Pathogen Overview
ABOUT THE BK VIRUS
BK is a member of the Polyomaviridae family, which are small, nonenveloped viruses with a closed, circular double-stranded DNA genome. Polyomaviruses are ubiquitous in nature and can be isolated from a number of species. BKV and JCV make up the members of the human polyomaviruses. BK virus was first isolated in 1971 from the urine of a renal transplant patient who developed ureteral stenosis postoperatively. The virus was named after the initials of this first patient. Primary infection with BKV typically occurs in childhood, probably as a mild upper respiratory infection. Studies suggest over 90% of the population has been infected with BK virus by the age of ten years. Following primary infection, the virus establishes latency in the urogenital tract where it remains for life. Reactivation of the virus can occur spontaneously or, more commonly, in an immunocompromised host.
BK VIRUS CLINICAL MANIFESTATIONS
BK virus associated renal allograft nephropathy (BKVAN) has emerged as a major cause of renal allograft dysfunction worldwide since the early 1990s. This emergence seems to have coincided with the widespread availability of potent immunosuppressive drugs. BKVAN can be a difficult clinical problem with a prevalence rate of 1-10% and a graft loss rate of 10-80%, depending on the center’s BK screening program and use of immunosuppression.
In renal allograft recipients, BK reactivation most frequently manifests itself as a nephropathy. However, in hematopoietic stem cell transplant (HSCT) patients, hemorrhagic cystitis is frequently seen. Less common presentations of BKV reactivation include echogenic mass, interstitial nephritis and ureteric stenosis. Pediatric renal transplant patients that are seronegative at the time of transplantation seem to be at particularly high risk of BKVAN, although this requires further study for confirmation. These patients may present with a viral prodrome consisting of low grade fever, myalgia and mild gastroenteritis prior to onset of allograft dysfunction.
Despite recent advances in BK diagnostics, it remains unclear why only a small number of renal transplant patients, the majority of who are seropositive for BKV, develop full blown renal disease. Several efforts have been made to identify risk factors for development of BKVAN. Specific immunosuppressive agents, such as tacrolimus and mycophenolate mofetil (MMF), are generally believed to be associated with a higher incidence of BKVAN. However, BKVAN has been observed with all immunosuppressive regimens. It may be more plausible that patients whose immunosuppression is maintained at a higher total level, rather than with a specific agent, have an increased incidence of BKVAN. Other risk factors that have been associated with an increased risk of BKVAN include:HLA mismatch, the use of corticosteroid pulses to treat graft rejection, cell injury due to acute rejection or cold ischemia, male gender and BKV serology. However, many other studies have contradicted these associations. Recently, host and viral genomic variation have also been correlated with development of BKVAN. DNA sequence variations in several putative transcription factor binding sites in the noncoding control region (NCCR) of the BK genome and polymorphisms of several cytokine genes have been proposed to play a role in the pathogenesis of BKVAN. The effect of mutations within the BKV genome on therapy outcome is unknown at this time. It seems that BKVAN is promoted by the concurrent presence of several risk factors, among which immunosuppression appears to be a prerequisite.
BK VIRUS LABORATORY DIAGNOSIS
The key to confirming the diagnosis of BKVAN remains the recognition of BKV inclusions in tubular and glomerular epithelial cells in renal allograft biopsy specimens. Viral inclusions in BKVAN are often associated with variable mononuclear interstitial infiltrates and focal tubulitis, which closely resembles acute rejection. Because of the focal nature of BKV replication in the kidney, negative biopsy results cannot rule out BKVAN. Interestingly, the diagnosis of BKVAN is often preceded by a diagnosis of acute rejection episode(s) in many patients. These episodes are, or tend to gradually become, nonresponsive to conventional therapy. It is unclear if these rejection episodes may be early stages of BKVAN, prior to the viral inclusions becoming conspicuous on biopsy. Thus, a high index of suspicion is needed for diagnosis of BKVAN, especially in patients who present an unexplained rise in serum creatinine or have episodes of acute rejection that are refractory to steroid therapy.
Molecular detection methods, such as real-time PCR, provide a sensitive and noninvasive means to detect BKV in urine and blood. Molecular detection of BKV allows patients to be placed on a regular monitoring program that allows detection of the virus prior to development of nephropathy (and therefore kidney damage). There are numerous studies in the literature demonstrating rising BK urinary loads, by real-time quantitative PCR, prior to presentation with full blown BKVAN. Such a scenario can often predict and predate BKVAN by several weeks to several months. Urinary viral load of more than 10,000,000 copies/ml has now been proposed to be a significant risk factor for BKVAN. A rising titer of several log orders can also be of clinical significance. Besides the role of urinary BKV viral load in BKVAN management, especially in early stages, real-time PCR analysis of blood samples to detect and quantify BKV DNA is rapidly becoming the test of choice for confirming diagnosis and monitoring progression of active BKVAN. The sensitivity of DNA PCR is considered to be 100% and the specificity approximately 85%. The interdisciplinary panel of BKV experts that met in Basel, Switzerland in October 2003 proposed a titer of > 10,000 copies/ml in plasma (or serum) to be a significant marker of BKVAN with a specificity of =93%. The panel recommended renal allograft recipients be screened for BKV replication in the urine every three months for the first two years following transplant and annually thereafter until the fifth year post-transplant, in addition to performing urinary screening whenever an allograft biopsy is performed, whether it be for allograft dysfunction or surveillance biopsy.
