About BK Virus

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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 10 years1. 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 1990s2. 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 to 10% and a graft loss rate of 10 to 80%, depending on the center's BK screening program and use of immunosuppression3.

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 stenosis2. Pediatric renal transplant patients who are seronegative at the time of transplantation seem to be at particularly high risk of BKVAN, although this requires further study for confirmation4,5. 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 whom 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 BKVAN1. However, BKVAN has been observed with all immunosuppressive regimens. 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 serology4-11. However, many other studies have contradicted these associations. Recently, host and viral genomic variation has 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 BKVAN12,13. 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 BKVAN3. Interestingly, the diagnosis of BKVAN is often preceded by a diagnosis of acute rejection episode(s) in many patients. 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 polymerase chain reaction (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 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 3 months for the first 2 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 biopsy3.

 

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%3. In most centers, BKVAN is initially treated by lowering immunosuppression and sometimes additionally by discontinuing drug regimens containing tacrolimus14,15. 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 program16,17. 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 cases18,19. Additionally, there have been reports of successful use of leflunomide in resolving BKVAN20.

 

CONCLUSION

There remains much to be learned regarding BK 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.

 

REFERENCES

1. Hirsch HH, Steiger J. Polyomavirus BK. The Lancet Infectious Diseases. Oct 2003;3(10):611-623.
2. Vats A RP, Shapiro R. Diagnosis and Treatment of BK Virus-Associated Transplant Nephropathy. Advances in Experimental Medicine and Biology. Vol 577:213-227.
3. Hirsch HH, Brennan DC, Drachenberg CB, et al. Polyomavirus-associated nephropathy in renal transplantation: interdisciplinary analyses and recommendations. Transplantation. May 27 2005;79(10):1277-1286.
4. Ginevri F, Pastorino N, de Santis R, et al. Retransplantation after kidney graft loss due to polyoma BK virus nephropathy: successful outcome without original allograft nephrectomy. American Journal of Kidney Diseases : The Official Journal of the National Kidney Foundation. Oct 2003;42(4):821-825.
5. Smith JM, McDonald RA, Finn LS, Healey PJ, Davis CL, Limaye AP. Polyomavirus nephropathy in pediatric kidney transplant recipients. American Journal of Transplantation : Official Journal of the American Society of Transplantation and the American Society of Transplant Surgeons. Dec 2004;4(12):2109-2117.
6. Mengel M, Marwedel M, Radermacher J, et al. Incidence of polyomavirus-nephropathy in renal allografts: influence of modern immunosuppressive drugs. Nephrology, Dialysis, Transplantation : Official Publication of the European Dialysis and Transplant Association - European Renal Association. Jun 2003;18(6):1190-1196.
7. Ramos E, Drachenberg CB, Papadimitriou JC, et al. Clinical course of polyoma virus nephropathy in 67 renal transplant patients. Journal of the American Society of Nephrology : JASN. Aug 2002;13(8):2145-2151.
8. Awadalla Y, Randhawa P, Ruppert K, Zeevi A, Duquesnoy RJ. HLA mismatching increases the risk of BK virus nephropathy in renal transplant recipients. American Journal of Transplantation : Official Journal of the American Society of Transplantation and the American Society of Transplant Surgeons. Oct 2004;4(10):1691-1696.
9. Trofe J, Gaber LW, Stratta RJ, et al. Polyomavirus in kidney and kidney-pancreas transplant recipients. Transplant Infectious Disease : An Official Journal of the Transplantation Society. Mar 2003;5(1):21-28.
10. Priftakis P, Bogdanovic G, Tyden G, Dalianis T. Polyomaviruria in renal transplant patients is not correlated to the cold ischemia period or to rejection episodes. Journal of Clinical Microbiology. Jan 2000;38(1):406-407.
11. Hirsch HH, Knowles W, Dickenmann M, et al. Prospective study of polyomavirus type BK replication and nephropathy in renal-transplant recipients. The New England Journal of Medicine. Aug 15 2002;347(7):488-496.
12. Sharma PM, Gupta G, Vats A, Shapiro R, Randhawa PS. Polyomavirus BK non-coding control region rearrangements in health and disease. Journal of Medical Virology. Aug 2007;79(8):1199-1207.
13. Tikhanovich I, Liang B, Seoighe C, Folk WR, Nasheuer HP. Inhibition of Human BK Polyomavirus Replication by Small Noncoding RNAs. Journal of Virology. Jul 2011;85(14):6930-6940.
14. Hardinger KL, Koch MJ, Bohl DJ, Storch GA, Brennan DC. BK-virus and the impact of pre-emptive immunosuppression reduction: 5-year results. American Journal of Transplantation : Official Journal of the American Society of Transplantation and the American Society of Transplant Surgeons. Feb 2010;10(2):407-415.
15. Almeras C, Foulongne V, Garrigue V, et al. Does reduction in immunosuppression in viremic patients prevent BK virus nephropathy in de novo renal transplant recipients? A prospective study. Transplantation. Apr 27 2008;85(8):1099-1104.
16. Gautam A, Patel V, Pelletier L, Orozco J, Francis J, Nuhn M. Routine BK virus surveillance in renal transplantation--a single center's experience. Transplantation Proceedings. Dec 2010;42(10):4088-4090.
17. Almeras C, Vetromile F, Garrigue V, Szwarc I, Foulongne V, Mourad G. Monthly screening for BK viremia is an effective strategy to prevent BK virus nephropathy in renal transplant recipients. Transplant Infectious Disease : An Official Journal of the Transplantation Society. Apr 2011;13(2):101-108.
18. Kadambi PV, Josephson MA, Williams J, et al. Treatment of refractory BK virus-associated nephropathy with cidofovir. American Journal of Transplantation : Official Journal of the American Society of Transplantation and the American Society of Transplant Surgeons. Feb 2003;3(2):186-191.
19. 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. Jan 15 2003;75(1):105-112.
20. Teschner S, Gerke P, Geyer M, et al. Leflunomide therapy for polyomavirus-induced allograft nephropathy: efficient BK virus elimination without increased risk of rejection. Transplantation Proceedings. Jul-Aug 2009;41(6):2533-2538.