90 0.59 <0.001
Total CW: total score in the COOP-WONCA charts. CCI: Comorbidity Index. The higher the score obtained in the LOT-R, the higher the dispositional optimism is and vice-versa. The higher the score in the CW charts, the worse the perceived health-related quality of life is. Nefrologia 2011;31(2):199-205
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p =.32 p <.001 p <.001

Dispositional pessimism (no.=142) Dispositional optimism (no.=97)
p <.001 p <.001
p=.45
p <.001 p=.03
p <.001
CW1 Physical fitness
CW2 Feelings
CW3 Daily activities
CW4 Social activities
CW5 Change CW6 Overall in health health
CW7 Pain
CW8 Social CW9 General support quality of life
Figure 2. Health and optimism-related quality of life
better ability to cope with the problems. Optimism is strongly linked to self-efficacy (the belief that one is capable of doing what is required in a given situation). There are several studies that associate certain personality traits with different coping strategies for stressful situations. According to the data published by Carver24 in 2001, people with an optimistic personality trait have an active or more adaptive style for coping with stress (planning, positive reinterpretation, personal growth and problem solving) compared with pessimists, who have a passive style (refusal, focus on emotions and behavioural distancing). The fact that DPs have this type of coping strategy means that they avoid solving problems and the problems continue. The studies carried out by Chico in 20029 and Roy in 201025 follow this line of thought as they state that, as well as the ability to cope with stress, another mechanism linking dispositional pessimism with physical symptoms may be that these patients persist with harmful habits to their health. All dimensions of a patient life change significantly during kidney replacement therapy and it is essential that patients prepare themselves correctly to achieve a good response to therapy. We see everyday how patients that adapt better to the treatment are able to follow strict diets low in potassium and phosphates; maintain a perfect weight between dialysis; comply better with drug treatments; come to recommended check-ups, etc. In summary, their behaviour seems to yield better results. One of the limitations of our study was that it was a short, cross204
sectional study and it is not possible to assess the relation between DO/DP and morbidity/mortality in the long term. This item could be the objective of another study. In this study we have observed how patients with an optimistic personality trait had a better HRQoL. This result was global (total CW) and for every aspect of the COOPWONCA charts (feelings, daily activities, social activities, health, pain, social support and quality of life) except in two: physical fitness and change in health. This finding seems to indicate that the level of DO is related to a greater extent with the more psychological and social dimensions of perceived health and not so much with the physical aspect (physical fitness) and with the observation of changes in health. The studies by Chang26 and Martnez-Correa1 show an association between DO/DP and state of physical health. Optimistic subjects had a lower number of immunological, gastrointestinal, cardiovascular, neurosensory, genitourinary and dermatological symptoms compared with pessimists during the last year assessed. No differences were found in respiratory and musculo-skeletal symptoms. To conclude, DO is another factor to be taken into account in the evolution of dialysis patients. In fact, pessimism seems to be associated with a higher number of hospital admissions, regardless of age, time on dialysis and comorbidity of the patient. Furthermore, patients with an optimistic personality trait perceive that they have a better HRQoL.
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study. Journal of Personality and Social Psychology 1988;55:23-7. 15. Otero JM, Luengo A, Romero E, Gmez JA, Castro C. Psicologa de personalidad. Manual de prcticas. Barcelona: Ariel Practicum, 1998. 16. Ferrando PJ, Chico E, Tous JM. Propiedades psicomtricas del test de optimismo Life Orientation Test. Psicothema 2002;14(3):673-80. 17. Lizan L, Reig A, Bartolom B, Moro JJ, Sancho A. The Spanish version of the COOP/WONCA charts: self-assessed quality of life in different populations. Quality of Life Research 1999;8:637. 18. Lizn Tudela L, Reig Ferrer A. Adaptacin transcultural de una medida de calidad de vida relacionada con la salud : la versin espaola de las vietas COOP-WONCA. Aten Primaria 1999;24:75-82. 19. Martn F, Reig Ferrer A, Ferrer Cascales R, Sarr F. Lminas COOP/WONCA: Un instrumento vlido para determinar la CVRS en el paciente en dilisis? Nefrologia 2004;24(2):192-3. 20. Arenas MD, Moreno E, Reig A, Milln I, Egea JJ, Amoedo ML, et al. Evaluacin de la calidad de vida relacionada con la salud mediante las lminas COOP-WONCA en una poblacin de hemodilisis. Nefrologia 2004;24(5):470-9. 21. Arenas MD, lvarez-Ude F, Reig-Ferrer A, Zito JP, Gil MT, Carretn MA, et al. Emotional distress and health-related quality of life in patients on hemodialysis: the clinical value of COOP-WONCA charts. J Nephrol 2007;20(3):304-10. 22. Charlson ME, Pompei P, Ales KL, MacKenzie CR. A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. J Chronic Dis 1987;40:373-83. 23. Beddhu S, Bruns FJ, Saul M, Seddon P, Zeidel ML. A simple comorbidity scale predicts clinical outcomes and costs in dialysis patients. Am J Med 2000;108:609-13. 24. Hudetz JA, Raymond G, Kathleen M, et al. Preoperative dispositional optimism correlates with a reduced incidence of postoperative delirium and recovery of postoperative cognitive function in cardiac surgical patients. Journal of Cardiothoracic and Vascular Anesthesia. Article in press 2010. 25. Carver CS, Pozo C, Harris SD et al. How coping mediates the effects of optimism on distress: a study of women with early stage breast cancer. Journal of Personality and Social Psychology 1993;65:375-90. 26. Roy B, Diez-Roux AV, Seeman T. Association of optimism and pessimism with inflammation and hemostasis in the multi-ethnic study of atherosclerosis (MESA). Psychosom Med 2010;72(2):134-40. 27. Chang EC, Maydeu-Olivares, DZurrilla TJ. Optimism and pessimism as partially independent constructs: relations to positive and negative affectivity and psychological well-being. Personality and Individual Differences 1997;23:433-40.
REFERENCES
1. Martnez-Correa A, Reyes GA, Garca-Len A, Gonzlez-Jareo MI. Optimismo/Pesimismo disposicional y estrategias de afrontamiento del estrs. Psicothema 2006;18:66-72. 2. Scheier MF, Carver CS, Bridges MW. Distinguishing optimism from neuroticism (and trait anxiety, self-mastery, and self-esteem): A reevaluation of the Life Orientation Test. Journal of Personality and Social Psychology 1994;67:1063-78. 3. Shepperd JA, Maroto JJ, Pbert LA. Dispositional optimism as a predictor of health changes among cardiac patients. Journal of Research in Personality 1996;30:517-34. 4. Davidson K, Prkachin D. Optimism and unrealistic optimism have an interacting impact of health-promoting behaviour and knowledge changes. Personality and Social Psychology Bulletin 1997;23:61725. 5. King KB, Owe MA, Kimble LP, Zerwic JJ. Optimism coping and longterm recovery from coronary artery bypass in women. Research in Nursing and Health 1998;21:15-26. 6. Friedman LC, Weinberg AD, Webb JA, et al. Skin cancer prevention and early detection intentions and behavior. American Journal of Preventive Medicine 1995;11:59-65. 7. Johnson JE. Coping with radiation therapy: optimism and the effect of preparatory interventions. Research in Nursing and Health 1996;19:3-12. 8. Schou MF, Ekeberg O, Ruland CM, et al. Pessimism as a predictor of emotional morbidity one year following breast cancer surgery. Psycho-oncology 2004;13:309-20. 9. Chico E. Optimismo disposicional como predictor de estrategias de afrontamiento. Psicothema 2002;14:544-50. 10. Scheier M, Carver CS. Optimism, Coping, and Health: Assessment and Implication of Generalized Outcome Expectancies. Health Psychology 1985;4:219-47. 11. Scheier M, Weintraub J, Carver CS. Coping with stress: Divergent strategies of optimists and pessimists. Journal of Personality and Social Psychology 1986;51:1257-64. 12. Chang EC, DZurilla TJ, Maydeu-Olivares A. Assessing the dimensionality of optimism and pessimism using a multimeasure approach. Cognitive Therapy and Research 1994;18:143-60. 13. Mroczek DK, Spiro III A, Aldwin CM., Ozer DJ, Bosse R. Construct validation of optimism and pessimism in older men: Findings from the normative aging study. Health Psychology 1993;12:406-9. 14. Peterson C, Seligman MEP, Vaillant GE. Pessimistic explanatory style is a risk factor for physical illness: A thirth-five year longitudinal
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Relationship between leptin and all-cause and cardiovascular mortality in chronic hemodialysis patients
J.J. Dez1, M. Bossola2, M.J. Fernndez-Reyes3, E. di Stasio2, L. Tazza2, G. Luciani2, R. Codoceo4, P. Iglesias1, A. Rodrguez3, E. Gonzlez5, R. Selgas5
Endocrinologa. Hospital Ramn y Cajal. Madrid, Spain Servizio Emodialisi. Universit Cattolica del Sacro Cuore. Roma (Italia) 3 Nefrologa. Hospital General de Segovia, Spain 4 Bioqumica. Hospital La Paz. Madrid, Spain 5 Nefrologa. Hospital La Paz. Madrid, Spain
1 2
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ABSTRACT Background: We aimed to evaluate the relationship between serum leptin and the leptin/body mass index (BMI) ratio with prevalent cardiovascular disease (CVD), and their influence on all-cause and CVD-related mortality in patients on hemodialysis (HD). Methods: 118 stable HD patients (50 women, median [interquartile range] age, 65.1 [54.7-72.2] years) were studied. All patients had baseline measurement of serum leptin concentrations. Relationships between leptin and all-cause and CVD mortality were studied by means of survival analysis and Cox regression analysis. Results: The leptin/BMI ratio was similar in patients with and without CVD at baseline (0.65 [0.29-2.23] vs. 0.68 [0.29-1.49] ngm2/mlkg, respectively, NS). Multiple logistic regression analysis showed that there was not an independent association between leptin/BMI ratio and prevalent CVD. During the follow-up time, 52 (44.1%) patients died. CVD was the cause of death in 27 out of 52 (51.9%) deceased patients. Survival analysis and Cox proportional multivariate regression analysis showed that there were no significant relationships between leptin levels or the leptin/BMI ratio and all-cause and CVD-related mortality. Conclusion: These results do not support that, in stable HD patients, serum leptin concentrations and the leptin/BMI ratio are related with prevalent CVD. Leptin/BMI ratio seems not to be a risk factor for mortality in these patients. Keywords: Leptin. End-stage renal disease. Hemodialysis. Mortality. Cardiovascular disease
Relacin entre leptina y mortalidad global y cardiovascular en pacientes en hemodilisis RESUMEN Introduccin: El objetivo del presente estudio ha sido evaluar la relacin entre la leptina srica y el cociente leptina/ndice de masa corporal (IMC) con la enfermedad cardiovascular (ECV) prevalente y su influencia en la mortalidad global y en la mortalidad por ECV en pacientes en hemodilisis (HD). Mtodos: Se estudiaron 118 pacientes estables en HD (50 mujeres, edad mediana [recorrido intercuartlico], 65,1 [54,772,2] aos). En todos los pacientes se cuantific la concentracin basal de leptina. La relacin entre leptina y la mortalidad se evalu mediante anlisis de supervivencia y anlisis de regresin de Cox. Resultados: El cociente leptina/IMC fue similar en pacientes con y sin ECV prevalente (0,65 [0,29-2,23] frente a 0,68 [0,29-1,49] ngm2/mlkg, respectivamente, NS). El anlisis de regresin logstica mostr que no exista una asociacin independiente entre el cociente leptina/IMC y la enfermedad cardiovascular prevalente. Durante el seguimiento 52 pacientes fallecieron (44,1%). La ECV fue causa de muerte en 27 de 52 pacientes fallecidos (51,9%). El anlisis de supervivencia y el anlisis multivariante de Cox mostraron que no hubo relacin significativa entre los niveles de leptina o el cociente leptina/IMC y la mortalidad global o por causa de ECV. Conclusin: Estos resultados no apoyan la hiptesis de que, en pacientes estables en HD, las concentraciones de leptina y el cociente leptina/IMC estn relacionados con la ECV prevalente. Ms an, el cociente leptina/IMC no parece ser un factor de riesgo de mortalidad en estos pacientes. Palabras clave: Leptina. Enfermedad renal terminal. Hemodilisis. Mortalidad. Enfermedad cardiovascular.
Correspondence: Juan Jos Dez Gmez Servicio de Endocrinologa. Hospital Ramn y Cajal. Madrid. Spain. jdiez.hrc@salud.madrid.org 206
INTRODUCTION Cardiovascular disease (CVD) is the major cause of death in chronic hemodialysis (HD) patients1. According to two of the
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Hemodialysis All patients were receiving conventional 4-hour hemodialysis, three times a week. The blood flow ranged from 250 to 400 ml/min with a dialysis rate flow of 500 ml/min. All patients were treated with high-permeability membranes. Most patients were taking recombinant human erythropoietin and antihypertensive medications.
largest end-stage renal disease (ESRD) registries, the US Renal Data System (USRDS) and the European Registry of patients on renal replacement therapy (ERAEDTA), the estimated risk for cardiac events such as myocardial infarction is 3.5-50 times higher among HD patients than in the general population. 2,3 In the last two decades, it has become evident that the increased frequency of CVD observed in HD patients is secondary to the combination of many traditional and novel and uremia-related risk factors. 4 Leptin promotes atherosclerosis, thrombosis, and vascular smooth muscle cell proliferation and migration. 5 In addition, clinical studies have demonstrated a significant correlation between leptin levels and hypertension, hyperlipidemia, perturbed fibrinolysis and chronic inflammation. 6,7 Leptin levels are significantly higher in HD patients than in healthy subjects. 8,9 Thus, it has been suggested that such high leptin levels may contribute to the increased cardiovascular risk of HD patients. The present study aimed at evaluating the relationship between serum leptin concentrations and the leptin/body mass index (BMI) ratio with prevalent CVD and their influence on all-cause and CVD-related mortality in ESRD patients undergoing maintenance HD.
Cardiovascular disease definition Patients were stratified according to the presence of cardiovascular diseases. Patients defined as having prevalent CVD included those with a documented history of angina pectoris, myocardial infarction, stroke, coronary revascularization procedures, transient cerebral ischemia, peripheral artery surgery, and peripheral vascular disease.
Laboratory analyses Serum leptin concentrations were measured by using a polyclonal antibody RIA raised in rabbits against highly purified recombinant human leptin (Linco Research, St Louis, MO, USA). The sensitivity for this leptin assay was 0.5 ng/ml, and the coefficients of variation intra- and interassay were 4.8% and 3.5%, respectively. The normal values of serum leptin concentrations in a group of healthy subjects, aged 28-70 years, was 10.0 (5.6-27.8) ng/ml. Other laboratory measurements were performed through certified methods in the Departments of Clinical Chemistry of the Universit Cattolica del Sacro Cuore of Rome (Italy) and the Hospital General of Segovia (Spain).
METHODS Patients and design This is a prospective observational study in which we measured leptin levels and the leptin/BMI ratio and correlated with prevalent CVD and all-cause and CVDrelated mortality. The study was performed in the Hemodialysis Units from the Universit Cattolica del Sacro Cuore of Rome (Italy) and from the Hospital General of Segovia (Spain). Italian patients (n=53) were recruited in March 2004 (cohort 1). Spanish patients were recruited in two phases. A group of 38 patients were studied between 1998 and 2002 (cohort 2), and a second group of 27 patients were evaluated in April 2008 (cohort 3). Incident patients considered eligible and included in the study were evaluated after at least 6 months of hemodialytic treatment. Patients were followed until census date (December 31 st, 2009), renal transplantation or death. Median time of follow-up was 24.7 (interquartile range 15.7-68.0) months. As expected, time of follow-up in cohort 3 (20.1 [20.1-20.4] months) was significantly (P=0.002) lower than those found in cohorts 1 (46.5 [15.0-76.3] months) and 2 (40.2 [12.3-73.7] months). The study was approved by the local ethics committees and written informed consent was obtained from all patients before enrollment in the study.
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Statistical analysis For mean comparisons the Kruskal-Wallis non parametric test was used for non-normally distributed continuous variables and analysis of variance was used for normally distributed variables. Correlations were calculated with the Spearman correlation coefficient. Survival time was estimated by the Kaplan-Meier method, with the log-rank test used to compare arms. Multivariate Cox regression models were used to assess the independent effects of several quantitative and qualitative variables on the risk of death. Statistical significance was set at the level of P<0.05.
RESULTS A total of 118 patients (50 women) were included in this study (table 1). Italian patients showed higher levels of leptin/BMI in comparison with Spanish patients.
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Leptin and leptin/BMI ratio The demographic, clinical and laboratory characteristics of patients stratified according to the leptin/BMI ratio are reported in table 2. In univariate analysis, the leptin/BMI ratio was positively correlated to total cholesterol (rho = 0.298, P=.001) and creatinine (rho = .183, P=.047). The multiple regression analysis confirmed that creatinine and total cholesterol were independent factors associated with the leptin/BMI ratio (R2=.146, P=.015).
Leptin/BMI and prevalent cardiovascular disease Forty seven (39.8%) and 33 (27.9%) patients had prevalent CVD and coronary disease, respectively, at baseline. The prevalence of CVD and of ischemic heart disease at baseline was similar between patients with leptin/BMI under the median value and above the median value. The results of the multivariate logistic regression analysis showed that there was not an independent association between leptin/BMI ratio and CVD (table 3). Moreover, this multivariate analysis did not show a significant association between cohort and prevalent CVD.
patients. The median serum leptin concentrations and the median leptin/BMI ratio was similar in patients who survived (18.0; 7.0-39.1 ng/ml, and 0.73; 0.29-1.50 ngm2/mlkg, respectively) and in those who died (12.0; 4.944.8 ng/ml, P=.524, and .49; .26-1.94 ngm2/mlkg; P = .529, respectively). No differences were found in serum leptin concentrations and leptin/BMI ratio between patients who died by CVD (9.6; 4.8-57.9 ng/ml, and .42; .25-1.99 ngm2/mlkg, respectively) and those who did not (16.1; 6.139.0 ng/ml, P=.863, and 0.68; 0.28-1.49 ngm2/mlkg, P=.985, respectively). We repeated this analysis in the three cohorts of studied patients and found that there were no significant relationships between leptin or leptin/BMI and mortality (data not shown). Kaplan-Meier analysis (figure 1) showed that patients with leptin levels above the median values showed mean survival times for all-cause mortality and for CVD-related mortality which did not significantly differ from those found in patients with leptin concentrations under the median value. In a similar way, patients with leptin/BMI above the median values showed mean survival for all-cause mortality times and for CVD-related mortality similar to those found in patients with leptin/BMI under the median value. We performed a Cox proportional hazards regression multivariate analysis including the covariate cohort because of the significant differences found among cohorts in leptin/BMI levels and mortality rates (table 1). This analysis
Leptin/BMI and survival During the follow-up period, 52 (44.1%) patients died. CVD was the cause of death in 27 out of 52 (51.9%) deceased
Table 1. Demographic, clinical and laboratory characteristic of the three cohorts of studied patients
Variable
Cohort 1 Italy 2004 (n = 53)
Cohort 2 Spain 1998 (n = 38) 64 (55-68) 16 (42.1) 31 (14-62) 10 (26.39) 16 (42.1) 11 (28.9) 29 (76.3) 25.23.9 9.2 2.2 7.3 (2.7-18.3) 3.9 0.4 178 (137-199) 9.7 (4.7-31.9) 0.39 (0.22-1.17) 24 (63.2) 11 (28.9)
Cohort 3 Spain 2008 (n = 27) 73 (68-78) 13 (48.1) 35 (17-60) 10 (37.0) 13 (48.1) 7 (25.9) 22 (81.5) 24.44.3 7.11.5 0.9 (0.3-1.7) 3.70.3 142 (128-179) 12.3 (5.8-31.1) 0.51 (0.25-1.17) 5 (18.5) 1 (3.7)
