Title: BK virus nephritis after renal transplantation
Abstract: BK viremia and nephritis are increasing problems in renal transplant recipients. The exact cause of the increasing prevalence of this condition remains poorly understood. Increasing prevalence has been correlated with newer immunosuppressive agents and the decline in acute rejection rates in recent years. The clinical manifestation varies from the asymptomatic state of viremia and nephritis to clinical renal dysfunction. The diagnosis of this infection is based on the combination of the presence of urinary decoy cells, virus in the urine/blood, and typical renal histological findings of interstitial nephritis. Routine post-transplant screening for BK viremia and viruria prior to the occurrence of nephritis and the reduction in immunosuppressive therapy for subjects with viremia appear to be attractive approaches. The treatment of BKV nephritis (BKVN) consists of reduction in immunosuppressive therapy and antiviral therapy with cidofovir or leflunomide or a combination of both. Approximately 30–60% of subjects with BKVN experienced irreversible graft failure. However, in recent years, the combinations of early detection, prompt diagnosis, and appropriate reduction in immunosuppressive therapy have been associated with better outcome. The pathogenesis of BK virus infection in renal transplant recipients needs to be explored. The source of BKV infection (donor as opposed to recipient), the role of host humoral, and cellular immunity to BKV, and the role of alloimmune activation in renal graft to the occurrence of nephritis are discussed in this review. BK viremia and nephritis are increasing problems in renal transplant recipients. The exact cause of the increasing prevalence of this condition remains poorly understood. Increasing prevalence has been correlated with newer immunosuppressive agents and the decline in acute rejection rates in recent years. The clinical manifestation varies from the asymptomatic state of viremia and nephritis to clinical renal dysfunction. The diagnosis of this infection is based on the combination of the presence of urinary decoy cells, virus in the urine/blood, and typical renal histological findings of interstitial nephritis. Routine post-transplant screening for BK viremia and viruria prior to the occurrence of nephritis and the reduction in immunosuppressive therapy for subjects with viremia appear to be attractive approaches. The treatment of BKV nephritis (BKVN) consists of reduction in immunosuppressive therapy and antiviral therapy with cidofovir or leflunomide or a combination of both. Approximately 30–60% of subjects with BKVN experienced irreversible graft failure. However, in recent years, the combinations of early detection, prompt diagnosis, and appropriate reduction in immunosuppressive therapy have been associated with better outcome. The pathogenesis of BK virus infection in renal transplant recipients needs to be explored. The source of BKV infection (donor as opposed to recipient), the role of host humoral, and cellular immunity to BKV, and the role of alloimmune activation in renal graft to the occurrence of nephritis are discussed in this review. BK virus belongs to the virus family polyomaviridae. Human polyoma viruses are of two types: JC manifests as viral encephalopathy and BK as viral nephritis. JC and BK represent initials of patients in whom they were first detected. There are other types of polyoma: a murine form that is known as murine polyoma virus and a simian form that is known as simian virus (SV)40. Viruses of the family polyomaviridae contain a 5000 base-pair genome composed of double-stranded deoxyribonucleic acid (DNA) that replicates in the host nucleus. Each polyoma virus encodes three capsid proteins, viral protein (VP)1, VP2, and VP3. VP1 is the only VP exposed on the outer shell of the virion, and contains a small groove that interacts with cellular receptors. BKV is classified into four major sero/genotypes: group I encodes the prototype strain Dunlop (Dun), MM, and GS; group II encodes the SB strain; group III encodes the AS strain; and group IV encodes the MG strains. The BK viral genome has a region that contains the origin of replication, transcriptional enhancer regions, and transcriptional promoter regions called the noncoding control region (NCCR). The terminology of BK virus originated from a renal transplant patient, initial BK, in whom it was first detected as a clinical disease in 1971.1.Gardner S.D. Field A.M. Coleman D.V. Hulme B. New human papovavirus (B.K.) isolated from urine after renal transplantation.Lancet. 