BK virus nephropathy (BKVN) has emerged as an important

Transcription

1 BK Virus Nephropathy in Pediatric Renal Transplant Recipients: An Analysis of the North American Pediatric Renal Trials and Collaborative Studies (NAPRTCS) Registry Jodi M. Smith,* Vikas R. Dharnidharka, Lynya Talley, Karen Martz, and Ruth A. McDonald* *Department of Pediatrics, Division of Nephrology, Children s Hospital and Regional Medical Center, University of Washington, Seattle, Washington; Division of Pediatric Nephrology, University of Florida College of Medicine, Gainesville, Florida; and EMMES Corp., Rockville, Maryland Background and Objectives: There is limited information regarding BK virus nephropathy in pediatric kidney transplantation. The objective of this study was to evaluate cases of BK virus nephropathy in the North American Pediatric Renal Trials and Collaborative Studies database. Design, Setting, Participants, & Measurements: Using a questionnaire that was sent to North American Pediatric Renal Trials and Collaborative Studies centers, we assessed the incidence, risk factors, clinical features, and outcomes of BK virus nephropathy in pediatric renal transplant recipients who received a transplant between 2000 and Results: BK virus nephropathy was reported in 25 (4.6%) of 542 patients at a median onset of 10.1 mo after transplantation. The median age was 11 yr. All patients who were tested reported BK viruria, and 19 (91%) of 21 who had plasma tested reported BK viremia. Treatment of BK virus nephropathy included reduction of immunosuppression (84%), cidofovir (24%), leflunomide (8%), and intravenous Ig (20%). Simultaneous rejection treatment was reported in four (16%). The median creatinine was 2.0 mg/dl at a mean follow-up of 24 mo. There were six (24%) graft failures in the patients with BK virus nephropathy at a mean of 24 mo after diagnosis. Rejection occurred in eight (32%) after diagnosis. Multivariate analysis showed that use of polyclonal induction therapy and zero HLA DR mismatch were associated with the development of BK virus nephropathy. Conclusions: This first multicenter, retrospective, cohort study of BK virus nephropathy in pediatric renal transplant recipients found a BK virus nephropathy incidence of 4.6% and identified polyclonal induction and zero HLA DR mismatch as significant risk factors for BK virus nephropathy. Clin J Am Soc Nephrol 2: , doi: /CJN Received December 4, Accepted June 20, Published online ahead of print. Publication date available at Address correspondence to: Dr. Jodi M. Smith, Division of Nephrology, Children s Hospital and Regional Medical Center, University of Washington, 4800 Sand Point Way NE, M1 5, Seattle, WA Phone: ; Fax: ; jodi.smith@seattlechildrens.org BK virus nephropathy (BKVN) has emerged as an important cause of progressive graft dysfunction in renal transplantation, with incidence rates ranging from 1 to 10% (1 5). Numerous potential risk factors have been identified, including specific immunosuppressive agents (tacrolimus, mycophenolate mofetil), previous rejection, male gender, age, ethnicity, HLA mismatch, and BKV serostatus (1,4,6 9). Since the early reports in 1997, graft outcomes have significantly improved, likely as a result of increased awareness with early diagnosis and intervention. Despite numerous studies in adults, there are limited reports of BKV and BKVN in the pediatric renal transplant population, likely because of the small number of cases that a single pediatric center may encounter (2,9,10 14). We performed a retrospective questionnaire cohort study of multiple pediatric renal transplant centers using the North American Pediatric Renal Trials and Collaborative Studies (NAPRTCS) transplant registry to describe the incidence, clinical features, risk factors, and outcomes of BKVN. Materials and Methods Study Population Since its inception in 1987, the scientific registry of NAPRTCS has enrolled 8000 patients who have received one or more renal