Age (yr) Female sex Duration of dialysis (mo) Diabetes mellitus Cardiovascular disease Coronary artery disease Hypertension Body mass index (kg/m2) Creatinine (mg/dl) C-reactive protein (mg/l) Albumin (g/dl) Total cholesterol (mg/dl) Leptin (ng/ml) Leptin/BMI (ngm /mlkg)
2
62 (51-72) 21 (39.6) 36 (12-90) 7 (13.2) 18 (34.0) 15 (28.3) 37 (69.8) 23.73.8 10.7 2.6 3.7 (2.2-8.4) 3.8 0.3 154 (130-185) 23.4 (7.0-64.2) 1.02 (0.34-2.55) 23 (43.4) 15 (28.3)
0.001 0.766 0.995 0.033 0.444 0.962 0.504 0.197 <0.001 <0.001 0.060 0.023 0.113 0.044 0.002 0.016
All-cause deaths CVD deaths
Data are presented as number of patients (percentage), median (interquartile range) or mean SD.
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Table 2. Demographic, clinical and laboratory characteristic of the patients included in the study stratified according to the leptin/BMI ratio
Variable All patients (n = 118) Age (yr) Female sex Primary cause of ESRD: Hypertension Glomerulonephritis Diabetes Interstitial nephritis Polycystic renal disease Unknown Other etiologies Duration of dialysis (mo) Diabetes mellitus Cardiovascular disease Coronary artery disease Hypertension Body mass index (kg/m2) Creatinine (mg/dl) C-reactive protein (mg/l) Albumin (g/dl) Total cholesterol (mg/dl) 21 22 23 9 9 22 12 36.0 (12.9-61.5) 27 (22.8) 47 (39.8) 33 (27.9) 88 (74.6) 24.33.9 9.38 2.66 3.82 (1.2-8.3) 3.83 0.33 153 (134-188) 11 10 7 5 7 14 5 28.9 (12.0-71.4) 9 (15.3) 25 (42.4) 16 (27.1) 47 (79.7) 22.83.4 8.96 2.64 4.63 (1.26-10.79) 3.82 0.36 145 (128-179) 10 12 16 4 2 8 7 36.0 (15.0-60.8) 18 (30.5)a 22 (37.3) 17 (28.8) 41 (69.5) 25.84c 9.80 2.63 2.95 (0.96-7.52) 3.83 0.30 176 (141-192)b 65.1 (54.7-72.2) 50 (42.4) Leptin/BMI <median (n = 59) 64.2 (54.0-72.5) 15 (25.4) Leptin/BMI >median (n = 59) 66.0 (56.0-72.0) 35 (59.3)c
Data are presented as number of patients (percentage), median (interquartile range) or mean SD.
a
P <.05; b P <.001; c P <.001.
showed that leptin/BMI was not an independent risk factor for all-cause and CVD-related mortality (table 4).
DISCUSSION Our results show that there is no significant relationship between serum leptin or the leptin/BMI ratio and the presence of CVD or coronary artery disease at baseline. Moreover, our follow-up data also show a lack of relationship between serum leptin or the leptin/BMI ratio and all-cause and cardiovascular mortality. Our crosssectional data are in agreement with our previous study that showed that leptin/BMI was not related to prevalent CVD.10 On the contrary, our longitudinal study results clearly differ from those reported by Scholze et al.11 Discrepancies may be accounted for by differences in the genetic background of studied patients, confounding influences of covariates, and different laboratory procedures. Furthermore, we used leptin values corrected by BMI because leptin is a sensor of body fat mass and a correlation between leptin levels and BMI has been demonstrated both in healthy subjects12 and in uremic patients.10
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Leptin increases sympathetic activity,13 promotes vascular smooth muscle cells proliferation, increases oxidative stress and has prothrombotic activity.5 Furthermore, leptin has been related to coronary artery calcification in type 2 diabetic patients14 and with several CV risk factors and vascular dysfunction in humans.15 The WOSCOP study16 have reported an association between leptin and the risk of CVD. However, a recent meta-analysis showed only a moderate association between leptin levels and the risk of coronary heart disease, which is largely dependent of BMI.17 In agreement with this we could not demonstrate any significant association of leptin/BMI with CVD mortality. A possible explanation to the lack of relationship between leptin and mortality in HD patients might be found in the reverse epidemiology of the cardiovascular risk factors which is frequently observed in patients with ESRD.18 Numerous reports have suggested that an increase in BMI is correlated with an increased survival in HD patients.19,20 In fact, recent European guidelines consider that BMI under 23 kg/m2 is suggestive of malnutrition in HD patients.21 In this context, high leptin levels can be considered as a marker of overnutrition and, therefore, associated to a favourable
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Table 3. Multivariate logistic regression analysis showing the influence of several qualitative and quantitative variables on the presence of CVD at the time of inclusion in the study
Independent Variables Age (yr) Diabetes Hypertension Leptin/BMI (ngm2/mlkg) Cohort Spain 1998 Cohort Spain 2008
Odds ratio 1.08 6.41 3.45 1.04 1.15 0.58
95% CI 1.03-1.13 2.08-19.77 1.14-10.44 0.76-1.43 0.41-3.26 0.16-2.02
P value 0.001 0.001 0.028 0.802 0.789 0.390
Data are odds ratios and 95% confidence intervals.
prognosis. Another possible explanation is that the actions of leptin on the cardiovascular system are not always detrimental. For example, although elevated leptin levels have been associated with poor vascular compliance in adolescents15 and impaired coronary vasoreactivity in otherwise healthy young obese subjects,22 some evidences suggest that leptin may have both vasoconstrictor and vasodilator effects through endothelium-dependent
mechanisms.23 Lastly, it is also conceivable that the prognostic value of serum leptin is different in the general population than in dialysis patients, as it has been suggested for adiponectin.24 Our study has some strengths and limitations. First, this is the first multicenter study assessing leptin values in HD patients and is also the first study that analyzes corrected
Figure 1. Kaplan-Meier survival analysis for all-cause mortality (left panels) and CVD-related mortality (right panels) in 118 HD patients stratified according to the serum leptin concentrations (upper panels) and the leptin/BMI ratio (lower panels).
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Table 4. Multivariate Cox regression analysis for all-cause and cardiovascular disease-related mortality
Covariates All-cause Mortality Hazard ratio (95% C.I.) Sex Age (yr) Diabetes Hypertension Cardiovascular disease Leptin/BMI (ngm2/mlkg) Cohort Spain 1998 Cohort Spain 2008 1.66 (0.81-3.40) 1.03 (0.99-1.06) 3.11 (1.45-6.66) 0.33 (0.16-0.68) 3.36 (1.66-6.70) 0.90 (0.71-1.14) 1.24 (0.65-2.37) 0.48 (0.14-1.60) P value 0.170 0.108 0.004 0.003 0.001 0.392 0.510 0.231 CVD Mortality Hazard ratio (95% CI) 1.77 (0.61-5.17) 1.04 (0.99-1.10) 6.33 (2.09-19.20) 0.24 (0.08-0.72) 8.29 (2.63-26.15) 0.80 (0.54-1.17) 0.74 (0.27-1.98) 0.06 (0.01-0.66) P value 0.297 0.147 0.001 0.011 <0.001 0.239 0.545 0.022
For categorical variables, reference hazard ratio (HR = 1) for female sex, absence of diabetes, hypertension and cardiovascular disease, and cohort Italy 2004.
leptin values in relation to all-cause and CVD-related mortality in these patients. A limitation of our study comes from the fact that classification of cardiovascular disease was made on the basis of clinically manifest event, and therefore the true prevalence of atherosclerotic disease may be underestimated. We could not correct leptin concentrations by fat mass, although we did correct for BMI values. Another limitation is its low statistical power and the fact that we studied three cohorts of patients at three different baseline times and, therefore, with different times of followup and mortality rates, and also with differences in some clinical and biochemical characteristics. In fact, in comparison with cohorts 1 and 2, cohort 3 patients had older age, higher proportion of diabetes and lower levels of creatinine and cholesterol. All-cause and CVD mortality was lower in cohort 3, a fact in direct relationship with the lower follow-up period in this cohort. However, laboratory procedures for leptin measurement and clinical protocols for patients follow-up were the same. Furthermore, survival analysis performed in the three cohorts of patients separately did not show any significant relationship between leptin/BMI and all-cause or cardiovascular mortality. The clinical corollary of our study would be stopping the qualification of leptin as a cardiovascular risk factor in HD patients. In a similar way, leptin has been considered by some authors as a causal factor of cachexia in uremic patients. However, previous data from our group showed not only a correlation between leptin and BMI, but also a direct relationship between this hormone and albumin, transferrin and cholesterol.10,25,26 Besides, our patients with anorexia exhibited low, rather than high, serum leptin levels.26 In conclusion, in this population of stable HD patients, obtained results do not support the hypothesis that serum
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leptin and leptin/BMI ratio are related with prevalent CVD and are risk factors for all-cause and cardiovascular mortality.
CONFLICT OF INTEREST STATEMENTS R. Selgas has received a non-restricted grant by Baxter to support part of this investigation.
Acknowledgements
The authors are especially indebted to the nurses of our dialysis units for their collaboration. This study has been partially supported by grants by Baxter (Extramural Grant Program, 2008), ISCIII by support to RS (PS 09/00641) and Rio Hortega Grant (2009) for EG. Several authors are integrated in REDinREN (RETICS 06/0016 from ISCIII,) supported by FEDER European Funds.
REFERENCES
1. Rucker D, Tonelli M. Cardiovascular risk and management in chronic kidney disease. Nat Rev Nephrol 2009;5:287-96. 2. Brunner FP, Selwood NH on behalf of the EDTA Registry Committee. Profile of patients on RRT in Europe and death rates due to major causes of death groups. Kidney Int 1992;42:S4-15. 3. Locatelli F, Manzoni C, Del Vecchio L, Di Filippo S. Changes in United States Renal Data System, 2006. 4. Herzog CA. Sudden cardiac death and acute myocardial infarction in dialysis patients: perspectives of a cardiologist. Semin Nephrol 2005;25:363-6. 211
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5. Bodary PF, Gu S, Shen Y, Hasty AH, Buckler JM, Eitzman DT. Recombinant leptin promotes atherosclerosis and thrombosis in apolipoprotein E-deficient mice. Arterioscler Thromb Vasc Biol 2005;25:e119-22. 6. Nakamura Y, Ueshima H, Okuda N, Murakami Y, Miura K, Kita Y, et al. Relation of serum leptin to blood pressure of Japanese in Japan and Japanese-Americans in Hawaii. Hypertension 2009;54:1416-22. 7. Bullo M, Garca-Lorda P, Megias I, Salas-Salvad J. Systemic inflammation, adipose tissue, tumor necrosis factor and leptin expression. Obes Res 2003;11:525-31. 8. Heimbrger O, Lnnqvist F, Danielsson A, Nordenstrm J, Stenvinkel P. Serum immunoreactive leptin concentration and its relation to the body fat content in chronic renal failure. J Am Soc Nephrol 1997;8:1423-30. 9. Bossola M, Muscaritoli M, Valenza V, Panocchia N, Tazza L, Cascino A, et al. Anorexia and serum leptin levels in hemodialysis patients. Nephron Clin Pract 2004;97:c76-82. 10. Dez JJ, Iglesias P, Fernndez-Reyes MJ, Aguilera A, Bajo MA, lvarez-Fidalgo P, et al. Serum concentrations of leptin, adiponectin and resistin, and their relationship with cardiovascular disease in patients with end-stage renal disease. Clin Endocrinol 2005;62:242-9. 11. Scholze A, Rattensperger D, Zidek W, Tepel M. Low serum leptin predicts mortality in patients with chronic kidney disease stage 5. Obesity (Silver Spring) 2007;15:1617-22. 12. Considine RV, Sinha MK, Heiman ML, Kriauciunas A, Stephens TW, Nyce MR, et al. Serum immunoreactive-leptin concentrations in normal-weight and obese humans. N Engl J Med 1996;334:292-5. 13. Eikelis N, Lambert G, Wiesner G, Kaye D, Schlaich M, Morris M, et al. Extra-adipocyte leptin release in human obesity and its relation to sympathoadrenal function. Am J Physiol Endocrinol Metab 2004;286:E744-52. 14. Reilly MP, Iqbal N, Schutta M, Wolfe ML, Scally M, Localio AR, et al. Plasma leptin levels are associated with coronary atherosclerosis in type 2 diabetes. J Clin Endocrinol Metab 2004;89:3872-8. 15. Singhal A, Farooqi IS, Cole TJ, ORahilly S, Fewtrell M, Kattenhorn M, et al. Influence of leptin on arterial distensibility: a novel link between obesity and cardiovascular disease? Circulation 2002;106:1919-24.
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16. Wallace AM, McMahon AD, Packard CJ, Kelly A, Shepherd J, Gaw A, et al. Plasma leptin and the risk of cardiovascular disease in the west of Scotland coronary prevention study (WOSCOPS). Circulation 2001;104:3052-6. 17. Sattar N, Wannamethee G, Sarwar N, Chernova J, Lawlor DA, Kelly A, et al. Leptin and coronary heart disease. Prospective study and systematic review. J Am Coll Cardiol 2009;53:167-75. 18. Kalantar-Zadeh K, Block G, Humphreys MH, Kopple JD. Reverse epidemiology of cardiovascular risk factors in maintenance dialysis patients. Kidney Int 2003;63:793-808. 19. Abbott KC, Glanton CW, Trespalacios FC, Oliver DK, Ortiz MI, Agodoa LY, et al. Body mass index, dialysis modality, and survival: analysis of the United States Renal Data System Dialysis Morbidity and Mortality Wave II Study. Kidney Int 2004;65:597-605. 20. Liu Y, Coresh J, Eustace JA, Longenecker JC, Jaar B, Fink NE, et al. Association between cholesterol level and mortality in dialysis patients: role of inflammation and malnutrition. JAMA 2004;291:4519. 21. Fouque D, Vennegoor M, Ter Wee P, Wanner C, Basci A, Canaud B, et al. EBPG Guideline on nutrition. Nephrol Dial Transplant 2007;Suppl. 2:ii45-87. 22. Sundell J, Huupponen R, Raitakari OT, Nuutila P, Knuuti J. High serum leptin is associated with attenuated coronary vasoreactivity. Obes Res 2003;11: 776-82. 23. Vecchione S, Maffei A, Colella S, Aretini A, Poulet R, Frati G, et al. Leptin effect on endothelial nitric oxide is mediated through Aktendothelial nitric oxide synthase phosphorylation pathway. Diabetes 2002;51:168-73. 24. Dez JJ, Estrada, Bajo MA, Fernndez-Reyes MJ, Grande C, Del Peso G, et al. High stable serum adiponectin levels are associated with a better outcome in prevalent dialysis patients. Am J Nephrol 2009;30:244-52. 25. Iglesias P, Dez JJ, Fernndez-Reyes MJ, Bajo MA, Aguilera A, Mndez J, et al. Effects of short-term recombinant human growth hormone therapy on plasma leptin concentrations in dialysis patients. Nephrol Dial Transplant 2002;17:260-4. 26. Aquilera A, Bajo MA, Rebollo F, Dez JJ, Daz C, Paiva A, et al. Leptin as a marker of nutrition and cardiovascular risk in peritoneal dialysis patients. Adv Perit Dial 2002;18:212-7.
Sent for review: 5 Sep. 2010 | Accepted: 13 Dic. 2010 212 Nefrologia 2011;31(2):206-12
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Pleuroperitoneal communication in patients on peritoneal dialysis. One hospital's experience and a review of the literature
R. Daz Mancebo, G. del Peso Gilsanz, M. Rodrguez, B. Fernndez, M. Ossorio Gonzlez, M.A. Bajo Rubio, R. Selgas Gutirrez
Nephrology Department. La Paz University Hospital. Madrid, Spain
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ABSTRACT Peritoneal dialysis is a treatment alternative in patients with advanced chronic kidney disease. The infusion of liquid into the peritoneal cavity leads to an increase in intra-abdominal pressure, which can sometimes produce leaks to the chest, giving rise to pleuroperitoneal communication. This is not a common complication, but it brings about high drop-out rates among patients using the technique. Diagnosis is easy and must be suspected in patients with sudden dyspnoea with low ultrafiltration and pleural effusion in the chest x-ray. Peritoneal rest and a temporary transfer to haemodialysis, and pleurodesis can be effective treatment strategies. Keywords: Peritoneal dialysis. Pleuroperitonal communication. Secondary hydrothorax. Pleurodesis.
Comunicacin pleuro-peritoneal en pacientes en dilisis peritoneal. Experiencia en un centro y revisin de la literatura RESUMEN La dilisis peritoneal es una alternativa de tratamiento en los pacientes con enfermedad renal crnica avanzada. La infusin de lquido en la cavidad peritoneal conlleva un aumento de presin intraabdominal que, en algunas ocasiones, puede producir la fuga del mismo hacia el trax dando lugar a una comunicacin pleuro-peritoneal. Es una complicacin poco frecuente, pero supone una alta tasa de abandono de la tcnica. El diagnstico es sencillo y se debe sospechar ante la existencia de disnea sbita con baja ultrafiltracin y derrame pleural en la radiografa de trax. El descanso peritoneal, con transferencia temporal a hemodilisis, y la pleurodesis pueden ser estrategias eficaces para su tratamiento. Palabras clave: Dilisis peritoneal. Comunicacin
pleuro-peritoneal. Hidrotrax secundario. Pleurodesis.
INTRODUCTION Peritoneal dialysis (PD) is a replacement therapy option for patients with advanced chronic kidney disease. During this procedure there is an increase in intra-abdominal pressure1,2 due to the accumulation of dialysate in the peritoneal cavity. Among the complications secondary to this increase in pressure is the leakage of peritoneal fluid through the diaphragm to the thorax, known as pleuroperitoneal communication3 or secondary hydrothorax, described in 1967 by Edward and Unger.4 The mean incidence has been estimated at between 1.6% and 10%,5,6 although it may be
Correspondence: Raquel Daz Mancebo Servicio de Nefrologa. Hospital Universitario La Paz. Paseo de la Castellana 261. 28046 Madrid. Spain. rdiazm.hulp@salud.madrid.org
higher as hydrothorax involving small amounts of fluid are difficult to diagnose. Its aetiopathogenesis is not fully understood, but it has been related to congenital or acquired pleuroperitoneal defects7 and to lymphatic drainage disorders. The aim of this article is to analyse the incidence of this complication in our hospital setting and expound our experience in diagnosing and treating it.
CASE REPORTS We have reviewed the medical records of all the patients treated with PD in our unit between 1997 and 2010. During this time, 328 patients began this therapy in the La Paz
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University Hospital in Madrid. Six were diagnosed with pleuroperitoneal communication. Here, we present the cases in chronological order, from the first to be diagnosed to the most recent. Table 1 shows a summary of the cases including the method of diagnosis and the initial treatment.
R. Daz Mancebo et al. Pleuroperitoneal communication
Case 1 A 55 year old woman with chronic renal failure (CRF) secondary to reflux nephropathy who began renal replacement therapy with automated PD (APD) in 1983. She received a kidney transplant 4 years later from a cadaveric donor, developing chronic graft nephropathy requiring renal replacement therapy 11 years later. She began APD again and 7 months later presented symptoms of dyspnoea with a significant volume overload and a loss of ultrafiltration in the preceding days. A chest x-ray showed mainly right-sided bilateral pleural effusion. In view of suspected pleuroperitoneal communication a peritoneal scintigraphy was performed which confirmed the diagnosis. Given the severity of her condition, the patient was transferred to haemodialysis (HD) on a definitive basis.
carried out, confirming the diagnosis of pleuroperitoneal communication. The patient was transferred to HD for 3 months, and then he began APD again. After 5 months treatment with APD there was evidence of a relapse of the pleuroperitoneal communication, so talc pleurodesis was carried out. After 2 months on HD the patient started PD again and had no other related complications in the following 3 years.
Case 3 A 52 year old man with CRF secondary to membranoproliferative glomerulonephritis (GN) under treatment with continuous ambulatory PD (CAPD) since February 2001. Two months after beginning treatment he presented acute respiratory failure with volume overload. He underwent a chest x-ray, thoracentesis and peritoneal scintigraphy, resulting in a diagnosis of pleuroperitoneal communication. Talc pleurodesis was performed with peritoneal rest for 2 months. A month after beginning CAPD again, he suffered a relapse of pleuroperitoneal communication, so pleurodesis was performed again. He began CAPD again 3 months later, continuing the treatment for 6 months until receiving a kidney transplant. The patient suffered no new complications during that period.
Case 2 A 60 year old man with CRF of unknown origin under treatment with APD since 2000. A month after beginning treatment he presented symptoms of progressive dyspnoea, loss of ultrafiltration and volume overload. A chest x-ray was performed showing massive right-sided pleural effusion. A thoracentesis was performed, the analysis of the pleural fluid showed a glucose concentration higher than the plasma concentration, suggesting possible pleuroperitoneal communication. Peritoneal scintigraphy with 99Tc-labelled albumin was
Case 4 A 74 year old man with CRF secondary to nephroangiosclerosis under treatment with CAPD since September 1998. In October 2001, after 2 years of treatment, he began to suffer symptoms of dyspnoea and a chest x-ray showed bilateral pleural effusion. Peritoneal scintigraphy provided confirmation of the
Table 1. Description of the series

