Prevention and management of BK virus-induced (polyomavirus-induced) nephropathy in kidney transplantation
- Ajit P Limaye, MD, FACP, FIDSA
Ajit P Limaye, MD, FACP, FIDSA
- Professor of Medicine
- University of Washington
- Daniel C Brennan, MD, FACP
Daniel C Brennan, MD, FACP
- Editor-in-Chief — Nephrology
- Section Editor — Renal Transplantation
- Professor of Medicine
- Medical Director and Co-Director of the Comprehensive Transplant Center, Department of Internal Medicine, Division of Nephrology
- Johns Hopkins Medical School
- Section Editor
- Barbara Murphy, MB, BAO, BCh, FRCPI
Barbara Murphy, MB, BAO, BCh, FRCPI
- Section Editor — Renal Transplantation
- Professor of Medicine
- Mount Sinai School of Medicine
- Deputy Editors
- Albert Q Lam, MD
Albert Q Lam, MD
- Deputy Editor — Nephrology
- Assistant Professor of Medicine
- Harvard Medical School
- Anna R Thorner, MD
Anna R Thorner, MD
- Co-Director, Editorial Projects — UpToDate
- Deputy Editor — Infectious Diseases
- Assistant Professor of Medicine, Part-time
- Harvard Medical School
Polyomaviruses are ubiquitous, small, nonenveloped, double-stranded DNA viruses that infect a variety of animals (including monkeys, humans, rabbits, rodents, and birds) but tend to be species specific. The polyomaviruses are highly seroprevalent in humans but only cause clinical disease among immunocompromised patients.
Multiple human polyomaviruses have been identified. BK virus (BKV) and JC virus are the two most common polyoma viruses associated with human disease and the only two associated with nephropathy (BKVN).
The major diseases caused by BKV are tubulointerstitial nephritis and ureteral stenosis in renal transplant recipients and hemorrhagic cystitis in bone marrow transplant recipients. BKV causes clinical disease of the genitourinary tract due in part to its tropism for genitourinary epithelium. JC virus causes a small proportion of polyomavirus nephropathy (<5 percent) among kidney transplant recipients and is typically associated with a milder clinical course.
BKVN reportedly occurs in up to 10 percent of kidney allograft recipients . Overall, the reported incidence of allograft failure ranges from 15 to 50 percent of affected individuals [2-5]. Approaches to prevention and management of BKVN in kidney transplant recipients are presented here. The clinical manifestations and diagnosis of this disorder and general overviews of these viruses are discussed separately. (See "Overview of JC polyomavirus, BK polyomavirus, and other polyomavirus infections" and "Virology, epidemiology, and pathogenesis of JC polyomavirus, BK polyomavirus, and other human polyomaviruses" and "Clinical manifestations and diagnosis of BK virus-induced (polyomavirus-induced) nephropathy in kidney transplantation".)
SCREENING AND PREVENTION
BKV infections progress through well-characterized stages [6-9]. Initially, BKV DNA is detected in the urine, followed by detection in the plasma, and, finally, in the kidney (ie, BKVN) (figure 1). (See "Clinical manifestations and diagnosis of BK virus-induced (polyomavirus-induced) nephropathy in kidney transplantation".)
Subscribers log in hereLiterature review current through: Jul 2017. | This topic last updated: May 26, 2016.References
- Hirsch HH, Brennan DC, Drachenberg CB, et al. Polyomavirus-associated nephropathy in renal transplantation: interdisciplinary analyses and recommendations. Transplantation 2005; 79:1277.
- Wadei HM, Rule AD, Lewin M, et al. Kidney transplant function and histological clearance of virus following diagnosis of polyomavirus-associated nephropathy (PVAN). Am J Transplant 2006; 6:1025.
- Drachenberg CB, Beskow CO, Cangro CB, et al. Human polyoma virus in renal allograft biopsies: morphological findings and correlation with urine cytology. Hum Pathol 1999; 30:970.
- Howell DN, Smith SR, Butterly DW, et al. Diagnosis and management of BK polyomavirus interstitial nephritis in renal transplant recipients. Transplantation 1999; 68:1279.
