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TREATMENT OF DIABETIC PATIENTS WITH PERITONEAL DIALISYS A COMPETENCY-BASED MODEL FOR MEDICAL SPECIALISTS EDUCATION BK POLYOMAVIRUS-ASSOCIATED NEPHROPATHY RENAL IMMUNOEXPRESSION OF GHRELIN IN HUMAN PROLIFERATIVE GLOMERULOPATHIES URAEMIC ANOREXIA TREATMENT WITH MEGESTROL ACETATE POST-TRANSPLANT LYMPHOPROLIFERATIVE DISORDERS IN RENAL TRANSPLANTATION
Sociedad Española de Nefrología
Órgano Oficial de la Sociedad Española de Nefrología Versión íntegra inglés y español en www.revistanefrologia.com
Nefrología Journal Editor-in-Chief: Carlos Quereda Rodríguez-Navarro Executive editor: Roberto Alcázar Arroyo Deputy editors: Andrés Purroy Unanua, Ángel Luis Martín de Francisco, Fernando García López Honorary editors: Luis Hernando Avendaño, David Kerr, Rafael Matesanz Acedos SUBJECT EDITORS (editors of thematic areas) Experimental Nephrology A. Ortiz* J. Egido de los Ríos S. Lamas J.M. López Novoa D. Rodríguez Puyol J.M. Cruzado
Clinical Nephrology M. Praga* J. Ara J. Ballarín G. Fernández Juárez F. Rivera A. Segarra
Diabetic Nephropathy F. de Álvaro* J.L. Górriz A. Martínez Castelao J.F. Navarro J.A. Sánchez Tornero R. Romero
Hereditary Nephropathies R. Torra* X. Lens J.C. Rodríguez Pérez M. Navarro E. Coto V. García Nieto
Chronic Kidney Disease A.L. Martín de Francisco* A. Otero E. González Parra I. Martínez J. Portolés Pérez
CRF-Ca/P Metabolism E. Fernández* J. Cannata Andía R. Pérez García M. Rodríguez J.V. Torregrosa
Arterial Hypertension R. Marín* J.M. Alcázar L. Orte R. Santamaría A. Rodríguez Jornet
Nephropathy and Cardiovascular Risk J. Díez* A. Cases J. Luño
Quality in Nephrology F. Álvarez-Ude* M.D. Arenas E. Parra Moncasi P. Rebollo F. Ortega
Acute Renal Failure F. Liaño* F.J. Gainza J. Lavilla E. Poch
Peritoneal Dialysis R. Selgas* M. Pérez Fontán C. Remón M.E. Rivera Gorrin G. del Peso
Haemodialysis A. Martín Malo* P. Aljama F. Maduell J.A. Herrero J.M. López Gómez J.L. Teruel
Renal Transplantation J. Pascual* M. Arias J.M. Campistol J.M. Grinyó M.A. Gentil A. Torres
Paediatric Nephrology I. Zamora* N. Gallego A.M. Sánchez Moreno F. Vilalta
Nephropathology J. Blanco* I.M. García E. Vázquez Martul A. Barat Cascante
Evidence-Based Nephrology Vicente Barrio* (Director of Supplements), Fernando García López (Methodology assessment), Editors: María Auxiliadora Bajo, José Conde, Joan M. Díaz, Mar Espino, Domingo Hernández, Ana Fernández, Milagros Fernández, Fabián Ortiz, Ana Tato. Continued Training (journal NefroPlus) Andrés Purroy*, R. Marín, J.M. Tabernero, F. Rivera, A. Martín 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. Sánchez Guisande J. Teixidó
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© Copyright 2010. Grupo Editorial Nefrología. All rights reserved. • ISSN: 2013-2514 © Sociedad Española de Nefrología 2010. 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. Nefrología is distributed exclusively among medical professionals.
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contents Included in ISI-WOK, MEDLINE, EMBASE, IME, IBECS, SCIELO
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Volume
30 - Number 6 - 2010 V o l u m e
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EDITORIAL COMMENT TREATMENT OF DIABETIC PATIENTS WITH PERITONEAL DIALISYS A COMPETENCY-BASED MODEL FOR MEDICAL SPECIALISTS EDUCATION
599
• The treatment of diabetic patients on peritoneal dialysis remains a challenge
BK POLYOMAVIRUS-ASSOCIATED NEPHROPATHY RENAL IMMUNOEXPRESSION OF GHRELIN IN HUMAN PROLIFERATIVE GLOMERULOPATHIES
25 years later J. Portolés Pérez
UREMIC ANOREXIA TREATMENT WITH MEGESTROL ACETATE. POST-TRANSPLANT LYMPHOPROLIFERATIVE DISORDERS IN RENAL TRANSPLANTATION
Sociedad Española de Nefrología
Órgano Oficial de la Sociedad Española de Nefrología Versión íntegra inglés y español en www.revistanefrologia.com
SPECIAL ARTICLE 604
• Reinventing specialty training of physicians? Principles and challenges J. Morán-Barrios, P. Ruiz de Gauna-Bahillo
Cover images. See on page 381. R. Peces et al. MALT B cell lymphoma with kidney damage and monoclonal gammopathy: A case study and literature review.