1971; 19: 1253-1257Abstract Scopus (1044) Google Scholar There were no reported cases of this disease for the next 24 years, until Purighalla and co-workers observed their first case in early 1995.2.Purighalla R. Shapiro R. McCauley J. Randhawa P. BK virus infection in a kidney allograft diagnosed by needle biopsy.Am J Kidney Dis. 1995; 26: 671-673Abstract Full Text PDF PubMed Scopus (178) Google Scholar Subsequently, there has been a surge of BKV nephritis (BKVN) cases from many transplant centers across US, including ours.3.Mathur V.S. Olson J.L. Darragh T.M. Yen T.S. Polyomavirus-induced interstitial nephritis in two renal transplant recipients: case reports and review of the literature.Am J Kidney Dis. 1997; 29: 754-758Abstract Full Text PDF PubMed Google Scholar, 4.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 (464) Google Scholar, 5.Binet I. Nickeleit V. Hirsch H.H. et al.Polyomavirus disease under new immunosuppressive drugs: a cause of renal graft dysfunction and graft loss.Transplantation. 1999; 67: 918-922Crossref PubMed Scopus (407) Google Scholar, 6.Hirsch H.H. Polyomavirus BK nephropathy: a (re-)emerging complication in renal transplantation.Am J Transplant. 2002; 2: 25-30Crossref PubMed Scopus (240) Google Scholar, 7.Ahuja M. Cohen E.P. Dayer A.M. et al.Polyoma virus infection after renal transplantation. Use of immunostaining as a guide to diagnosis.Transplantation. 2001; 71: 896-899Crossref PubMed Scopus (114) Google Scholar, 8.Hussain S. Bresnahan B.A. Cohen E.P. Hariharan S. Rapid kidney allograft failure in patients with polyoma virus nephritis with prior treatment with antilymphocyte agents.Clin Transplant. 2002; 16: 43-47Crossref PubMed Scopus (36) Google Scholar The key factor associated with this increasing incidence remains unclear. Introduction of immunosuppressive agents such as mycophenolate mofetil (MMF) and Tacrolimus (Tac) has been thought to play a causative role in BKVN. However, this infection is also seen in patients who have never received the above combinations of immunosuppressive agents, as well as those receiving sirolimus, and those with steroid avoidance protocols. Thus, in recent years, the incidence of this infection has increased in renal transplant recipients and now poses a threat to improving graft survival.6.Hirsch H.H. Polyomavirus BK nephropathy: a (re-)emerging complication in renal transplantation.Am J Transplant. 2002; 2: 25-30Crossref PubMed Scopus (240) Google Scholar, 7.Ahuja M. Cohen E.P. Dayer A.M. et al.Polyoma virus infection after renal transplantation. Use of immunostaining as a guide to diagnosis.Transplantation. 2001; 71: 896-899Crossref PubMed Scopus (114) Google Scholar Approximately 80% of the general population has a detectable antibody to BKV, which appears early in life and remains elevated throughout life.9.Stolt A. Sasnauskas K. Koskela P. et al.Seroepidemiology of the human polyomaviruses.J Gen Virol. 2003; 84: 1499-1504Crossref PubMed Scopus (245) Google Scholar, 10.Flaegstad T. Ronne K. Filipe A.R. Traavik T. Prevalence of anti BK virus antibody in Portugal and Norway.Scand J Infect Dis. 1989; 21: 145-157Crossref PubMed Scopus (34) Google Scholar Antibodies to antigen VP1 crossreact with SV40, BKV, and JCV;11.Shah K.V. Daniel R.W. Kelly Jr, T.J. Immunological relatedness of papovaviruses of the simian virus 40-polyoma subgroup.Infect Immun. 