transplants. Data collection methods have been previously reported (15). Briefly, the NAPRTCS has 150 participating medical centers in the United States, Canada, Mexico, and Costa Rica. The data on pediatric transplantation are derived from centers that collect information at the time of transplantation, 1 and 6 mo after transplantation, and every 6 mo thereafter. The initial transplant information consists of recipient age, gender, race, primary disease, type and duration of dialysis, type of transplant, degree of HLA mismatch, ischemia time, peak panel reactive antibody, induction therapy, height, and weight. At 30 d, data collected include graft outcome, initial immunosuppressive therapy, complications, and re-hospitalizations. Thereafter, information is collected every 6 mo regarding height, weight, serum creatinine, type and dosage of immunosuppressive therapy, and the use of other concomitant medications. Copyright 2007 by the American Society of Nephrology ISSN: /

2 1038 Clinical Journal of the American Society of Nephrology Clin J Am Soc Nephrol 2: , 2007 For this study, a specific BKVN questionnaire was sent to 86 participating centers and included questions on diagnosis, clinical features, viral load, immunosuppression, treatment, and outcome. These centers were selected on the basis of whether they had contributed data in the years 2000 to 2004 (the period of the study). Definitions Cases of BKVN were defined by the center. The definition of BKVN was made by the centers on the basis of histologic diagnosis and the intention to treat as BKVN. We included cases that occurred in patients who received a transplant after January 1, 2000, to analyze patients who were on immunosuppressive medications of the current era. In addition, patients had to have at least 12 mo of follow-up to have adequate time to evaluate outcomes. Statistical Analyses Univariate analysis of risk factors was done using the two-tailed Fisher exact, 2,ort test, as appropriate. A multivariate logistic regression analysis was used to identify variables related to the development of BKVN. The full model included age, race, gender, transplant year, primary diagnosis, donor source, acute tubular necrosis, cold ischemia time, HLA-A, HLA-B, HLA-DR, initial immunosuppression (prednisone, cyclosporin A [CsA], tacrolimus, mycophenolate mofetil [MMF], and sirolimus), and induction antibody therapy. A backward selection procedure was used to select the most parsimonious model for BKVN development. Results Study Population Eight-six institutions and 1246 patients were eligible for the study and received questionnaires. Results were returned from 52 (60%) institutions and 542 patients. Table 1 shows the characteristics of the study population. Twenty-five (4.6%) patients were identified by their centers as having BKVN. The median onset of BKVN was 10.1 mo (range 1.8 to 38.3 mo) after transplantation. Diagnosis of BKVN At the time of diagnosis, 21 (100%) of 21 reported viruria (17 by PCR and four by decoy cells) and 19 (91%) of 21 reported viremia. There was histologic evidence of BKVN in 24 (96%) of 25 cases at the time of diagnosis. The mean creatinine at time of diagnosis was 1.8 mg/dl (SE 0.2). The baseline mean creatinine defined as stable creatinine before the diagnosis of BKVN was 1.1 mg/dl (SE 0.1). Treatment and Outcome of BKVN Twenty-one (84%) patients had a reduction of their immunosuppression. Specifically, 11 (53%) of 21 had their CsA/tacrolimus reduced or stopped, 18 (86%) of 21 had their MMF reduced or stopped, and five (24%) of 21 had their sirolimus reduced or stopped. Three patients had both their calcineurin inhibitor and sirolimus reduced or stopped. Cidofovir was used in six (24%) cases, leflunomide in 2 (8%), and intravenous Ig in five (20%). Four (16%) patients had simultaneous treatment of rejection. Of the 21 patients with BK viruria, 17 were retested and 10 cleared the viruria at a median of 6 mo (range 1 to 17 mo). Of the 19 patients with