To view the panel’s recommendation in further detail go to: Transplantation; Volume 79, Number 10, May 27, 2005
BK VIRUS TREATMENT
Although various therapeutic strategies have been tried for BKVAN, the results are variable with graft loss rate ranging from 10 to 80%. In most centers, BKVAN is initially treated by lowering immunosuppression and sometimes additionally by discontinuing drug regimens containing tacrolimus. These therapeutic attempts can result in good clinical success if BKVAN is diagnosed during an early stage, thus emphasizing the need for regular monitoring. Several centers have reported significantly improved graft survival rates upon initiation of a monitoring program. If lowering of immunosuppression does not result in resolution of nephropathy, a consideration for the institution of additional therapy should be made in an expeditious manner. Currently, specific antiviral strategies for BKVAN are poorly defined, although low dose cidofovir (0.25-1 mg/kg without probenecid) has been successful in a number of cases. Additionally, there have been reports of successful use of leflunomide in resolving BKVAN.
CONCLUSION
There remains much to be learned regarding risk factors, both viral and recipient, as well as in treatment and prevention strategies. There is a critical need for development of antiviral drugs that will inhibit the replication of BK virus.
Selected References
Hirsch HH, Brennan DC, Drachenburg CB, et al. Polyomavirus-associated nephropathy in renal transplantation: interdisciplinary analyses and recommendations. Transplantation. 2005;79(10):1277-1286.
Knipe D, Howley P. Fields Virology. 5th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2006.
Limaye AP, Jerome KR, Kuhr CS, et al. Quantitation of BK virus load in serum for the diagnosis of BK virus-associated nephropathy in renal transplant recipients. J Infect Dis. 2001;(183):1669-1672.
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):1309-1315.
Scantlebury V, Randhawa P, Shapiro R, et al. Cidofovir: A Method of Treatment for BK Virus-Associated Transplant Nephropathy. Graft. 2002;5(suppl):S82-S87.
Vats A, Shapiro R, Scantelbury V, et al. BK Virus associated nephropathy and cidofovir: long term experience. [abstract]. Am J Transplant. 2003;3(suppl 5):A190.
PAO-02-0707 PCR tests are performed pursuant to a license agreement with Roche Molecular Systems, Inc.
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Abstracts & Publications
Barri YM, Ahmad I, Ketel BL, et al. Polyoma viral infection in renal transplantation: the role of immunosuppressive therapy. Clin Transplant. 2001;(15):240-246.
BACKGROUND: Polyoma virus infection in renal transplant recipients has been observed with increasing frequency in recent years. Renal allograft involvement in this condition may occur as a result of primary infection or secondary to reactivation of the latent virus. Interstitial nephritis, ureteric stenosis, rise in serum creatinine and allograft function loss have been attributed to this viral infection. METHODS: In this study we reviewed our experience with 8 patients who developed polyoma viral infection confirmed by allograft biopsy. All patients were receiving mycophenolate mofetil as part of the immunosuppression and 7 of the 8 patients were on tacrolimus. All patients have biopsy proven polyoma viral infection. The following therapeutic maneuvers were carried out following the diagnosis of polyoma viral infection: 1) stopping mycophenolate and 2) switching tacrolimus to cyclosporine or reducing the tacrolimus dose to adjust it at a lower therapeutic trough level. The clinical course and outcome of our patients were reviewed in relation to manipulation of immunosuppressive medications. RESULTS: The incidence of this infection in our transplant program in the last 3 yr was 5.3%. Seventy-five percent of the patients had at least one rejection episode and 63% had more than one rejection episode. The main risk factor for the development of polyoma viral infection was related to the intensity of immunosuppression. The use of antirejection therapy after histological diagnosis of polyoma virus infection was not associated with improvement of renal function despite the histological appearance of acute rejection. Thus, the interstitial nephritis associated with polyoma viral infection appears to be an inflammatory response to the virus rather than acute rejection. Six out of the 8 patients stabilized renal function with reduction in immunosuppression. CONCLUSIONS: Reduction in immunosuppression was associated with the stabilization of renal function when instituted early. However, these patients were left with a degree of allograft dysfunction and their outcome may be significantly compromised. The lack of effective antiviral therapy for polyoma virus may limit the use of newer and more potent immunosuppressive medications.
Boldorini R, Omodeo-Zorini E, Suno A, et al. Molecular characterization and sequence analysis of polyomavirus strains isolated from needle biopsy specimens of kidney allograft recipients. Am J Clin Pathol. 2001;(116):489-494.
We retrospectively examined 29 renal allograft biopsy specimens from 42 kidney transplant recipients by means of molecular biologic techniques (nested polymerase chain reaction), immunohistochemical analysis (anti-SV40 antibody), and histologic examination to evaluate the presence of polyomaviruses (PVs), viral genotypes, genomic mutations, and their pathologic significance.