Caso 1 PD method Time on PD until diagnosis Diagnosis Chest x-ray Thoracentesis Peritoneal scintigram Location of the fluid Initial treatment Outcome Treatment after relapse Bilateral Definitive transfer to HD HD Relapse at 5 months Talc pleurodesis + HD No new relapse Chest x-ray Thoracentesis Peritoneal scintigram Right side 3 months HD Chest x-ray Thoracentesis Peritoneal scintigram Right side Talc pleurodesis + 2 months HD Relapse at 1 month Talc pleurodesis + HD No new relapse No relapse Chest x-ray Thoracentesis Peritoneal scintigram Bilateral 4 months HD Chest x-ray Thoracentesis Peritoneal scintigram Right side Talc pleurodesis + 2 months HD Relapse at 6 months 6 months HD No new relapse Peritoneal scintigram Right side Talc pleurodesis + 2 months HD No relapse Chest x-ray APD 7 months Caso 2 APD 1 month Caso 3 CAPD 2 months Caso 4 CAPD 2 years Caso 5 APD 9 months Caso 6 APD 5 months
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series we observed an incidence of 1.84%, which is a slightly lower percentage than in other series in the literature.5,6 Although most of the cases traditionally described have been women, only one patient in our series was female, with the added peculiarity that she had been treated with DP for 4 years in a previous stage without any complications. The cause of the CRF has also been associated with this complication, it being more common in patients with hepatorenal polycystic disease9 due to an added increase in intra-abdominal pressure. In our series there were no patients with polycystic kidney disease. With regard to the location, 2 of our patients suffered from bilateral pleuroperitoneal communication, which is uncommon according to the medical literature, where a higher prevalence of right-sided only hydrothorax is reported.10 It has been suggested that this could be related to a malformation in this location.1,6,11 Gagnon and Daniels proposed the existence of embryonic remnant, the persisting pneumatoenteric recess, which allows fluids to pass from the peritoneal cavity to the right pleural space.3 Diagnosing this problem is simple but clinical suspicion is crucial. It is necessary to rule out pleuroperitoneal communication when faced with a patient treated with DP presenting with dyspnoea of more or less sudden onset, loss of ultrafiltration and pleural effusion.7 If a pleural fluid sample obtained from a thoracentesis shows that the glucose concentration is higher than that of the plasma, positive diagnosis can be suspected.12,13 Peritoneal scintigraphy has been shown to be very effective at confirming the diagnosis of this anatomic disorder.14,15 It shows how the radioactive isotope passes from the peritoneal cavity through the pleura to the thorax. Figure 1 shows the different images corresponding to a peritoneal scintigram of a patient with this complication. There are several treatment options: the conservative option, pleurodesis or surgery. None of these has been shown to be better than the others so the decision depends on the patients clinical condition and their preference. Patients should be previously informed of the risks and benefits of the different options.16 Pleuroperitoneal communication is a clinical situation with little relevance outside the context of PD, thus, conservative treatment may be the most suitable option for patients who will be transferred to haemodialysis. In our series, one of the patients has not had a relapse since beginning HD. Once the diagnosis has been confirmed, the most important step to take is the temporary, or even permanent, interruption of PD, which is determined by the magnitude of the communication and the needs of the individual patient. Conservative treatment has been seen to be effective in approximately 50% of patients,5 however, our attempt to treat one patient with peritoneal rest was unsuccessful. In some patients with preserved residual diuresis low-volume
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diagnosis with tracer uptake in the base of the left hemithorax. He was transferred to HD and after 4 months peritoneal scintigraphy was performed showing that a small amount of tracer still entered both hemithoraxes. PD was begun again as it was requested by the patient. After 6 months he was transferred to definitive HD due to Candida albicans peritonitis, before which there had been no evidence of a relapse.
Case 5 A 51 year old man with CRF secondary to chronic pyelonephritis due to a neurogenic bladder and vesicoureteral reflux. After 10 years treatment with HD he was transferred to APD in June 2006 because of vascular access problems. After 9 months treatment with DP he began to suffer from progressive dyspnoea and a CT scan of the abdomen and thorax confirmed moderate right-sided pleural effusion. A diagnostic thoracentesis was performed revealing higher levels of glucose in relation to plasma in the peritoneal fluid. The diagnosis of pleuroperitoneal communication was confirmed with peritoneal scintigraphy with 99Tc-labelled albumin. Talc pleurodesis was performed and the patient was transferred temporarily to HD. After 2 months peritoneal rest he began APD again with a dry day. Six months later, after beginning continuous cyclic peritoneal dialysis (CCPD), he presented symptoms of dyspnoea and a chest x-ray revealed right-sided pleural effusion, probably related to a relapse of the prior pleuroperitoneal communication, so he was transferred to HD for 6 months. At present he is under APD treatment with a dry day, with no new complications after 2 years follow-up.
Case 6 A 47 year old woman with CRF secondary to nephroangiosclerosis under treatment with CCPD since June 2009. After 5 months of treatment, she presented symptoms of dyspnoea with minimal effort and was unable to tolerate the decubitus position. A chest x-ray was carried out showing massive right-sided pleural effusion. The diagnosis was confirmed using peritoneal scintigraphy, which showed the flow of peritoneal fluid from the abdominal cavity to the right lung field. Talc pleurodesis was performed and the patient transferred to HD for 2 months. Then, she returned to DP without relapse of the pleuroperitoneal communication after 10 months on this treatment.
DISCUSSION Pleuroperitoneal communication is a rare complication in patients on DP, but it results in a high drop-out rate. In our
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CAPD could be continued17,18 or low volume APD and a dry day.19,20 However, this option could lead to under-dialysis and is not viable with anuric patients. In our hospital, patients were treated with peritoneal rest with a temporary transfer to HD,21 which is an essential decision, particularly if the pleural effusion results in breathing conditions. Talc pleurodesis is a safe and effective treatment for pleuroperitoneal communication.22 In our series, it was performed on 3 patients, 2 at onset and one after a relapse. With one patient it was necessary to carry out the procedure twice, but there were no complications during the procedure in any of the cases. These patients wanted to continue on PD and pleurodesis was chosen for this reason. PD was never maintained because there was a contraindication for a definitive transfer to HD, as would be the case if there were no vascular access. There are other treatment options such as tetracycline pleurodesis, which provides similar results to talc pleurodesis,23 or pleurodesis with autologous blood, which has had inconsistent results.24-26 Video-assisted thoracoscopic surgery allows for the direct visualisation of the diaphragm and malformations in this area.27 If the condition is associated with a morphological disorder, a thoracotomy and direct repair is mandatory. Although it is an aggressive treatment, it offers a high rate of success. However, although surgery is very effective, 28 it is reserved as the last treatment option as it is not devoid of risks. In general, with both conservative or surgical treatment, up to 58% of patients can continue on PD treatment.21 However, the relapse rate is generally high, which is why the results with the different treatments are not very encouraging6,29 and a high percentage of cases require a definitive transfer to
HD30. This means that it is not possible to give clear directions in favour of one treatment or the other.
CONCLUSION Pleuroperitoneal communication is a rare complication in patients on PD, but it leads to a high drop-out rate from the treatment. Its diagnosis is easy and its clinical suspicion is extremely important. The treatment involves peritoneal rest accompanied or not by pleurodesis.
REFERENCES
1. Mahale AS, Katyal A, Khanna R. Complications of peritoneal dialysis related to increased intra-abdominal pressure. Adv Perit Dial 2003;19:130-5. 2. Garca R, Miguel A. Hidrotrax secudnariio: una complicacin de la dilisis peritoneal poco frecuente. Diagnstico y tratamiento. Nefrologia 1998;28:2. 3. Gagnon RF, Daniels E. The persisting pneumatoenteric recess and the infracardiac bursa: possible role in the pathogenesis of right hydrothorax complicating peritoneal dialysis. Adv Perit Dial 2004;20:132-6. 4. Edwards SR, Unger AM. Acute hydrothorax. A new complication of peritoneal dialysis. JAMA 1967;199:853-5. 5. Szeto CC, Chow KM. Pathogenesis and management of hydrothorax complicating peritoneal dialysis. Curr Opin Pulm Med 2004;10:315-9. 6. Nomoto Y, Suga T, Nakajima K, Sakai H, Osawa G, Ota K, et al. Acute hydrothorax in continuous ambulatory peritoneal dialysis-a collaborative study of 161 centers. Am J Nephrol 1989;9:363-7.
Anterior peritoneum
Anterior peritoneum
Ant. Peritoneum V
Figure 1. Peritoneal scintigram with Tc-99m nanocolloid tracer. A) Anterior view, filling of the abdominal cavity. B) Leakeage of dialysis fluid into the right hemithorax through a right pleuro-peritoneal communication C) Pathological tracer uptake by drawing a silhouette in the right lung.
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19. Strauss FG, Holmes DL, Dennis RL, Nortman DF. Shortdwell peritoneal dialysis: increased use and impact on clinical outcome. Adv Perit Dial 1993;9:49-51. 20. Townsend R, Fragola JA. Hydrothorax in a patient receiving continuous ambulatory peritoneal dialysis: successful treatment with intermittent peritoneal dialysis. Arch Intern Med 1982;142:1571-2. 21. Chow KM, Szeto CC, Li PK. Management options for hydrothorax complicating peritoneal dialysis. Semin Dial 2003;16:389-94. 22. Okada H, Ryuzaki M, Kotaki S, Nakamoto H, Sugahara S, Kaneko K, et al. Thoracoscopic surgery and pleurodesis for pleuroperitoneal communication in patients on continuous ambulatory peritoneal dialysis. Am J Kidney Dis 1999;34:170-2. 23. Benz RL, Schleifer CR. Hydrothorax in continuous ambulatory peritoneal dialysis: successful treatment with intrapleural tetracycline and a review of the literature. Am J Kidney Dis 1985;5:136-40. 24. Catizone L, Zuchelli A, Zucchelli P. Hydrothorax in a PD patient: successful treatment with intrapleural autologous blood instillation. Adv Perit Dial 1991;7:86-90. 25. Chao SH, Tsai TJ. Recurrent hydrothorax following repeated pleurodesis using autologous blood. Perit Dial Int 1993;13:321-2. 26. Ariza M, Lpez M, Quesada T. Complications of CAPD in children: six years experience in Caracas, Venezuela. Adv Perit Dial 1991;7:269-71. 27. Hosoda H, Nishio Y, Fujisaki H, Sunamori M. Videoscopic surgical treatment for the patient of pleuroperitoneal communication complicating (CAPD) [Japanese]. Kyobu Geka 2000;53:251-3. 28. Allen SM, Matthews HR. Surgical treatment of massive hydrothorax complicating continuous ambulatory peritoneal dialysis. Clin Nephrol 1991;36:299-301. 29. Oviedo Gmez V, Snchez Garca I, Martn Escuer P, Hernndez Garca E, Martn Gago J, Sousa Prez F, et al. Hydrothorax in peritoneal dialysis: a rare peritonitis complication. Nefrologia 2010;30(5):594-5. 30. Garca Ramn R, Miguel Carrasco A. Hydrothorax in peritoneal dialysis. Perit Dial Int 1998;18:540-5.
7. Lew SQ. Hydrothorax: pleural effusion associated with peritoneal dialysis. Perit Dial Int 2010;30:13-8. 8. Lepage S, Bisson G, Verreault J, Plante GE. Massive hydrothorax complicating peritoneal dialysis. Isotopic investigation (peritoneopleural scintigraphy). Clin Nucl Med 1993;18:498-501. 9. Fletcher S, Turney JH, Brownjohn AM. Increased incidence of hydrothorax complicating peritoneal dialysis in patients with adult polycystic kidney disease. Nephrol Dial Transplant 1994;9:832-3. 10. Nassberger L. Left-sided pleural effusion secondary tocontinuous ambulatory peritoneal dialysis. Acta Med Scand 1982;211:219-20. 11. Grefberg N, Danielson BG, Benson L, Pitkanen P. Rightsided hydrothorax complicating peritoneal dialysis. Report of 2 cases. Nephron 1983;34:130-4. 12. Chow KM, Szeto CC, Wong TY, Li PK. Hydrothorax complicating peritoneal dialysis: diagnostic value of glucose concentration in pleural fluid aspirate. Perit Dial Int 2002;22:525-8. 13. Michel C, Devy A, Lavaud F, Lavaud S, Lebargy F. A sweet hydrothorax. Presse Med 2001;30:1401-3. 14. Huang JJ, Wu JS, Chi WC, Lan RR, Yang LF, Chiu NT. Hydrothorax in continuous ambulatory peritoneal dialysis: therapeutic implications of Tc-99m MAA peritoneal scintigraphy. Nephrol Dial Transplant 1999;14:992-7. 15. Spadaro JJ, Thakur V, Nolph KD. Technetium-99m-labelled macroaggregated albumin in demonstration of trans-diaphragmatic leakage of dialysate in peritoneal dialysis. Am J Nephrol 1982;2:36-8. 16. Remn-Rodrguez C, et al. Complicaciones propias de la tcnica: hernias, escapes, hidrotrax, hemotrax, neumotrax y quiloperitoneo. Guas de prctica clnica en dilisis peritoneal. Guas Sociedad Espaola de Nefrologa. Nefrologia 2006;26(Suppl 4):1-184. 17. Girault-Lataste A, Abaza M, Valentn JF. Small volume APD as alternative treatment for peritoneal leaks. Perit Dial Int 2004;24:294-6. 18. Christidou F, Vayonas G. Recurrent acute hydrothorax in aCAPD patient: successful management with small volumesof dialysate [Letter]. Perit Dial Int 1995;15:389.
Sent for review 4 Dec. 2010 | Accepted 17 Jan. 2011 Nefrologia 2011;31(2):213-7 217
letters to the editor

A) BRIEF PAPERS ON RESEARCH AND CLINICAL INVESTIGATION
Risk factors for abdominal hernias in patients undergoing peritoneal dialysis

Nefrologia 2011;31(2):218-9
To the Editor, The development of abdominal hernias is a factor that can lead to peritoneal dialysis (PD) failure. Infusing dialysis fluid causes intraabdominal pressure to increase, which promotes abdominal hernias in PD patients. The aim of this study is to understand the risk factors that contribute to abdominal hernia in PD patients, so as to inform the clinician of preventative measures. We will also review how hernias can be treated and how they evolve. The study included all incident and prevalent PD patients at the Arnau de Vilanova Hospital, Lleida (Spain), over the past 6 years (2003-2009). The following variables were analysed: age, sex, primary kidney disease, diabetes mellitus (DM), body mass index (BMI), PD modality, PD time, interval between dialysis start-up and catheter insertion, maximum daytime infusion volume (MDV) and body surface (BS)-adjusted MDV (MDV/BS), maximum night-time infusion volume (MNV) and BS-adjusted MNV (MNV/BS), abdominal surgery and hernias prior to PD. We included a total of 146 patients with an average age of 58.151.4 years; 101 men (69.2%) and 45 women (30.8%); 33.56% were diabetic. Accumulated PD monitoring time was 3738.2 months and PD time was 26.2622.75 months. PD modality: 73 patients (50%) were treated with continuous ambulatory PD (CAPD) and 73 (50%) with automated PD
218
(APD). Our patients primary kidney diseases were: diabetic nephropathy (26.71%), nephroangiosclerosis (24%), systemic diseases (19.86%), interstitial nephropathy (14%), unknown (12.31%), polycystic kidney disease (2%) and other diseases (2%). Twelve patients (8.3%) developed abdominal hernias (seven were inguinal, four umbilical, and one crural). No incisional or pericatheter hernias were observed in the followup period. Hernia rate was 0.04/patient/year. Hernias developed after an average of 5.3 months of PD. All hernias were intervened by placing a mesh; none were recurrent. Table 1 shows data comparing patients with and without hernias. The hernia rate in our PD population is comparable to those published in other studies.1,2 The only factor that predisposed patients to hernia development was history of abdominal hernias before inclusion in the study.
However, patients with hernias were elderly, almost ten years older than those patients that did not develop hernias during PD. As it has been observed in other studies, 1,3 the infusion volume did not influence abdominal hernia development during PD. Intraperitoneal hydrostatic pressure proportionally increased with augmenting the infused volume. Furthermore, it could not predict whether the patient will develop abdominal hernias,3 although pressure should not exceed 20cm H2O. Despite these results, infusion volume increase should be limited, especially in older patients, those with a history of abdominal hernia or ultrafiltration problems. In our unit, the volume prescription varied, according to the patients needs, from 1-1.5l/m2 of the body surface-area. A higher incidence of hernias has been described for patients undergoing PD with polycystic disease,4,5 due to an
Table 1. Comparative data between populations with and without hernia

Without hernia (n=134) Age (years) Sex (% males/% females) BMI (kg/m )
2
With hernia (n=12) 66.16 7.9/8.8 24.49 18.18 41.6 8.3 27.66 41.6 1.658.33 110.41 1.833.33 108.24 951 368.56 1.104.81 184.54
p 0.09 0.84 0.33 0.33 0.01 0.92 NS 0.76 0.36 0.19 0.16 0.12
57.44 17.16 92.1/91.2 25.71 35.33 8.95 20.3 27 50.7 1.768.44 40.42 2.206.40 108.02 1.040.97 191.99 1.193.72 191.97
Diabetes (%) Previous hernia (%) Previous abdominal surgery (%) Initial PD time APD (%) MDV (ml) MNV (ml) MDV/BS (ml/m2) MN/VBS (ml/m2)
BMI body mass index, PD: peritoneal dialysis; APD: automated peritoneal dialysis; MDV: maximum daytime infusion volume; MNV: maximum night-time infusion volume; MDV/BS: body surface adjusted-maximum daytime infusion volume; MNV/BS: body surface adjusted-maximum night-time infusion volume
Nefrologia 2011;31(2):218-40

intraabdominal pressure increase caused by polycystic kidneys or primary collagen disorders. In our study, only 2 patients had polycystic kidney disease, which did not allow us to analyse the impact that the polycystic disease has on the risk of developing hernias during PD. Some studies 1,2 state that there is lower prevalence of hernias in APDtreated patients than in CAPDtreated patients. We have not found any statistically significant difference between the two techniques. However, APD patients used the same daytime volume as the CAPD patients (1756+ml compared with 1763+ml, respectively; P=0.92/0.45). These results do not correlate with those of other studies where greater daytime volumes were used for APD patients, which could explain why the results were different. Furthermore, it supports the hypothesis that increasing intraabdominal pressure in a sitting and decubitus position could cause an increase in hernia development during CAPD. We treated all hernias with surgery, placing a mesh, and evolution was successful, with no recurrences. A mesh significantly reduces recurrence6 and should be used when repairing hernias in patients at risk of recurrence or new hernias, such those undergoing PD. To summarise, PD patients with a history of hernia have a greater risk of developing abdominal hernias upon starting treatment. We recommend systematically examining for abdominal hernias in patients before starting PD treatment, and if patients present with clinical signs compatible with abdominal hernia, this complication should be suspected. If surgical repair is necessary, a mesh should be placed. Although abdominal hernias are a relatively frequent complication during PD, if treated correctly the patients condition improves,
Nefrologia 2011;31(2):218-40
proving that that this complication should not be a motive for not using this technique.
1. Del Peso G, Bajo MA, Costero O, Hevia C, Gil F, Daz C, et al. Risk factors for abdominal wall complications in peritoneal dialysis patients. Perit Dial Int 2003;23(3):249-54. 2. Hussain SI, Bernardini J, Piraino B. The risk of hernia with large exchange volumes. Adv Perit Dial 1998;14:105. 3. Durand FY, Chanliau J, Gamberoni J, Hestin D, Kessler M. Routine Measurement of Hydrostatic Intraperitoneal Pressure. Perit Dial Int 1996(Issue Suppl 1):S84-S87. 4. Morris-Stiff G, Coles G, Moore R, Jurewicz A, Lord R. Abdominal wall hernia in autosomal dominant polycystic disease. Br J Surg 1997;84:615-7. 5. Modi K, Grant AC, Garret A, Rodger RS. Indirect inguinal hernia in CAPD patients with polycystic kidney disease. Adv Perit Dial 1989;5:846. Martnez-Mier G, Garca-Almaza E, ReyesDevesa HE, Garca-Garca V, CanoGutirrez S, Mora R, et al. Abdominal wall hernias in end-stage renal disease patients on peritoneal dialysis. Perit Dial Int 2008;28(4):391-6.
Successful pregnancy in a patient with chronic renal failure undergoing haemodialysis

