Screening and Management Practices for Polyoma (BK) Viremia and Nephropathy in Kidney Transplant Recipients From the Lands Down Under: Addressing the Unknowns and Rationale for a Multicenter Clinical Trial

Abstract

BK polyomavirus infection in transplanted kidneys that leads to BK virus–associated nephropathy (BKVAN) is an important cause of allograft loss and has limited treatment options.1Bohl D.L. Brennan D.C. BK virus nephropathy and kidney transplantation.Clin J Am Soc Nephrol. 2007; 2: S36-S46Crossref PubMed Scopus (174) Google Scholar Recent data suggest that BK viremia affects approximately 10% of people within the first 12 months following kidney transplantation.2Kable K. Davies C.D. O'Connell P.J. et al.Clearance of BK virus nephropathy by combination antiviral therapy with intravenous immunoglobulin.Transplant Direct. 2017; 3: e142Crossref PubMed Scopus (34) Google Scholar Among recipients with BKVAN, the overall risk of allograft loss is substantially increased, estimated to be 50% within 5 years of diagnosis. Geographic variation in the rates of BK infection also has been recognized. Depending on local epidemiology and immunosuppression practices, the prevalence of viruria, viremia, and histological features of BKVAN is reported to be between 35% and 40%, 12% and 15%, and 3% and 8%, respectively.3Hirsch H.H. Brennan D.C. Drachenberg C.B. et al.Polyomavirus-associated nephropathy in renal transplantation: interdisciplinary analyses and recommendations.Transplantation. 2005; 79: 1277-1286Crossref PubMed Scopus (809) Google Scholar Early detection of BK viremia through screening may allow judicious reduction in immunosuppression dose preventing the detrimental effects of BKVAN, such as premature allograft loss. Current screening methods are highly variable between centers and include a combination of quantitative detection of BK DNA in whole blood (BK viremia) using real-time polymerase chain reaction assay or the detection of BK viruria. The Kidney Disease Improving Global Outcomes 2009 guidelines for the care of kidney transplant recipients recommended routine monthly screening for BK viremia using BK nucleic acid testing for the first 3 to 6 months and then 3 monthly thereafter for the first year post transplantation.4Kidney Disease: Improving Global Outcomes Transplant Work GroupKDIGO clinical practice guideline for the care of kidney transplant recipients.Am JtTansplant. 2009; 9: S1-S155PubMed Google Scholar Observational data also suggest a higher number of BK copies detected (BK viral load) is associated with an increased risk of BKVAN. Prior studies have indicated a test threshold of 1 × 104 viral copies per milliliter has a test specificity and sensitivity for BKVAN of 95.0 (77.5–99.7) and 83.4 (78.4–84.7), respectively, with positive and negative predictive values of 61.9 (50.5–64.9) and 98.3 (92.4–99.9), assuming an overall prevalence of 5%.5Myint T.M. Turner R.M. Craig J.C. et al.Test performance characteristics of quantitative nucleic acid testing for polyomaviruses in kidney and kidney-pancreas transplant recipients.Clin Transplant. 2013; 27: E571-E579PubMed Google Scholar A single-center study reported reduction in immunosuppression may result in decrease in the BK viral load and a concomitant decrease in the risk of BKVAN,6Brennan D.C. Agha I. Bohl D.L. et al.Incidence of BK with tacrolimus versus cyclosporine and impact of preemptive immunosuppression reduction.Am J Transplant. 2005; 5: 582-594Crossref PubMed Scopus (561) Google Scholar but the optimal treatment strategies are uncertain. Trials of prophylactic treatment with quinolones also showed lack of treatment efficacy in the prevention of disease.7Knoll G.A. Humar A. Fergusson D. et al.Levofloxacin for BK virus prophylaxis following kidney transplantation: a randomized clinical trial.JAMA. 2014; 312: 2106-2114Crossref PubMed Scopus (90) Google Scholar The current options include complete withdrawal of the antimetabolites, or switching from mycophenolate mofetil (MMF) to azathioprine, 50% dose reduction in calcineurin inhibitors, conversion from tacrolimus to ciclosporin, introduction of mammalian target of rapamycin inhibitors, or replace antimetabolite agents with leflunomide.1Bohl D.L. Brennan D.C. BK virus nephropathy and kidney transplantation.Clin J Am Soc Nephrol. 2007; 2: S36-S46Crossref PubMed Scopus (174) Google Scholar Once BKVAN develops, current treatment regimens are limited and largely unproven, beyond reducing the intensity of immunosuppression, as described previously. Recent work has shown possible benefits in the clearance of BK viruses from blood and renal tissues with i.v.Ig and the antiviral agent cidofovir, but this is limited to a single-center study.2Kable K. Davies C.D. O'Connell P.J. et al.Clearance of BK virus nephropathy by combination antiviral therapy with intravenous immunoglobulin.Transplant Direct. 