PV genomes were found in six cases (21%); restriction fragment length polymorphism analysis characterized 4 as JC virus (JCV) and 2 as BK virus (BKV). The latter also were positively stained immunohistochemically and showed histologically typical intranuclear viral inclusions; JCV cases were negative. DNA sequence analysis revealed only minor changes in the 4 JCV cases (3 archetypes and 1 JCV type 3, not associated with a known pathogenic genotype) but identified 2 specific variants in the BKV isolates (AS and WW strains). Given the different histologic findings (mixed inflammatory infiltration in the AS and no inflammation in the WW strain), we speculate that different BKV strains may cause differential damage in transplanted kidneys. Finally, the negative histologic and immunohistochemical JCV results, as well as the absence of viral mutations, indicate that JCV renal infection is latent in transplant recipients.
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):987-994.
Background. Polyoma virus type BK (BKV) nephritis has emerged as an important cause of renal allograft dysfunction and graft failure. Its diagnosis is contingent on the invasive procedure of allograft biopsy. A noninvasive diagnostic test for BKV nephritis could improve clinical outcome.
Methods. We obtained 25 urine specimens from 8 renal allograft recipients with biopsy-confirmed BKV nephritis, 31 samples from 28 recipients in whom BKV nephritis was excluded by allograft biopsy, and 74 specimens from 34 patients with stable allograft function. RNA was isolated from the urinary cells and reverse transcribed to complementary DNA. We designed gene-specific oligonucleotide primers and probes for the measurement of messenger RNA (mRNA) encoding BKV VP1 protein and a constitutively expressed 18S ribosomal RNA (rRNA) by real-time quantitative polymerase chain reaction. We explored the hypothesis that BKV VP1 mRNA levels predict BKV nephritis.
Results. The levels of BKV VP1 mRNA but not the levels of 18S rRNA predicted BKV nephritis. Analysis involving the receiver operating characteristic curve demonstrated that BKV nephritis can be predicted with a sensitivity of 93.8% and a specificity of 93.9% with the use of a cutoff value of 6.5x105 BKV VP1 mRNA copy number per nanogram of total RNA (P <0.00001). In the receiver operating characteristic curve analysis, the calculated area under the curve was 0.949 (95% confidence interval, 0.912 to 0.987, P <0.00001) for BKV VP1 mRNA levels and 0.562 (95% confidence interval, 0.417 to 0.708, P >0.2) for 18S rRNA.
Conclusions. Measurement of BKV VP1 mRNA in urinary cells offers a noninvasive and accurate means of diagnosing BKV nephritis.
Drachenberg RC, Drachenberg CB, Papadimitriou JC, et al. Morphological spectrum of polyoma virus disease in renal allografts: diagnostic accuracy of urine cytology. Am J Transplant. 2001;(1):373-381.
The morphological features of polyoma virus disease (PVDz) in 571 concurrent urine and biopsy samples from 413 patients are described. In 54 patients PV was found in both biopsy and urine samples. Histologically, PV presented as: (a) mild, viral cytopathic/cytolytic changes, with absent or minimal inflammation involving isolated tubules; (b) moderate and severe, cytopathic/cytolytic changes associated with patchy or diffuse tubulo-interstitial inflammation and atrophy; (c) advanced, graft sclerosis with rare or absent viral cytopathic changes, indistinguishable from chronic allograft nephropathy. Histological progression from mild to moderate or severe disease was seen in 28 patients. The mean post-transplantation time at diagnosis was similar in patients with mild or moderate-severe renal involvement (1.05 and 1.3 years, respectively). All patients presented with similarly increased values of serum creatinine (mean 1.35 mg/dL). There was strong correlation between the number of PV infected cells in urine and the concurrent biopsies (p = 0.0001). In 13 patients PV was found only in urine; of these, two developed PVDz later. The positive predictive value of a positive urine was 90%, the negative predictive value of a negative urine was 99% and the accuracy of the test was 97%. We conclude that urine cytology is useful to evaluate renal transplant patients with PV reactivation because sloughed tubular cells are found in urine and positive urine samples are a consistent manifestation of PV renal involvement.
Gardner SD, Field AM, Coleman DV, et al. New human papovavirus (B.K.) isolated from urine after renal transplantation. Lancet. 1971;(1):1253-1257.
Ginevri F, De Santis R, Comoli P, et al. Polyomavirus BK infection in pediatric kidney-allograft recipients: a single-center analysis of incidence, risk factors, and novel therapeutic approaches. Transplantation. 2003;(75):1266-1270.
BACKGROUND. Although a growing body of literature regarding polyoma BK virus (BKV) infection and associated interstitial nephritis in kidney-allograft recipients is becoming available, the impact of BKV infection in the pediatric population has not been fully evaluated.
METHODS. In a retrospective analysis, we performed polymerase chain reaction (PCR) assays for BKV DNA in serum and urine samples from 100 pediatric kidney-allograft recipients referred to our institution in the last 5 years.