Nefrologia 2011;31(2):219-21
To the Editor, Frequency of pregnancies during haemodialysis is low (between 0.3% and 0.75% per year in women of childbearing age).1 This fact is due to different hormonal factors which produce amenorrhoea.2-4 Maternal complications include: miscarriage, placenta abruptio, anaemia, infection, premature breakage of membranes, polyhydramnios, preterm labour, arterial hypertension, preeclampsia and eclampsia, haemorrhage, need for caesarean section, and maternal death. Foetal complications include: slow foetal growth, acute or chronic foetal distress, premature birth, newborn respiratory problems, increased stay in neonatal intensive care, and stillbirths or neonatal deaths.5,6 We present the case of a 31-year-old patient with chronic renal failure (CRF) secondary to interstitial and tubular kidney disease due to a neurogenic bladder. She started renal replacement therapy with haemodialysis 15 months before. Her medical history included: lipomyelomeningocele, cauda equina syndrome; neurogenic bladder; 3 pregnancies (2 miscarriages and 1 live birth). In April 2010, she reported amenorrhoea for one week, and ultrasound confirmed that she was 10 weeks pregnant. At this time, the patient had a creatinine clearance of 10ml/minute and residual diuresis of 2000ml/day (via self-catheterisation which has been performed since she was 5 years old due to her neurogenic bladder).
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M. Gracia Toledo1, M. Borrs Sans2, A. Gabarrell3, J. Durn4, E. Fernndez Girldez2

1
Nephrology Department. Biomedical
Research Institute of Lleida. Arnau de Vilanova Hospital. University of Lleida, Spain.

2
Nephrology Unit. Arnau de Vilanova General Surgery Department. Santa Mara Nephrology Department. Arnau de Vilanova
Hospital. Lleida, Spain.

3
Hospital. Lleida, Spain.

4
Hospital. Lleida, Spain. Correspondence: M. Gracia Toledo Servicio de Nefrologa. Institut de Recerca Biomdica de Lleida. Hospital Universitari Arnau de Vilanova. Universitat de Lleida. Doctora Castells, 42, 1. A, 25001 Lleida. Spain. martagt679@hotmail.com martagt679@gmail.com

The following regimen was established: Haemodialysis dosage was increased to six weekly sessions of 180 minutes, which resulted in: improved blood volume control (with no hypertensive or hypotensive events), less restriction on liquid intake solute fluctuation prevention, less episodes of low foetoplacental blood flow, reducing predialysis urea levels, and increasing protein intake. We used a polysulfone dialyser with an ultrafiltration coefficient (KUf) of 82mL, and porous membrane thickness 40m. Qb was set at 300-350ml/minute and Qd at 500ml/minute. The maximum ultrafiltration per hour was established at 400ml/hour to prevent hypotension. Weight adjustment was performed in accordance with the patients blood pressure and clinical profile. Weekly analytical tests were performed. Drug treatment was: erythropoietin, iron i.v., oral bicarbonate and folic acid. Paracalcitol was withdrawn given the lack of experience with this drug in pregnant patients. We did not observe any alterations in blood sugar levels and the three OSullivans tests were normal. The adjusted protein catabolism rate was 0.8 (same as before pregnancy) and the average standard Kt/V during the 9 months was 3.16. Weighted growth rate was 9kg. Table 1 shows the remaining analytical parameters: blood pressure, dry weight, and erythropoietin dosage. She did not have any fistula complications. She was not prescribed antihypertensive drugs at any moment. Complications included: acute phlegmonous appendicitis (successfully repaired);
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haematuria with pathological urine sediments (treated with antibiotics). Haematuria disappeared and sediment normalised; and three urinary infection episodes (treated with antibiotics). The patient was hospitalised at 36 weeks, having a forceps-assisted vaginal delivery. The baby weighed 2.9kg and Apgar score was 9/10. The patient recovered satisfactorily. Residual diuresis and creatinine clearance results after 1 month were similar to pre-pregnancy results: 2000ml/day and 9ml/min, respectively. The other biochemical parameters were normal and she returned to her dialysis regimen of three sessions a week with good tolerance. In 1980, the European Dialysis Transplant Association (EDTA) published a case study on 13 000 women of fertile age. There were 115 conceptions among them: 45 therapeutic abortions, 53 miscarriages, and of the remaining pregnancies, the birth rate was 23% 2 In 1996, Hou published another case study conducted in 206 North American dialysis units in 1990 and 1991. The sample included 1281 women between 18 and 44 years old.
Almost 70% of the pregnancies before 1990 ended in miscarriage, while less than 40% after 1990 ended in abortion or miscarriage.2 There are very few cases described during recent years, and those which we have found have been from some centres isolated experience. Most report successful pregnancy rates, above 70%.7.8 In 2005, Haase et al9 published the first prospective study on 5 patients treated between 2000 and 2004 at the Charit University Hospital in Berlin with a 100% birth rate. Recently, Luders published a case study in the AMJ of all the pregnancies that occurred between 1988 and 2008 (it is the largest record to date) in women undergoing dialysis in the nephrology department of the San Paulo University Hospital, Brazil. Fifty-two pregnancies were studied, and 86.5% of them were successful.10 The survival rate of the babies born of mothers undergoing haemodialysis has improved, from 23% in 1980 11 to almost 90% during the last decade.9,10 However, foetal mortality is higher for women undergoing haemodialysis than the general population.5-9
Table 1. Clinical and laboratory variables and drug dose during pregnancy
Month Blood pressure predialysis (mm Hg) Blood pressure postdialysis (mm Hg) Dry weight (kg) Haemoglobin (g/dl) EPO (units/week) Weekly doses of iron Calcium (mg/dl) Phosphorus (mg/dl) Urea predialysis (mg/dl) 100 9.4 3.9 119 100 9.9 4.1 90 100 9.8 2.6 60 100 9.8 3.2 61 100 9.7 3 70 100 9.8 2.4 61 100 9.9 3.2 64 100 9.9 3 57 83 11.6 2000 83 10.6 6000 83.5 10.3 84 10.7 85 11 88.5 11.4 91 11.7 92 12 100/65 100/65 105/75 100/70 95/70 100/80 100/70 110/75 1 2 3 4 5 6 7 8
110/75 115/70 110/75 115/70 105/75 110/75 110/70 120/80
10 000 15 000 20 000 20 000 20 000 18 000
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To date, a systematic nephrological or gynaecological treatment for this type of patient has yet to reported in the medical literature.9 Various measures are mentioned in publications, such as: increase the erythropoietin dosage, increase dialysis time, use low ultrafiltration rates to improve blood volume control, avoid hypotension events, reduce liquid intake restrictions and maintain low predialysis urea levels.9,10,12,13 Pregnancy during dialysis continues to be rare and it occurs in various units. This makes it a difficult research point,14 but nevertheless these pregnancies should be included in a register, in the same way that other Societies and the EDTA have done.
1. Lpez Menchero R, Albero MD, Cabeza B, lvarez L, Del Pozo C, Snchez L. Successful pregnancy in a patient with systemic lupus erythematosus on hemodialysis. Nefrologia 2004;24(1):70-4. 2. Luque Vadillo E, Matamala Gastn A, Places Balsalobre J, Alconchel Cabezas S, Torres Jans M, Das Cocera M. Gestacin en una paciente con IRC en programa de hemodilisis. Rev Soc Esp Enf Nefrol 2002;19:47-9. 3. Swaroop R, Zabaneh R, Parimoo N. Pregnancy in end-stage renal disease patients on hemodialysis: two case reports. Cases J 2009;12(2):8139. 4. Gangji AS, Windrim R, Gandhi S, Silverman JA, Chan CT. Successful pregnancy with nocturnal hemodialysis. Am J Kidney Dis 2004;44(5):912-6. 5. Okundaye l, Abrinko P, Hou S. Registry of pregnancy in dialysis patients. Am J Kidney Dis 1998;31(5):766-73. 6. Vzquez-Rodrguez JG. Hemodilisis and pregnancy: technical aspects. Cir Ciruj 2010;78(1):99-102. 7. Piccoli GB, Conijn A, Consiglio V, Vasario E, Attini R, Deagostini MC, et al. Pregnancy in dialysis patients: is the evidence strong enough to lead us to change our counseling policy? Clin J Am Soc Nephrol 2010;5(1):62-71. 8. Barua M, Hladunewich M, Keunen J, Pierratos A, McFarlane P, Sood M, et al. Successful Pregnancies on Nocturnal Home Hemodialysis. Clin J Am Soc Nephrol 2008;3(2):392-6. 9. Haase M, Morgera S, Bamberg CH, Halle H, Martini S, Hocher B, et al. A Systematic approach to managing pregnant dialysis patients-the importance of an intensified haemodiafiltration protocol. Nephrol Dial Transplant 2005;20:2537-42. 10. Luders C, Castro MC, Titan SM, De Castro I, Elias RM, Abensur H, Romo JE. Obstetric Outcome in Pregnant Women on Long-term Dialysis: A Case Series. Am J Kidney Dis 2010;56(1):77-85. Report from the Registration Committee of the EDTA. Successful pregnancies in women treated by dialysis and kidney transplantation. Br J Obstet Gynecol 1980;87(10):839-45. Giatras I, Levy DP, Malone FD, Carlson JA, Jungers P. Pregnancy during dialysis: case report and management guidelines. Nephrol Dial Transplant 1998;13:326672. Hou S. Pregnancy in chronic renal insufficiency and end-stage renal disease. Am J Kidney Dis 1999;33(2):235-52. Hou S. Pregnancy in women treated with dialysis: lessons from a large series over 20 years. Am J Kidney Dis 2010;56(1):5-6.
11.
12.
13.
14.
K.R. Furaz Czerpak, A. Puente Garca, E. Corchete Prats, M.A. Moreno, R. Martn Hernndez Nephrology Department. Los Llanos Centre. FRIAT. Mstoles, Madrid, Spain. Correspondence: K.R. Furaz Czerpak Servicio de Nefrologa. Centro Los Llanos. FRIAT. C/Ro Segura, N 5. 28935 Mstoles, Madrid. Spain. karina_furaz@hotmail.com kfuraz@friat.es
B) BRIEF CASE REPORTS Nephropathy following administration of angiogenesis inhibitors

Nefrologia 2011;31(2):221-2
Various studies have shown that the anti-VEGF monoclonal antibody, bevacizumab, can reduce angiogenesis and inhibit solid tumour growth.1 Various secondary effects have been associated with bevacizumab use. Two of the most common effects are moderate proteinuria (up to 64% of cases) and hypertension. Nephroticrange proteinuria only occurs in 1%2% of bevacizumab-treated patients.2 We present the case of a 42-year-old man, diagnosed with grade II
fibrosarcoma in the thigh and leftscapular region in November 1999. Tumour resection was indicated. Three years later, he developed progressive pulmonary metastatic disease, which was treated with surgery and chemotherapy (MAID protocol: mesna, adriamycin, ifosfamide and dacarbazine). In May 2004, he developed progressive pulmonary metastatic disease again and was treated with taxotere and gemcitabine, completing 6 cycles. He
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To the Editor, Angiogenesis has an important role in metastasis development. In recent years, the vascular endothelial growth factor (VEGF) has become one of the main objectives in treating tumourinduced angiogenesis.
Nefrologia 2011;31(2):218-40

then completed 21 cycles of therapy with gemcitabine only. In August 2008, he started gemcitabine and bevacizumab treatment, due to a disease relapse. Following the second bevacizumab dosage, the patient was admitted due to headache, arterial hypertension (AHT) (BP: 190/100mm Hg) and general oedema. Upon admission, he had creatinine at 1.8mg/dl, nephroticrange proteinuria and microhaematuria. Moderate normocytic/normochromic anaemia without schistocytes on the peripheral blood smear. Kidney ultrasound was normal. Immunological study only had low C3 levels. He had no previous history of AHT or kidney disease. On the sixth day of his hospital stay, a renal biopsy was performed finding mesangiocapillary glomerulonephritis type II. Gemcitabine and bevacizumab treatment was suspended and angiotensin II receptor antagonist (ARA-II) treatment started. Renal function improved, finally reaching creatinine levels of 1.1mg/dl; proteinuria decreased significantly and optimum blood pressure control was achieved. Proteinuria in anti-VEGF-treated patients has been related to damage in the podocyte-endothelial-VEGF axis. VEGF production by podocytes is necessary for the glomerular endothelial to remain intact. 2 VEGF is expressed in the podocytes and its receptors are found in the endothelial cells of the normal glomerular capillaries. 3 When VEGF binds to its receptor, it promotes an increase in the microvasculatures permeability, cell migration and division, apoptosis inhibition and endothelial damage repair. 4 In animal studies, a defect in the VEGF expression causes glomerular diseases characterised by nephrotic-range
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proteinuria, endotheliosis and hyaline deposits, which are similar to the kidney damage found in pre-eclampsia patients.5 We only found a few glomerulonephritis cases associated with anti-VEGF antibodies in the medical literature, and most were thrombotic microangiopathies. Bevacizumab-induced mesangiocapillary glomerulonephritis seems to be very rare. We believe that more cases will gradually appear due to the increased use of these antibodies in oncology in recent years. Proteinuria which appears as a result of bevacizumab-induced glomerular damage seems to be reversible, at least partially, when this chemotherapy agent is suspended. Our case, and other similar cases of patients with metastasis which develop bevacizumab-induced proteinuria had been treated with other, potentially nephrotoxic agents. Our patient also received high doses of gemcitabine over a long period of time. Little is still known about gemcitabines mechanism of action on kidney damage, although we know that it is dose-dependent. In most cases, it is associated with haemolytic uremic syndrome,6 although we have also found isolated cases associated with mesangiocapillary glomerulonephritis.7 Given that a kidney biopsy was not performed before bevacizumab treatment, we are not able to confirm that gemcitabine was not responsible for the patients symptoms. However, given that the kidney damage was not evident until the start of anti-VEGF antibody treatment, we believe that the agent responsible for these symptoms was bevacizumab. It is possible that gemcitabine treatment produces initial renal damage, which may have been exacerbated by bevacizumab administration. We recommend a strict control of the arterial pressure and kidney function in
patients undergoing antibody therapies.
monoclonal
1. Rugo HS. Bevacizumab in the treatment of breast cancer: rationale and current data. The Oncologist 2004;9(Suppl 1):439. 2. Eremina V, Jefferson JA, Kowalewska J, et al. VEGF inhibition and renal thrombotic microangiopathy. 2008;358:1129-36. 3. Stokes M, Erazo M, DAgati V. Glomerular disease related to anti-VEGF therapy. Kidney Int 2008;74:1487-91. 4. Zhu X, Wu S, Dahut WL, Parikh CR. Risks of proteinuria and hypertension with bevacizumab, vascular an antibody growth against factor: endothelial N Engl J Med
systematic review and meta-analysis. Am J Kidney Dis 2007;49:186-93. 5. George BA, Zhou XJ, Toto R. Nephrotic syndrome after bevacizumab: case report and literature review. Am J Kidney Dis 2007;49:E23-E29. 6. Saif MW, McGee PJ. Hemolytic-uremic syndrome associated with gemcitabine: a case report and review of literature. J Pancreas 2005;6(4):369-74. 7. Fracasso PM, Tan BR, Grieff JM, et al. Membranoproliferative glomerulonephritis following gemcitabine and vinorelbine chemotherapy for peritoneal mesothelioma. Journal of the National Cancer Institute 1999;91(20):1779-80.
A. Vello Romn1, M. Samprn Rodrguez1, B. Pazos Arias1, C. Romero Reinoso2, A. Peteiro Cancelo3
1
Nephrology Department. Povisa Hospital.
Vigo, Pontevedra, Spain.