BK viremia, 13 had clearance at a median of 5 mo (range 0.5 to 14 mo). The median creatinine was 2.0 mg/dl (range 0.5 to 14.6) at a mean follow-up of 24 mo. Looking at rejection, BK cases have eight (32%) documented rejections. A time-to-first rejection (after development of BKVN) analysis indicates a 1-yr rejection rate of 25.1% ( 8.9) and a 2-yr rejection rate of 39.0% ( 11.5). There were six (24%) graft failures in the patients with BKVN at a mean of 24 mo after diagnosis. Two of these six graft failures were in the patients who had both their calcineurin inhibitor and sirolimus reduced or stopped. A time-to-event analysis estimates a graft survival rate (SE) of 87.8% ( 6.6) at 1 yr and 69.7% ( 10.8) at 2 yr after development of BKVN. Analysis of Risk Factors Table 1 shows the results of univariate analyses of potential risk factors for the development of BKVN. There was no significant difference in rates of BKVN when considering gender, ethnicity, age, transplant year, donor source, cause of primary disease, cold ischemia time, acute tubular necrosis, or type of maintenance immunosuppression. Induction with polyclonal antibody therapy was associated with BKVN (P ). Table 2 shows the univariate analysis of HLA A, B, and DR mismatch data where zero HLA-A (P ), zero HLA-B (P ), and zero HLA-DR mismatch (P ) were associated with BKVN. Table 3 shows the results of a multivariate logistic regression analysis. Variables in the model included age, gender, race, donor source, HLA, era of transplant, primary diagnosis, and immunosuppression (induction and maintenance). Use of polyclonal induction therapy (odds ratio [OR] 11.04; 95% confidence interval [CI] 2.94 to 41.52) and zero HLA-DR mismatch were significant predictors of BKVN (OR 7.31; 95% CI 2.58 to 20.71). Discussion BKVN has emerged as an important cause of graft dysfunction in renal transplantation. Analysis of the NAPRTCS registry found that the incidence of BKVN was 4.6% among recent pediatric renal transplant recipients, similar to adult data. Polyclonal induction antibody use and zero HLA mismatch were associated with a significantly higher risk for BKVN. Previously identified risk factors including age, gender, ethnicity, type of maintenance immunosuppression, and rejection history were not identified as risk factors in this analysis. The majority of patients were treated with reduction of immunosuppression alone, with graft survival of 76% and a median creatinine of 2.0 mg/dl at a mean follow-up of 24 mo. The intensity of immunosuppression has been identified as a risk factor for the development of BKVN. No specific maintenance immunosuppressive agent is exclusively associated with BKVN development, but patients who receive the combination of tacrolimus, MMF, and prednisone have been found to be at high risk (1,16). Our study did not identify a specific maintenance immunosuppressive medication to be associated with BKVN. We did observe an association between use of polyclonal induction therapy and BKVN (OR 11.04; 95% CI 2.94 to 41.52). Polyclonal induction therapy was recently associated with an increased risk for infectious complications in pediatric renal transplant patients (17). Other studies have reported that

3 Clin J Am Soc Nephrol 2: , 2007 BK Virus Nephropathy in Pediatrics 1039 Table 1. Univariate analysis of patient and donor characteristics a Characteristic BK No BK Total n % n % n % Exact 2 P b Total Gender male female Race white black Hispanic other Age (yr) 0 to to to Transplant year Donor source missing living donor deceased donor Primary diagnosis structural GN FSGS other Cold ischemia time live donor h h missing ATN (dialysis in first week) yes no missing Induction therapy none monoclonal polyclonal Primary immunosuppression CsA tacrolimus MMF azathioprine sirolimus prednisone a ATN, acute tubular necrosis; CsA, cyclosporin A; GN, glomerulonephritis; MMF, mycophenolate mofetil. b Because of small sample sizes, exact P values are presented.