1977; 18: 558-560PubMed Google Scholar however, a specific monoclonal antibody can be used to differentiate various viruses. The prevalence of this virus in the end-stage renal disease population, kidney donors, and transplant recipients has not been well defined. The prevalence of BK viruria, viremia, and nephritis after renal transplantation has been estimated at 30, 13, and 8%, respectively.12.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 (923) Google Scholar The overall prevalence of BKVN at the Medical College of Wisconsin from 1996 to 2004 is 4.2%, that is, 48 out of 1139 renal transplants. Viremia and viruria are also seen in liver, heart, and lung transplant recipients, but with a lower prevalence than in renal transplant recipients. Although reported, the incidence of clinical native renal BKVN is rare following other solid organ transplant recipients such as liver, heart, and lung. Clinical BKVN has occasionally been seen in immunosuppressed human immunovirus patients as well as in individuals with immunodeficiency syndromes, and rarely in other immunosuppressed individuals with systemic lupus erythematosus.13.Rosen S. Harmon W. Krensky A.M. et al.Tubulo-intertial nephritis associated with polyomavirus (BK type) infection.N Engl J Med. 1983; 308: 1192-1196Crossref PubMed Scopus (115) Google Scholar, 14.Smith R.D. Galla J.H. Skahan K. et al.Tubulointerstitial nephritis due to a mutant polyomavirus BK virus strain, BKV(Cin), causing end-stage renal disease.J Clin Microbiol. 1998; 36: 1660-1665PubMed Google Scholar Most renal transplant recipients with BKVN manifest with renal dysfunction.4.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 (464) Google Scholar, 7.Ahuja M. Cohen E.P. Dayer A.M. et al.Polyoma virus infection after renal transplantation. Use of immunostaining as a guide to diagnosis.Transplantation. 2001; 71: 896-899Crossref PubMed Scopus (114) Google Scholar, 8.Hussain S. Bresnahan B.A. Cohen E.P. Hariharan S. Rapid kidney allograft failure in patients with polyoma virus nephritis with prior treatment with antilymphocyte agents.Clin Transplant. 2002; 16: 43-47Crossref PubMed Scopus (36) Google Scholar, 15.Pappo O. Demetris A.J. Raikow R.B. Randhawa P.S. Human polyoma virus infection of renal allografts: histopathologic diagnosis, clinical significance, and literature review.Mod Pathol. 1996; 9: 105-109PubMed Google Scholar, 16.Drachenberg C.B. Beskow C.O. Cangro C.B. et al.Human polyoma virus in renal allograft biopsies: morphological findings and correlation with urine cytology.Hum Pathol. 1999; 30: 970-977Abstract Full Text PDF PubMed Scopus (224) Google Scholar Occasionally, subjects can also present with ureteric obstruction and hydronephrosis, and cases of cystitis have been reported.17.Gupta M. Miller F. Nord E.P. Wadhwa N.K. Delayed renal allograft dysfunction and cystitis associated with human polyomavirus (BK) infection in a renal transplant recipient: a case report and review of literature.Clin Nephrol. 2003; 60: 405-414Crossref PubMed Google Scholar In recent years, routine post-transplant protocol biopsy has also detected BKVN in the absence of serum creatinine elevation.18.Gloor J.M. Cohen A.J. Lager D.J. et al.Subclinical rejection in tacrolimus-treated renal transplant recipients.Transplantation. 2002; 73: 1965-1968Crossref PubMed Scopus (91) Google Scholar, 19.Buehrig C.K. Lager D.J. Stegall M.D. et al.Influence of surveillance renal allograft biopsy on diagnosis and prognosis of polyomavirus-associated nephropathy.Kidney Int. 2003; 64: 665-673Abstract Full Text Full Text PDF PubMed Scopus (160) Google Scholar Progressive renal failure has been reported in approximately 30–60% of cases.7.Ahuja M. Cohen E.P. Dayer A.M. et al.Polyoma virus infection after renal transplantation. Use of immunostaining as a guide to diagnosis.Transplantation. 2001; 71: 896-899Crossref PubMed Scopus (114) Google Scholar, 8.Hussain S. Bresnahan B.A. Cohen E.P. Hariharan S. Rapid kidney allograft failure in patients with polyoma virus nephritis with prior treatment with antilymphocyte agents.Clin Transplant. 