Therapeutic options in BK virus-associated interstitial nephritis

CASE PRESENTATION A female in her 30s developed renal failure secondary to mixed connective tissue disease-associated immune complex glomerulonephritis. Her past medical and family history was otherwise unremarkable. She underwent a pre-emptive renal transplantation from her mother, receiving induction with dacluzimab and had an uneventful post-transplant course. Her immunosuppressive regimen at discharge included prednisone 5 mg daily, mycophenolate mofetil 1000 mg twice daily, tacrolimus 4 mg twice daily, and prophylaxis with oral gancyclovir and trimethoprim–sulfamethoxazole, atenolol for hypertension, and famotidine, iron and calcium/vitamin D supplements. Her baseline serum creatinine after the transplant was 1.5 mg/dl. Two years after receiving the transplant, she developed fever and dysuria and was treated for a presumed urinary tract infection (negative urine cultures). Her serum creatinine during this episode increased to 1.9 mg/dl and remained elevated in this range. Her physical examination was unremarkable and her blood pressure was 130/80 mm Hg. A renal ultrasound did not show any abnormalities. A renal biopsy was performed. Sampling for light microscopy consisted of a single core of renal cortex containing eight glomeruli, all of which appeared histologically unremarkable. There was diffuse, moderate to severe interstitial inflammation involving the entire cortex sampled, and composed of lymphocytes and less prominent plasma cells. The interstitial inflammation extended across tubular basement membranes to produce extensive tubulitis with multiple tubules containing greater than 10 lymphocytes. Proximal tubules also displayed diffuse degenerative changes and interspersed, enlarged, hyperchromatic nuclei with intranuclear viral inclusions typical of BK virus. This diagnosis was subsequently confirmed by immunohistochemical staining for SV40. There was moderate tubular atrophy and interstitial fibrosis involving 50% of the cortex sampled. Blood vessels appear unremarkable (Figure 1). The renal biopsy findings were diagnostic of BK virus-associated interstitial nephritis (BKVIN). In the light of the diffuse distribution of the interstitial inflammation and tubulitis but more localized viral inclusions, the possibility of coexistent acute cellular rejection could not be excluded. BK virus is a circular, double-stranded DNA virus.1.Gardner S.D. Field A.M. Coleman D.V. Hulme B. New human papovavirus (B.K.) isolated from urine after renal transplantation.Lancet. 1971; 1: 1253-1257Abstract PubMed Scopus (1116) Google Scholar In total, 70–85% of people are infected at some point in their lifetime, most frequently during childhood. The virus is likely transmitted through the respiratory route before establishing life-long latency in the urinary epithelium. It normally remains quiescent unless the immune system is impaired. It appears that T-cell mediated immunity keeps viral replication in check; renal transplant patients with antibodies directed against BK virus may still progress to nephropathy. Studies show that viral reactivation occurs in patients after solid organ transplantation, bone marrow transplantation, and in patients with human immunodeficiency virus/acquired immunodeficiency syndrome. Despite case reports of BKVIN after heart transplantation and in patients with HIV/AIDS, BKVIN as a cause of renal dysfunction is rare outside of renal transplantation.2.Menahem S.A. McDougall K.M. Thomson N.M. Dowling J.P. Native kidney BK nephropathy post cardiac transplantation.Transplantation. 2005; 79: 259-260Crossref PubMed Scopus (33) Google Scholar, 3.Nebuloni M. Tosoni A. Boldorini R. et al.BK virus renal infection in a patient with the acquired immunodeficiency syndrome.Arch Pathol Lab Med. 1999; 123: 807-811PubMed Google Scholar Reactivation of BK virus may manifest in several different forms (Table 1). Asymptomatic viral replication, hemorrhagic cystitis, ureteral stricture, and viral interstitial nephritis/BK virus associated nephropathy have all been described. Among renal transplant recipients, the incidence of asymptomatic urinary shedding of virus ranges from 30 to 40%. The rate of BKVIN is lower, ranging from 1 to 10% in recent series, but may be increasing.4.Hirsch 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 Rates of graft loss range from 10 to 80%. Most cases present within the first year after transplantation, although the disease can develop at any time. Risk factors for BKVIN have not fully been defined, but intensity of immunosuppression likely plays a key role. Treatment of rejection with intravenous steroids or antilymphocyte preparations increases the risk of developing BKVIN, but induction therapy with these preparations may not be associated.5.Hirsch H.H. 