2
Oncology Department. Povisa Hospital.
Vigo, Pontevedra, Spain.

3
Anatomical Pathology Department. Povisa
Hospital. Vigo, Pontevedra, Spain. Correspondence: A. Vello Romn Servicio de Nefrologa. Hospital Povisa. Salamanca 5. 36211 Vigo. Pontevedra. Spain. arantxavr6@hotmail.com
Nefrologia 2011;31(2):218-40

First case of peritoneal infection due to Oerskovia turbata (Cellulosimicrobium funkei)
Nefrologia 2011;31(2):223-5
transitional cell carcinoma. He presented with his first Pasteurella multocida PI in October 2008, which was presumably induced by contact with a cat. In July 2009, he had his second PI. He started drug treatment with vancomycin, intraperitoneal gentamicin, and ciprofloxacin orally. On the third day, gram-positive bacilli growth was found with a preliminary identification of Oerskovia sp. On the sixth day, the antibiogram showed an intermediate sensitivity to ciprofloxacin and sensitivity to cotrimoxazole. Ciprofloxacin was then replaced with oral co-trimoxazole, intraperitoneal vancomycin regimen was continued every 5 days, and gentamicin was withdrawn. On the tenth day, peritoneal fluid was clear. Antibiotic treatment was maintained for 22 days. Thirteen days after finishing the antibiotic treatment, the patient had a PI relapse. Treatment using vancomycin, intraperitoneal gentamicin and oral cotrimoxazole was restarted, using fluconazole as prophylaxis. On the third day, fluid was clear and Oerskovia sp growth was resistant to co-trimoxazole, and sensitive to ciprofloxacin. The antibiotic regimen was therefore changed: gentamicin was withdrawn and vancomycin maintained. Twentyone days after antibiotic treatment, he had a second PI relapse. The PD was removed and the patient was transferred to haemodialysis. Catheter culture was negative.
To the Editor, Peritoneal infection (PI) or peritonitis is a common complication in peritoneal dialysis (PD). It can damage the peritoneal membrane, compromise the techniques survival rate and is the main cause for transfer to haemodialysis.1 Most PI episodes are due to gram-positive cocci, although an increase in PI due to gram-negative bacilli is being observed, with worse clinical prognosis.2 Oerskovia infections are rare in humans. There are only four oerskovia PI cases published. 3-6 It consists of two large species: Oerskovia xanthineolytica (O. xanthineolytica) and Oerskovia turbata (O. turbata), which are currently known as Cellulosimicrobium cellulans 7 and Cellulosimicrobium funkei, respectively, 8 according to comparative phylogenetic analysis based on 16S ribosomal rRNA gene sequences. They are gram-positive bacilli found in the ground, pastures and water from different parts of the world. Colonies are characterised by a yellow pigment with branching vegetative hyphae which penetrate in the agar.9,10 Below, we describe the first peritonitis case caused by O. turbata in a patient undergoing automated peritoneal dialysis (APD), and have also reviewed published cases. We present the case of a 62-year-old man, with a history of high blood pressure, dyslipaemia, stroke and ischaemic heart disease. He started APD in August 2006 following bilateral kidney nephrectomy for
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Figure 1. Oerskovia culture on a blood agar plate
(CNA) agar were reseeded on blood agar plates, which were incubated at 35C in 5% CO. Some colony growth was observed at 48-72 hours. It was the characteristic pastel yellow colour (Figure 1). The colonies were catalasepositive and oxidase-negative, and were identified using API Coryne galleries (bioMrieux, Marcy Ltoile, France). It had the code 7572727, with an Oerskovia sp. percentage of 99.9%. Later, we completed the 16S rRNA sequencing, and the phylogenetic gene sequence analysis confirmed Cellulosimicrobium funkei.
Review of the PI due to Oerskovia cases We have found four cases of PI due to O. xanthineolytica PD in the literature. Catheter removal was necessary in two of these cases.3,6 Cases with good progress were treated with intraperitoneal antibiotics for 15 days4,5 (Table 1). We would like to present the first PI due to O. turbata. This species is less frequent in human infections than O. xanthineolytica according to the review published in 2006.7 This is the first case of infection caused by Oerskovia diagnosed in our health centre. At present, according to the comparative phylogenetic analysis based on 16S rRNA gene sequence, it is called Cellulosimicrobium. Human infections due to Oerskovia develop in immunosuppressed patients
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Microbiology The peritoneal fluids were collected in aerobic and anaerobic bottles for BacT/Alert blood culture test (bioMrieux, Durham, NC, USA). Both bottles were found to be positive at between 23 and 24 hours, and the gram staining revealed branching gram-positive bacilli. Chocolate agar, blood agar, and colistin-nalidixic acid

Table 1. Review of cases of PI caused by Oerskovia
Reference Rihs JD, CM 1990 Patient 70-year-old man Species O. xanthineolytica PD time Treatment Withdra wal PD type antibiotic catheter 11 years Vancomycin and Yes CAPD gentamicin 6 weeks Vancomycin and No CAPD Doxycycline 11 month Vancomycin No CAPD 4 years Vancomycin Yes CAPD 3 years CAPD Vancomycin ciprofloxacin and co-trimoxazole Yes Oerskovia xanthineolytica en paciente en dilisis peritoneal. Publicacin Pster. La Corua: VII Reunin nacional de Dilisis Peritoneal, 4-6 de febrero de 2010. Rowlinson MC, Bruckner DA, Hinnebusch C, Nielsen K, Deville JG. Clearance of Cellulosimicrobium cellulans bacteriemia in a Child without Central Venous Catheter Renoval. J Clin Microbiol 2006;44:2650-4. Brown JM, Steigerwalt AG, Money RE, Daneshvar MI, Romero LJ, McNeil MM. Characterization of clinical isolates previously identified as Oerskovia turbata: proposal of Cellulosimicrobium funkei sp. Nov. and emended description of the genus Cellulosimicrobium. Intern J Syst Evol Microbiol 2006;56:801-4. Reller LB, Maddoux GL, Mark MD, Eckman R, Pappas G. Bacterial Endocarditis Caused by Oerskovia turbata. Ann Intern Med 1975;83:664-6. Cruickshank JG, Gawler AH, Shaldon C. Oerskovia species: Rare opportunistic pathogens. J Med Microbiol 1979;12:5135. Harrington RD, Lewis CG, Aslanzadeh J, Stelmach P, Woolfrey AE. Oerskovia xanthineolytica Infection of a Prosthetic Joint: Case report and Review. J Clin Microbiol 1996;34:1821-4. Tucker JD, Montecino R, Winograd JM, Ferraro MJ, Michelow IC. Pyogenic Flexor Tenosynovitis Associated with Cellulosimicrobium cellulans. J Clin Microbiol 2008;46:4106-8. LeProwse CR, McNeil MM, Mc Carty JM. Catheter-Related Bacteriemia Caused by Oerskovia turbata. J Clin Microbiol 1989;27:571-2. Reina J, Llompart I, Altes J. Absceso axilar producido por Oerskovia turbata en un paciente de SIDA. Rev Clin Esp 1991;188:485-6. Lair MI, Bentolila S, Grenet D, Cahen D, Honderlick P. Oerskovia turbata and Comamonas acidovorans Bacteremia in a Patient with AIDS. Eur J Clin Microbiol Infect Dis 1996;15:424-6.
Borra S, AJKD 1996 59-year-old woman O. xanthineolytica Lujan-Zilbermann, J PIDJ 1999 Moyano MJ, Annual meeting DP 2010 Our case, 2010 13-year-old man 75-year-old man O. xanthineolytica O. xanthineolytica
7.
8.
62-year-old man
O. turbata
and foreign body carriers: central catheters, valvular and joint prostheses, and peritoneal dialysis catheters.3-7,9,11 In some cases, the origin of the infection has been related to working or living in rural areas.5,10 More than one antibiotic may be necessary and the foreign body may need to be removed. In all cases the germ has been sensitive to the antibiotic treatment in in vitro tests, although in vivo results have been poor.7 Our case, despite correct antibiotic treatment, did not manage to eradicate the infection and the PD catheter had to be removed. This bacterium is resistant, although not especially virulent, given that no deaths have been recorded.7,12 Most infections caused by O. turbata have been in immunosuppressed patients.13-15 Our patient lived in an urban area and had a pet cat, but there are no references that show a relationship between infections caused by Oerskovia and domestic animals. The Oerskovia genus is often in vitro resistant to penicillin, aminoglycosides, macrolides and cephalosporins, and intermediate resistance to ciprofloxacin. It is considered in vitro sensitive to vancomycin and rifampicin.7,12 In this instance, the germ was sensitive to vancomycin, rifampicin, meropenem and co224
trimoxazole, and was intermediate sensitive to ciprofloxacin. Given that there are no standardised minimal inhibitory concentration (MIC) values to study the sensitivity of this bacterium, we used the MIC for Corynebacterium sp. To conclude, PIs caused by Oerskovia are rare despite it being a germ that is widely distributed in nature. 1.
1. Davenport A. Peritonitis remains the major clinical complications of peritoneal dyalisis: the London, UK, peritonitis audit 2002-2003. Perit Dial Int 2009;29:297302. 2. Jarvis EM, Hawley CM, McDonald SP, Brown FG, Rosman JB, Wiggins KL, et al. Predictors, treatment and outcomes of nonPseudomona Gram-negative peritonitis. Kidney Int 2010; May 26 (epub). 3. Rihs JD, McNeil MM, Brown JM, Yu VL. Oerskovia xanthineolytica Implicated in Peritonitis Associated with Peritoneal Dialysis: Case Report an review of Oerskovia Infections in Humans. J Clin Microbiol 1990;27:1934-7. 4. Borra S, Kleinfeld M. Peritonitis caused by Oerskovia xanthineolytica in a patient on chronic ambulatory peritoneal dialysis (CAPD). Am J Kidney Dis 1996;27:458. 5. Lujan-Zilbermann J, Jones D, DeVincenzo J. Oerskovia xanthineolytica peritonitis: Case Report and Review. Pediatr Infect Dis J 1999;18:738-9. 6. Moyano MJ, Arest N, Surez A, Pez C, Ortega R, Miln JA. Peritonitis por
9.
10.
11.
12.
13.
14.
15.
L. Betancourt Castellanos1, E. Ponz Clemente1, D. Fontanals Aymerich2, C. Blasco Cabaas1, D. Marquina Parra1, C. Grau Pueyo1, M. Garca Garca1 Nefrologia 2011;31(2):218-40

Nephrology Department. Parc Taul Health Corporation. Parc Taul University Institute (UAB). Sabadell, Barcelona, Spain.
1
Microbiology Laboratory. Parc Taul Health Corporation. Parc Taul University Institute. Correspondence: L. Betancourt Castellanos Servicio de Nefrologa. Corporacin Sanitaria Parc Taul. Institut Universitari Parc Taul (UAB), Parc Taul s/n. 08203 Sabadell. Barcelona. Spain. lorelaybc@hotmail.com eponz@tauli.cat
2
Figure 1. Subconjunctival bleeding due to difuse episcleritis.
A patient with acute renal failure and episcleritis, is there more than meets the eye?
Nefrologia 2011;31(2):225-6
Dear Editor, The kidney and the eye, with their characteristic vascular anatomy, are vulnerable to vasculitis syndromes like antineutrophil cytoplasmic antibodies (ANCA) associated small vessel vasculitis.1-3. Here we present a case of a 44 year old male patient complained of asthenia for one month. Two weeks before he developed bilateral subconjunctival hemorrhage without photophobia or ocular pain. The patient denied epistaxis, hemoptysis, abdominal pain, arthralgias or myalgias. On examination he had subconjunctival bleeding due to bilateral difuse episcleritis (Figure 1). There were no cardiopulmonary auscultatory findings, no purpura and no signs of arthritis. The patient past medical history was remarkable for chronic sinusitis with frequent episodes of epistaxis. The blood panel showed severe azotemia (serum creatinine 11,2 mg/dl, BUN 100 mg/dl), normocytic normochromic anaemia (Hb 11,3 g/dl; Ht 33,3%), Creactive protein 16,9 mg/L (0-10 mg/L), active urinary sediment (30 red blood cells per high-power field, 4 red blood cell casts), and a 24 hour proteinuria of
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2,2 g. Renal imaging revealed normal size kidneys and normal corticomedular diferentiation. Hemodialysis was initiated due to uremic syndrome. Chest X-ray and chest CT scan did not show any evidence of active disease in the lower respiratory tract. Nasal sinus CT scan was compatible with a previous history of chronic sinusitis involving right etmoidal and both maxillary sinus. Nasal mucosa biopsy showed a nonspecific inflammatory process. Serologic panel was negative for HIV1 and 2, HBV and HCV infection, complement fractions were within normal range. The immunological study was positive for circulating C-ANCA with antiproteinase 3 (PR3) activity confirmed by enzimatic imunoassay (ELISA), and negative for anti-nuclear, anti DNAds and anti- glomerular basement membrane (anti-GBM) antibodies. The renal biopsy revealed a segmentar necrotizing glomerulonephritis with circumferential crescents in more than 80% of glomeruli (Figure 2). Immunofluorescence microscopy was compatible with a pauci-imune glomerulonephritis The above investigation confirmed the diagnosis of ANCA associated small vessel vasculitis and the patient initiated treatment with cyclophosphamide (100 mg id po), methylprednisolone (1 g id ev) changed to prednisolone (70 mg id po) after 3 days, and prophylactic antibiotherapy with trimethoprim/sulfamethoxazole. On hospital day four, he had a complete remission of the oftalmic disease, maintaining severe renal failure. Three months later, our patient remained on hemodialysis due to severe azotemia, without glomerular hematuria. Since renal function did not recover and there was no evidence of active extrarenal
Figure 2. Cellular circumferential crescents in more than 80% of glomeruli (Silver stain, x100).
disease, immunosuppressants discontinued.
were
The authors present a case report of systemic vasculitis associated with ANCAs with specificity for antiproteinase 3 (PR3), with renal, upper respiratory tract and eye involvement suggestive of Wegener granulomatosis. The specificity of ANCA and its role on prognosis was shown by a retrospective study by Sven Weidner, involving 80 patients with confirmed pathological diagnosis of pauci-imune glomerulonephritis. In this study, patients with PR3 ANCAs had a higher risk of progressing to end-stage renal disease (ESRD) 4. The patient in our case report, besides having PR3 ANCAs, also presented with a pre-treatment serum creatinine above 500 mol/L (5,7 mg/dl), which also predicts a worse outcome 4. As for the type and number of crescents, the presence of circumferencial crescents in more
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than 80% of glomeruli, determines a dismal prognosis, indicating a worse response to immunosuppressive treatment. 5 Our case report illustrates that an uncommon extra-renal involvement like an episcleritis, can be the form of presentation of a systemic disease with lethal potential. Although the prognosis in terms of progression for ESRD is mainly determined by the renal histology, the type of ANCA involved and serum creatinine value when treatment is begun, the patient survival is still dependent on the level of clinical suspicion leading to an early diagnosis and treatment.
1. Falk R, Nachman P, Hogan S, Jennette JC. ANCA Glomerulonephritis and Vasculitis: A Chapel Hill Perspective. Semin Nephrol 2000;20:233-43. 2. Savige J, Davies D, Falk R, Jennette JC, Wiik A. Antineutrophil cytoplasmic antibodies and associated diseases: a review of the clinical and laboratory features. Kidney Int 2000;57:846-62. 3. Harper SL, Letko E, Samson CM, Zafirakis P, Sangwan V, Nguyen Q, et al. Wegeners granulomatosis: the relationship between ocular and systemic disease. J Rheumatol 2001;28(5):1025-32. 4. Weidner S, Geuss S, Hafezi-Rachti S, Wonka A, Rupprecht H. ANCAassociated vasculitis with renal involvement: an outcome analysis. Nephrol Dial Transplant 2004;19:140311. 5. Jennette JC. Rapidly progressive crescentic glomerulonephritis. Kidney Int 2003;63:1164.
Severe ethanol poisoning treated by haemodialysis

Nefrologia 2011;31(2):226-7
To the Editor, Standard treatment for severe ethanol poisoning consists of an aggressive treatment with cardiovascular and respiratory support, and close monitoring of the electrolytes, preventing hypothermia and hypoglycaemia. There are many cases of severe ethanol poisoning that have been successfully treated with conservative treatment. Haemodialysis is recommended for patients with signs of severe poisoning, and serum ethanol levels above 600mg/dl, (this figure is less for adolescents).1 We present the case of a patient with severe ethanol poisoning treated with haemodialysis, whose serum ethanol levels decreased rapidly. The patient was a 57 year-old man, with epilepsy from 30 years of age, former alcoholic. He had experienced traumatic brain injury in 2008 as the result of an epileptic seizure. He was found unconscious in his home, with two empty whisky bottles and was suspected to have taken 4g of carbamazepine. In the examination we observed that he was in a state of coma, with slightly anisocoric pupils, pulse: 67 beats/min, blood pressure 80/50mm Hg, temperature 36.2C; and pulmonary auscultation revealed reduced vesicular murmur in the left haemothorax. There were no other significant findings. He was haemodynamically unstable, and upon admission to the intensive care unit, vasopressor treatment and respiratory support were indicated. Toxic levels of ethanol (650mg/dl) were found. The biochemistry analysis showed: Na: 137mmol/l; K: 4mmol/l; Cl: 106mmol/l; glucose 173mg/dl; urea
42mg/dl; creatinine: 1.39mg/dl; anion gap: 18mOs/kg; osmolar gap: 126mOs/kg. Blood gasometry: pH: 7.05; HCO3: 16.6mmol/l; pCO2: 60mm Hg; pO2 : 47mm Hg. Due to instability and poor response to conservative treatment, haemodialysis was performed for 3 hours with a polysulfone dialyser at a blood flow of 250ml/min. After this session, serum ethanol levels reduced to 373mg/dl and metabolic acidosis was corrected. The patient then had symptoms of bronchial aspiration and acute pancreatitis, which was resolved with antibiotic and conservative treatment. Dialysis was recommended to treat severe ethanol poisoning for the first time in 1960, given that it is four times quicker than physiological elimination of ethanol.2 However, deciding which patients with severe poisoning are eligible to undergo haemodialysis is a controversial matter. Some authors suggest that it is sufficient with a conservative treatment,3 while others believe that haemodialysis should be considered for those patients with a serum level above 600mg/dl,4 given that it could reduce the length of the coma and the risk of bronchial aspiration, correct hypothermia and hypoglycaemia, improve metabolic acidosis, and reduce the risk of arrhythmia. Furthermore, that alcohol is easily eliminated by haemodialysis as it is a small, water-soluble molecule which does not bind to proteins. Its volume of distribution is also limited. We recommend indicating haemodialysis as a therapeutic option for patients with signs of severe ethanol poisoning, whose clinical profile does not improve following conservative treatment, provided that the acute complications of haemodialysis are assessed.
1. Morgan D, Durso M, Rich B, Kurt T. Severe ethanol intoxication in a adolescent. Am J Emerg Med 1995;4:4168. 2. Atassi W, Noghnogh A, et al. Hemodialysis as a treatment of severe Nefrologia 2011;31(2):218-40
A.P. Bernardo, J.M. Montalbn, E. Rocha Department of Nephrology. Hospital Amato Lusitano. Castelo Branco, Castelo Branco (Portugal). Correspondence: A.P. Bernardo Department of Nephrology. Hospital Amato Lusitano. Quinta Dr. Beiro, n. 27, 5. D. 6000-140 C. Castelo Branco. Castelo Branco. Portugal. anabernardo@portugalmail.pt 226