RESULTS. BKV viruria was observed in 26 of 100 patients, whereas BKV viremia was demonstrated in 5 patients. Serum creatinine was significantly higher in recipients with positive BK viremia compared with BKV DNA-negative patients (mean 2.66 vs. 1.14 mg/100 mL). Renal biopsy performed in 3 of 5 patients showed graft damage consistent with interstitial nephropathy. In the univariate analysis, negative antibody status of the recipient and the presence of mycophenolate mofetil in baseline immunosuppression were the two factors predictive of active BKV infection.
CONCLUSION. Our study shows that BKV-associated nephropathy is a relevant complication in the pediatric kidney transplantation setting also. Identification of patients at risk of developing virus-associated nephropathy, through prospective quantification of viral load, could improve clinical outcome by allowing the use of timely preemptive therapy guided by BKV DNA levels.
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):488-496.
BACKGROUND. Nephropathy associated with the polyomavirus type BK (BKV) nephropathy has emerged as a cause of allograft failure linked to immunosuppressive regimens containing tacrolimus or mycophenolate mofetil. The presence of viral inclusions, known as "decoy cells," in urine and the presence of BKV DNA in plasma have been proposed as markers for the replication of BKV and associated nephropathy, but data from prospective studies have been lacking.
METHODS. In a prospective, single-center study, we followed 78 renal-transplant recipients who were receiving immunosuppressive therapy that included tacrolimus (37 patients) or mycophenolate mofetil (41 patients). Urine was tested for the presence of decoy cells at routine visits. BKV DNA was measured 3, 6, and 12 months after transplantation and whenever decoy cells were detected. The viral load in plasma was quantified with the use of a real-time polymerase-chain-reaction method. Renal biopsy was performed if allograft function deteriorated.
RESULTS. Twenty-three patients had decoy-cell shedding a median of 16 weeks after transplantation (range, 2 to 69), 10 patients had BKV viremia at a median of 23 weeks (range, 4 to 73), and 5 had BKV nephropathy at a median of 28 weeks (range, 8 to 86). Kaplan–Meier estimates of the probability of decoy-cell shedding, viremia, and nephropathy were 30 percent (95 percent confidence interval, 20 to 40 percent), 13 percent (95 percent confidence interval, 5 to 21 percent), and 8 percent (95 percent confidence interval, 1 to 15 percent), respectively. Antirejection treatment, particularly with corticosteroids, was associated with BKV replication and nephropathy. The viral load in plasma was higher in patients with BKV nephropathy than in those without nephropathy (P<0.001 by the Mann–Whitney test). BKV antibodies were detected in 77 percent of the 78 patients before transplantation, including 4 of 5 with BKV nephropathy.
CONCLUSIONS. BKV nephropathy in renal-transplant recipients represents a secondary infection associated with rejection and its treatment in most cases and could be monitored by measuring the viral load in plasma.
Hirsch HH, Mohaupt M, Klimkait T. Prospective monitoring of BK virus load after discontinuing sirolimus treatment in a renal transplant patient with BK virus nephropathy. J Infect Dis. 2001;(184):1494-1495; author reply 1495-1496.
Hirsch HH, Steiger J. Polyomavirus BK. Lancet Infect Dis. 2003;(3):611-623.
Polyomavirus hominis 1, better known as BK virus (BKV), infects up to 90% of the general population. However, significant clinical manifestations are rare and limited to individuals with impaired immune functions. BKV has been associated with diverse entities such as haemorrhagic cystitis, ureteric stenosis, vasculopathy, pneumonitis, encephalitis, retinitis, and even multi–organ failure. In addition, BKV has been implicated in autoimmune disease and possibly cancer. Due to high prevalence and frequent reactivation, the role of BKV in some of these pathologies has been difficult to define. Development of BKV diseases is likely to require complementing determinants in the host, the target organ, and possibly the virus, that are subject to modulators such as immunosuppression. These complex aspects are highlighted in Polyomavirus associated nephropathy (PAN), an emerging disease in renal allograft recipients that may jeopardise the progress in renal transplantation accomplished in the past 10 years. Intervention is difficult due to the lack of specific antivirals and relies mostly on improving immune control. Diagnostic strategies using urine cytology and BKV load measurements in plasma have led to earlier diagnosis of PAN, which increased the success rate of intervention. Case series suggest that cidofovir might be effective, especially when combined with reduced immunosuppression.
Kadambi PV, Josephson MA, Williams J, et al. Treatment of refractory BK virus-associated nephropathy with cidofovir. Am J Transplant. 2003;(3):186-191.
BK virus-associated nephropathy (BKVN) has become recognized as an important cause of allograft dysfunction in renal transplant recipients and despite reduction in immunosuppression, 30-40% of recipients ultimately progress to allograft loss. Cidofovir is an antiviral agent that demonstrates in vitro activity against murine polyomavirus and has been proposed for treatment of BKVN in renal allograft recipients. We describe the clinical course, renal function, serial renal histology and urine and blood viral load measurements in two consecutive patients with refractory BKVN who were treated with low-dose cidofovir (0.25 mg/kg IV). In each case, renal dysfunction and BK viral load progressed despite reduced immunosuppression, and persistent BK virus infection was documented in serial renal allograft biopsy specimens. Administration of low-dose cidofovir was associated with clearance of BK virus DNA from blood and allograft, and stabilization of renal function in both patients, without significant toxicity. These preliminary data suggest that low-dose cidofovir may be tolerated, even among renal transplant recipients with significant renal dysfunction due to BKVN. Prospective, controlled trials are warranted to further define the optimal dose, toxicity and potential role of cidofovir in renal transplant recipients with BK virus nephropathy.