4 1040 Clinical Journal of the American Society of Nephrology Clin J Am Soc Nephrol 2: , 2007 Table 2. Univariate analysis of HLA mismatches and BKVN a Parameter BK No BKVN Total n % n % n % 2 P b Total HLA-A HLA-B HLA-DR a BKVN, BK virus nephropathy. b Because of small sample sizes, exact P values are presented. Table 3. Multivariate logistic analysis of risk factors for BKVN a Factor Comparison Group Reference Group OR 95% CI P HLA-DR 0 mismatches 2 mismatches to overall P mismatches to Induction therapy Monoclonal None to overall P Polyclonal to a CI, confidence interval; OR, odds ratio. use of antilymphocyte agents for the treatment of steroid-resistant rejection is associated with BKV replication in patients who are on tacrolimus or MMF maintenance therapy (7,18,19). However, other studies that examined BKV specifically did not find an association between use of antilymphocyte preparations and risk for BK viruria, viremia, or BKVN (7,16,18,20). HLA mismatching has been identified as a risk factor for BKVN in both retrospective and prospective studies among adult renal transplant patients (7,19). The increased rejection risk with HLA mismatching (21,22) through its treatment with escalation of immunosuppression and/or via direct rejectionrelated inflammatory responses has been proposed as a potential mechanism for this association. Other studies have not identified HLA mismatching as a risk factor (4,16,23). Limited data exist on the role of HLA as a risk factor in pediatrics. In our study, we found that zero HLA-DR mismatch was associated with a 7.3-fold higher risk for BKVN. There are several potential explanations for this finding. Those with zero mismatch may represent younger donors who are BKV seronegative, a previously identified risk factor. We were not able to evaluate BKV serostatus because this test was not routinely performed at centers. Recipient age was not a significant risk factor in the univariate or multivariate analyses. Higher levels of immunosuppression would have placed those with zero HLA-DR mismatch at increased risk for BKVN. We did find that more patients with BKVN had received polyclonal induction therapy, which one could postulate may represent overimmunosuppression of a relatively low-risk group. In terms of maintenance immunosuppression, we found no difference in the levels of CsA, tacrolimus, or sirolimus. NAPRTCS does not routinely collect data on mycophenolic acid levels. In addition, there was no difference in the number of rejection episodes. Finally, there is evidence for increased risk for viral complications in the setting of well-hla-matched transplants. A dualistic effect of HLA has been proposed with HLA compatibility reducing rejection risk but also potentially augmenting MHCrestricted cellular immune mechanisms of injury (24). In liver transplantation, HLA matching has been associated with cytomegalovirus hepatitis and the development of chronic rejection thought to be precipitated by cytomegalovirus-induced HLA antigen expression in susceptible patients (24 26). On the basis of the evidence that BK viremia and viruria do appear before the onset of histologic BKVN, prospective screening for BKV is recommended as part of routine posttransplantation follow-up (27). Screening was performed in the majority of NAPRTCS centers with 21 (84%) of 25 centers using urine either by cytology or by PCR and 21 (84%) of 25 testing blood by PCR.

5 Clin J Am Soc Nephrol 2: , 2007 BK Virus Nephropathy in Pediatrics 1041 Reduction of immunosuppression is the primary mode of intervention for the treatment of BKVN (3,27,28). This approach was successful in the majority (84%) of patients in this study. Biopsy-proven rejection after immunosuppression reduction is reported in up to 25% of patients (29), which compares to 32% seen in the NAPRTCS cohort. Although there have been no controlled trials, antiviral therapy with cidofovir has been reported in cases in which immunosuppression reduction is not sufficient (13,14,30). In our study, cidofovir was used in six (24%) of 25 cases. Rates of graft loss have improved with