- Ramos E, Drachenberg CB, Papadimitriou JC, et al. Clinical course of polyoma virus nephropathy in 67 renal transplant patients. J Am Soc Nephrol 2002; 13:2145.
- Ramos E, Drachenberg CB, Wali R, Hirsch HH. The decade of polyomavirus BK-associated nephropathy: state of affairs. Transplantation 2009; 87:621.
- Bohl DL, Brennan DC, Ryschkewitsch C, et al. BK virus antibody titers and intensity of infections after renal transplantation. J Clin Virol 2008; 43:184.
- Coleman DV, Gardner SD, Field AM. Human polyomavirus infection in renal allograft recipients. Br Med J 1973; 3:371.
- Agha IA, Alvarez A, Lopez L, et al. Human polyoma virus infects a high proportion of renal allograft recipients and the incidence is not affected by choice of calcineurin inhibitor (abstract). J Am Soc Nephrol 2001; 12:A4577.
- Buehrig CK, Lager DJ, Stegall MD, et al. Influence of surveillance renal allograft biopsy on diagnosis and prognosis of polyomavirus-associated nephropathy. Kidney Int 2003; 64:665.
- Brennan DC, Agha I, Bohl DL, et al. Incidence of BK with tacrolimus versus cyclosporine and impact of preemptive immunosuppression reduction. Am J Transplant 2005; 5:582.
- Drachenberg CB, Papadimitriou JC, Hirsch HH, et al. Histological patterns of polyomavirus nephropathy: correlation with graft outcome and viral load. Am J Transplant 2004; 4:2082.
- Hirsch HH, Knowles W, Dickenmann M, et al. Prospective study of polyomavirus type BK replication and nephropathy in renal-transplant recipients. N Engl J Med 2002; 347:488.
- Hardinger KL, Koch MJ, Bohl DJ, et al. BK-virus and the impact of pre-emptive immunosuppression reduction: 5-year results. Am J Transplant 2010; 10:407.
- Knight RJ, Gaber LW, Patel SJ, et al. Screening for BK viremia reduces but does not eliminate the risk of BK nephropathy: a single-center retrospective analysis. Transplantation 2013; 95:949.
- Elfadawy N, Flechner SM, Schold JD, et al. Transient versus persistent BK viremia and long-term outcomes after kidney and kidney-pancreas transplantation. Clin J Am Soc Nephrol 2014; 9:553.
- Hirsch HH, Randhawa P, AST Infectious Diseases Community of Practice. BK polyomavirus in solid organ transplantation. Am J Transplant 2013; 13 Suppl 4:179.
- Randhawa P, Brennan DC. BK virus infection in transplant recipients: an overview and update. Am J Transplant 2006; 6:2000.
- Randhawa PS, Finkelstein S, Scantlebury V, et al. Human polyoma virus-associated interstitial nephritis in the allograft kidney. Transplantation 1999; 67:103.
- Nickeleit V, Hirsch HH, Zeiler M, et al. BK-virus nephropathy in renal transplants-tubular necrosis, MHC-class II expression and rejection in a puzzling game. Nephrol Dial Transplant 2000; 15:324.
- Nickeleit V, Klimkait T, Binet IF, et al. Testing for polyomavirus type BK DNA in plasma to identify renal-allograft recipients with viral nephropathy. N Engl J Med 2000; 342:1309.
- Humar A, Michaels M, AST ID Working Group on Infectious Disease Monitoring. American Society of Transplantation recommendations for screening, monitoring and reporting of infectious complications in immunosuppression trials in recipients of organ transplantation. Am J Transplant 2006; 6:262.
- Vasudev B, Hariharan S, Hussain SA, et al. BK virus nephritis: risk factors, timing, and outcome in renal transplant recipients. Kidney Int 2005; 68:1834.
- The American Society of Transplantation Infectious Diseases Guidelines. Am J Transplant 2009; 9(Suppl 4):S92.
- Celik B, Shapiro R, Vats A, Randhawa PS. Polyomavirus allograft nephropathy: sequential assessment of histologic viral load, tubulitis, and graft function following changes in immunosuppression. Am J Transplant 2003; 3:1378.
- Saad ER, Bresnahan BA, Cohen EP, et al. Successful treatment of BK viremia using reduction in immunosuppression without antiviral therapy. Transplantation 2008; 85:850.