Kazory A, Ducloux D. Renal transplantation and polyomavirus infection: recent clinical facts and controversies. Transpl Infect Dis. 2003;(5):65-71.
Although many articles have been published on polyomavirus-induced pathologies in transplant recipients, our knowledge regarding their clinical aspects remains relatively limited. In fact, the number of questions and controversies on the subject seems even to be increasing as new publications continue to appear. This article presents some of these controversies through a brief review of recent clinical facts about the three polyomaviruses that infect humans--JC virus, simian virus 40, and BK virus--as they relate to renal transplantation.
Limaye AP, Jerome KR, Kuhr CS, et al. Quantitation of BK virus load in serum for the diagnosis of BK virus- associated nephropathy in renal transplant recipients. J Infect Dis. 2001;(183):1669-1672.
BK virus-associated nephropathy is an increasingly recognized cause of graft dysfunction among kidney transplant recipients, and definitive diagnosis requires renal biopsy. By using a newly developed, quantitative, real-time polymerase chain reaction (PCR) assay for BK virus DNA, a retrospective analysis was done of sequential serum samples (n=28) from 4 transplant recipients with histopathologically documented BK virus nephropathy and from samples (n=76) from 16 transplant recipient control patients. BK virus DNA was detected in serum samples from all 4 case patients versus 0 of 16 control patients (P< .0001, Fisher's exact test) at a median of 32 weeks (range, 17-61 weeks) before the diagnosis of BK virus nephropathy. BK virus load decreased in 3 of 3 patients after the reduction of immunosuppression and/or nephrectomy. It is concluded that quantitative PCR for BK virus DNA in serum is useful both for identifying transplant recipients at risk for BK virus nephropathy and for monitoring the response to therapy.
Manna P, Arnoldi S, Vats A, Grimley M, Wall D. Detection and viral load monitoring of BK virus in hemorrhagic cystitis complicating bone marrow transplant patients. Poster presented at: American Society for Blood and Marrow Transplantation; February 16, 2004.
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Nickeleit V, Hirsch HH, Binet IF, et al. Polyomavirus infection of renal allograft recipients: from latent infection to manifest disease. J Am Soc Nephrol. 1999;(10):1080-1089.
Polyomavirus (PV) exceptionally causes a morphologically manifest renal allograft infection. Five such cases were encountered in this study, and were followed between 40 and 330 d during persistent PV renal allograft infection. Transplant (Tx) control groups without PV graft infection were analyzed for comparison. Tissue and urine samples were evaluated by light microscopy, immunohistochemistry, electron microscopy, and PCR. The initial diagnosis of PV infection with the BK strain was made in biopsies 9+/-2 mo (mean +/- SD) post-Tx after prior rejection episodes and rescue therapy with tacrolimus. All subsequent biopsies showed persistent PV infection. Intranuclear viral inclusion bodies in epithelial cells along the entire nephron and the transitional cell layer were histologic hallmarks of infection. Affected tubular cells were enlarged and often necrotic. In two patients, small glomerular crescents were found. In 54% of biopsies, infection was associated with pronounced inflammation, which had features of cellular rejection. All patients were excreting PV-infected cells in the urine. PV infection was associated with 40% graft loss (2 of 5) and a serum creatinine of 484+/-326 micromol/L (mean +/- SD; 11 mo post-Tx). Tx control groups showed PV-infected cells in the urine in 5%. Control subjects had fewer rejection episodes (P<0.05) and stable graft function (P = 0.01). It is concluded that a manifest renal allograft infection with PV (BK strain) can persist in heavily immunosuppressed patients with recurrent rejection episodes. PV mainly affects tubular cells and causes necrosis, a major reason for functional deterioration. A biopsy is required for diagnosis. Urine cytology can serve as an adjunct diagnostic tool.
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):1309-1315.
BACKGROUND. Reactivation of polyomavirus type BK (BK virus) is increasingly recognized as a cause of severe renal-allograft dysfunction. Currently, patients at risk for nephropathy due to infection with the BK virus are identified by the presence of cells containing viral inclusion bodies ("decoy cells") in the urine or by biopsy of allograft tissue.
METHODS. In a retrospective analysis, we performed polymerase-chain-reaction assays for BK virus DNA in plasma samples from 9 renal-allograft recipients with BK virus nephropathy; 41 renal-allograft recipients who did not have signs of nephropathy, 16 of whom had decoy cells in the urine; and as immunocompromised controls, 17 patients who had human immunodeficiency virus type 1 (HIV-1) infection (stage C3 according to the classification of the Centers for Disease Control and Prevention) and who had not undergone transplantation.