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: 488-496Crossref PubMed Scopus (983) Google Scholar It is suggested that the combination of tacrolimus (TAC) and mycophenolate (MMF) may be particularly potent at inducing BKVIN, but this too is not entirely clear. In a recent prospective study that included BK virus monitoring, 46% of patients on TAC+MMF developed viruria, as did 41% of patients on a regimen of cyclosporine and azathioprine (AZA). There was no independent effect of TAC, cyclosporine, MMF, or AZA on viruria or viremia.6.Brennan 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 Early reports suggest that immunosuppression superimposed on mechanical and ischemic damage could predispose to BK virus-associated ureteral stenosis.7.Coleman D.V. Mackenzie E.F. Gardner S.D. et al.Human polyomavirus (BK) infection and ureteric stenosis in renal allograft recipients.J Clin Pathol. 1978; 31: 338-347Crossref PubMed Scopus (183) Google Scholar Additional factors that may predispose to BKVIN include: male gender, white race, human leukocyte antigen mismatch, and ureteral stent usage.4.Hirsch 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 The frequent presence of tubulitis makes concomitant rejection difficult to diagnose and may not respond to antirejection therapies.8.Randhawa P.S. Finkelstein S. Scantlebury V. et al.Human polyoma virus-associated interstitial nephritis in the allograft kidney.Transplantation. 1999; 67: 103-109Crossref PubMed Scopus (476) Google ScholarTable 1Spectrum of manifestations of BK virus infectionAsymptomatic viral sheddingViral interstitial nephritisUreteral strictureHematuria, hemorrhagic cystitis Open table in a new tab The recommendations of the 2003 consensus conference are that all renal transplant recipients should be screened for BK virus replication in the urine: (1) every 3 months during the first 2 years post-transplant; (2) when allograft dysfunction is noted; and (3) when allograft biopsy is performed. A positive screening result should be confirmed within 4 weeks and assessed by quantitative assays (e.g. BK viral load in plasma or urine). Definitive diagnosis of BKVIN requires allograft biopsy. If BKVIN and concurrent acute rejection is diagnosed, antirejection treatment should be considered, followed by reduction in immunosuppression.4.Hirsch 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 Treatment recommendations must be tempered by the fact that there are no well-conducted randomized trials on treatment strategies and no universally effective antiviral medications. Principles of treatment fall in two categories: modification of immunosuppression to restore antiviral immunity and specific antiviral therapy to reduce viral replication (Table 2).Table 2Treatment options for BK virus-associated nephropathyReduction of immunosuppressionCalcineurin-free immunosuppressionCidofovirLeflunomide Open table in a new tab Prior to the discovery of medications with antiviral activity, treatment was limited to reducing immunosuppression. The optimal way to do this while providing adequate immunosuppression to prevent rejection remains debated. In a report on 100 patients by Ramos et al.,9.Ramos E. Drachenberg C.B. Portocarrero M. et al.BK virus nephropathy diagnosis and treatment: experience at the University of Maryland renal transplant program.in: Terasaki P. Cecka M. Clinical Transplants. Ucla Tissue Typing Laboratory, MD2002: 143-153Google Scholar patients maintained on a single immunosuppressant (TAC, cyclosporine, sirolimus) and prednisone were more likely to clear the virus and had less graft loss than those maintained on reduced dose of two immunosuppressants with continued prednisone. However, this was not a randomized trial. A successful immunosuppression reduction strategy may be gleaned from the prospective trial mentioned above.6.Brennan 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 Two hundred patients received rabbit antithymocyte globulin (Thymoglobulin® from Sangstat, Fremont, CA, USA) for induction followed by TAC or cyclosporine, prednisone, and AZA (low risk) or MMF (high risk) as the third drug. Patients were prospectively screened for BK virus replication with plasma and urine polymerase chain reaction, and patients with BK viremia had AZA or MMF withdrawn. If this was unsuccessful at clearing viremia, calcineurin inhibitor doses were reduced. Thirty-five percent of patients developed viruria; 11.5% developed viremia. Viremia resolved in 22 of 23 patients with reduction in immunosuppression, but only five of 23 cleared their viruria. Seven patients responded to withdrawal of AZA/MMF alone, two patients responded to reduction in calcineurin inhibitor dosage alone, six patients required cessation of AZA/MMF and additional reduction in calcineurin inhibitor, and seven