SHORT REVIEWS 613
• BK virus-associated nephropathy D. Burgos, C. Jironda, M. Martín, M. González-Molina, D. Hernández
618
• Sodium-glucose cotransporter type 2 inhibitors (SGLT2): from familial renal glycosuria to the treatment of type 2 diabetes mellitus G. Pérez López, O. González Albarrán, M. Cano Megías
ORIGINALS 626
• Morbidity and mortality in diabetic patients on peritoneal dialysis. Twenty-five years of experience at a single centre
633
• Renal immunoexpression of ghrelin is attenuated in human proliferative glomerulopathies
F. Coronel, S. Cigarrán, J.A. Herrero M. Danilewicz, M. Wagrowska-Danilewicz
639
• Pentosan polysulfate sodium prevents kidney morphological changes and albuminuria in rats with type 1 diabetes Y. Mathison Natera, H.J. Finol, Z. Quero, R. González, J. González
646
• Treatment of uraemic anorexia with megestrol acetate M. Fernández Lucas, J.L. Teruel, V. Burguera, H. Sosa, M. Rivera, J.R. Rodríguez Palomares, R. Marcén, C. Quereda
653
• Decreased glomerular filtration rate using the Cockgroft-Gaultand MDRD formulas does not always predict cardiovascular morbidity and mortality in hypertensive primary care patients
661
• Insulin resistance in chronic kidney disease: its clinical characteristics and prognostic significance
F.J. Tovillas-Morán, M. Vilaplana-Cosculluela, A. Dalfó-Pibernat, E. Zabaleta-del-Olmo, J.M. Galcerán, A. Coca, A. Dalfó-Baqué F. Caravaca, I. Cerezo, R. Macías, E. García de Vinuesa, C. Martínez del Viejo, J. Villa, R. Martínez Gallardo, F. Ferreira, R. Hernández-Gallego
669
• Post-transplant lymphoproliferative disorders in renal transplantation: two decades of experience A. Franco, l. Jiménez, C. Sillero, M. Trigueros, D. González, E. Alcaraz, J. Olivares
BRIEF REPORT 676
• Scientific presentations at the meetings of the Spanish Paediatric Nephrology Association (AENP), 1988-2007 L.M. Rodríguez-Fernández, V. Recio-Pascual, M. Fernández-Fernández, M. Rosón-Varas, C. Rodríguez-Fernández, R. Morales-Sánchez, D. Mata-Zubillaga
contents Included in ISI-WOK, MEDLINE, EMBASE, IME, IBECS, SCIELO
Volume
30 - Number 6 - 2010
CASE REPORT 681
• MALT B cell lymphoma with kidney damage and monoclonal gammopathy: A case study and literature review R. Peces, C. Vega-Cabrera, C. Peces, A. Pobes, M.F. Fresno
RESEARCH PROTOCOLS 687
• Clinical and genetic bases of hypertensive nephrosclerosis. NEFROSEN Study B. Diez Ojea, R. Marín, E. Coto, F. Fernández Vega, R. Álvarez Navascués, G. Fernández Fresnedo, A. Pobes Martínez de Salinas, A. Suárez Laurés, C. García Monteavaro, M. Gorostidi, E. Sánchez, M. Arias, F. Ortega
LETTERS TO THE EDITOR A) Brief papers on research and clinical experiments 698
• Cadaveric donor procurement units faced with living donation A. Ríos, A.I. López-Navas, P. Ramírez, P. Parrilla, Proyecto colaborativo internacional donante
699
• Internal jugular vein access in a semi-seated position for catheterisation to enable haemodialysis in orthopnoeic patients R. Karatanasopuloz, V. Balbuena, M. Paiz, G. Levy, C. Martín
B) Brief Case Reports 701
• Granulomatous interstitial nephritis free from extrarrenal sarcoids M. Cuxart, M. Picazo, R. Sans Lorman, M.J. Muntané
702
• Acute phosphate nephropathy after bowel cleansing: still a menace P. Santos, A. Branco, S. Silva, A. Paiva, J. Baldaia, J. Maximino, A. Loureiro, R. Henrique
704
• Paravirus B19 infection: diagnosing and treating a kidney transplant patient L.R. León, D. Curcio, D. Casadei
704
• Disseminated tuberculosis with splenic abscesses during haemodialysis
706
• Cocaine use, high blood pressure and chronic kidney disease
B. Moragrega, R. Dolz, I. López Alejandre, A. Núñez Sánchez M. Picazo Sánchez, M. Cuxart Pérez, F. Martín Romero, R. Sans Lorman
707
• Delayed spontaneous rupture of the kidney graft J. Kanter Berga, C. Cáceres Borrero, T. Ripollés González, A. Ávila Bernabeu, E. Gavela Martínez, L. Pallardó Mateu
709
• Coexistence of anti-GBM antibodies and MPO-ANCA in a patient with systemic vasculitis and crescentic glomerulonephritis
710
• Treatment with rituximab for a patient with p-ANCA glomerulonephritis, alveolar bleeding and multiple relapses during haemodialysis
P. Fernandes, J.A. Lopes, L. Correia, S. Gonçalves, S. Jorge
M.A. Azancot, I. Agraz Pamplona, J. Fort Ros, A. Marín Valencia, I. Gil Carballeira, J. Camps Domenech
712
• Kidney failure and diabetes. Diagnostic inertia? R. Blanco García, J.J. Bravo López, A. Pérez, M. Moreiras Plaza
714
• IN MEMORY OF PROFESSOR SAULO KLAHR
http://www.revistanefrologia.com © 2010 Revista Nefrología. Official Publication of the Spanish Nephrology Society
editorial comment
See original article on page 626
The treatment of diabetic patients on peritoneal dialysis remains a challenge 25 years later J. Portolés Nephrology Department. University Hospital Foundation of Alcorcón (REDinREN Carlos III. Red 06/0016). Alcorcón, Madrid, Spain
Nefrologia 2010;30(6):599-603 doi:10.3265/Nefrologia.pre2010.Oct.10682
RELEVANCE OF DIABETES MELLITUS IN NEPHROLOGY Diabetes mellitus (DM) is the most important disease related to renal replacement therapy (RRT), due to its prevalence and clinical, economic and social impact. It is estimated that 0.3% of the general population suffer from type 1 DM and 7% from DM type 2.1 The prevalence of DM is dependent on the diagnostic criteria used and varies throughout the world, but the increase in the incidence of type 2 DM is estimated between 3 and 5% annually.1 This is due largely to poor health habits; therefore, its growth is even higher in developing countries. Progression to chronic kidney disease (CKD) in stage 5D increases due to a more prolonged exposure to hyperglycaemia, its association with high blood pressure (HTN), obesity, sedentary lifestyle and other risk factors, and its lower mortality, which leads to patients undergoing RRT. Therefore, the term “epidemic of the 21st century” is no exaggeration. It is estimated that the overall cost of treating patients with type 2 diabetes with target organ damage is at least €2,136 per year and may exceed €54,000 per year for patients on haemodialysis (HD). Finally, DM is a cardiovascular (CV) risk factor and a source of clinical complications, hospital admissions, poor quality of life and loss of years in full health and at work. This disease has a significant impact. Data from monitoring more than 5,000 patients in the UKPDS study allowed us to establish the clinical course of Correspondence: José Portolés Pérez Servicio de Nefrología. Hospital Universitario Fundación Alcorcón. (REDinREN Carlos III. Red 06/0016). Budapest, 1. 28922 Alcorcón. Madrid. Spain.