RESULTS. In all nine patients with BK virus nephropathy, BK virus DNA was detected in the plasma at the time of the initial histologic diagnosis (a mean [±SD] of 46±28 weeks after transplantation) and during the course of histologically diagnosed, persistent BK virus disease. In three of the six patients with nephropathy who were studied serially after transplantation, BK virus DNA was initially undetectable but was detected 16 to 33 weeks before nephropathy became clinically evident and was confirmed by biopsy. Tests for BK virus DNA in plasma became negative and the nephropathy resolved after the doses of immunosuppressive drugs were decreased in two patients and after removal of the renal allograft in three patients. BK virus DNA was found in the plasma of only 2 of the 41 renal-allograft recipients who had no signs of nephropathy and in none of the patients with HIV-1 infection.
CONCLUSION. Testing for BK virus DNA in plasma from renal-allograft recipients with use of the polymerase chain reaction is a sensitive and specific method for identifying viral nephropathy.
Nickeleit V, Singh HK, Mihatsch MJ. Polyomavirus nephropathy: morphology, pathophysiology, and clinical management. Curr Opin Nephrol Hypertens. 2003;(12):599-605.
PURPOSE OF REVIEW: Viral nephropathies, particularly those caused by polyomaviruses of the BK-virus strain, are serious complications following renal transplantation. The review will highlight the morphological, pathophysiological and clinical aspects of BK-virus nephropathy. New patient management strategies are discussed.
RECENT FINDINGS: Immunosuppression with tacrolimus and mycophenolate-mofetil promotes the activation of latent BK-virus in the urinary tract and increases the odds ratio for developing BK-virus nephropathy significantly. A productive infection with BK-viruses shows viral replication in tubular epithelial cells and acute tubular injury. BK-virus nephropathy can be further complicated by concurrent acute rejection episodes contributing to graft demise. Risk assessment after transplantation and patient management during ongoing viral nephropathy have undergone revision by the introduction of real time quantitative polymerase chain reaction techniques measuring BK-virus genome load fluctuations in the serum. Treatment strategies for BK-virus nephropathy include not only low-dose immunosuppression but also drugs with antiviral effects: cidofovir and leflunomide. Transient anti-rejection therapy, including anti-lymphocytic preparations, is a therapeutic option in cases of BK-virus nephropathy and concurrent acute rejection. Recent advances in patient management strategies have resulted in markedly improved graft survival. In cases of graft loss due to BK-virus nephropathy, re-transplantation should be considered.
SUMMARY: BK-virus nephropathy is a significant complication following renal transplantation. Recent advances have improved our understanding of the morphological changes, potential risk factors and patient management strategies would be optimized. The availability of quantitative viral load measurements now offers the opportunity for a more accurate and timely clinical intervention.
Nickeleit V, Steiger J, Mihatsch MJ. BK virus infection after kidney transplantation. Graft. 2002;5(suppl 1):S46-S57.
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):2145-2151.
Polyoma virus (PV) can cause interstitial nephritis and lead to graft failure in renal transplant recipients. The clinical course of patients with polyoma virus nephritis (PVN) is not well understood, partially due to its relatively low incidence. This study is a retrospective analysis of our experience over 4 yr. The specific purpose is to outline the clinical course and outcome of patients with PVN and to study the relationship between immunosuppression and the disease process. Between June 1997 and March 2001, 67 patients with graft dysfunction were found to have biopsy-proven PVN. The diagnosis was made at a mean of 12.8 +/- 9.9 mo posttransplantation. The majority of patients were men (79%) with a mean age of 54 +/- 14 yr (range, 28 to 75). All patients received immunosuppression with a calcineurin inhibitor (tacrolimus in 89% of patients). All patients except two received mycophenolate mofetil and prednisone. After the diagnosis of PVN, maintenance immunosuppression was reduced in 52 patients and remained unchanged in 15 patients. After reduction of immunosuppression, eight patients (15.3%) developed acute rejection and six (11.5%) became negative for PV in biopsy and urine. After a mean observation period of 12.6 mo (mean of 26 mo posttransplantation), 16.4% of patients had lost their grafts (8 of 52 in the reduction group and 3 of 15 in the no change group). In comparison to a case-matched polyoma virus-negative control group, the PVN patients were older (P =.0004) and there was a predominance of men (P = 0.02). Kaplan-Meier analysis demonstrated that patients with PVN had reduced graft survival compared with negative controls (P =.0004). It is concluded that PVN is a serious hazard for renal transplant recipients and contributes directly to graft loss. Antiviral drugs are needed, as the reduction of immunosuppression alone may not significantly improve graft function in patients with already established PVN. Although multiple factors probably play a role in the development of PVN, judicious use of immunosuppressive agents is indicated to minimize the occurrence of this infection.
Ramos E, Drachenberg CB, Portocarrero M, et al. BK virus nephropathy diagnosis and treatment: experience at the University of Maryland Renal Transplant Program. Clin Transpl. 2002:143-153.