- Wiseman AC. Polyomavirus nephropathy: a current perspective and clinical considerations. Am J Kidney Dis 2009; 54:131.
- Gerbase MW, Fathi M, Spiliopoulos A, et al. Pharmacokinetics of mycophenolic acid associated with calcineurin inhibitors: long-term monitoring in stable lung recipients with and without cystic fibrosis. J Heart Lung Transplant 2003; 22:587.
- Wali RK, Drachenberg C, Hirsch HH, et al. BK virus-associated nephropathy in renal allograft recipients: rescue therapy by sirolimus-based immunosuppression. Transplantation 2004; 78:1069.
- Josephson MA, Williams JW, Chandraker A, Randhawa PS. Polyomavirus-associated nephropathy: update on antiviral strategies. Transpl Infect Dis 2006; 8:95.
- Randhawa P, Pastrana DV, Zeng G, et al. Commercially available immunoglobulins contain virus neutralizing antibodies against all major genotypes of polyomavirus BK. Am J Transplant 2015; 15:1014.
- Sener A, House AA, Jevnikar AM, et al. Intravenous immunoglobulin as a treatment for BK virus associated nephropathy: one-year follow-up of renal allograft recipients. Transplantation 2006; 81:117.
- Randhawa P, Bohl D, Brennan D, et al. longitudinal analysis of levels of immunoglobulins against BK virus capsid proteins in kidney transplant recipients. Clin Vaccine Immunol 2008; 15:1564.
- Bohl DL, Storch GA, Ryschkewitsch C, et al. Donor origin of BK virus in renal transplantation and role of HLA C7 in susceptibility to sustained BK viremia. Am J Transplant 2005; 5:2213.
- Josephson MA, Gillen D, Javaid B, et al. Treatment of renal allograft polyoma BK virus infection with leflunomide. Transplantation 2006; 81:704.
- Chong AS, Zeng H, Knight DA, et al. Concurrent antiviral and immunosuppressive activities of leflunomide in vivo. Am J Transplant 2006; 6:69.
- Hardinger KL, Wang CD, Schnitzler MA, et al. Prospective, pilot, open-label, short-term study of conversion to leflunomide reverses chronic renal allograft dysfunction. Am J Transplant 2002; 2:867.
- Knight DA, Hejmanowski AQ, Dierksheide JE, et al. Inhibition of herpes simplex virus type 1 by the experimental immunosuppressive agent leflunomide. Transplantation 2001; 71:170.
- Farasati NA, Shapiro R, Vats A, Randhawa P. Effect of leflunomide and cidofovir on replication of BK virus in an in vitro culture system. Transplantation 2005; 79:116.
- Waldman WJ, Knight DA, Lurain NS, et al. Novel mechanism of inhibition of cytomegalovirus by the experimental immunosuppressive agent leflunomide. Transplantation 1999; 68:814.
- Leca N, Muczynski KA, Jefferson JA, et al. Higher levels of leflunomide are associated with hemolysis and are not superior to lower levels for BK virus clearance in renal transplant patients. Clin J Am Soc Nephrol 2008; 3:829.
- Krisl JC, Taber DJ, Pilch N, et al. Leflunomide efficacy and pharmacodynamics for the treatment of BK viral infection. Clin J Am Soc Nephrol 2012; 7:1003.
- Guasch A, Roy-Chaudhury P, Woodle ES, et al. Assessment of efficacy and safety of FK778 in comparison with standard care in renal transplant recipients with untreated BK nephropathy. Transplantation 2010; 90:891.
- Vandercam B, Moreau M, Goffin E, et al. Cidofovir-induced end-stage renal failure. Clin Infect Dis 1999; 29:948.
- Vats A, Shapiro R, Singh Randhawa P, et al. Quantitative viral load monitoring and cidofovir therapy for the management of BK virus-associated nephropathy in children and adults. Transplantation 2003; 75:105.
- Keller LS, Peh CA, Nolan J, et al. BK transplant nephropathy successfully treated with cidofovir. Nephrol Dial Transplant 2003; 18:1013.