the increased awareness and introduction of routine viral screening. More recent studies report graft loss rates between 10 and 50%. In the NAPRTCS cohort, there was a 76% graft survival at 24 mo after diagnosis. We acknowledge the limitations of our study. The NAPRTCS database is a voluntary database; therefore, a sampling bias may be present. The retrospective nature of the study with questionnaires as the data collection method introduces the possibility of recall bias and a general underestimation of the true incidence of BKVN. However, given the restriction to cases from 2000 to 2004 and that each pediatric center typically encounters only one to two cases, we hope that this underestimation is minimal. The definition of BKVN was made by the centers themselves on the basis of histologic diagnosis and the intention to treat as BKVN. We did not define specific histologic diagnostic criteria. As such, there is a risk for misclassification of noncases as cases, and this could have an impact on the results. We do not have information on the viral surveillance strategies of the participating centers, which may have had an impact on the severity of disease at diagnosis. In addition, treatment approaches differed, which limits the interpretability of the outcome data. Conclusions This first multicenter, retrospective, cohort study of BKVN in pediatric renal transplant recipients found a BKVN incidence of 4.6% and graft survival of 76%, which are similar to adult reports. Polyclonal induction therapy use and zero HLA mismatch were identified as significant risk factors for BKVN. Further studies to confirm these findings are warranted. Acknowledgments The North American Pediatric Renal Trials and Collaborative Studies (NAPRTCS) is supported by unrestricted educational grants from Novartis, AMGEN, and Genentech. This study was presented in part at the annual meeting of the American Society of Nephrology, November 8 through 13, 2005; Philadelphia, PA. Disclosures None. References 1. Mengel M, Marwedel M, Radermacher J, Eden G, Schwarz A, Haller H, Kreipe H: Incidence of polyomavirus-nephropathy in renal allografts: Influence of modern immunosuppressive drugs. Nephrol Dial Transplant 18: , Ginevri F, De Santis R, Comoli P, Pastorino N, Rossi C, Botti G, Fontana I, Nocera A, Cardillo M, Ciardi MR, Locatelli F, Maccario R, Perfumo F, Azzi A: Polyomavirus BK infection in pediatric kidney-allograft recipients: A single-center analysis of incidence, risk factors, and novel therapeutic approaches. Transplantation 75: , Hirsch HH, Steiger J: Polyomavirus BK. Lancet Infect Dis 3: , Ramos E, Drachenberg CB, Papadimitriou JC, Hamze O, Fink JC, Klassen DK, Drachenberg RC, Wiland A, Wali R, Cangro CB, Schweitzer E, Bartlett ST, Weir MR: Clinical course of polyoma virus nephropathy in 67 renal transplant patients. J Am Soc Nephrol 13: , Buehrig CK, Lager DJ, Stegall MD, Kreps MA, Kremers WK, Gloor JM, Schwab TR, Velosa JA, Fidler ME, Larson TS, Griffin MD: Influence of surveillance renal allograft biopsy on diagnosis and prognosis of polyomavirus-associated nephropathy. Kidney Int 64: , Nickeleit V, Klimkait T, Binet IF, Dalquen P, Del Zenero V, Thiel G, Mihatsch MJ, Hirsch HH: Testing for polyomavirus type BK DNA in plasma to identify renal-allograft recipients with viral nephropathy. N Engl J Med 342: , Hirsch HH, Knowles W, Dickenmann M, Passweg J, Klimkait T, Mihatsch MJ, Steiger J: Prospective study of polyomavirus type BK replication and nephropathy in renaltransplant recipients. N Engl J Med 347: , Mathur VS, Olson JL, Darragh TM, Yen TS: Polyomavirusinduced interstitial nephritis in two renal transplant recipients: Case reports and review of the literature. Am J Kidney Dis 29: , Smith JM, McDonald RA, Finn LS, Healey PJ, Davis CL, Limaye AP: Polyoma virus nephropathy in pediatric kidney transplant recipients. Am J Transplant 4: , Muller A, Beck B, Theilemann K, Stapenhorst L, Licht C, Michalk D, Franzen C, Hoppe B: Detection of polyomavirus BK and JC in children with kidney diseases and renal transplant recipients. Pediatr Infect Dis J 24: , Hymes LC, Warshaw