ethanol poisoning. Int J Artif Organs 1999;1:18-20. 3. Kraut J, Kurtz I. Toxic alcohol ingestions: clinical features, diagnosis, and management. Clin J Am Soc Nephrol 2008;3:208-25. 4. Adinoff B, Bone H, Linnoila M. Acute ethanol poisoning and the ethanol withdrawal syndrome. Medical Toxicology 1988;3:172-93.
J.O. Quispe Gonzales, B. Gmez Giralda, C. Ruiz-Zorrilla Lpez, M.I. Acosta Ochoa, K. Ampuero Anachuri, A. Molina Miguel Nephrology Department. Ro Hortega University Hospital. Valladolid, Spain Correspondence: C. Ruiz-Zorrilla Lpez Seccin de Nefrologa. Hospital Universitario Ro Hortega. Dulzaina, 2. 47012 Valladolid. Spain. carlosruizzorrilla@hotmail.com
defect located in the hepatocyte peroxisome, which enhances glyoxylate conversion to poorly soluble oxalate.4 The AGXT gene is affected in primary hyperoxaluria type I, which is found in the chromosome 2q36-37. It corresponds with the alanine-glyoxylate aminotransferase enzyme (43kDa protein)2, which needs vitamin B6 (pyridoxine) to function correctly. Various mutations in the AGXT gene have been observed, involving multiple defects, among which the most frequent is the lack of immunoreactive and catalytic activity (42%).5 The only treatment performed successfully in these patients is liver or liver and kidney transplant, which may supplement enzymatic activity and kidney function, respectively. We present the case of a 24-year-old Maghreb man, with a history of chronic renal failure (CRF) secondary to nephrocalcinosis. He presented with several infections, two abscesses in the right psoas muscle and the left sternoclavicular joint, although the aetiological origin could not be identified in either of the two cases. In the same year he had a thalamic stroke and right perimesencephalic haemorrhage. He was admitted to his area hospital with severely deteriorated condition, with recurrent fever and episodes of arthritis in his right shoulder due to S. epidermis and in his left sternoclavicular joint due to enterococcus. Both were secondary to permanent catheter-related bacteraemia in the right jugular vein (he previously presented with thrombosis in several vascular accesses). During hospital stay (which lasted a year) numerous complications occurred: chronic severe anaemia, upper digestive haemorrhage, uraemic pericarditis, and pneumonia with pleural effusion. In the last few weeks of the hospital stay, he had left-side neck pains, significantly limited functions, fasciculations, fever, and negative blood culture tests. Magnetic resonance imaging (Figure 1) was performed. Secondary spondylodiscitis was suspected and the patient was referred to our health centre for a decompressive laminectomy.
During the physical examination upon arrival, we found deterioration of his general condition, cachexia with muscular atrophy (which prevented him from walking), hypotension, tachycardia and fever. He had a normal heart rate and a pansystolic murmur with hypoventilation of the lung bases. He had painless hepatosplenomegaly. Both knees were swollen and the right shoulder was visibly swollen. Anaemia was discovered in the laboratory tests (Hb: 8.3g/dl), leukocytosis: 18 900, parathyroid hormone (PTH): 83pg/ml and changes to inflammatory and nutritional parameters (GGT: 544IU/l; albumin: 0.7g/dl and ferritin: 5.93ng/ml PCR). A bone scan was performed, which showed signs of advanced secondary hyperthyroidism. The main alterations can be seen in Figure 1. The cervical CT revealed a significant kyphosis at the C5-C6 vertebral body height, alteration in their morphology and a severe reduction in the anteroposterior diameter, which significantly compressed the medulla at that point and caused foraminal stenosis. A biopsy and a bone marrow aspiration were performed which found multinucleated giant cells derived from monocyte macrophages containing oxalate crystals birefringent to polarised light. In the bone marrow the medullar space had been substituted by concentrically disposed crystals, grouped together in a star or rosette shape, which were refringent to polarised light, with peripheral reaction of giant cells and trabecular bone destruction (Figure 2). With these findings the patient was diagnosed with primary hyperoxaluria. Palliative treatment with vitamin B and intensive dialysis was indicated, but the patient died 30 days after hospitalisation. This case illustrates the harmful consequences associated with the delayed diagnosis of this rare disease, which is fatal if aggressive treatment is not indicated early. Current therapeutic alternatives for patients with CRF are
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Delayed diagnosis of primary hyperoxaluria in a young patient with advanced chronic renal failure
Nefrologia 2011;31(2):227-9
To the Editor, Primary hyperoxaluria (PHO) is a fairly rare metabolic alteration. Its annual incidence is 0.11-0.26/100 000 births and its prevalence is 1-2.9/1000 000 inhabitants, approximately.1 In Spain, there is a relatively high number of cases, given its increased incidence on the Canary Islands (especially La Gomera).2 Diagnosis is usually delayed: with an average interval of 3.4 years between the onset of the symptoms and its diagnosis. Only 30% of cases are diagnosed early.3 As such, in most cases, patients present with oxalate deposits in the definitive diagnosis, even in the cardiovascular system, which inevitably leads to death. PHO is caused by an enzymatic
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palliative (kidney transplant) or curative, although they have a high morbidity rate (liver and kidney transplant).2 In 1997, Hoppe found a very low PHO frequency in the dialysis population. He observed delayed diagnosis in 42% of the patients and 30% were diagnosed when they already had endstage kidney disease.3 The most common and earliest manifestations of the disease are nephrocalcinosis (due to oxalate crystals forming in the kidney parenchyma) and urolithiasis (being excreted through the pyelocaliceal system). Manifestations vary depending on the patients age. In small children, it is characterised by CRF with massive parenchymal oxalosis. Older children present with symptoms of urolithiasis and in some cases, complete obstruction with acute renal failure. It often occurs with end-stage kidney disease in adult patients. 6 Unfortunately, PHO diagnosis was delayed for our patient, leading to his death. A simple method for detecting this disease can be measuring urinary oxalate excretion. In normal conditions, excretion is 0.5mmol/1.73m2/day or 45mg/1.73m2/day. People with PHO have a significant increase in urinary oxalate excretion (>1mmol/1.73m2/day or 90mg/1.73m 2/day). 6 This excretion rate is less useful for kidney failure patients, as in our case, given that the patient already had advanced CRF. In these cases, the increase in plasma oxalate would help to reach a diagnosis, alongside calcium oxalate in tissues, 7 although not all laboratories have this possibility. A liver biopsy is the only test which confirms definitive diagnosis of PHO. Depending on the laboratory, it can provide information on whether there is immunoreactive protein or not (Western blot), subcellular localisation (IF) and even the type of mutation (sequencing). 9
228
Figure 1.
In our case, diagnosis was performed by biopsy and bone marrow aspiration. As a general rule, oxalate deposits appear in end-stage kidney failure, developing more quickly during chronic haemodialysis. These
oxalate deposits with surrounding reaction provoke lesions similar to secondary hyperparathyroidism lesions8 and severe anaemia resistant to erythropoietin (EPO), as has been described previously.10
E F
Figure 2. Multinucleated giant cells with oxalate crystals (panels A and B). Oxalate crystals birefringent to polarised light (panel C). Star or rosette-shaped oxalate crystal deposits (panel D), Refringent to polarised light (panel E). Peripheral reaction and destruction of bone trabeculae (panel F).
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Lastly, we must stress the importance of detecting this disease early, given that the effectiveness of treatment depends on how quickly it is diagnosed. A delayed diagnosis leads to CRF and massive oxalate deposits in organs and tissues. This must be considered for the population at risk: i.e. people from the Canary Islands and Maghrebians. The Canarian population with PHO are not Maghreb but Caucasian, but given that it is an island, a cross over has occurred.
1. Levy M, Feingold J. Estimating prevalence in single gene kidney diseases progressing to renal failure. Kidney Int 2000;58:925. 2. Santana A, Torres A, Salido E. Patologa molecular de la hiperoxaluria primaria. Nefrologia 2003;23(Supl 1):90. 3. Hoppe B, Langman CB. A United States Surrey on diagnosis, treatment, and outcome of primary hyperoxaluria. Pediatr Nephrol 2003;18:986. 4. Danpure CJ. Metabolic and clinical heterogeneity of primary hyperoxaluria type I. Am J Kidney Dis 1991;17:366. 5. Danpure CJ. Advances in the enzymology and molecular genetics of primary hyperoxaluria type 1. Prospects for gene therapy. Neprol Dial Trasplant 1995;10(Suppl 8):24. 6. Hoppe B, Leumann E. Diagnostic and therapeutic strategies in hyperoxaluria: a plea for early intervention. Neprol Dial Trasplant 2004;19:39. 7. Hoppe B, Kemper MJ, et al. et all. Plasmacalcium-oxalate saturation in children with renal insufficiency and in children with primary hyperoxaluria. Kidney Intern 1998;54:921. 8. Lorenzo V, Torres A, Hernandez D, et al. Evolucin de la enfermedad sea en pacientes con hiperoxaluria primaria en hemodilisis. Nefrologia 1990;10(1):53. 9. Lorenzo V, lvarez, A, Torres A, et al. Presentation and role of transplantation in adult patients with type 1 primary hyperoxaluria and the I244T AGXT mutation: Single-center experience. Kidney Int 2006;1115-9. 10. Lorenzo V, Hernndez D, Domnguez M, et al. Oxalosis as a cause of absolute resistance to EPO in chronic hemodialysis patients. Neprol Dial Trasplant 1992;7:1163-4. Nefrologia 2011;31(2):218-40 M. Martn1, G. Martn Reyes1, A. Torres de Rueda1, R. Toledo Rojas1, C. Jironda1, I. Garca2, T. Garca de la Oliva3, M.L. Prez Vaca4, D. Hernndez1 1 Nephrology Department. Carlos Haya Hospital. Mlaga, Spain. 2 Anatomical Pathology Department. Carlos Haya Hospital. Mlaga, Spain. 3 Radiology Department. Carlos Haya Hospital. Mlaga, Spain. 4 Haematology Department. Carlos Haya Hospital. Mlaga, Spain. Correspondence: G. Martn Reyes Servicio de Nefrologa. Hospital Regional Universitario Carlos Haya. Almirante Enrquez 10, Bajo D. 29017 Mlaga. Spain. gmartinr@senefro.org
the outpatient nephrology unit. In the physical examination BP was 162/100mm Hg and heart rate (HR) 74 systoles. She had no distal oedemas or other data of interest. Supplementary tests 1. Haemogram: normal. 2. Biochemistry: creatinine: 0.92mg/dl; glomerular filtration rate (GFR) calculated using MDRD-4 equation: 67ml/min; sodium: 140mEq/l; potassium: 3.3mEq/l; calcium: 9.7mg/dl; uric acid: 4.7mg/dl; GOT: 26IU/dl; GPT: 21IU/dl; LDH: 337IU/l; total bilirubin: 0.3mg/dl; normal coagulation, negative indirect Coombs test. 3. Venous gasometry: normal. 4. Urine: negative systematic and sedimentary tests, microalbuminuria/creatinine index: 8g/mg; uricosuria: 0.3g/24h. 5. Chest X-ray: no pathological findings. 6. Electrocardiogram: sinus rhythm, no blockages or signs of ischaemia. 7. Funduscopy: normal. 8. Anatomopathological exam of the placenta: normal. The abdominal ultrasound and renal Doppler scan were normal. Drug treatment was started with calcium antagonists and doxazosin, achieving better pressure control, although it was insufficient. A second analysis found plasma aldosterone of 1161pg/ml and urinary aldosterone of 22.68g/24h, with a plasma renin activity at baseline of 0.6ng/ml/h and aldosterone/renin rate of 193.3. The remaining parameters (catecholamines in urine, thyroid hormones and plasma cortisol) were all normal. Given the suspected primary hyperaldosteronism (PHA), a saline overload test was performed and 2 litres of physiological saline solution administered over 4 hours. Previous treatment did not have to be modified, however, we do recommend suspending angiotensin-converting enzymes (ACE), angiotensin II receptor antagonists (ARA-II), beta-blockers
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Diagnosis of secondary hypertension causing miscarriage during the first trimester of pregnancy
Nefrologia 2011;31(2):229-31
To the Editor, Uncontrolled arterial hypertension (AHT) during pregnancy compromises correct gestation development. We describe the case of a 41-year-old pregnant woman who was referred to our unit after having suffered a miscarriage in the tenth week of gestation. The patient had no personal or family history of interest, and ATH was detected in the eighth week of pregnancy. She visited the emergency department on several occasions due to metrorrhagia and asthenia, with blood pressure (BP) at around 160-170/100110mm Hg. Alpha-methyldopa was prescribed at 500mg every 8 hours, gradually increasing doses but without adequately controlling AHT. In the tenth week of pregnancy, the patient had a miscarriage and was referred to

and diuretics beforehand.1 Following the saline overload, aldosterone was not suppressed, being 27.6ng/dl (normal: <10ng/dl). PHA was confirmed as the cause of her secondary AHT and treatment with spironolactone was started, achieving better blood pressure control and relieving her asthenia. The examination was completed with a CT with contrast medium and magnetic resonance imaging, which revealed a 1cmadenoma in the left suprarenal gland (Figure 1). At present, BP is controlled with 50mg of spironolactone per day, and the patient is waiting for a left suprarenalectomy to avoid complications in future pregnancies. This case illustrates the serious complications that are secondary to poorly controlled ATH during pregnancy, such as miscarriage, abruptio placentae, and delayed foetal growth, which is likely to be related to vasoconstriction and placental The endothelial dysfunction.2 differential diagnosis of ATH during pregnancy involves testing for essential hypertension, pregnancy-related ATH, pre-eclampsia or secondary aetiology.3 Essential ATH. It is difficult to diagnose it during pregnancy if the patient has not been diagnosed with ATH previously or has not had any BP readings. Pregnant patients diagnosed with chronic ATH present with BP equal or above 140/90mm Hg on two occasions before the twentieth week of the pregnancy, which continues to persist 6 weeks postpartum. Our patient claimed that she had no history of ATH and no lesions to the target organ were found due to ATH. Pregnancy-related ATH. It is the main cause of hypertension during pregnancy, 4 and appears during the second half of the pregnancy in patients that were previously normotensive. It is not usually associated with oedemas or proteinuria and BP normalises after the birth, although high BP levels can persist up to 10 days following delivery. Pre-eclampsia. It is a pregnancyrelated disorder, which develops from the 20 th week. The patient has arterial hypertension and proteinuria above 0.3g/24h. 5 Proteinuria may become apparent in advanced phases of the pregnancy, meaning that in principle, pre-eclampsia should not be ruled out when there is no sign of proteinuria, especially if ATH is diagnosed after 20 weeks of pregnancy, with headaches, oedemas or altered laboratory findings (thrombocytopaenia, altered hepatic enzymes, hyperuricaemia). New low calciuria levels has been reported to be an early pre-eclampsia marker. 6 The patient in this case, had ATH before 20 weeks, no analytical alterations were found which would suggest pre-eclampsia. Secondary ATH. Some authors recommend assessing metanephrine and normetanephrine levels and performing an ultrasound scan of the suprarenal gland for patients with recently diagnosed ATH. 5 This is because a pheochromocytoma could be completely asymptomatic and fatal if not diagnosed before the birth. In our study, having dismissed previous essential ATH and pre-eclampsia, we investigated the possibility of secondary ATH, and finally diagnosed primary hyperaldosteronism from the supplementary tests mentioned above. The treatment of choice for ATH secondary to PHA is eplerenone or spironolactone but both of them should not be used during pregnancy due to the potential feminising effect that aldosterone has on male foetuses. 7 We have found very little evidence of eplerenone use during pregnancy. 8 Alpha-methyldopa, labetalol and amlodipine can be used as alternative treatments. Surgery should only be indicated during pregnancy for cases that are refractory to conventional treatment 9 or if patients have adenomas more than 4cm in diameter. 9 New laparoscopic surgical techniques during pregnancy have lead to greater effectiveness and less surgical risk for the mother and the baby. The retroperitoneal approach has more advantages than the transperitoneal one, given that organ movement is more restricted during the surgical procedure and because it uses much lower intraabdominal pressure.10,11 To conclude, PHA diagnosis is very rare during pregnancy, but it must be taken into consideration because early treatment could reduce severe complications related to poor blood pressure control.
1. Young WF Jr, Kaplan N, Rose B. Approach to the patient with hypertension and hypokalemia. UpToDate 2010. Available at: http://www.uptodate.com. 2. Saito Y, Omoto T, Fukuda M. Lobular pattern of choriocapillaris in pre-eclampsia with aldosteronism. Ophthalmol 1990;74(11):702-3. 3. Matsumoto J, Miyake H, Isozaki T, Koshino T, Araki T. Primary aldosteronism in pregnancy. J Nippon Med Sch 2000;67(4):275-9. 4. Marn R, et al. Hipertensin arterial en el embarazo: estudio 864 casos consecutivos Nefrologia 2011;31(2):218-40
A left, enlarged adrenal gland and a 1cmlesion indicative of adenoma (arrow).
Figure 1. MR of left adrenal gland