[email protected]
nephropathy in type 2 diabetes mellitus.2 Statistically, it takes 19 years to develop the disease, 11 years to go from microalbuminuria to macroalbuminuria and a decline in renal function starts 10 years later. However, patients who were included in the UKPDS with a Cr greater than 2mg/dl were undergoing RRT in just 2 years, which is the patient profile faced regularly. The objective of intervention in DM is clearly in the initial stages, focusing on renoprotection and cardioprotection, reducing CV events and the need for RRT. In fact, there is now evidence that intervention and close monitoring of patients with type 1 diabetes reduces the need for RRT in these patients. A Finnish study of 20,000 patients followed between 1965 and 1999, had dialyisis incidence rates of only 2.2% aftet 20 years, and a trend to decrease in the more recent years.3 Nevertheless, the challenge of treating DM patients on dialysis is an ongoing one. Articles like the one presented in this issue by the group from the Hospital Universitario San Carlos, Madrid, gives a historical perspective on the treatment of diabetic patients on peritoneal dialysis (PD 4). There are not many PD programmes with a experience of 25 years, as in this study. The most relevant result is the description of a worse outcome for patients with DM and the quantification of this risk in our area. 4 Patients with DM in this study have higher rates of mortality, transfer to HD, hospital admissions, non-peritoneal infections and peritonitis, in line with previous published studies. 5 For example, in the study of the Grupo Centro de Diálisis Peritoneal, GCDP (Peritoneal Dialysis Group Centre), the probability of survival at 2 years was 86.7% in patients without DM and 75.2% in patients with type 2 DM.6 In the study published in this issue, however, two different historical PD periods were compared. The most recent 599
editorial comment
J. Portolés Pérez.The treatment of diabetic patients on peritoneal dialysis
(post-1992) had double-bag systems, the first glucose-free solutions and the widespread use of automated systems, as well as erythropoietin. In this second phase, the rate of peritonitis was reduced accordingly and global outcome indicators improved, although the risk of death attributable to DM was not significantly reduced. The first stage of the article referred back to the 1980s (pre1992), when some groups raised concerns about the appropriateness of including patients with DM in dialysis programmes due to its high morbidity and mortality. This period (pre-1992) has some striking data reflecting a negative selection of patients for PD, which was not specifically outlined in the article. For example, the prevalence of diabetic patients on PD was 55% compared to the average reported by the register of 18% on HD, or 20% recorded by the GCDP between 2003 and 2009.5 In addition, they reported a high percentage of patients with blindness and other comorbidities, which limited the number of patients stopping the therapy to undergo transplant surgery to only 5.8% in the total follow-up of patients with type 2 DM. The low HD transfer rate could be due to the previous technique being maintained well or because patients were not able to change from one technique to another. In other words, it would be patients indicated for PD rather than those choosing PD, which is a risk factor in itself.7 Against this backdrop, the “new” integrated RRT 3.0 model offers an integrated approach for dialysis techniques and transplantation with a fluid exchange between them, as each reaches a plateau in a particular patient.8 This model is becoming a reality in many Spanish hospitals. The study published by Coronel et al. also serves as a reference for comparison for other groups starting PD. In general, these PD programmes are not large. For example, the Community of Madrid has an average size of around 25 patients, with a high turnover, fluctuations in the number and difficulties with growth. Therefore, retrospective studies of this type have been used so far as a reference to reflect the reality of PD in our area and time, highlighting differences with studies in other health systems and other countries. The collaboration between institutions is necessary to begin to have benchmarks for comparison with recent larger multicentre data.9 DM is the most important risk factor for PD patients and this poor prognosis is related to the CV pathology of patients entering PD, as indicated by other studies.6 The study by Coronel et al. shows an overall risk of death from DM of 1.96 compared to non-DM patients on PD. Although they did not have their own data on the evolution of DM patients on HD, as it was not the objective of the study, the comparison between techniques is inevitable. External references show a similar picture on the evolution of DM patients on HD. 600
According to the 2009 USRDS report, only 30% of DM patients survive 5 years after starting HD, and these data would be even worse if the early mortality of patients who did not reach 3 months in HD were included (excluded from that register10). The paper reports that half of the deaths were associated with CV events. The morbidity of DM is associated with predialysis CV damage, the concomitance of other risk factors (dyslipidaemia, HTN, etc.) and tissue deposition of advanced glycation end products (AGE). AGEs that accumulate in CKD have a direct effect on the vascular wall, promoting accelerated atherosclerosis and protein-calorie malnutrition. In fact, in some series, the risk attributable to DM greatly diminishes if corrected for the presence of previous cardiovascular events and albumin levels.11 For example, the data presented by the GCDP indicate that the risk of death in type 2 diabetes patients is 2.5 times that of non-DM after correction for age. The association between type 2 diabetes and previous cardiovascular events excludes the variable type 2 DM due to trying to put it in the same model DM and CV event prior to PD.6,7 The comparison of survival between HD and PD remains controversial, especially because the information comes from records and observational studies or from post-hoc analyses. Such questions cannot be resolved with a clinical trial design, so the information must come from observational studies with a prospective design and sufficient sample size and control of covariates and confounding factors. A recent comprehensive review in our journal concluded that both techniques were