The first case of BK virus allograft nephropathy at the University of Maryland Renal Transplant Program was diagnosed in 1997. Since then more than 100 cases have been identified. The incidence of BKAN has increased from 1% for patients transplanted in 1997 to 5.8% for patients transplanted in 2001. BKAN is an important cause of premature kidney graft loss at the University of Maryland Transplant Program. One-third of the patients diagnosed with BKAN since 1997 have already lost graft function, and a third of the remaining patients have creatinine levels over 3 mg/dl. We could not determine that a specific immunosuppressive drug increased the incidence of BKAN. Older patients had an increased risk of developing the disease. The histological diagnosis of BKAN was made at a mean time of 14.4 months after transplantation (range 1.2-53 months). BKAN occurred in 4.3% of all patients biopsied during the period described. The diagnosis of BK allograft nephropathy was based on a combination of renal biopsy to demonstrate viral cytopathic chages, urine cytology and quantitative viral load in plasma. A threshold of >10,000 copies of BK virus per ml of plasma is proposed as an indication of BKAN. Following diagnosis of BKAN, patients on a single immunosuppressve drug (FK506, CsA, sirolimus or MMF) in addition to prednisone had less graft loss and higher viral clearance in comparison to patients on prednisone and 2 immunosuppressant drugs (FK506, CsA or sirolimus and MMF). There was no difference in the rate of acute allograft rejection among different immunosuppression reduction protocols. Three patients who lost their grafts to BKAN were retransplanted. For these patients there has not yet been evidence of recurrence of BKAN. After reduction of immunosuppression, the course of BKAN in most patients followed one of 2 pathways: 1) Clearance of the infection and disappearance of the viral cytopathic changes in biopsies and urine (20%); 2)Persistence of viral replication with continuous associated tubular damage (70%). Renal transplant patients should be routinely screened with urine cytology. The presence of decoy cells in the urine is an indication for quantitative measurement of viral load in plasma. Patients with any evidence of BK viral reactivation should be followed closely. In patients biopsied early due to persistence of BK virus-infected cells in urine, there is a higher rate of conversion from positive to negative urine cytology after reduction of immunosuppression.
Ramos E, Vincenti F, Lu WX, et al. Retransplantation in patients with graft loss caused by polyoma virus nephropathy. Transplantation. 2004;(77):131-133.
The characteristics and outcome in 10 patients who underwent retransplantation after losing their renal grafts to BK virus-associated nephropathy (BKAN) are described. The patients underwent retransplantation at a mean of 13.3 months after failure of the first graft. Nephroureterectomy of the first graft was performed in seven patients. Maintenance immunosuppression regimens after the first and second grafts were similar, consisting of a combination of a calcineurin inhibitor, mycophenolate mofetil, and prednisone. BKAN recurred in one patient 8 months after retransplantation, but stabilization of graft function was achieved with a decrease in immunosuppression and treatment with low-dose cidofovir. After a mean follow-up of 34.6 months, all patients were found to have good graft function with a mean creatinine of 1.5 mg/dL. From this collective experience from five transplant centers (although the follow-up after retransplantation was not extensive), it can be concluded that patients with graft loss caused by BKAN can safely undergo retransplantation. The risk of recurrence does not seem to be increased in comparison with the first graft.
Randhawa P, Baksh F, Aoki N, et al. JC virus infection in allograft kidneys: analysis by polymerase chain reaction and immunohistochemistry. Transplantation. 2001;(71):1300-1303.
BACKGROUND: Polyoma virus nephropathy after transplantation is believed to be primarily due to the BK virus. We hypothesized that some cases may be associated with the JC polyoma virus (JCV), which is also known to be latent in the kidney.
METHODS: We sought polymerase chain reaction evidence of JCV infection in needle biopsy specimens with and without viral nephropathy. Cases positive by polymerase chain reaction were studied by immunohistochemistry for VP-1 antigen expression.
RESULTS: JCV DNA was found in 7 (36.8%) of 19 allograft kidney biopsy specimens with viral nephropathy and 0 (0%) of 19 native or allograft biopsy specimens without viral nephropathy. Immunohistochemistry localized JCV to the nuclei of tubular epithelial cells in one case.
CONCLUSIONS: JCV is detectable in a subset of renal allograft kidneys with polyoma virus nephropathy. The tubular epithelium is identified as a site capable of supporting JCV viral capsid protein VP-1 expression, and hence viral replication.
Randhawa PS, Demetris AJ. Nephropathy due to polyomavirus type BK. N Engl J Med. 2000;(342):1361-1363.
Randhawa PS, Vats A, Weck K, et al. BK virus: discovery, epidemiology, and biology. Graft. 2002;5(suppl 1):S19-S27.
Randhawa PS, Vats A, Zygmunt D, et al. Quantitation of viral DNA in renal allograft tissue from patients with BK virus nephropathy. Transplantation. 2002;(74):485-488.
BACKGROUND: BK virus (BKV) allograft nephropathy (BKVAN) is a complication in renal transplantation recipients. Histopathology is the gold standard for diagnosis. Quantitative polymerase chain reaction (PCR) assay for renal biopsy has not been evaluated as a diagnostic test. Determination of renal BKV load may identify patients at risk for disease before histologic nephropathy.
METHODS: Quantitative PCR assay for BKV DNA was performed in 28 biopsies of patients with BKVAN; 50 biopsies were performed before a diagnosis of BKVAN, and 126 control biopsies were from patients without a history of BKVAN.