2002; 16: 43-47Crossref PubMed Scopus (36) Google Scholar, 20.Ramos E. Drachenberg C.B. Papadimitriou J.C. et al.Clinical course of polyoma virus nephropathy in 67 renal transplant patients.J Am Soc Nephrol. 2002; 13: 2145-2151Crossref PubMed Scopus (366) Google Scholar Rare fatal disseminated BK virus infection after cadaveric transplantation has also been reported.21.Petrogiannis-Haliotis T. Sakoulas G. Kirby J. et al.BK-related polyomavirus vasculopathy in a renal-transplant recipient.New Engl J Med. 2001; 345: 1250-1255Crossref PubMed Scopus (114) Google Scholar The diagnosis of BKV infection is based on the documentation of viral cytopathic effects (urinary decoy cells), the virus itself (in blood, urine, and/or renal tissue), immunity to virus (BKV-specific antibody), and renal histological findings of nephritis. Each diagnostic modality and its limitations are shown in Table 1. Urinary decoy cells are a good diagnostic screening test, but the positive predictive value is around 20%. Thus, demonstration of urinary decoy cells suggests the presence of BKV in urothelium, but does not confirm BKVN.Table 1Diagnosis of BK virus nephritisTestsFindingsCommentsUrine cytologyPresence of decoy cellsSeen in 40–60% of transplant recipients, good screening test, positive predictive value around 20%Viremia (plasma BKV DNA)Copies >7000 per ml of plasmaSeen in 10–20% of transplant recipients, good screening test, positive predictive value around 60%Viruria (urinary BKV DNA)Copies 100-fold higher than plasma valuesSeen in 30–40% of transplant recipients, good screening test, positive predictive value around 40%Urinary BKV mRNA (active viral replication)Copies diagnostic of BKVNTo be confirmed in other studies, research toolBKV DNA in renal tissueDetection of BKV DNA in renal biopsy tissueNegative predictive value 100%, positive predictive value around 70%Renal histologyInflammatory changes with viral cytopathic effects, positive immunoperoxidase reaction with SV40 stain, predominant CD20-positive lymphocytic infiltratesGold standard, invasive procedure, focal lesions, chronic state with minimal viral cytopathic effects, mimics acute rejectionSerum BKV-specific antibodiesDiagnostic levels of IgM and IgG?Seen in 80–90% of general populationBKV-specific antibodies and BKV DNADiagnostic levels of BKV-specific antibodies IgM, IgG and BKV DNA?Research toolT-cell immunityDiagnostic measurement?Research tool Open table in a new tab Circulating BKV DNA in plasma has been seen in approximately 10–40% of renal transplant recipients.22.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 (507) Google Scholar, 23.Hussain S. Orentas R. Walczak J. et al.Prevention of BKV nephritis by monitoring BK viremia in renal transplant recipients: a prospective study.Graft. 2004; 7: 28-30Google Scholar However, not all viremic subjects have clinical nephritis. Demonstration of viremia by blood polymerase chain reaction (PCR) is a reliable test for nephritis, as it is seen in nearly 100% of the cases with BKVN. However, the positive predictive value for nephritis is only 60%. Viruria is seen in 30–40% of renal transplant recipients and the quantity is 100-fold over that of blood.6.Hirsch H.H. Polyomavirus BK nephropathy: a (re-)emerging complication in renal transplantation.Am J Transplant. 2002; 2: 25-30Crossref PubMed Scopus (240) Google Scholar, 12.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 (923) Google Scholar, 24.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 (426) Google Scholar Similar to blood BKV DNA, the utility of urinary BKV DNA has an excellent negative predictive value, but a poor positive predictive value; an alternative approach is to amplify viral VP1 messenger ribonucleic acid (mRNA) in urine, as it may represent active BKV replication.25.Ding R. Medeiros M. Dadhania D. et al.Noninvasive diagnosis of BK virus nephritis by measurement of messenger RNA for BK virus VP1 in urine.Transplantation. 