Human polyoma virus (PV), which includes BK virus (BKV), JC virus (JCV) and SV40 viruses, can subclinically infect a large portion of the general population. After the primary infection in early childhood, BKV can remain latent in renal tubular epithelium and can become reactivated as a result of immunosuppression. Although BKV was first isolated from the urine of a renal allograft recipient, the etiological role of BKV and other PV infections in renal graft dysfunction [referred to as polyoma virus associated nephropathy (PVAN)] is not clear. The pathologic alterations noted in cases with significant graft dysfunction are scant, and emphasize the presence of ureteric stenosis or tubules. Infection of the renal allograft parenchyma is infrequently reported. In patients with BKV-associated tubulointerstitial nephritis, a significant risk for graft loss was noted in our studies. The mechanism of allograft injury in BKV infection remains unclear, and it is thought that the virus can initiate or perpetuate acute rejection, possibly by up-regulating histocompatibility antigens. Although, the primary infection occurs during childhood, the role of BKV in renal dysfunction in the pediatric population in general and graft dysfunction in pediatric renal transplant recipients is even less clear than in adults, and there is very little information available about the epidemiology of PVAN. To further compound the problem, the clinical management of BKV infection in the face of allograft dysfunction poses major difficulties, as there is no defined treatment for this condition. We recently developed and evaluated a quantitative polymerase chain reaction (PCR) assay for polyomavirus (BK Virus) which uses a highly automated real time PCR using the TagMan technology. All the patients with graft biopsies showing BKV inclusions had positive urinary BKV PCR assays. Also, the patients had continued to have ongoing but fluctuant BKV viruria and viremia. Viruria was also found in some asymptomatic patients undergoing routine biopsies. The significance of finding viruria in these cases is not clear but may be related to a carrier state, or a subclinical infection that cannot be picked up by biopsy yet. Although high viral loads generally are associated with graft dysfunction, the relationship is not perfect. We have also found that the proposed studies include anti-viral agent cidofovir that, when used in low doses, can eradicate the virus from both urine and blood and can help improve the outcome of PVAN. We have noted that many patients continue to do poorly despite a reduction or clearing of the viral load. Clearly there are other markers of PVAN that are associated with renal transplant outcome and severity of infection. Recently, biomarkers are being developed for a number of clinical conditions that can aid in the diagnosis and care of various clinical situations. We now wish to evaluate new tests for various """"""""biomarkers"""""""" that may correlate with the quantitative PCR tests and / or the outcome of polyoma virus infection. The proposed studies include doing a retrospective analysis of samples and clinical data already in our possession initially. The study will thus initially utilize already stored samples of blood and urine obtained during our ongoing and completed BKV and PV studies. We would then confirm these findings in a prospective cohort study that will be initiated at UPMC and affiliated hospitals as a part of this project.