similar, with a slight advantage for PD in the first 2-3 years of evolution and HD later. In the specific case of patients with DM, younger people seem to have better outcomes with PD and the elderly with HD.12 A recent retrospective study goes beyond the multivariate analysis using the propensity score to reduce the selection bias of either technique.13 This study gives an advantage to patients on PD, particularly in the initial period, with a probability of survival of 85.5% compared with 80.7% in HD, and 71.1% versus 68% in HD after 2 years (P48 000 transplants, 1474 of which were treated within 24 months. The cumulative incidence of TBKV increased with time, going from 3.45% at 24 months to 6.6% at 60 months after the transplantation. Graft failure secondary to BKVN occurs at a rate of 50%–100% at 24 months in centres with no screening programs, which highlights the importance of an early diagnosis of the disease.5 Different IS protocols have been identified as risk factors for the development of BKVN, especially the use of triple therapies with anticalcineurinic drugs, mycophenolate mofetil (MMF), and steroids,5,6 but BKVN cases have also been described when using other IS regimens, which indicates that the intensity of IS treatment, and not the specific drug itself, is the risk factor in this case. Other types risk factors also exist, such as patient factors (males >50 years of age, BKV seronegative recipient), graft factors (BKV seropositive donor, HLA incompatibilities, immunological or ischaemic injury), and viral factors (latent viral load, capsid serotype, and capacity for replication).7
BKVN HISTOLOGICAL DIAGNOSIS AND PROGRESSION Decoy cells, viruria, and viremia only indicate viral replication, not nephropathy, but they are key tools for preventing and monitoring the disease. The only clinical sign of BKVN is the deterioration of kidney function, and when this occurs, it is already too late to intervene, since the renal damage has already been produced. The diagnosis of the disease can only be performed with a graft biopsy in which the typical basophilic nuclear viral inclusions are found in the epithelial cells (tubular, Bowman’s capsule, and/or urothelium), and signs of inflammation with tubulitis (Figure 1A), similar findings to those that appear in acute transplant rejection by T-cells. Only by using the immunohistochemical technique for SV-40 LTAg can we observe a positive nuclear staining and identify the polyomavirus (BK, JC) as that responsible for the inflammation, thus discarding the diagnosis of acute T-cell rejection (Figure 1B) and confirming the diagnosis of BKVN. BKVN histological lesions are focal and heterogeneous, and so a negative biopsy cannot exclude the diagnosis. As such, this test must be repeated if the viral load in the patient’s blood remains persistently high. The histological patterns of BKVN2,8,9 are based on the identification and extension of the inflammatory infiltrate Nefrologia 2010;30(6):613-7
D. Burgos et al. BK Virus Nephropathy
short reviews consequence of viral reactivation and replication in the urinary tract, with the appearance of typical decoy cells, (Figure 4) which are easy to identify using routine urine cytology tests. However quantification of Vr using PCR techniques is more sensitive than using cytology, and allows for distinguishing between BKV and JCV infections.
A
When viruria is >10 5 copies/ml and persists, it is followed weeks or months later by the development of viremia (Vm) at >10 7 copies/ml and, finally, BKVN. BK Vr is not diagnostic of renal parenchymal damage, but the simultaneous appearance of Vm and Vr is pathognomonic of renal parenchymal damage (BKVN). Maintained, or more typical, increasing Vm is a predictive factor for deteriorating kidney function, and is correlated with the presence and severity of histological lesions. In patients with normal or moderately low kidney function, the probability of finding histological indicators of BKVN is directly proportional to the duration and severity of viremia. Elevated and sustained viremia identifies those patients with uncontrolled viral replication that leads to kidney damage.
B
Figure 1. Basophilic nuclear viral inclusions in epithelial cells and tubulitis in the BK-virus nephropathy (A) and immunohistochemistry for the antigen SV-40 LTAg (B).
In conclusion, early diagnosis and intervention minimises the damage to the transplant. Figure 5 demonstrates a diagnostic algorithm based on previous publications. 4,9
BKVN TREATMENT and viral infection-associated fibrosis, which allows for three histological patterns to be established (Figure 2).
CLINICAL EVOLUTION AND OPPORTUNITIES FOR EARLY PREVENTION AND DIAGNOSIS The common clinical evolution of BKVN9 is represented in Figure 3, which shows how the development of the disease is predicted by the appearance of BK viruria (BK Vr), a
Pattern A - Viral cytopathic changes in normal renal parenchyma - Insignificant or absent FIAT and inflammation
The best treatment for BKVN is an early diagnosis of the disease in order to act before renal damage is caused. For this reason, KDIGO Guides10 suggest using a screening process for all kidney transplant patients by testing monthly Vm levels during the first 3 months (2D) and every three moths until the end of the first year (2D), whenever renal dysfunction is produced with no visible alternative cause (2D), and after treatment for en episode of acute rejection (2D).
Pattern B - Combination of viral cytopathic changes and areas of FIAT and focal/multifocal inflammation
Pattern C - Few cytopathic changes - Extensive FIAT and inflammation
B150% FIAT
Figure 2. Histological patterns of the BK virus-associated nephropathy. Nefrologia 2010;30(6):613-7
615
D. Burgos et al. BK Virus Nephropathy
short reviews
Stereotypical evolution of polyoma virus allograft nephropathy (PVAN) Viruria + Viremia
Increasing viruria, viremia, serum creatinine & PVAN
Viruria
Viruria + Viremia + PVN
Endstage PVN
Vr Vm Cc Bx+
E
F
G
Post-trasplant follow up (months)
Figure 3. Phases of evolution of the BK virus-associated nephropathy.
Figure 4. Disperse decoy cells and cellular cylinders containing compacted decoy cells. When they appear, these cylinders are pathognomic of kidney damage.
A reduction in IS is also suggested when Vm is persistently greater than 107 copies/ml (2D).
determine because they have not been administered in combination with a reduction in IS and because of the lack of controlled and randomised prospective studies.