2002; 74: 987-994Crossref PubMed Scopus (109) Google Scholar From this single study, positive and negative predictive values for mRNA in urine are above 90%; however, this must be confirmed in further studies. The levels of circulating plasma BKV DNA correlating with BKVN remain controversial; Hirsch et al.12.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 (923) Google Scholar reported copies greater than 7000 with acute BKVN. However, BKVN can occur even with copies as low as 1000 copies (personal observation) and better correlation has been noted with persistent viremia. The diagnosis of BKVN is usually made by the demonstration of viral cytopathic effect in renal histology with inflammatory response. Renal involvement can be focal in earlier stages and could have predominant fibrotic changes with minimal inflammatory changes in the later stages of the disease.26.Drachenberg C.B. Papadimitriou J.C. Hirsch H.H. et al.Histological patterns of polyomavirus nephropathy: correlation with graft outcome and viral load.Am J Transplant. 2004; 4: 2082-2092Crossref PubMed Scopus (304) Google Scholar Nonetheless, histological findings remain the gold standard diagnostic test (Figure 1) and typical findings are focal interstitial mononuclear inflammatory cell infiltrates, presence of plasma cells, necrotic tubular epithelium, and presence of homogenous intranuclear inclusion bodies. Renal interstitial inflammation with BKVN cannot always be differentiated from acute rejection. Immunohistochemistry with SV40 staining has been used as an indirect method to document the presence of BKV in renal tissue. Demonstration of predominant CD20-positive lymphocytes (B cells) in renal histology is suggestive of BKV infection.7.Ahuja M. Cohen E.P. Dayer A.M. et al.Polyoma virus infection after renal transplantation. Use of immunostaining as a guide to diagnosis.Transplantation. 2001; 71: 896-899Crossref PubMed Scopus (114) Google Scholar The degree of acuity and chronicity can be differentiated by the degree of inflammatory response and fibrosis.26.Drachenberg C.B. Papadimitriou J.C. Hirsch H.H. et al.Histological patterns of polyomavirus nephropathy: correlation with graft outcome and viral load.Am J Transplant. 2004; 4: 2082-2092Crossref PubMed Scopus (304) Google Scholar Prior exposure to this virus can be demonstrated by the presence of BKV-specific immunoglobulin (IgG) antibody in the circulation. The high prevalence of this infection in the general population rules out BKV-specific antibody as a diagnostic test for BKVN.27.Andrews C.A. Shah K.V. Daniel R.W. et al.A serological investigation of BK virus and JC virus infections in recipients of renal allografts.J Infect Dis. 1988; 158: 176-181Crossref PubMed Scopus (132) Google Scholar The detection of Immunoglobular-M(IgM) and degree of rise of IgM levels remain to be proven as a diagnostic method for acute BKVN. Recently, we have evaluated the role of BKV-specific antibody along with BKV DNA in cases of clinical BKVN.28.Hariharan S. Cohen E.P. Vasudev B. et al.BKV specific antibodies and BKV DNA in renal transplant recipients with BKV nephritis.Am J Transplant. 2005; 5: 2719-2724Crossref PubMed Scopus (60) Google Scholar Individuals with BKVN generally have a very high BKV DNA and low BKV-specific IgG levels. The subjects who recover from BKVN have undetectable viral copies in circulation with elevated BKV-specific IgG levels. Combinations of BKV-specific antibody and BKV DNA are a novel approach to diagnose as well as manage subjects with BKVN. Deficient humoral immunity in subjects with viremia and those with BKVN may be an important factor in the pathogenesis of this disease. Prompt increase in BKV-specific IgG antibody, with clearance of viremia and stabilization of renal function, was noted with reduction in immunosuppression in our series.28.Hariharan S. Cohen E.P. Vasudev B. et al.BKV specific antibodies and BKV DNA in renal transplant recipients with BKV nephritis.Am J Transplant. 