patients cleared their infection with standard tapering of immunosuppression after transplantation. Remarkably, there were no cases of biopsy-proven BKVIN in this cohort. Patients were only biopsied for graft dysfunction, not viremia, so mild cases of intrarenal viral replication may have been missed. Reduction in immunosuppression was associated with only one episode of rejection. As an alternative to removing immunosuppressant agents, some authors have tried switching to calcineurin inhibitor-free regimens on the premise that renal epithelial cell toxicity of calcineurin inhibitors may be permissive to viral replication. Wali et al.10.Wali R.K. Drachenberg C. Hirsch H.H. et al.BK virus-associated nephropathy in renal allograft recipients: rescue therapy by sirolimus-based immunosuppression.Transplantation. 2004; 78: 1069-1073Crossref PubMed Scopus (76) Google Scholar reported switching three patients from a regimen of TAC/MMF/prednisone to sirolimus/prednisone for biopsy-proven BKVIN. All three patients cleared their viremia at 18 months follow-up with improvement in mean serum creatinine from 1.8 to 1.5. It is important to recognize that this regimen does not distinguish a generalized effect of immunosuppression reduction from a specific benefit of sirolimus in BKVIN. Several cases of BKVIN have recently been reported in patients receiving sirolimus-based regimens.11.Lipshutz G.S. Flechner S.M. Govani M.V. Vincenti F. BK nephropathy in kidney transplant recipients treated with a calcineurin inhibitor-free immunosuppression regimen.Am J Transplant. 2004; 4: 2132-2134Crossref PubMed Scopus (60) Google Scholar A final immunomodulation strategy that may become available in the future is the ex vivo manipulation of T cells to enhance BK virus-specific immunity.12.Comoli P. Basso S. Azzi A. et al.Dendritic cells pulsed with polyomavirus BK antigen induce ex vivo polyoma BK virus-specific cytotoxic T-cell lines in seropositive healthy individuals and renal transplant recipients.J Am Soc Nephrol. 2003; 14: 3197-3204Crossref PubMed Scopus (65) Google Scholar This leaves open the possibility of providing specific immunity against the virus, while avoiding the increased risk of rejection associated with decreased immunosuppression. Cidofovir (Vistide®) is a cytidine nucleotide analog that has been used to treat cytomegalovirus (CMV) retinitis and JC virus associated progressive multifocal leukoencephalopathy. The use of cidofovir in renal transplantation is limited by its nephrotoxicity. In trials using cidovir to treat CMV retinitis, 50% of patients developed proteinuria (>100 mg/dl), and 24% developed serum creatinine concentrations >1.5 mg/dl. The first reported use of cidofovir specifically for BK virus infection was the successful treatment of hemorrhagic cystitis in a bone marrow transplant recipient.13.Held T.K. Biel S.S. Nitsche A. et al.Treatment of BK virus-associated hemorrhagic cystitis and simultaneous CMV reactivation with cidofovir.Bone Marrow Transplant. 2000; 26: 347-350Crossref PubMed Scopus (102) Google Scholar Bjorang et al.14.Bjorang O. Tveitan H. Midtvedt K. et al.Treatment of polyomavirus infection with cidofovir in a renal-transplant recipient.Nephrol Dial Transplant. 2002; 17: 2023-2025Crossref PubMed Scopus (55) Google Scholar treated one renal transplant recipient with BKVIN with cidovir at a reduced dose to limit nephrotoxicity (taking advantage of the fact that cidovir is concentrated in the kidney providing adequate tissue concentration at a lower dose). Treatment was initiated at 0.25 mg/kg after 2 h of hydration with normal saline and was increased to 0.45 mg/kg per dose given every 2 weeks. Treatment resulted in clearance of virus from the blood and reduction in viruria. Since then, there have been several other case reports using cidofovir at doses ranging from 0.25 to 1 mg/kg every 2–3 weeks showing clearance of viremia in many.15.Vats A. Shapiro R. Singh R.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: 105-112Crossref PubMed Scopus (223) Google Scholar These patients also underwent reduction in immunosuppression so it is difficult to distinguish the direct antiviral effect of cidofovir from the benefit of enhanced immune response. Unfortunately, many patients in these reports were also left with a significant amount of renal dysfunction and interstitial fibrosis. Leflunomide (Arava®) is metabolized to its active metabolite A77 1726, which inhibits dihydroorate dehydrogenase, an enzyme involved in pyrimidine synthesis. Leflunomide has mainly been used to treat rheumatoid arthritis, but it has also been used in solid organ transplantation as primary immunosuppression. In vitro experiments suggest that leflunomide may also inhibit tyrosine kinase activity and that this inhibition of protein phosphorylation may be responsible for its antiviral effects.16.Knight D.A. Hejmanowski A.Q. Dierksheide J.E. et al.Inhibition of herpes simplex virus type 1 by the experimental immunosuppressive agent leflunomide.Transplantation. 