Regarding the reduction in IS, the first step consists of implementing the standard protocol (not giving CAN or antiproliferative treatments above the levels indicated for the therapeutic range), followed by measuring viremia every 4 weeks, reducing NAb by 15%-20%, reducing MMF and/or MMF suppression by 50%, and/or substituting TAC by CsA or an ISP (Figure 6).11 With regard to antiviral treatments, i.v. immunoglobulins, ciclofovir, leflunomide, and quinolones have been used empirically, and their efficacy is currently difficult to
BK Management
Test results
NBK
Indication Intervention
1.st Step
Screening Urine cytology decoy cells BKV DNA urine
Possible
No
2.nd Step
Confirmation Probable Yes BKV DNA Urine > 107 cop ml BKV DNA Plasma > 104 cop ml Probable Yes
3.rd Step
Biopsy BKVN A BKVN B BKVN C
Definitive Yes
Monitoring Plasma BKV DNA Negative
Resolved
Finally, we would like to comment on kidney retransplantation in patients that have lost a graft due to BKVN. The recurrence of the disease in short studies is 12%. The recommendations that must be taken into account in these situations are: 1) inform the patient as to the increased potential risk of recurrence of BKVN; 2) confirm the absence of viral replication (blood and urine PCR when the patient is included on the transplant list and every 6 months thereafter), the patient must receive the transplant with negative PCR results from blood samples, and 3) adapt the IS to the pathology.12-14
Ginevri, et al. AJT 2007;7:2727. - Implement standard protocol - Viremia >4 weeks ACN 15-20% -
4.th Step
Figure 5. BKVN diagnostic algorithm. 616
MMF 50% Stop MMF
- Substitute TAC by CsA or ISP
Figure 6. BKVN treatment algorithm. Nefrologia 2010;30(6):613-7
D. Burgos et al. BK Virus Nephropathy
short reviews
KEY CONCEPTS 1. The powerful and modern forms of immunosuppression could be responsible for the increasing prevalence of this infection 2. BK virus infection in immunocompromised patients could affect the function and survival of kidney transplants
3. Early diagnosis by strictly monitoring urine decoy cell count and/or viruria and viremia is crucial for avoiding the negative impacts of this complication 4. No evidence exists of a specific effective treatment for this infection. Only a reduction in immunosuppression treatment can minimise virulence.
REFERENCES
1. Polo C, Pérez JL, Mielnichuk A, et al. Prevalence and patterns of polyomarvirus urinary excretion in immunocompetent adults and children. Clin Microbiol Infect 2004;10:640. 2. Drachemberg CB, Hirsh HH, Ramos E, et al. Polyomavirus disease in renal transplantation: Review of Pathological findings and diagnostic methods. Hum Pathol 2005;36:1245. 3. Drachemberg CB, Hirsh HH, Papadimitriou JC, et al. Cost efficiency in the prospective diagnosis and follow-up of polyomavirus allograft nephropathy. Transplant Proc 2004;36:3028. 4. Hirsh HH, Brennan DC, Drachemberg CB, et al. Polyomavirus associated nephropathy in renal transplantation: Interdisciplinary analysis and recommendations. Transplantation 2005;79:1277. 5. Ramos E, Drachemberg CB, Portocarrero M, et al. BK virus nephropathy diagnosis and treatment: Experience at the University of Maryland Renal Transplant Program. Clin Transpl 2002;43. 6. Hirsh HH, Friman S, Wiecek A, et al. Prospective study of Polyomavirus BK viruria and viremia in the novo renal transplantation. Am J Transplant 2007;7:150. 7. Binggeli S, Engli A, Schaub S, et al. Polyomavirus BK specific-cellular immnune response to VP1 and large T-antigen in kidney transplant recipients. Am J Transplant 2007;7:1131.
8. Drachemberg CB, Papadimitriou JC, Hirsh HH, et al. Histological patterns of polyomavirus nephropathy: Correlation with graft outcome and viral load. Am J Transplant 2004;4:2082. 9. Ramos E, Drachemberg CB, Wali R, Hirsh HH. The decade of polyomavirus BK-Associated Nephropathy: State of Affairs. Transplantation 2009;87:621. 10. Kidney Diseases Improving Global Outcomes (KDIGO). Transplant Work Group. Am J Transplant 2009;9(Suppl 3):S1-S157. 11. Ginevri F, Azzi A, Hirsch HH, Bassoo S, Fontana I, Cioni M, et al. Prospective Monitoring of Poliomavirus BK Replication and Impact of Pre-Emptive Intervention in Pediatric Kidney Recipients. Am J Transplant 2007;7:2727. 12. Nickeleit V. Animal Models of Polyomavirus Nephropathy: Hope and Reality. Am J Transplant 2006;6:7. 13. Ramos E, Vincenti F, Lu WX, Shapiro R, Trofe J, Stratta RJ, et al. Retransplantation in patients with graft loss caused by polyoma virus nephropathy. Transplantation 2004;77:131. 14. Womer KL, Meier-Kriesche HU, Patton PR, Dibadj K, Bucci CM, Foley D, et al. Preemptive Retransplantation for BK Virus Nephropathy: Successful Outcome Despite Active Viremia. Am J Transplant 2006;6:209.
Sent for Review: 28 July 2010 | Accepted: 5 Oct. 2010 Nefrologia 2010;30(6):613-7
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http://www.revistanefrologia.com © 2010 Revista Nefrología. Official Publication of the Spanish Nephrology Society
Sodium-glucose cotransporter 2 (SGLT2) inhibitors: from renal glycosuria to the treatment of type 2 diabetes mellitus G. Pérez López, O. González Albarrán, M. Cano Megías Endocrinology Department. Ramón y Cajal Hospital. Madrid, Spain
Nefrologia 2010;30(6):618-25 doi:10.3265/Nefrologia.pre2010.Sep.10494
ABSTRACT For centuries, the kidney has been considered primarily an organ of elimination and a regulator of salt and ion balance. Although once thought that the kidney was the structural cause of diabetes, which in recent years has been ignored as a regulator of glucose homeostasis, is now recognized as a major player in the field of metabolic regulation carbohydrate. During fasting, 55% of the glucose comes from gluconeogenesis. Only 2 organs have this capability: the liver and kidney. The latter is responsible for 20% of total glucose production and 40% of that produced by gluconeogenesis. Today we have a better understanding of the physiology of renal glucose transport via specific transporters, such as type 2 sodiumglucose cotransporter (SGLT2). A natural compound, phlorizin, was isolated in early 1800 and for decades played an important role in diabetes and renal physiology research. Finally, at the nexus of these findings mentioned above, recognized the effect of phlorizin-like compounds in the renal glucose transporter, which has offered a new mechanism to treat hyperglycemia. This has led to the development of several potentially effective treatment modalities for the treatment of diabetes. Key words: Type 2 diabetes mellitus. Familial renal glucosuria. SGLT2 inhibitors.