BL: Polyomavirus (BK) in pediatric renal transplants: Evaluation of viremic patients with and without BK associated nephritis. Pediatr Transplant 10: , Alexander RT, Langlois V, Tellier R, Robinson L, Hebert D: The prevalence of BK viremia and urinary viral shedding in a pediatric renal transplant population: A single-center retrospective analysis. Pediatr Transplant 10: , Vats A, Shapiro R, Singh Randhawa P, Scantlebury V, Tuzuner A, Saxena M, Moritz ML, Beattie TJ, Gonwa T, Green MD, Ellis D: Quantitative viral load monitoring and cidofovir therapy for the management of BK virus-associated nephropathy in children and adults. Transplantation 75: , Araya CE, Lew JF, Fennell RS 3rd, Neiberger RE, Dharnidharka VR: Intermediate-dose cidofovir without probenecid in the treatment of BK virus allograft nephropathy. Pediatr Transplant 10: 32 37, McEnery P, Arbus G, Stablein DM, Tejani A: Renal transplantation in children: A report of the North American

6 1042 Clinical Journal of the American Society of Nephrology Clin J Am Soc Nephrol 2: , 2007 Pediatric Renal Transplant Cooperative Study (NAPRTCS). N Engl J Med 326: , Brennan DC, Agha I, Bohl DL, Schnitzler MA, Hardinger KL, Lockwood M, Torrence S, Schuessler R, Roby T, Gaudreault-Keener M, Storch GA: Incidence of BK with tacrolimus versus cyclosporine and impact of preemptive immunosuppression reduction. Am J Transplant 5: , Puliyanda DP, Stablein DM, Dharnidharka VR: Younger age and antibody induction increase the risk for infection in pediatric renal transplantation: A NAPRTCS report. Am J Transplant 7: , Binet I, Nickeleit V, Hirsch HH, Prince O, Dalquen P, Gudat F, Mihatsch MJ, Thiel G: Polyomavirus disease under new immunosuppressive drugs: A cause of renal graft dysfunction and graft loss. Transplantation 67: , Awadalla Y, Randhawa P, Ruppert K, Zeevi A, Duquesnoy RJ: HLA mismatching increases the risk of BK virus nephropathy in renal transplant recipients. Am J Transplant 4: , Wong W, Pascual M, Hirsch HH, Goggins W, Bae J, Farrell ML, Delmonico FL, Cosimi AB, Tolkoff-Rubin N: BK virus replication in kidney transplant recipients who received thymoglobulin induction. J Am Soc Nephrol 14: SU-PO539, Cecka JM: The role of HLA in renal transplantation. Hum Immunol 56: 6 16, Opelz G: Impact of HLA compatibility on survival of kidney transplants from unrelated live donors. Transplantation 64: , Bohl DL, Storch GA, Ryschkewitsch C, Gaudreault-Keener M, Schnitzler MA, Major EO, Brennan DC: Donor origin of BK virus in renal transplantation and role of HLA C7 in susceptibility to sustained BK viremia. Am J Transplant 5: , Donaldson P, Underhill J, Doherty D, Hayllar K, Calne R, Tan KC, O Grady J, Wight D, Portmann B, Williams R: Influence of human leukocyte antigen matching on liver allograft survival and rejection: The dualistic effect. Hepatology 17: , O Grady JG, Alexander GJ, Sutherland S, Donaldson PT, Harvey F, Portmann B, Calne RY, Williams R: Cytomegalovirus infection and donor/recipient HLA antigens: Interdependent co-factors in pathogenesis of vanishing bileduct syndrome after liver transplantation. Lancet 2: , Manez R, White LT, Linden P, Kusne S, Martin M, Kramer D, Demetris AJ, Van Thiel DH, Starzl TE, Duquesnoy RJ: The influence of HLA matching on cytomegalovirus hepatitis and chronic rejection after liver transplantation. Transplantation 55: , Hirsch HH, Brennan DC, Drachenberg CB, Ginevri F, Gordon J, Limaye AP, Mihatsch MJ, Nickeleit V, Ramos E, Randhawa P, Shapiro R, Steiger J, Suthanthiran M, Trofe J: Polyomavirus-associated nephropathy in renal transplantation: Interdisciplinary analyses and recommendations. Transplantation 79: , Randhawa PS, Demetris AJ: Nephropathy due to polyomavirus type BK. N Engl J Med 342: , Randhawa PS, Finkelstein S, Scantlebury V, Shapiro R, Vivas C, Jordan M, Picken MM, Demetris AJ: Human polyoma virus-associated interstitial nephritis in the allograft kidney. Transplantation 67: , Kadambi PV, Josephson MA, Williams J, Corey L, Jerome KR, Meehan SM, Limaye AP: Treatment of refractory BK virus-associated nephropathy with cidofovir. Am J Transplant 3: , 2003