2001; 71: 170-174Crossref PubMed Scopus (88) Google Scholar Williams et al.17.Williams J.W. Javaid B. Kadambi P.V. et al.Leflunomide for polyomavirus type BK nephropathy.N Engl J Med. 2005; 352: 1157-1158Crossref PubMed Scopus (213) Google Scholar recently reported on outcomes of 17 patients treated with leflunomide for BKVIN. Fifteen of 17 patients showed either clearance of viremia (7 of 15) or reduction in serum viral load. Interestingly, the two patients without virologic response also showed persistent levels of A77 1726 below 40 μg/ml suggesting the need for a minimum therapeutic concentration. Serum creatinine stabilized or improved in the 15 patients with blood levels above 40 μg/ml. Leflunomide's main side effects are leucopenia, rash, and hair loss. The half-life of the active metabolite, A77 1726 is approximately 2 weeks. FK778, an analog of the active metabolite of leflunomide with a shorter half-life, is currently undergoing clinical trials both for maintenance immunosuppression in renal transplantation and in a trial to specifically treat patients with BKVIN. In patients who lose their allografts due to BKVIN, questions remain whether retransplantation is safe and whether transplant nephrectomy would reduce the rate of recurrent infection. Transplant nephrectomy has been associated with resolution of viremia, although immunosuppression was reduced at the same time.18.Nickeleit V. Klimkait T. Binet I.F. et al.Testing for polyomavirus type BK DNA in plasma to identify renal-allograft recipients with viral nephropathy.N Engl J Med. 2000; 342: 1309-1315Crossref PubMed Scopus (437) Google Scholar Retransplantation in 10 patients after graft loss from BK virus infection was associated with recurrent infection in only one patient after a mean of 13.3 months follow-up. The recurrent infection occurred in a patient who had previously undergone transplant nephrectomy.19.Ramos E. Vincenti F. Lu W.X. et al.Retransplantation in patients with graft loss caused by polyoma virus nephropathy.Transplantation. 2004; 77: 131-133Crossref PubMed Scopus (84) Google Scholar There are inadequate data to give firm recommendations on retransplantation after allograft loss due to BKVIN, but it seems prudent to ensure clearance of viremia, either through withdrawal of immunosuppression alone or possibly removal of the allograft if viremia persists. In our patient, plasma BK virus titers at time of biopsy were 8 × 106 copies/ml and urine titers were >1.3 × 109 copies/ml. The doses of TAC and sirolimus were reduced to target levels <5 ng/ml. Cidofovir 0.25 mg/kg/dose was administered at 2-weekly intervals. Her creatinine increased to 2.5 mg/dl. Repeat renal allograft biopsy again revealed diffuse and severe interstitial inflammation and tubulitis. Intranuclear viral inclusions were less prominently seen and a smaller percentage of cells stained positively for SV40 (a marker of BK virus infection). As a result, the patient was thought to possibly have BKVIN and concurrent acute cellular rejection. She received three-500 mg doses of intravenous methylprednisolone, and sirolimus was replaced with leflunomide at a dose of 20 mg every other day. The patient was noted to be pregnant 5 months after starting leflunomide (contraceptive failure). Leflunomide was discontinued and 11 days of cholestyramine was administered to facilitate leflunomide removal. AZA was initiated at 75 mg/day at this time. She delivered a preterm infant after which leflunomide was resumed. Both mother and child are doing well at this time and the patient's serum creatinine at last follow-up (2 years after diagnosis of BK virus nephropathy) was 1.6 mg/dl. Her plasma BK virus (quantitative) remains negative. Reactivation of BK virus is being increasingly recognized as a cause of allograft dysfunction and can lead to allograft loss. All renal transplant recipients should be screened for BK virus replication early in the transplant course or when allograft dysfunction is noted. Definitive diagnosis of BKVIN requires allograft biopsy. If BKVIN and concurrent acute rejection is diagnosed, antirejection treatment should be considered, coupled with subsequently reducing immunosuppression. Reduction of immunosuppression has been associated with clearance of viremia in asymptomatic patients. Leflunomide may be associated with clearance of viremia and stabilization of renal function. Cidofovir at low doses (0.25–0.33 mg/kg intravenously biweekly) without probenicid could be considered for refractory cases. Retransplantation after renal allograft loss to BKVIN remains a treatment option for patients who have cleared viremia.