Inhibidores del cotransportador sodio-glucosa tipo 2 (SGLT2): de la glucosuria renal familiar al tratamiento de la diabetes mellitus tipo 2 RESUMEN Durante siglos, el riñón se ha considerado principalmente un órgano de eliminación y un regulador de la sal y del equilibrio iónico. A pesar de que una vez se pensó que era la causa estructural de la diabetes, y que en los últimos años ha sido ignorado como regulador de la homeostasis de la glucosa, actualmente es reconocido como un actor importante en el ámbito de la regulación del metabolismo glucídico. Durante el ayuno, el 55% de la glucosa proviene de la gluconeogénesis. Sólo 2 órganos tienen esta capacidad: el hígado y el riñón. Este último es responsable del 20% de la producción total de glucosa y del 40% de la producida por la gluconeogénesis. Hoy en día tenemos una mejor comprensión de la fisiología del transporte de glucosa renal a través de transportadores específicos, como el cotransportador sodio-glucosa tipo 2 (SGLT2 por sus siglas en inglés: Sodium Glucose Cotransporter). Un compuesto natural, floricina, se aisló a principios de 1800 y durante décadas desempeñó un papel importante en la diabetes y la investigación de la fisiología renal. Finalmente, en el nexo de estos descubrimientos antes mencionados, se reconoció el efecto de compuestos floricina-like en los transportadores de glucosa renal, lo que ha ofrecido un nuevo mecanismo para el tratamiento de la hiperglucemia. Esto ha llevado al desarrollo de varias modalidades terapéuticas potencialmente eficaces para el tratamiento de la diabetes. Palabras clave: Diabetes mellitus tipo 2. Glucosuria renal familiar. Inhibidores de SGLT2.
INTRODUCTION In 2009, De Fronzo1 described the rapid advances in the knowledge of the various pathophysiological pathways related to the development of diabetes. Correspondence: Gilberto Pérez López Servicio de Endocrinología. Hospital Universitario Ramón y Cajal. Carretera de Colmenar Viejo, km 9,100. 28034 Madrid. Spain.
[email protected],
[email protected] 618
This was explained by the change from the triumvirate to the ominous octet, referring to the important role seemed to be played in carbohydrate metabolism by the kidney2-4 (increasing the reabsorption of glucose), the small intestine and alpha cells (decreasing the incretin effect and increasing the production of glucagon), and the dysfunction of neurotransmitters in the central nervous system, together with the classic insulin resistance
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components (decreased insulin production, increased hepatic glucose production, decreased glucose uptake by skeletal muscle and increased lipolysis).
short reviews Clinically, the most common cause of glycosuria is diabetes. Patients do not excrete glucose in the urine until the concentration of blood glucose is over 180mg/dl, which does not normally occur in people without diabetes.
THE KIDNEY AND GLUCOSE HOMEOSTASIS The kidney was traditionally considered as one of the main organs responsible for glucose homeostasis. However, we now understand that it plays an important role in glucose homeostasis in two ways: 1) gluconeogenesis, and 2) glomerular filtration and reabsorption of glucose in the proximal convoluted tubules. With a better understanding of the renal mechanisms responsible for glucose homeostasis and the ability to manipulate that system, the kidney has become a key component in the treatment of hyperglycaemia.
Filtration and the reabsorption of glucose For a healthy adult, approximately 180g of glucose is filtered by the glomerulus every day. 5 Under normal circumstances, almost all of this glucose is reabsorbed with less than 1% being excreted in the urine. 6 Glucose reabsorption in the tubules is a multi-step process involving several transport mechanisms. Glucose is filtered through the tubule and then transported via the tubular epithelial cells through the basolateral membrane into the peritubular capillary. Under optimal conditions, when tubular glucose load is approximately 120mg/min or less, there is no glucose loss in urine. However, when the glucose load exceeds approximately 220mg/min (glucose threshold), glucose starts to appear in the urine. The blood glucose level required to provide such a tubular load covers a range of values in humans. A study of this process reported that the blood glucose concentration required to exceed the tubular glucose threshold ranged between 130 and 300mg/dl.7 In addition, the study found a relationship between age and increased threshold levels. 90% of filtered glucose is reabsorbed by the high absorption capacity of SGLT2 transporter in the convoluted segment of the proximal tubule, and the remaining 10% of filtered glucose is reabsorbed by the SGLT1 transporter in the straight segment of the descending proximal tubule.2 As a result, no glucose appears in the urine. The maximum renal capacity for tubular reabsorption (Tm) of glucose is greater in animal models with type 1 and type 2 diabetes. 8 In people with type 1 diabetes, Mogensen et al.9 showed that the glucose Tm is increased. Conflicting results have been reported in patients with type 2 diabetes. Nefrologia 2010;30(6):618-25
Role of the SGLT2 transporter The first step in the reabsorption of urine glucose involves the transport of glucose from the tubules to peritubular capillaries via tubular epithelial cells. 10 This is accomplished with the family of sodium-glucose cotransporters (SGLT), see Figure 1. The SGLTs include a variety of membrane proteins that act on the transport of glucose, amino acids, vitamins, ions and osmolytes across the brush border membrane of the renal proximal tubules and the intestinal epithelium. 11 SGLT1 is a low capacity and high affinity carrier. It is found mainly in the gastrointestinal tract, but can also be found in the S3 segment of the renal proximal tubule. Although SGLT1 is the key transporter for glucose absorption in the gastrointestinal tract, its impact on the kidney is less important; representing about 10% of glucose reabsorption. This has been of some pharmacological interest because blocking this transporter theoretically reduces the gastrointestinal absorption of glucose and may provide a method for inducing weight loss or reducing postprandial hyperglycaemia. By contrast, SGLT2 transporter has a high capacity and low affinity, and is found mainly in the kidney. Table 1 compares the SGLT1 and SGLT2 transporters. A third member of this family, SGLT3, is widely found in skeletal muscle and the nervous system. SGLT3 is not believed to be a glucose transporter, but acts as a sensor. 12 Although other members of this family have been identified (SGLT4, SGLT5 and SGLT6), their role in humans is not known at this time (Table 2). The most prevalent and functionally most important transporter in the kidney is SGLT2. It is responsible for 90% of glucose reabsorption in the kidney, and has become the subject of much interest in the diabetes field. This transporter is found in a relatively high proportion in the initial segment of the proximal tubule (S1). SGLT2 transports glucose by using the energy gradient of sodium reabsorption in the tubular filtration. This process is called secondary active transport and is driven by the electrochemical gradient of sodium in the tubular filtration. 619
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Capillary
Santer et al.13 conducted a genetic study on 23 families diagnosed with renal glycosuria and found 21 different mutations of the SLC5A2 gene. Fourteen out of the 21 families were homozygous and had glycosuria between 15 and 200g/day. Heterozygotes typically had glycosuria of under 4.4g/day, although some did not.