2017; 3: e142Crossref PubMed Scopus (34) Google Scholar To better understand the current screening and management patterns for BK viremia and BKVAN, and to inform the design of a multicenter randomized controlled intervention trial in the management of BK infection in kidney transplant recipients, we conducted a survey among relevant Australian and New Zealand clinicians. Of the 557 practicing nephrologists in Australia and New Zealand, 113 (20.2%) completed the survey. The baseline characteristics of the respondents are shown in Table 1. Most respondents were men (n = 73, 61%), aged 40 years and older (n = 82, 72.6%), had more than 10 years of experience in nephrology (n = 66, 58.4%), worked in a transplanting unit (n = 68, 62.4%), and lived in Australia (n = 93, 82.3%). The Australian and New Zealand Society of Nephrology and the Transplantation Society of Australia and New Zealand male membership is approximately 55% to 60%. This is consistent with the gender distribution of the survey.Table 1Baseline characteristics of the survey participantsDemographics, n (%)N = 113Male71 (63)Female38 (34)Prefer not to say4 (3)Age groups in years, n (%) 20–294 (3.5) 30–3927 (23.9) 40–4939 (34.5) 50–5935 (31.0) ≥ 608 (7.1)State/Territoryan = 23 did not provide details of which states they reside in. Australian Capital Territory4 (4.4) New South Wales39 (43.3) Northern Territory3 (3.3) Queensland15 (16.7) South Australia4 (4.4) Tasmania1 (1.2) Victoria19 (21.1) West Australia5 (5.6)Years of practicing as a nephrologist 1–534 (30.1) 6–1012 (11.4) 11–1519 (16.8) >1547 (41.6)Country of practice Australia93 (82.3) New Zealand20 (17.7)Transplanting unitbn = 4 did not provide details of their practice location. Yes68 (62.4) No41 (37.6)a n = 23 did not provide details of which states they reside in.b n = 4 did not provide details of their practice location. Open table in a new tab Table 2 shows the reported incidence, screening, and management strategies of BK infection in kidney transplant recipients. Approximately 50% of respondents reported an estimated incidence of BK viremia of approximately 10% to 20% and 1% to 3% for BKVAN.Table 2Reported incidence, screening, and management strategies of BK viral infection in kidney transplant recipients (n = 113)Incidence of BK viremia, n (%) < 10%42 (37.2) 10–15%48 (42.5) 16–20%9 (7.9) >20%4 (3.5) No response10 (8.9)Incidence of BKVAN, n (%) <1%20 (17.7) 1–3%70 (62) >3%12 (10.6) No response11 (9.7)Frequency of screening, n (%) Monthly30 (26.6) Every second month10 (8.6) Every 3 months20 (17.7) Every 6 months2 (1.8) Never12 (10.6) Other29 (25.7) No response10 (8.9)Types of screening, n (%)aNot mutually exclusive. Urine decoy cells6 (5.3) Real-time plasma BK polymerase chain reaction90 (80) Urinary viral load14 (12.3)Performance of kidney biopsy to exclude BKVAN, n (%)aNot mutually exclusive. Presence of viruria and no viremia0 (0) Presence of viremia only29 (25.7) Presence of graft dysfunction78 (69) Presence of graft dysfunction and viremia80 (71)Scenarios which reduction in immunosuppression are considered, n (%)aNot mutually exclusive. Persistent BK viruria without viremia11 (9.7) Persistent BK viremia without graft dysfunction76 (67.3) Persistent BK viremia with allograft dysfunction81 (71.7) Presence of biopsy-proven BKVAN85 (75.2)Reduction in immunosuppression in the presence of viremia, n (%)aNot mutually exclusive. Reduction in tacrolimus and MMF dose76 (67.2) Change to an alternative CNI and antimetabolites37 (32.7) Change from CNI to mTORIs14 (12.4) Change to low-dose CNI and mTORIs20 (17.7) Change from MMF to leflunomide only30 (26.5)Use of adjuvant treatment options when BKVAN was diagnosed, n (%)Quinolones Practice routinely5 (4.4) Consider only in some patients27 (23.9) Do not use61 (54.0) No response20 (17.7)Cidofovir Practice routinely11 (9.7) Consider only in some patients38 (33.6) Do not use44 (38.9) No response20 (17.7)i.v.Ig Practice routinely16 (14.1) Consider only in some patients55 (48.7) Do not use22 (19.5) No response20 (17.7)Trial participation, n (%) Yes77 (68.1) No14 (12.4) No response22 (19.5)BKVAN, BK viral associated nephropathy; CNI, calcineurin inhibitors; MMF, mycophenolate mofetil; mTORIs, mammalian target of rapamycin inhibitorsa Not mutually exclusive. Open table in a new tab BKVAN, BK viral associated nephropathy; CNI, calcineurin inhibitors; MMF, mycophenolate mofetil; mTORIs, mammalian target of rapamycin inhibitors There was substantial variability in reported screening practices. The most common screening modality was BK quantitative real-time polymerase chain reaction on plasma (80%). The use of urine viruria and decoy cells