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observados durante un perodo de 24 aos. Revista Nefrologa 1999;19(4):30817. Mancia G, Grassi G, Kjldsen S. Manual de hipertensin de la European Society of Hipertensin. J & C Ediciones Mdicas, S.L., 2009;281-7. Conde-Agudelo A, Belizn JM, Lede R, Bergel E. Prediction of hypertensive disorders of pregnancy by calcium/creatinine ratio and other laboratory tests. Int J Gynaecol Obstet 1994;47:285-6. Okawa T, Asano K, Hashimoto T, Fujimori K, Yanagida K, Sato A. Diagnosis and management of primary aldosteronism in pregnancy: case report and review of the literature. Am J Perinatol 2002;19(1):31-6. Villa Alczar L. Indicacin de la eplerenona en la gestacin: no hay experiencia, evitar o sopesar riesgo/beneficio de su uso. Medimecum 2008. Young WF Jr, Kaplan NM. The adrenal incidentaloma: treatment, unilateral adrenal masses. UpToDate 2010. Available at: http://www.uptodate.com. Kosaka K, Onoda N, Ishikawa T, Iwanaga N, Yamamasu S, Tahara H, et al. Laparoscopic adrenalectomy on a patient with primary aldosteronism during pregnancy. Endocr J 2006;53(4):461-6. Epub 2006 Jul 5. Zafer Nursal T, Caliskan K, Ertorer E, Parlakgumus A, Moray G. Laparoscopic treatment of primary hyperaldosteronism in a pregnant patient. Can J Surg 2009;52(5):E188-E190. PMCID: PMC2769106.
5.
Flare lupus during induction teraphy with ciclophosphamide in difusse proliferative lupus nephritis
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7.2mg/dl; albumin: 1.7g/dl; total protein: 4.2g/dl; and the remaining parameters were normal. The haemogram showed: haematocrit: 31.3%, thrombocytopenia: 52 000, and an erythrocyte sedimentation rate (ESR) of 22mm/first hour. In the systematic haematuria sample and white blood count, the 24-hour urine protein was 5.90g/24h and creatinine clearance was 71ml/min. Immunological test had hypocomplementaemia C3: 45mg/dl (normal value [NV]: 79-152mg/dl); C4: 6mg/dl (NV:16-38mg/dl); normal immunoglobulins; and C-reactive protein: 1.23mg/dl (NV: 0-0.8mg/dl). The autoimmunity test: ANA +1/160 (speckled pattern); anti-DNA: >400; rest of antibodies, negative. Indirect Coombs test was negative. In the blood electrophoretic profile, hypoproteinaemia and hypoalbuminaemia were detected. The coagulation test was normal, with positive IgG and IgM anticardiolipins. There were no relevant findings from the chest X-ray. We saw that the patients kidneys were 14.5cm and hyperechogenic in the kidney ultrasound. The SLE diagnosis was made and a kidney biopsy was performed to assess the kidney damage: 40 glomeruli per cross-section were found and one of them was sclerotic. All of the glomeruli had a similar diffuse proliferative appearance, and more than 50% (36 glomeruli) were associated with an extracapillary proliferation (crescents). Fibrinoid necrosis was also observed in some glomeruli, as well as wire loops and haematoxylin bodies, with positive immunofluorescence: IgG (+++), IgM (+++), IgA (+++) and C3 (+++). No fibrosis or atrophy was found in the interstitial space, but mild nonspecific lymphocytic infiltration could be seen. The activity index was 18/24 and chronicity 1/12. The definitive diagnosis was lupus nephropathy type IV.
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To the Editor, Lupus nephropathy (LN) has a direct impact on the survival of patients with systemic lupus erythematosus (SLE). 1 Twenty percent of LN patients develop an end-stage chronic kidney disease 5-10 years after being diagnosed. 2 Two phases have been established for treating LN: induction therapy and maintenance therapy.3 We present the case of a patient diagnosed with SLE, who had severe kidney damage. While the patient was undergoing LN induction treatment with steroids and cyclophosphamide, his kidney condition worsened, having developed a severe nephritic syndrome. The patient was a 22-year-old man, smoker, with personal history of migraines and ventricular extrasystoles. He had been examined by the rheumatology and haematology departments due to thrombocytopenia. He was not allergic to any medication. The patient attended the emergency department with a fever of >38C over a 10day period, with asthenia and joint pain. On physical examination, he was in a generally good condition, conscious and aware of his surroundings. Blood pressure was 120/80mm Hg; temperature: 38C; heart rate: 90 beats/min. He had a bilateral malar erythema and mucocutaneous paleness. He had piercings and tattoos. He did not have jugular ingurgitation, and the rest of the examination was normal. Biochemical analysis (blood): creatinine: 1.3mg/dl; uric acid:
11.
O. Fikri Benbrahim1, R. Garca Agudo1, F. Cazalla Cadenas1, A. Martnez Calero1, J. Gonzlez-Spnola2 1Nephrology Department. La Mancha-Centro Hospital Complex. Alczar de San Juan, Ciudad Real, 2 Radiology Department. La Mancha-Centro Hospital Complex. Alczar de San Juan, Ciudad Real, Spain Correspondence: O. Fikri Benbrahim Seccin de Nefrologa. Hospital La Mancha Centro. Avenida de La Constitucin, 3. 13600 Alczar de San Juan. Ciudad Real. Spain. fikrioussamah@yahoo.fr
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Given the biopsy findings, treatment with 1g i.v. of 6-methylprednisolone (three pulses), followed by prednisone 1mg/kg/day p.o. and 1g cyclophosphamide. The patient was discharged and monitored on an outpatient basis. After being discharged (14 days after having received the first cyclophosphamide pulse), the patient attended the emergency department once again with joint pain for 2-3 days, oedemas in the lower limbs and facial oedema; gross haematuria (coca-cola coloured), and fever. The patient said that he had completed the treatment prescribed upon discharge and had no other clinical findings that indicated infection. On physical examination, he was in a generally good condition; he was conscious and aware of his surroundings. Blood pressure was 161/83mm Hg; temperature 36.5C; and heart rate 95 beats/min. He still had bilateral malar erythema and mucocutaneous paleness. During the rest of the examination we found oedemas on the lower limbs up to the top of the thigh. Biochemical analysis (blood): creatinine: 1.2mg/dl; albumin: 2.7g/dl; total protein: 4.6g/dl. The haemogram showed that the haematocrit had decreased to 24.4%, and the thrombocytopenia remained at 51 000. The remaining parameters were normal. The new sediment revealed macroscopic haematuria and haematic casts. 24-hour urine protein had increased to 31g. In the immunological test we found a reduction in immunoglobulin G to 55mg/dl, with C3: 83mg/dl (NV:79152mg/dl); C4: 1.6mg/dl (NV: 1638mg/dl) and C-reactive protein: 0.12mg/dl. The autoimmunity test: ANA +1/80 (speckled), negative antiDNA and cryoglobulins.
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The chest X-ray and Doppler kidney ultrasound did not show any pathological findings. The blood culture, urine culture and joint fluid culture (knee) were all negative. We repeated treatment with pulses of 1g of 6-methylprednisolone (three pulses) followed by prednisone at 1mg/kg/day and increased the cyclophosphamide pulse to 1.5g, which was brought forward. This decision was made because the patient presented with well-developed nephritic syndrome, he had lupus activity and had previously been diagnosed with type IV lupus nephropathy. We also considered that renal vein thrombosis, infectious processes and therapy nonadherence had already been ruled out. The patient then received pulses of cyclophosphamide 1.5g/month (6 months) and cyclophosphamide 1.5g (every three months, two cycles), with a tapering regimen of steroids. He was later administered a maintenance treatment with azathioprine. With this treatment, progress was favourable. The patient was not hospitalised again, and kidney function normalised (plasma creatinine: 1.1mg/dl) and negative proteinuria. Although slight microhaematuria persisted, the haemogram and immunological test normalised. Cyclophosphamide is considered to be the immunosuppressant with the best results in induction treatment of severe forms of proliferative LN.4 After having completed the induction treatment, it is possible that up to 20% of LN patients do not respond adequately to induction immunosuppression.5 In our case, less than 2 weeks had passed since the treatment had started to be able to consider the patient non-responsive. In non-responsive patients, compliance must be ensured, and renal vein thrombosis and infections ruled out.3 In our case, the patient had received cyclophosphamide 1g in the hospital (together with pulses of glucocorticoids i.v. and oral steroids, which the patient told us he had not stopped taking). We
also ruled out infectious processes, as well as renal vein thrombosis. Nevertheless, systemic manifestations relapsed and his renal condition worsened, presenting with welldeveloped nephritic syndrome. For refractory cases, various therapeutic options are indicated, including: increasing glucocorticoid doses (repeating pulses of 6methylprednisolone), repeating induction treatment with cyclophosphamide, using calcineurin inhibitors, mycophenolic acid, plasma turnover, depleting lymphocytes with rituximab.3 Recent meta-analyses deem induction therapy with mycophenolate more efficient than cyclophosphamide in severe LN.6 However, these results should be interpreted with caution given the limitations:3 Although most studies included severe LN, others also included other LN forms, i.e. type III and V. That is why, cyclophosphamide is the best immunosuppressant with the best result in severe LN relapse.4 In our case, given the severity of the process, together with the biopsy findings, we decided to repeat the regimen that was initially established at 1g i.v. pulses of 6-methylprednisolone and one pulse of cyclophosphamide i.v., increasing dosage to 1.5g in this case. After this moment, the patients progress was satisfactory. The American National Institute of Health (NIH)7 promotes a gold standard cyclophosphamide dose of 0.75-1g/m2, while the Euro-Lupus Nephropathy Trial2 states that 500mg every 15 days should be administered. In our case, we administered cyclophosphamide 1g at the start of treatment and in less than 15 days the patient presented systemic and renal activity again. Given the favourable response after increasing the cyclophosphamide pulse to 1.5g/month, it is possible that this lupus flare could have been due to the initial underdosing of cyclophosphamide. To conclude, it is important to take into consideration the cyclophosphamide dosage administered before considering it to be inefficient and/or assess other alternative therapy regimens, as
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cyclophosphamide underdosing could be the cause of non-responsive patients.
1. Cervera R, Khamastha MA, Font J, Sebastin GD, Gil A, Lavilla P, et al. Morbidity and mortality in systemic lupus erythematosus during a 10-year period: a comparison of early and late manifestations in a cohort of 1,000 patients. Medicine (Baltimore) 2003;82:299-308. 2. Houssiau FA, Vasconcelos C, DCruz D, Sebastiani GD, De Ramn Garrido E, Danieli MG, et al. Immunosupressive therapy in lupus nephritis: the Euro-lupus Nephritis Trial, a randomized trial of lowdose versus high dose intravenous cyclophosphamide. Arthritis Rheum 2002;46:2121-31. 3. Espinosa Garriga G, Cervera Segura R. Nuevos conceptos en el tratamiento de la nefropata lpica. Rev Clin Esp 2007;207:570-2. 4. Burchardi C, Schlndorff D. Induction therapy for active lupus nephritis: mycophenolate mofetil versus cyclophosphamide. Nat Clin Pract Nephrol 2006;2:314-5. 5. Mok CC, Ying KY, Ng WL, Lee KW, To CH, Lau CS, et al. Long term outcome of diffuse proliferative lupus glomerulonephritis treated with ciclophosphamide. Am J Med 2006;119:e25-33. 6. Zhu B, Chen N, Lin Y, Ren H, Zhang W, Wang W, et al. Mycophenolate mofetil in induction and maintenance theraphy of severe lupus nephritis: a metaanalysis of randomised controlled trials. Nephrol Dial Transplant 2007;3(doi:10.193/ndt/gfm066). 7. Houssiau FA. Cyclophosphamide in lupus nephritis. Lupus 2005;14:53-8. M. Heras1, A. Saiz2, M.J. Fernndez-Reyes1, R. Snchez1, P. Zurita3, C. Urrego3 1 Nephrology Department. General Hospital of Segovia. Segovia, Spain 2 Anatomical Pathology Department. Ramn y Cajal Hospital. Madrid, Spain 3Rheumatology Department. General Hospital of Segovia. Segovia, Spain. Correspondence: M. Heras Servicio de Nefrologa. Hospital General de Segovia. Spain manuhebe@hotmail.com Nefrologia 2011;31(2):218-40
Multiple myeloma, severe hypercalcaemia, acute renal failure and multiple organ failure due to calcinosis
Nefrologia 2011;31(2):233-4
To the Editor, Renal failure in multiple myeloma is frequent; it is found in 20%-40% of cases at diagnosis and is an unfavourable prognostic factor. Myeloma kidney and hypercalcaemia are the most frequent causes. Other contributing factors are dehydration, hyperuricaemia, nephrotoxic drugs and iodine contrasts. Repeated episodes of hypercalcaemia can produce calcium salt deposits in tissues, especially those with an alkaline medium, such as kidneys, lungs or gastric mucosa. We present the case of a 38-year-old man, with multiple myeloma, severe hypercalcaemia, acute renal failure, metastatic calcinosis and multiple organ failure. The patient had no pathological history, was a smoker of 40 cigarettes/day, and an alcohol consumer. He visited the emergency department with general polymyalgia, nocturia, and oedemas around the ankles for one week. For 48 hours before his visit, he had taken paracetamol every 8 hours. In the physical examination he had mucocutaneous paleness. Blood pressure: 120/70; temperature: 37.4C; auscultation: normal. Abdominal palpation: no findings. Lower limbs had no oedemas. Laboratory tests showed creatinine: 9.8mg/dl; urea: 198mg/dl; haemoglobin: 9.8g/l; potassium: 4.7mEq/l; sodium: 134mEq/l; haemoglobin: 9.6mg/dl; haematocrit: 27%; leukocytes: 15 900 with 71% neutrophils; platelets: 135 000; creatine phosphokinase (CPK): 4.62IU/l; calcium: 15mg/dl; ionic calcium: 7.71mg/dl. Sediment:
proteinuria: 300mg/dl; red blood cells: 5/10/high power field (HPF); leukocytes: 0-5/HPF. The kidney ultrasound showed that the kidneys were of normal size, no hydronephrosis, and increased echogenicity. The chest X-ray was normal. Tests pointed towards acute renal failure with severe hypercalcaemia. Daily haemodialysis was started with low calcium concentrations in the solution and subcutaneous calcitonin. On the third day after admission, the patient developed acute respiratory failure and neurological deterioration. He was therefore transferred to the ICU, with suspected tumoural hypercalcaemia requiring thoracic and cranial CT scans and proteinogram. We observed bilateral alveolar infiltration, right fronto-tempoparietal subdural haematoma with subfalcine and transtentorial herniation. The haematoma was surgically drained and the patient died 8 hours after the intervention. Monoclonal IgG kappa was detected in the proteinogram. An autopsy was carried out, diagnosing multiple myeloma kappa, affecting the bone marrow; metastatic calcification mainly in the kidneys, stomach, lungs, liver and vessels, and pulmonary haemorrhage with respiratory distress. Hypercalcaemia is produced in patients with multiple myeloma due to the increased bone resorption caused by osteoclast activation, especially due to the hyperactivity of the RANK/RANKL receptor. Kidney failure is produced by lesions on the renal tubular epithelium, which alters the ability to concentrate urine and sometimes causes epithelial cell necrosis and obstruction of the tubules. This can then lead to stasis and calcium deposits in the kidney. Treatment should be started quickly, ensuring the patient is hydrated and using anti-myeloma therapy, including steroids. Calcitonin inhibits bone resorption without risk of nephrotoxicity, but its hypocalcaemic effect is modest and transitory. Bisphosphonates, potent osteoclast inhibitors, are very effective for severe hypercalcaemia, but are a risk for kidney toxicity and hypocalcaemia. The most used are pamidronate, and
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zoledronic acid, but the latter is not recommended when creatinine levels are above 3mg/dl. Some studies recommend using ibandronate for patients with renal failure, as it is less nephrotoxic, and some authors have even used ibandronate for patients with myeloma and renal failure caused by hypercalcaemia or nephrocalcinosis, recovering renal function and calcium levels. Haemodialysis must be started for oliguric renal failure cases. In our case, we started treatment with calcitonin and daily haemodialysis, but the patients condition progressed rapidly, with multiple organ failure and respiratory distress due to tumoural calcinosis. In conclusion, we must highlight the need to closely monitor calcium levels in patients with multiple myeloma and start therapeutic measures early. For cases of malignant hypercalcaemia, we recommend bisphosphonates as be the most effective therapy, and for renal failure the least nephrotoxic drugs at an adjusted dosage.
1. Dimopulos MA, Kastritis E, Rosnol L, Blade J, Ludwig H. Pathogenesis and treatment of renal failure in multiple myeloma. Leukemia 2008;22:1485-93. 2. Weber CK, Prummer O, Frickhofen N, Friedrich JM, Hoffmeister A, Merkle E, et al. Reversible metastatic pulmonary calcification in a patient with multiple myeloma. Ann Hematol 1996;72:329-32. 3. Garca-Sanz R, Mateos MV, San Miguel JF. Mieloma mltiple. Med Clin (Barc) 2007;129(3):104-15. 4. Triner WR, Birdwell MD. Severe Hypercalcemia presenting with multisystem organ failure. Am J Emerg Med 13(6):673-6. 5. Weide R, Koppler H, Antras L, Smith M, Chang E, Green J, et al. Renal toxicity in patients with multiple myeloma receiving zoledronic acid vs ibandronate: A retrospective medical records review. J Can Res Ther 2010;6:31-5. 6. Henrich D, Hoffmann M, Uppenkamp M, Bergner R. Ibandronate for the Treatment of Hypercalcemia or Nephrocalcinosis in Patients with Multyple Myeloma and Acute Renal Failure: Case Reports. Acta Haematol 2006;116:165-72. 234 J.G. Martnez Mateu, G.P. Losada Gonzlez, M.A. Munar Vila, M. Uriol Rivera, G. Gmez Marqus, A.C. Tugores Nephrology Department. Son Dureta Hospital. Palma de Mallorca, Balearic Islands, Spain Correspondence: J.G. Martnez Mateu Departamento de Nefrologa. Hospital Son Dureta. Palma de Mallorca, Islas Baleares. Spain josefag.martinez@ssib.es
ingurgitation. Blood pressure was 135/85mm Hg, heart rate was 82 beats/min and SatO2: 92%. The heart auscultation was rhythmic and pulmonary auscultation presented hypoventilation with isolated wheezing. The rest of the examination was normal. The blood analysis (emergency department) was: creatinine: 2.9mg/dl (previous creatinine: 1.2mg/dl); potassium: 5.3mEq/l; haemoglobin: 11.5g/dl; haematocrit: 34.7%; remaining analyses, including venous gasometry and the coagulation test, were normal. Systematic urine analysis showed: protein +++, blood ++. The sediment test showed haematuria, with isolated hyaline casts. Chest X-ray and abdominal ultrasound did not show any pathological findings, the kidneys were of normal size, and the excretory tract was not dilated. The subsequent blood analysis (common) showed: creatinine: 3.9mg/dl; urea: 181mg/dl; albumin: 2.7g/dl; total protein: 5g/dl; calcium: 6.9mg/dl; phosphorus: 8.1mg/dl; uric acid: 8.3mg/dl; sodium: 132mEq/l. 24hour urine test found microalbuminuria, which was 620g/min (normal range: 015g/min). Other supplementary tests performed were normal (including viral serology, blood culture, tumour markers and thyroid hormones). The immunological test only showed a decrease in IgG of 574mg/dl (normal value: 751-1560) and an increase in Creactive protein to 8.7mg/dl. No monoclonal peak was detected on the electropherogram. The patient had been admitted to the internal medicine department, where progressive deterioration of the renal failure and oligoanuria were confirmed. Renal replacement therapy with haemodialysis was started. Given the rapidly progressive acute renal failure, a kidney biopsy was performed, finding the following: 12 glomeruli per crosssection, none of which was sclerotic.
Nefrologia 2011;31(2):218-40
Rapidly progressive renal failure as the onset of an IgA nephropathy in an elderly patient
Nefrologia 2011;31(2):234-6 doi:10.3265/Nefrologia.pre2010.Nov.10661
To the Editor, IgA nephropathy is the most frequent primary glomerulopathy in the world.1,2 It is often presented as macroscopic haematuria (generally preceded by a respiratory infection in the upper airways, especially in children), and persistent microhaematuria with mild proteinuria. Nephrotic syndrome and acute renal failure are the least common manifestations. We describe the case of an elderly patient that was diagnosed with IgA nephropathy, as a result of rapidly progressive renal failure (RPRF). The patient was a 78-year-old man with a history of prostate carcinoma, treated with brachytherapy and radiotherapy check-ups every 6 months; carpal tunnel syndrome; right hip operation; and no known drug allergies. His doctor had referred him to the emergency department due to tiredness and pain in his lower limbs. The patients medical records indicated that he had suffered from nocturia on two occasions. The physical examination performed upon admission indicated that the patients general condition was fair. He was conscious and aware of his surroundings. He did not have jugular
letters to al director cartas the editor

We observed an expansion of the mesangial matrix with cellular proliferation in all of the glomeruli examined. On occasions, they affected the whole glomerulus, with pseudo-lobe images of the vascular tuft. There were fibrinoid necrosis foci in three glomeruli. The immunofluorescence showed intense positivity for IgA and C3, being negative for IgG and IgM. All the alterations found pointed to mild acute tubular necrosis with mixed inflammatory infiltration. The final diagnosis was IgA nephropathy with diffuse proliferation and fibrinoid necrosis foci (Figures 1 and 2). As well as the support therapy with furosemide, enalapril was administered at 40mg/day, irbesartan 150mg/day and doxazosin 8mg/day. The biopsy findings lead to administration of three pulses i.v. of 1g of 6-methylprednisolone followed by prednisone at a dose of 1mg/kg/day. Diuresis was recovered with these measures, and kidney function gradually improved without the need for dialysis (creatinine reduced from 5.4mg/dl to 2mg/dl upon hospital discharge). Table 1 shows the follow-up and progress following hospital discharge. There are mild forms of IgA nephropathy that can go unnoticed. In fact, in some autopsy and biopsy studies conducted to assess renal grafts, IgA nephropathy can be found in around 1.5% of the normal population.3 We describe the case of an elderly patient, who had no previous nephrology problems, who was diagnosed with IgA nephropathy following a kidney biopsy to confirm the cause of RPRF. IgA nephropathy can appear at any age, but most frequently during the second and third decades of the life.4 It is possible that the prevalence in the elderly population is higher than has been described in the literature, possibly due to kidney biopsy indication. Persistent urinary alterations may attribute to other concomitant disorders (prostatitis, infections, etc.) and if a kidney biopsy is not performed, IgA
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Figure 1. Haematoxylin and eosin (20x) with two glomeruli with intense diffuse proliferation of the capillaries.
Figure 2. Haematoxylin and eosin (40x) with one glomerulus with intense diffuse proliferation and fibrinoid necrosis foci.
Although this nephropathy is the most frequent one, an optimum treatment has not been wellestablished. 6 Based on a review of 20 years experience, a third of these patients can develop end-stage chronic kidney disease (ECKD). 7 Two studies have recently been published which have shown the benefits of co-administering corticoids (short-term) and angiotensin-converting enzymes (ACE) to treat IgA nephropathy with moderated histological lesions, with proteinuria above 1g/day.8,9 Combined immunosuppressant therapy is indicated in patients with rapidly progressive active severe disease and with histological evidence of active severe inflammation (crescents).10 In our case, we treated a patient with a history of prostate cancer and rapidly progressive renal failure, with diffuse proliferation, with diffuse proliferation and fibrinoid necrosis foci and with no chronicity data. We decided to treat the patient with i.v. pulsed steroids followed by oral steroids with ACE and angiotensin II receptor antagonists. The patient progressed satisfactorily. In summary, we have reported one more IgA case in an elderly patient, which probably would have gone unnoticed if the aggressive clinical symptoms had not started.
nephropathy may be underdiagnosed.5 Given our patients history of prostate carcinoma, this nephropathy could have gone unnoticed if it had not been for obvious manifestations of acute renal failure.
Table 1. 12-month clinical follow-up following hospital discharge 10 days

Cr plasma (mg/dl) P (O) (g/24 h) Basic urine test Blood pressure (mmHg) Enalapril Telmisartan Prednisona 40 mg/day 80 mg/day 80 mg/day 2 5.7
2 months
1.6 1.67 >40RBC/HPF 130/70 40 mg/day 80 mg/day 80 mg/day
3 months
1.7 0.71 >35RBC/HPF 124/72 20 mg/day 80 mg/day 70 mg/day
6 months
1.5 () 4-6RBC/HPF 123/67 40 mg/day 20 mg/day
1 year
1.4 () 1-3RBC/HPF 110/70 2.5 mg/day
CR plasma: serum creatinine; P (O): proteinuria
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1. Galla JH. IgA nephropathy. Kidney Int 1995;47(2):377-87. 2. Donadio JV, Grande JP. IgA nephropathy. N Engl J Med 2002;347(10):738-48. 3. Suzuki K, Honda K, Tanabe K, Nihei H, Yamaguchi Y. Incidence of latent mesangial IgA deposition in renal allograft donors in Japan. Kidney Int 2003;63:2286-94. 4. Clarkson AR, Woodroffe AJ, Bannister KM, Lomax-Smith JD, Aarons I. The syndrome of IgA nephropathy. Clin Nephrol 1984;21:7-14. 5. Heras M, Saiz A, Snchez R, Fernndez-Reyes MJ, Molina A, Rodrguez MA, et al. La biopsia renal en pacientes de 65 o ms aos: existen diferencias en la indicacin y en la histopatologa respecto al resto de pacientes? Rev Esp Geriat Gerontol 2010;45(6):316-9. 6. Appel GB, Waldman M. The IgA nephropathy treatment dilemma. Kidney Int 2006;69(11):1939-44. 7. DAmico G. Natural history of idiopathic IgA nephropathy: role of clinical and histological prognostic factors. Am J Kidney Dis 2000;36:227-37. 8. Manno C, Torres DD, Rossini M, Pesce F, Schena FP. Randomized controlled clinical trial of corticosteroids plus ACE-inhibitors with long-term follow-up in proteinuric IgA nephropathy. Nephrol Dial Transpl 2009;24:3694-701. 9. Lu J, Zhang H, Chen Y, Li G, Jiang L, Singh AK, Wang H. Combination therapy of prednisone and ACE inhibitors versus ACE-inhibitors alone in patients with IgAnephopathy: a randomized controlled trial. Am J Kidney Dis 2009;53(1):26-32. 10. Ballardie FW, Roberts IS. Controlled prospective trial of prednisolone and cytotoxics in progressive IgA nephropathy. JASN 2002;13(1):142-8.
Cytomegalovirusassociated haemophagocytic syndrome in a kidney transplant patient