ATPase
S1 Proximal tubule
protein. Autosomal dominant and recessive inheritance patterns have been reported. As a result of this mutation, patients with renal glycosuria excrete in their urine more than 100g of glucose in 24 hours.
Glucose
Glucose
Figure 1. Mechanism of action of SGLT2 On the luminal side of the S1 segment of the proximal tubule, the absorption of sodium creates an energy gradient which allows glucose uptake via SGLT2 (sodium-glucose cotransporter type 2). On the other side of the cell, sodium is transported through the blood capillary basement membrane by the sodium-potassium ATPase pump. This phenomenon in turn creates another energy gradient and glucose is transported to capillary flow by glucose transporter 2 (GLUT210).
RENAL GLYCOSURIA: SGLT2 TRANSPORTER INHIBITION MODEL
Renal glycosuria is a genetic condition where the effects of the inhibition of SGLT2 transporter can be observed. Patients with this condition are asymptomatic, even though in most cases they have a SLC5A2 gene mutation (solute carrier family 5A), responsible for encoding SGLT2 transporter
Two families diagnosed with renal glycosuria did not have the SLC5A gene mutation, but may have had mutations of the genes encoding GLUT2 (type 2 glucose transporter), HNF-1· (hepatic nuclear factor 1 alpha) which regulates the transcription of SGLT2 or genes related with SGLT1 or SGLT3. Except for glycosuria, there were no other associated diseases. Plasma glucose was high or low, and blood volume remained essentially normal due to sodium reabsorption via other transporter channels. Renal and bladder function was normal, and this group of patients had no increased incidence of diabetes, kidney disease or urinary tract infections, compared with the general population.14 Figure 2 schematically shows the reabsorption of glucose in normal individuals and patients with renal glycosuria. As mentioned previously, the maximum renal capacity of tubular reabsorption (Tm) for glucose is variable, although for physiological studies (theoretical, continuous black line) it is about 198mg/dl (11mmol/l). The glucose Tm usually observed is below this figure (broken black line), and is saturated with glucose concentrations near 180mg/dl (10mmol/l15). Renal glycosuria can be classified into two types.13 Type A has a glucose Tm lower than in normal subjects (blue line).
Table 1. Comparison of SGLT1 and SGLT2 transporters SGLT1
SGLT2
Location
Small intestine and kidney
Kidney
Substrates
Glucose or galactose
Glucose
Glucose affinity
High
Low
Glucose transport capacity
Low
High
Function
- Intestinal absorption of glucose and galactose - Renal reabsorption of glucose
Renal reabsorption of glucose
In the kidney, SGLT2 transporter is responsible for 90% of tubular reabsorption of glucose, whereas SGLT1 is responsible for the remaining 10%. The low affinity for glucose and its high carrying capacity, make inhibition of SGLT2 a pharmacological mechanism for the treatment of type 2 diabetes mellitus.14 620
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Table 2. Sodium-glucose cotransporter family Transporter
Substrate
Tissue distribution
SGLT1
Glucose and galactose
Kidney, small intestine, heart and trachea
SGLT2
Glucose
Kidney
SGLT3
Glucose sensor
Small intestine, thyroid, testes, uterus and lung
SGLT4
Mannose, glucose, fructose, galactose and AG
Kidney, small intestine, liver, stomach and lung
SGLT5
Glucose and galactose
Kidney
SGLT6
Myo-inositol, glucose, xylose and chiro-inositol
Kidney, small intestine, spinal cord and brain
1,5 AG: 1,5-anhydro-D-glucitol12
These patients have decreased SGLT2 transporter activity as well as more significant glycosuria.
from healthy individuals and diabetic patients, and were cultured in a hyperglycaemic medium.
In type B renal glycosuria, the SGLT2 transporter has no affinity for glucose, resulting in a decrease in the reabsorption rate of glucose, but a normal glucose Tm (green line).
As shown in Figure 3, the HEPTC of diabetic patients showed a statistically significant higher expression of SGLT2 and GLUT2 compared with non-diabetic individuals. They also determined the renal glucose uptake using methyl-α-D[U14C]-glucopyranoside (AMG), which is an analogue of glucose. More glucose uptake was also observed in diabetes patients? HEPTC than in individuals without diabetes.