RESULTS: BKV DNA was present in 19 of 50 (38%) biopsies performed 1 to 164 weeks before diagnosis of BKVAN. The viral load (mean 216 copies/cell) was lower than in biopsies of patients with BKVAN (mean 6063 viral copies/cell, <0.05). In 10 of 127 (7.8%) control biopsies, a low level of BKV DNA (mean 3.8 copies/cell) was found in three biopsies from chronic allograft nephropathy patients; two biopsies with acute rejection; four biopsies with borderline change; and one biopsy with cytomegalovirus nephritis. CONCLUSION: BKV load exceeding 59 copies per cell identified all cases of BKVAN. The diagnostic sensitivity, specificity, positive predictive value, and negative predictive value of quantitative PCR were 100%, 92.1%, 73.6%, and 100%, respectively. Lower levels of BKV DNA were identified in biopsies performed before viral nephropathy development. Future research will determine if earlier recognition of at-risk patients allows application of antiviral strategies to improve graft outcome.
Scantlebury V, Randhawa P, Shapiro R, et al. Cidofovir: a method of treatment for BK virus-associated transplant nephropathy. Graft. 2002;5(suppl 1):S82-S87.
Trofe J, Gaber LW, Stratta RJ, et al. Polyomavirus in kidney and kidney-pancreas transplant recipients. Transpl Infect Dis. 2003;(5):21-28.
PURPOSE: To report the incidence and clinical characteristics of polyomavirus (PV) nephritis in kidney (KTX) and kidney-pancreas transplant (KPTX) recipients. METHODS: Single center retrospective analysis of all cases of PV nephritis in KTX and KPTX patients transplanted between 1994 and 1999. RESULTS: Thirteen (5 KTX and 8 KPTX) patients (2.1%) had PV nephritis diagnosed on multiple biopsies (n = 22) among 504 KTX and 106 KPTX recipients. The incidence of PV nephritis was higher in cadaver donor transplants (2.6% cadaver vs. 0.7% living donors), after KPTX (1% KTX vs. 7.5% KPTX), in males (3.3% male vs. 0.7% female), and in diabetic patients (4.4% diabetic vs. 0.8% nondiabetic). The mean time to diagnosis of PV nephritis was 18 (range 6-48) months after KTX and 17 (range 9-31) months after KPTX. Three KTX patients and 5 KPTX patients had calcineurin inhibitor toxicity on biopsy prior to developing PV nephritis. Reduction in immunosuppression occurred in 100% of KTX and 63% of KPTX patients. Three patients (23%) developed rejection within 3 months of diagnosis of PV, 1 after a reduction in immunosuppression. Despite multiple antiviral treatment regimens, renal allograft failure requiring dialysis occurred in 60% of KTX and 50% of KPTX patients. All KPTX patients remain insulin independent and 2 were successfully retransplanted with living donor kidneys. 2 patients (15%) died but there was no mortality directly related to the virus. CONCLUSIONS: Polyomavirus nephritis may be increasing in incidence and appears to be unresponsive to either conventional antiviral agents or a reduction in immunosuppression. Most of our cases occurred in male diabetic patients undergoing cadaveric donor transplantation and were preceded by biopsy-proven nephrotoxicity. Further studies are needed to better define the pathogenesis of PV and effective antiviral treatment.
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):105-112.
BACKGROUND: BK virus (BKV)-associated nephropathy (BKVAN) has been increasingly recognized as an important cause of renal transplant dysfunction. We report the role of quantitative viral load monitoring in the management of BKVAN.
METHODS: We developed a real-time quantitative polymerase chain reaction (PCR) assay for BKV detection in urine and plasma. Four renal allograft recipients, including two children, with BKVAN were treated with low-dose cidofovir and followed prospectively.
RESULTS: The PCR assay showed a detection limit of 10 viral copies with an intra-assay coefficient of variation of 19%. All four patients with BKVAN demonstrated intranuclear inclusions on allograft biopsy and a progressive rise in serum creatinine; three patients underwent multiple biopsies before the diagnosis of BKVAN was made. Three of the patients experienced a "viral syndrome" before the onset of renal dysfunction. One child also demonstrated an echogenic renal mass. All of the patients demonstrated strongly positive urinary PCR values (>100,000 copies/microL). BKV DNA was also detected in the plasma of three patients. All the patients were treated with intravenous low-dose cidofovir (0.25-1 mg/kg per dose, every 2-3 weeks, without probenecid). BK viruria resolved within 4 to 12 weeks (after 1-4 doses) of the cidofovir therapy, and all patients remain with stable renal function 6 to 26 months posttherapy.
CONCLUSIONS: Quantitative PCR for BKV is a sensitive and reliable method for following the course of the infection in renal transplant patients. In addition, cidofovir therapy may be useful in the treatment of some of these patients, and its role needs to be investigated further.
BKV has emerged as an important pathogen in nephropathy in kidney transplant patients and hemorrhagic cystitis in HSCT patients. Early diagnosis of BK nephropathy has been shown to positively impact organ survival. Early diagnosis can be accomplished through a regular monitoring program for reactivation of BKV. Monitoring is effectively accomplished through the use of ViraCor’s quantitative BKV DNA PCR assay, which can also be used to track the course of infection and monitor response to treatment.