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M. Heras1, A. Saiz2, J. Pardo3, M.J. Fernndez-Reyes1, R. Snchez1, F. lvarez-Ude1 1 Nephrology Department. General Hospital. Segovia, Spain. 2 Anatomical Pathology Department. Ramn y Cajal Hospital. Madrid, Spain. Internal Medicine Department. General Hospital. Segovia, Spain. Correspondence: M. Heras Servicio de Nefrologa. Hospital General. Ctra. de vila. 40002 Segovia. Spain. manuhebe@hotmail.com mherasb@saludcastillayleon.es 236
To the Editor, Haemophagocytic syndrome is a rare clinical condition characterised by a generalised, benign proliferation of histiocytes with significant haemophagocytic activity.1-3 The aetiology of these symptoms can be separated into two groups: primary or genetically determined, or secondary: virus, bacteria, fungus, parasites, neoplasia, collagen, immunodeficiency or drugs.1-7 Clinical symptoms include fever, hepatosplenomegaly, lymphadenomegaly, neurological symptoms, oedema and rashes.1,2,8,9 The most important laboratory findings are: pancytopaenia, hypertriglyceridaemia, hypofibrinogenaemia, hyponatraemia, hypoproteinaemia, increased levels of hepatic enzymes, increased amount of LDH and ferritin, pleocytosis in LCR and defective activity of natural killer (NK) cells.10 The histological analysis found haemophagocytosis in the bone marrow, spleen and lymph nodes. There were no malignant findings and diagnosis was possible with 2% of haemophagocytic cells.1-3 Haemophagocytic syndrome has a poor prognosis despite treatment, with an average survival of 2 weeks after the onset of the clinical symptoms. Survival can reach 60% at 5 years if there is an adequate response to treatment.11,12 Agents that interrupt histiocyte function and macrophage activation are therapeutic alternatives, such as etoposide, steroids, high-dose i.v. Ig, cyclosporine A, anti-thymocyte globulin, anti- TNF antibodies, and in some cases, bone marrow transplant.13,14 We present the case of a 53-year-old man, subjected to kidney transplant, who came to the emergency department with fever, temperature
38.5C over a 24-hour period, with shivers, mild diffuse abdominal pain, asthenia, anorexia, and a decrease in diuresis volume. The physical examination was normal and no important pathology was found from the tests performed at the emergency department: normal X-ray; normal blood and urine tests; negative blood and urine cultures; negative cytomegalovirus (CMV) early-antigen (at that time, CMV polymerase chain reaction (PCR) assays were not available in our hospital). The symptoms worsened, abdominal pain increased, and on the CT scan we observed dilated small bowel loops due possibly to ischaemia or infection. Given the findings and the worsening clinical symptoms, we performed an exploratory laparotomy, without observing anomalies. A coagulasenegative staphylococcus grew in the peritoneal fluid, which was treated with meropenem at 500mg every 12 hours. Following the intervention, the clinical symptoms improved despite having developed a post-operative paralytic ileus, which improved spontaneously. After a few days, the patient presented with fever again, and diarrhoea. There were initially no traces of blood, but he then presented with melaena, associated with neurological deterioration, hepatosplenomegaly and hepatic function alterations, anaemia and thrombocytopaenia. New tests were requested: positive CMV early-antigen; CMV PCR assay above 100 000 copies/ml. Eso-Gastro-Duodenoscopy (EGD): infected oesophagus. Analytical tests showed: GOT/GPT: 135/156IU/l; LDH: 558IU/l; sodium: 130mEq/l, fibrinogen:133mg/dl, haemoglobin: 9.2 g/dl; and haematocrit: 26.8%; platelets: 48 000l with normal leukocytes (normal formula: 5500l), significant increase in triglycerides (738mg/dl), progressive deterioration of kidney function (creatinine around 4-5mg/dl). Normal haptoglobin, negative indirect Coombs test. Peripheral blood smear: few schistocytes with no reticulocyte. Bone marrow aspiration: compatible with haemophagocytic syndrome (Figure 1).
Nefrologia 2011;31(2):218-40

Given these findings, the patient was diagnosed with CMV-associated haemophagocytic syndrome. The patient visited infection diseases unit and the following therapeutic regimen was started: anti-CMV with ganciclovir 50mg/12h and non-specific i.v. gamma globulin 30g/48h, and methylprednisolone bolus were indicated for haemophagocytic syndrome. The patient continued to take cyclosporine at low doses (around 50ng/ml). Despite being treated, the patients general and neurological condition worsened and he was finally admitted to the ICU for saturation, where he died 12 hours after admission due to multiple organ failure. The autopsy showed: disseminated CMV infection, mainly affecting the digestive tract and lung (Figure 2) and reactive haemophagocytic syndrome (Figure 1). The prevalence of haemophagocytic syndrome in kidney transplant patients is 0.4%, 11 which makes it a rare complication in this patient group. Furthermore, the most common aetiology for these patients is that secondary to an infection. 14 These patients have poor prognosis meaning that early diagnosis is essential to enable starting therapy early. There is no consensus on treatment strategies, and several treatments have been proposed, such as steroids and cyclosporine, 14 specific immunoglobulin, treating the aetiological agent, etc. On the other hand, CMV-associated infections in kidney transplant patients is a common complication, although its incidence and repercussion is decreasing due to the prophylaxis employed.15 In spite of this, it is a diagnosis that we should take into account when a transplant patients general condition deteriorates, because the complications for this infectious profile are all serious. Early diagnosis and starting correct therapy greatly improves prognosis. Haemophagocytic syndrome is a rare complication following kidney
Nefrologia 2011;31(2):218-40 1. McClain KL. Up to Date. Haemophagocytic lymphohistiocytosis. Available at: http://www.uptodate.com/contents/hemo phagocytic-lymphohistiocytosis. Version 18.2. May 2010. 2. Artigues Barcel A, Ferragut Reus M, Snchez C, Amengual L, Matanza L, Sanz Parras MS. Sndrome hemofagoctico y linfoma cutneo de clulas T. An Med Interna (Madrid) 2004;21:131-4. 3. Janka G, Imashuku S, Elinder G, Schneider M, Henter JI. Infection- and malignancyassociated hemophagocytic syndromes. Secondary hemophagocytic lymphohistiocytosis. Hematol Oncol Clin North Am 1998;12:435-44. 4. Stephan JL, Kone-Paut L, Galambrun C, Mouy R, Bader-Meunier B, Prieur AM. Reactive haemophagocytic syndrome in children with inflammatory disorders. A retrospective study of 24 patients. Rheumatology 2001;40(11):1285-92. 5. Boehler A, Schaffner A, Salomon F, et al. CMV disease of late onset following renal transplantation: a potentially fatal entity. Scand J Infect Dis 1994;26:369. 6. Krsat S, Cagirgan S, Ok E, et al. Haemophagocytic-histiocytic syndrome in renal transplantation. Nephrol Dial Transplant 1997;12:1058. 7. Mroczek E, Weisenburger D, Grierson H, Markin R, Purtilo D. Fatal infectious mononucleosis and virus associated hemophagocytic syndrome. Arch Pathol Lab Med1987;111:530-5. 8. De Kerguenec C, Hillaire S, Molinie V, et al. Hepatic manifestations of haemophagocytic syndrome: a study of 30 cases. Am J Gastroenterol 2001;96(3):852-7. 9. Wong K, Chan J. Reactive hemophagocytic syndrome: a clinicopathologic study of 40 patients in an Oriental population. Am J Med 1992;93:177-80. 10. Esumi N, Ikshima S, Hibi S, Todo S, Imashuku S. High serum ferritin level as a marker of malignant histiocytosis and virus-associated haemophagocytic syndrome. Cancer 1988;61(10):2071-6. 11. Karras A, Thervet E, Legendre C. Haemophagocytic syndrome in renal transplant recipients: report of 17 cases and review of literature. Transplantation 2004;77(2):238-43. 12. Risdall RJ, McKenna RW, Nesbit ME, et 237
Figure 1. Trichrome staining. Histiocytes with red blood cells indicating haematophagous activity in bone marrow.
Figure 2. Immunoperoxidase staining. Cells containing CMV in the intestinal tissue.
transplantation. Furthermore, it is a clinical entity that must be considered during the differential diagnosis of these patients, especially if associated with fever, organomegaly and pancytopenia. Bone marrow aspiration allows for a clearer diagnosis, whereas blood test analyses only enable us to make presumptions (pancytopaenia, hepatic kidney function alteration, increase in LDH, decreased fibrinogen, increased triglycerides, hyponatraemia, etc). Viral infection is the most common triggering agent for immunosuppressed patients. The problem is that there is still no specific treatment, meaning that transplant patient survival is very low, and if patients were to survive, the kidney graft does not often function correctly.

al. Virus-associated hemophagocytic syndrome: a benign histiocytic proliferation distinct
proteinuria). When it is present in tubules is histologically called myeloma kidney.1 We report the case of a 53-year-old patient, diagnosed with MM IgA lambda stage IIIB according to the Durie Salmon staging system. He presented with acute renal failure, likely to be secondary to myeloma kidney. He was indicated haemodialysis at diagnosis. He started front line chemotherapy with bortezomib, adriamycin and dexamethasone (PAD combination therapy) prior to AHPCT with melphalan, with excellent clinical tolerance, which allowed him to achieve complete remission (CR). However, he had no kidney response. Eleven months after starting the dialysis programme, the patient presented with an improved glomerular filtration rate (GFR) and was able to stop dialysis treatment definitively 14 months after diagnosis (Table 1). The degree of renal dysfunction has an impact on MM patients prognosis, especially in those that need dialysis, reporting lower survival rates, higher short-term mortality (estimated 4 months), greater susceptibility to infections, longer hospital stays and greater compromise to the patients quality of life. High-dose chemotherapy and AHPCT have traditionally been contraindicated for all of these reasons.5 However, the treatment of choice is polychemotherapy in patients under 65 years with a generally good condition. As well as dexamethasone, regimens include vincristine, adriamycin and cyclophosphamide, together with new myelomatosis drugs: thalidomide, lenalidomide and bortezomib, followed by AHPCT,5,6 as well as dialysis support when necessary, given that it increases the likelihood of CR for 20%-40% of cases. It has a progression-free survival of 2.5-4 years and a general survival of 4-5 years,7-9 with total or partial GFR recovery in 25%-58%, which entails improved survival.4,10
S. Bea Granell1, I. Beneyto Castello1, D. Ramos Escorihuela1, J. Snchez Plumed1, P. Snchez Prez1, J. Hernndez-Jaras1, S. Rivas2 1 Nephrology Department. La Fe University Hospital. Valencia, Spain. 2 Anatomical Pathology Department. La Fe University Hospital. Valencia, Spain. Correspondence: S. Bea Granell Servicio de Nefrologa. Hospital Universitario La Fe. Avda Campanar, 21. 46009 Valencia. Spain. serbegra@yahoo.es
Tauro et al, and other authors, have reported that patients who receive chemotherapy and AHPCTs can obtain partial kidney function recovery, reducing their dialysis dose and frequency. However, very few patients are able to definitively stop dialysis following treatment. They also describe that the type of paraprotein used (IgA and IgM are associated with a higher risk of progression than IgG), MM evolution time, and renal failure evolution time influence partial kidney function recovery.4,10,11 Badros et al conducted the first prospective study on MM patients undergoing AHPCT. They reported that patients under 70 years old with MM and renal failure including those on dialysis, should be treated with lower chemotherapy doses (melphalan at 140mg instead of 200mg), as it reduces the incidence of adverse effects. They also describe early AHPCT as being a safe treatment, which increases the likelihood of CR, total or partial GFR recovery, and therefore, overall survival. However, results show that 12 months after renal failure, GFR recovery is highly unlikely.4 Matsue recently published a study on the possibility of reversing dialysisdependent renal failure, and its relation to light chains. This study considered high-dose dexamethasone to be the gold standard treatment for patients with MM and renal failure, given its rapid response, and that it should be co-administered with new drugs such as thalidomide and bortezomib, which have proven to be greatly effective at treating MM associated with GFR deterioration. In their study, 67% of patients who had been undergoing dialysis for 2 months stopped dialysis following treatment with dexamethasone and thalidomide. Bortezomib was used successfully as a second-line treatment for 3 dialysis-dependent patients, and did not show any major adverse effects. They also observed a greater survival in those patients who had been undergoing dialysis
Nefrologia 2011;31(2):218-40
Partial recovery of kidney function for an autologous transplant in a patient with chronic kidney disease and multiple myeloma
Nefrologia 2011;31(2):238-40
doi:10.3265/Nefrologia.pre2010.Aug.10496
To the Editor, Multiple myeloma (MM) is a treatable, although incurable disease.1-3 Its prognosis has improved during recent years, with an average survival of 2-3 years, given a therapeutic change with the advent of autologous haematopoietic progenitor cell transplantation (AHPCT) and three new myeloma drugs: thalidomide, lenalidomide and bortezomib,4 which have proven to be safe for patients with MM and renal failure.1 Renal failure is one of the main factors associated with the diseases poor prognosis.2 I develops in 25%-30% of cases and 2%-3% of them need dialysis, with an average survival rate of between 4 months to a year.3,4 It has a multifactorial origin, although its most frequent cause is the elimination of light chains (Bence-Jones
238

Table 1. Analytical evolution
Haemodialysis PAD Date Cr (mg/dl) U (mg/dl) MDRD Ca (mg/dl) Tp (g/dl) Alb (g/dl) IgA (mg/dl) IgG (mg/dl) IgM (mg/dl) Alfa-2 (%) Gamma (%) B-2-m (mg/l) Lambda (g/dl) Proteinuria (g/24 h) 0.69 0.18 0.67 0.08 0.07 10.4 10.3 2.9 7 220 68 0 3.1 64.6 12.6 7.2 0 8.7 6.2 4.2 24 223 32.2 14.6 4.3 13.1 9.1 14.6 8.4 18.48 0 13.8 10.7 7.3 0 12.9 10.5 7 0 8.9 7.2 4 9.2 6.9 4.4 23/01/09 11.3 217 13/05/09 6.36 104 HPC 15/07/09 5.1 98 23/09/09 5.03 80 21/11/09 5.2 82 13.9 8.9 6.5 4.2 10/12/09 3.81 94 18.4 8.4 6.1 4.3 24/02/10 3.32 121 24 8.6 6.4 4.4 10/03/2010 3.38 110 20.3 8.7 6.7 4.7 25/05/10 2.7 96 26.8 9.5 7 4.7 12/06/2010 2.4 89 29 9.3 6.9 4.5 Peritoneal dialysis Advanced chronic kidney diseasea a
Cr: creatinine; U: urea; MDRD: glomerular filtration rate calculated using MDRD (not very valuable given dialysis situation); calcium; Tp: total proteins; Alb: albumin; IgA: immunoglobulin A; IgG: immunoglobulin G; IgM: immunoglobulin M; Alpha 2: alpha-2 globulin; Gamma: gamma globulin; B-2-m: beta-2-microglobulin; Lambda: lambda light chain. a Advanced chronic kidney disease consultation.
for less than 4 months, and longterm survival similar to patients without renal failure. GFR recovery was therefore associated with a reduction in light chain serum concentration for all patients included in the study. An excess of light chains synthesised by myeloma cells is the main cause of renal function deterioration, as they accumulate in the renal tubules. Rapidly reducing them is therefore of utmost importance for recovering kidney function.12 To conclude, our case reported a patient under 65 years of age, diagnosed with MM IgA stage IIIB (and therefore with greater risk of progression), with severe renal failure at the time of diagnosis and who needed dialysis (low survival and
Nefrologia 2011;31(2):218-40
high morbidity and mortality). He obtained CR but had no kidney response. He was indicated a PAD combination regimen and AHPCT + melphalan. He presented with gradual GFR progression a year after diagnosis, and stopped dialysis at 14 months (which is an exceptional case as we have seen in the medical literature review). We are therefore able to conclude that a safe and effective treatment to ensure remission in dialysis-dependent patients is the induction regimen with dexamethasone, alongside a myeloma drug such as bortezomib, before AHPCT and low doses of melphalan, which in addition to a gradual reduction in light chain formation and excretion, promotes GFR recovery, and improves long-term patient survival.
1. Garca Sanz R, Mateos MV, San Miguel JF. Mieloma mltiple. Med Clin (Barc) 2007;129:104-15. 2. Greipp PR, San Miguel JF, Durie BGM, et al. International Staging System for Multiple Myeloma. J Clin Oncol 2005;23:3412-20. 3. Knudsen LM, Nielsen B, Gimsing P, et al. Autologous stem cell trasplantation in multiple myeloma: outcome in patients with renal failure. Eur J Haematol 2005;75:27-33. 4. Badros A, Balorgie B, Siegel E, et al. Results of autologous stem cell transplant in multiple myeloma patients with renal failure. Br J Haematol 201;114:822-9. 5. Blade J, Rosinol L. Renal, hematologic and infections complications in mltiple myeloma. Best Pract Res Clin Haematol 2005;18:635-52. 6. Irish AB, Winearls CG, Littlewood T. Presentation and survival of patients with 239

severe renal failure and myeloma. Q J Med 1997;90:773-80. 7. Bernardo J, Gonzlez G, Hernndez L. Tratamiento del mieloma mltiple con talidomida y dexametasona: avanzando lentamente. Med Clin (Barc) 2007;128(4):133-4. 8. Ashser A, Chanan-Khan A, Kaufman J, et al. Activity and safety of bortezomib in multiple myeloma patients with advanced renal failure: a multicenter retrospective study. Blood 2007;109:2604-6. 9. Qayum A, Aleem A, Rehman A, et al. Rapid improvement in renal function in patients with multiple myeloma and renal failure treated with bortezomib. Saudi J Kidney Dis Transpl 2010;21(1):63-8. 10. Alexanian R, Barlogie B, Dixon D, et al. Renal failure in multiple myeloma. Pathogenesis and prognostic implications. Arch Intern Med 1990;150:1693-5. 11. Tauro S, Clark FJ, Duncan N, et al. Recovery of renal function after autologous stem cell trasplantation in myeloma patients with end-stage renal failure. Bone Marrow Transplant 2002;30:471-3. 12. Matsue K, Fujiwara H, Iwama K, et al. Reversal of dialysis-dependent renal failure in patients with advanced multiple myeloma: single institutional experiences over 8 years. Ann Hematol 2010;89:291-7.
R.M. de Alarcn Jimnez, S. Roca Meroo, G.M. lvarez Fernndez, M.A. Garca Hernndez, M.J. Navarro Parreo, C. Jimeno Gri, E. Zarco Pedrinaci, M. Molina Nez Nephrology Department. Santa Mara del Rosell University Hospital. Murcia, Spain.. Correspondence: R.M. de Alarcn Jimnez Servicio de Nefrologa. Hospital Universitario Santa Mara del Rosell. Murcia. Spain. rmalarcon.rosa@gmail.com
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Nefrologia 2011;31(2):218-40

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