2005; 5: 2719-2724Crossref PubMed Scopus (60) Google Scholar The natural history of BKVN varies from case to case, as illustrated in Figure 2. Our ability to diagnose BKVN was delayed owing to misdiagnosis of acute rejection, lack of knowledge about this disease in the mid-1990s, and unavailability of diagnostic tools such as BKV DNA and BKV-specific antibodies. Rapid progression of renal disease was common, with aggressive treatment for presumptive acute rejection, as shown by the evaluation of renal failure as 100/serum creatinine (Figure 2a). However, recent cases have been detected early using appropriate tools such as BKV DNA and BKV-specific antibodies. Prompt treatment with reduction in immunosuppression perhaps prevented further renal injury and arrested progressive renal failure in a case as shown in Figure 2b. Investigators have explored various risk factors associated with the occurrence of BKVN. However, no specific donor, recipient and transplant variables have been implicated in the occurrence of this disease. Seronegative subjects who receive kidneys from seropositive donors appear to have a higher chance of nephritis in a small pediatric study.29.Smith J.M. McDonald R.A. Finn L.S. et al.Polyomavirus nephropathy in pediatric kidney transplant recipients.Am J Transplant. 2004; 4: 2109-2117Crossref PubMed Scopus (125) Google Scholar Deficient humoral and/or cellular immunity in subjects with BKVN may lead to a poorer outcome. In our recent analysis, individual immunosuppressive medications, cold ischemia time, plasma renin activity (PRA), organ source (living vs deceased), and human lymphocyte antigen (HLA) mismatches did not appear to point out single or multiple risk factors.30.Vasudev B. Hariharan S. Hussian S.A. et al.BK virus nephritis: risk factors, timing and outcomes in renal transplant recipients.Kidney Int. 2005; 68: 1834-1839Abstract Full Text Full Text PDF PubMed Scopus (185) Google Scholar The level of renal dysfunction, defined as serum creatinine >2.2 mg/dl at the time of diagnosis of BKVN, correlated with poorer long-term graft survival.30.Vasudev B. Hariharan S. Hussian S.A. et al.BK virus nephritis: risk factors, timing and outcomes in renal transplant recipients.Kidney Int. 2005; 68: 1834-1839Abstract Full Text Full Text PDF PubMed Scopus (185) Google Scholar In a recently published series, renal histological features of moderate to severe fibrosis have been shown to have poorer outcome.26.Drachenberg C.B. Papadimitriou J.C. Hirsch H.H. et al.Histological patterns of polyomavirus nephropathy: correlation with graft outcome and viral load.Am J Transplant. 2004; 4: 2082-2092Crossref PubMed Scopus (304) Google Scholar Approximately 40–60% of renal grafts with BKVN develop progressive graft loss. We observed lower graft survival in recipients with BKVN in 2001.7.Ahuja M. Cohen E.P. Dayer A.M. et al.Polyoma virus infection after renal transplantation. Use of immunostaining as a guide to diagnosis.Transplantation. 2001; 71: 896-899Crossref PubMed Scopus (114) Google Scholar In 2002, rapid graft failure was noted when intense treatment with antilymphocyte agent was implemented as a result of misdiagnosis as acute rejection.8.Hussain S. Bresnahan B.A. Cohen E.P. Hariharan S. Rapid kidney allograft failure in patients with polyoma virus nephritis with prior treatment with antilymphocyte agents.Clin Transplant. 2002; 16: 43-47Crossref PubMed Scopus (36) Google Scholar Investigators from the University of Maryland have reported a similar experience.20.Ramos E. Drachenberg C.B. Papadimitriou J.C. et al.Clinical course of polyoma virus nephropathy in 67 renal transplant patients.J Am Soc Nephrol. 2002; 13: 2145-2151Crossref PubMed Scopus (366) Google Scholar As of March 2005, we have diagnosed a total of 48 cases of BKVN out of 1139 transplants performed from January 1996 to December 2004. The actuarial renal graft survival of these 48 cases is lower than the rest of the transplant population, as shown in Figure 3. Graft failure occurred in 19 of 48 (39%) cases. In recent years, however, there is a trend toward lower graft loss, due to the combination of better diagnostic tools, prompt diagnosis, and prompt reduction in immunosuppressive therapy. The management of BKV infection has been aimed at eliminating the virus, avoiding acute rejection, and preserving renal function. Potential therapeutic options and limitations are shown in Table 2. These include reducing immunosuppression alone and reducing immunosuppression as well as antiviral therapy such as cidofovir or leflunomide.31.