TYPE 2 DIABETES MELLITUS AND THE SGLT2 TRANSPORTER Type 2 diabetes mellitus is associated with increased expression and activity of SGLT2. In a study16 of the SGLT2 transporter, human exfoliated proximal tubular epithelial cells (HEPTC) were used, which were obtained from urine samples. HEPTC were isolated
These findings prove that the renal system noticeably contributes to the body’s energy balance by regulating glucose uptake, and that diabetic patients appear to be poorly adapted to this mechanism. In diabetes, glucose reabsorption may be increased in absolute terms by an increase of glucose Tm.
SGLT2 TRANSPORTER INHIBITORS FOR THE TREATMENT OF TYPE 2 DIABETES MELLITUS Theoretical Observed
Normal Type B
Glucose reabsorption
Type A
5
10 15 Plasma Glucose Concentration (mmol/l)
Figure 2. Comparison of the maximum tubular glucose reabsorption capacity (Tm) The solid black line shows the theoretical glucose Tm, while the broken line shows the glucose Tm in healthy subjects. The glucose Tm in patients with type A renal glycosuria is shown by the blue line and type B in green.13 Nefrologia 2010;30(6):618-25
In 1835, French chemists isolated a substance called phlorizin from the roots of apple trees. Although it was believed that phlorizin was a compound for treating fever, infectious diseases and malaria, it was not until 50 years after its discovery that it was found that high doses of phlorizin caused glycosuria.17 For several decades, phlorizin was used in the assessment of renal physiology. Then in 1970, it was discovered that glycosuria could be caused by phlorizin inhibiting an active transport system for tubular reabsorption of glucose. Between 1980 and 1990, the SGLT2 transporter was identified, and the inhibition of this transporter began to be profiled as a treatment for type 2 diabetes mellitus. Phlorizin was therefore the first known SGLT2 inhibitor. However, phlorizin could not be used as a treatment for type 2 diabetes mellitus for several reasons. Firstly, because intestinal absorption is very poor and, secondly, because it 621
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Glucose transporter expression
AMG Uptake
SGLT2 inhibition essentially resets the maladaptive diabetic kidney by reducing the affinity of the transporter and increasing glycosuria, which decreases blood glucose and, therefore, glucotoxicity.18 Recently, phlorizin analogues selective for SGLT2 with better intestinal absorption have been developed. Table 3 shows some drugs in this group, including dapagliflozin and canagliflozin, which are currently in phase III clinical trials.
Figure 3. Comparison of the glucose tubular transporters in diabetics and non-diabetics. Comparison of the expression of SGLT2 and GLUT2, and the methyl-α-D-[U14C]-glucopyranoside (AMG) uptake in human exfoliated proximal tubular epithelial cells (HEPTCs) in healthy individuals and diabetic patients.16 CPM: counts per minute.
In addition, one laboratory is currently in phase I clinical trials19 with a molecule called ISIS-388626 to reduce expression of SGLT2. This compound is an oligonucleotide that decreases transcription of the gene encoding the SGLT2 transporter. In murine and canine models, treatment with ISIS-388626 is highly selective, as it reduces the mRNA (messenger ribonucleic acid) of SGLT2 by 80% without modifying SGLT1. There was a significant reduction in fasting blood glucose, postprandial blood glucose and HbA1c (glycated haemoglobin) in animal models, while no changes were observed in plasma and urine electrolyte concentrations.20 Of the SGLT2 inhibitors, the most developed is dapagliflozin.
does not just inhibit SGLT2, it is also capable of inhibiting SGLT1, causing osmotic diarrhoea in most cases. SGLT2 inhibition can reduce plasma glucose levels by reducing the glucose Tm, resulting in increased urinary excretion of glucose. In animals without diabetes, inhibition of SGLT2 has no effect on plasma glucose, because hepatic glucose production is increased to compensate for glycosuria. However, in diabetic animals, administration of SGLT2 inhibitors produces dose-dependent glycosuria and a significant reduction in plasma glucose.
Dapagliflozin is rapidly absorbed after oral administration in an average time of 1 hour (0.5hr-4.0hr) in patients with type 2 diabetes mellitus. A phase I study (in healthy volunteers) suggested that absorption was slower when given with meals, although this difference was minimal.21 The half-life of dapagliflozin is approximately 16 hours. Glycosuria is dosedependent. Dapagliflozin renal clearance is minimal (3-6ml/min) and renal excretion is low (less than 2.5% in urine over 24h). In vitro studies have suggested that dapagliflozin is metabolised by metabolic inactivation of the enzyme glucuroniltransferase.22
Table 3. SGLT2 transporter inhibitor drugs and development phase Active ingredient
Company
Clinical trials phase
Dapagliflozin
BMS/Astra Zeneca
III
Canagliflozin
Johnson & Johnson
II
Sergliflozin
GSK
Failed in phase I
Remogliflozin (KGT-1611)
Kiseei Pharmaceuticals
Failed in phase I
BI-10773
Boehringer Ingelheim
II
BI-44847
Boehringer Ingelheim
II
YM-543
Astellas
II
AVE-2268
Sanofi-Aventis
II
Information source: www.clinicaltrials.gov. BMS: Bristol Myers Squibb; GSK: GlaxoSmithKline. 622
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Dapagliflozin has showed a hypoglycaemic effect at daily doses of 2.5mg, 5mg, 10mg, 20mg and 50mg in phase II clinical trials. Most of the ongoing phase III trials are evaluating the effects of daily doses of 2.5mg, 5mg and 10mg. The randomised, double-blind, placebo-controlled phase II study on dapagliflozin assessed dosedependent effects in patients with type 2 diabetes mellitus. A total of 389 type 2 diabetic patients without treatment and with HbA 1c higher than 7% were randomly assigned to a placebo group or a group treated with increasing doses of dapagliflozin for 12 weeks. 23 Metformin XR was the active comparator, although no statistical comparisons were made. Fasting blood glucose, postprandial blood glucose using prolonged oral glucose overload (3h) and HbA 1c were assessed. Baseline HbA 1c ranged between 7.7% and 8.0% in all groups. In the dapagliflozin group, the decrease in HbA 1c was around 0.8%, while in the placebo group it was 0.2% (P