- Kuypers DR, Vandooren AK, Lerut E, et al. Adjuvant low-dose cidofovir therapy for BK polyomavirus interstitial nephritis in renal transplant recipients. Am J Transplant 2005; 5:1997.
- Bagnis C, Izzdine H, Deray G. [Renal tolerance of cidofovir]. Therapie 1999; 54:689.
- Smith JM, McDonald RA, Finn LS, et al. Polyomavirus nephropathy in pediatric kidney transplant recipients. Am J Transplant 2004; 4:2109.
- Naesens L, De Clercq E. Recent developments in herpesvirus therapy. Herpes 2001; 8:12.
- Rinaldo CH, Gosert R, Bernhoff E, et al. 1-O-hexadecyloxypropyl cidofovir (CMX001) effectively inhibits polyomavirus BK replication in primary human renal tubular epithelial cells. Antimicrob Agents Chemother 2010; 54:4714.
- Marty FM, Winston DJ, Chemaly RF, et al. Brincidofovir for prevention of cytomegalovirus (CMV) after allogeneic hematopoietic cell transplantation (HCT) in CMV-seropositive patients: A randomized, double-blind, placebo-controlled, parallel-group phase 3 trial. Biol Blood Marrow Transplant 2016; 3:S23.
- Reisman L, Habib S, McClure GB, et al. Treatment of BK virus-associated nephropathy with CMX001 after kidney transplantation in a young child. Pediatr Transplant 2014; 18:E227.
- Papanicolaou GA, Lee YJ, Young JW, et al. Brincidofovir for polyomavirus-associated nephropathy after allogeneic hematopoietic stem cell transplantation. Am J Kidney Dis 2015; 65:780.
- Leung AY, Chan MT, Yuen KY, et al. Ciprofloxacin decreased polyoma BK virus load in patients who underwent allogeneic hematopoietic stem cell transplantation. Clin Infect Dis 2005; 40:528.
- Chang CY, Gangji A, Chorneyko K, Kapoor A. Urological manifestations of BK polyomavirus in renal transplant recipients. Can J Urol 2005; 12:2829.
- Ali SH, Chandraker A, DeCaprio JA. Inhibition of Simian virus 40 large T antigen helicase activity by fluoroquinolones. Antivir Ther 2007; 12:1.
- Gabardi S, Waikar SS, Martin S, et al. Evaluation of fluoroquinolones for the prevention of BK viremia after renal transplantation. Clin J Am Soc Nephrol 2010; 5:1298.
- Lee BT, Gabardi S, Grafals M, et al. Efficacy of levofloxacin in the treatment of BK viremia: a multicenter, double-blinded, randomized, placebo-controlled trial. Clin J Am Soc Nephrol 2014; 9:583.
- Knoll GA, Humar A, Fergusson D, et al. Levofloxacin for BK virus prophylaxis following kidney transplantation: a randomized clinical trial. JAMA 2014; 312:2106.
- Anwar S, Brennan DC. Treatment of BK viremia after renal transplantation: are fluoroquinolones a false dawn? Clin J Am Soc Nephrol 2014; 9:445.
- Talmage DA, Listerud M. Retinoic acid suppresses polyoma virus transformation by inhibiting transcription of the c-fos proto-oncogene. Oncogene 1994; 9:3557.
- Ramos E, Vincenti F, Lu WX, et al. Retransplantation in patients with graft loss caused by polyoma virus nephropathy. Transplantation 2004; 77:131.
- Dharnidharka VR, Cherikh WS, Neff R, et al. Retransplantation after BK virus nephropathy in prior kidney transplant: an OPTN database analysis. Am J Transplant 2010; 10:1312.
- Womer KL, Meier-Kriesche HU, Patton PR, et al. Preemptive retransplantation for BK virus nephropathy: successful outcome despite active viremia. Am J Transplant 2006; 6:209.
- SCREENING AND PREVENTION
- Approach to screening
- Decreased immunosuppression
- Antiviral agents
- - Intravenous immune globulin
- - Leflunomide
- - Cidofovir
- - Brincidofovir (formerly CMX001)
- - Quinolone antibiotics
- - Retinoic acid
- MONITORING RESPONSE TO TREATMENT
- KIDNEY RETRANSPLANTATION
- SUMMARY AND RECOMMENDATIONS