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: 105-112Crossref PubMed Scopus (215) Google Scholar, 32.Kadambi P.V. Josephson M.A. Williams J. et al.Treatment of refractory BK virus-associated nephropathy with cidofovir.Am J Transplant. 2003; 3: 186-191Crossref PubMed Scopus (145) Google Scholar, 33.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 (204) Google Scholar Decreasing the level of immunosuppression in individuals with BKVN can lead to acute graft rejection. Thus, prevention of BKVN remains an optimal therapeutic approach.Table 2Treatment of BKV nephritisMode of actionCommentsAmantindineAntiviralPoor efficacy?VidarabineAntiviralUsed in cystitis, efficacy in nephritis unknownCidofovirAntiviralNephrotoxicity, potential benefit with reduction in immunosuppression, however, needs evaluationLeflunomideAntiviralPotential clinical efficacy with therapeutic trough level (50–100 μg/ml) with reduction in immunosuppressionFK 778AntiviralShorter-acting leflunomide, investigational agent, and efficacy unknownGammaglobulinAugments immunityEfficacy unknownReduction, discontinuation, and/or change in immunosuppressive agents (MMF, Tac, CSA, sirolimus, prednisone)Decreasing immunosuppressionSafe and appears effective, risk of acute rejection in selected recipientsPrevention: monitoring viral disease (urinary decoy cells, viremia, viruria, and surveillance biopsy) and altering immunosuppressionDiagnosis of preclinical, subclinical, or early nephritisSafe and effective with proper monitoring, risk of acute rejection with immunosuppressive alterations Open table in a new tab Prevention of BKVN by monitoring BK viral loads in renal transplant patients is an important option, as BKV infection is diagnosed prior to or at an early stage of nephritis. This research is in its early stage, as what constitutes a normal, abnormal, and pathologic elevation in viral load is still being defined. In a recent analysis, using quantitative real-time PCR, we have measured the BK viral loads in kidney transplant patients and have seen that patients who are PCR-positive in the peripheral blood present with a wide range of viral loads.23.Hussain S. Orentas R. Walczak J. et al.Prevention of BKV nephritis by monitoring BK viremia in renal transplant recipients: a prospective study.Graft. 2004; 7: 28-30Google Scholar Pre-emptive reduction of immunosuppression alone as a preventive therapy for BKVN appears to be a safe and attractive option.22.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 (507) Google Scholar, 23.Hussain S. Orentas R. Walczak J. et al.Prevention of BKV nephritis by monitoring BK viremia in renal transplant recipients: a prospective study.Graft. 2004; 7: 28-30Google Scholar In a recent large prospective study by Brennan et al.,22.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 (507) Google Scholar pre-emptive reduction of immunosuppression was successfully performed in response to BK viremia and BKVN was prevented. Thus, prevention of nephritis by regular monitoring for viremia/viruria seems to be a good approach. Leflunomide is an immunosuppressive agent, yet its metabolite A77 1726 has antiviral activity in vitro and in animals. In a recent report, leflunomide was used in 17 subjects with BKVN.33.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 (204) Google Scholar MMF was discontinued and Tac dose was decreased with loading dose of leflunomide at 100 mg/day for 5 days, followed by 20–60 mg daily, with a target trough blood level of 50–100 μg/ml. Marked reduction in viremia and viruria occurred in subjects who tolerated leflunomide, with a targ