was much less frequent (less than 10%). The frequency of screening varied between monthly (27%) to 3-monthly (18%) within the first 12 months of transplantation, typically with more frequent screening in the first 3 months posttransplant. Approximately 10% of nephrologists stated they do not routinely perform screening; however, once persistent viremia was detected, 30% would perform allograft biopsy to exclude BKVAN, whereas most (approximately 70%) would consider a biopsy only when graft dysfunction occurred. Most respondents reported that they would reduce the dose of immunosuppressive drugs (70%) in recipients with persistent BK viremia. Reduction in the doses of calcineurin inhibitors and antimetabolites (such as MMF) was the first-line practice for most respondents (n = 75, 66.4%), followed by a switch to alternative calcineurin inhibitors (tacrolimus to cyclosporine) and antimetabolite therapy (such from MMF to leflunomide, or MMF to azathioprine) (n = 34, 30%), then changing from MMF to leflunomide (n = 30, 26.5%) without altering calcineurin inhibitor doses, followed by alteration to a combination of low-dose tacrolimus and mammalian target of rapamycin inhibitors (n = 9, 8%). Once BKVAN developed, a range of adjuvant treatment options were available to the respondents. Cidofovir and i.v.Ig were considered in some patients and most did not recommend the use of quinolones. Most nephrologists (68%) agreed they would participate in a multicenter intervention trial of BK infection in kidney transplant recipients. This binational survey suggests that BK viral infection is an important early posttransplant complication in kidney transplant recipients. The reported incidence of BK viremia and BKVAN appear to be consistent across Australia and New Zealand, varying between 10% and 15% for viremia and up to 3% for BKVAN. Routine BK polymerase chain reaction testing is the most common screening modality used, but inconsistencies exist between the reported screening frequencies and the international recommended guidelines.4Kidney Disease: Improving Global Outcomes Transplant Work GroupKDIGO clinical practice guideline for the care of kidney transplant recipients.Am JtTansplant. 2009; 9: S1-S155PubMed Google Scholar In most circumstances, persistent viremia with an elevation in serum creatinine would prompt a diagnostic biopsy to detect BKVAN and exclude other or concurrent causes of allograft dysfunction. Although modification of immunosuppression is universal for all participating units, there is considerable variability in the approaches used to achieve this. More than two-thirds of the nephrologists would reduce the doses of immunosuppressive drugs in the presence of BK viremia or BKVAN, and although there is a wide variation in the immunosuppression reduction strategy, reduction in the total dose of tacrolimus and MMF remains the most favored approach. Adjuvant treatments are not routinely used by the respondents in the treatment of BKVAN, but 43% and 63% would consider prescribing cidofovir and i.v.Ig, , respectively, when other options have failed, or graft function is deteriorating rapidly. BKVAN remains an important cause of allograft failure in kidney transplant recipients. Despite the high prevalence of BK viremia and the established association between BK viremia and development of BKVAN, the lack of clinical evidence to guide management is likely responsible for the variety of management strategies used, as reported in this survey. Reducing immunosuppression remains the mainstay treatment for BK viremia and BKVAN, but the optimal approach to reducing or substituting immunosuppressive agents remains uncertain. In this survey, knowledge of the incidence of BK infection and the variability between sites will inform the design of a health care–embedded platform trial. More importantly, we have collected the information to conduct a process of research prioritization, in consultation with consumer groups, to define platform objectives that evaluate key intervention strategies and treatment arms that are currently preferred and commonly used by nephrologists. As most respondents to this survey supported the conduct of a randomized controlled trial to address this research question, a collaborative multicenter clinical study in Australia and New Zealand with a pragmatic trial design is a unique opportunity to address some of these evidence gaps and to inform future clinical management of recipients with BK viremia or BKVAN. All the authors declared no competing interests. GW is supported by the National Health and Medical Research Council Career Development Fellowship (APP1147657). Download .pdf (.15 MB) Help with pdf files Supplementary File (PDF)

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