My immediate and long-term objectives for this renewal application are the same as my initial application.
I aim to continue and to improve Patient-Oriented Research in renal transplantation and to improve the training and mentoring of students, residents, fellows, and junior faculty in Patient-Oriented Research at Washington University. I believe my past mentoring and research endeavors have fostered collaboration that crossed divisional and departmental barriers to provided multidisciplinary research and mentoring. Importantly we accomplished all 3 of our Specific Aims of the original application, "Polyomavirus and Mentoring in Renal Transplantation". We found that the incidence of polyomavirus (BK) in the urine and blood was the same in patients randomized to receive tacrolimus or cyclosporine. We found that BK appears in the urine before the blood and that levels in the urine are far greater in the urine than the blood--a billion copies/mL in urine vs 10-100,000 copies/mL in blood. We found that with frequent monitoring early after transplant that discontinuation of mycophenolate or azathioprine when BK was detected in the blood led to clearance of BK and prevented progression to BK nephropathy. We also found that 3 other viruses CMV, HHV-6 and HHV-7 were not co-factors for polyomavirus infection or vice versa. Thus, we reported several important findings that have changed the transplant community's approach to this vexing virus for which there is no effective anti-viral treatment.
The Specific Aims for the proposed study are:
Specific Aim 1. To determine whether viral variants of BK occurred and whether these are risk factors that promote progression of BK viral infections in renal transplant patients. We will do this by analyzing stored DNA from the urine and plasma from the original study.
Specific Aim 2. To determine the role of pretransplant antibody status to the polyomaviruses, BK and JC, and the antibody response to infection or non-infection in renal transplant recipients. We will do this by analyzing stored plasma from the original study. Specfic Aim 3. To determine the long-term outcomes of a monitoring strategy for BK and preemptive withdrawal of the antimetabolite component of immunosuppression upon detection of BK viremia in patients randomized to receive either tacrolimus or cyclosporine as the calcineurin component of immunosuppression. To do this we will analyze data extracted from our electronic medical record, clinic notes, and hospital charts.
|Lim, Efrem S; Reyes, Alejandro; Antonio, Martin et al. (2013) Discovery of STL polyomavirus, a polyomavirus of ancestral recombinant origin that encodes a unique T antigen by alternative splicing. Virology 436:295-303|
|Pastrana, Diana V; Brennan, Daniel C; Cuburu, Nicolas et al. (2012) Neutralization serotyping of BK polyomavirus infection in kidney transplant recipients. PLoS Pathog 8:e1002650|
|Machnicki, Gerardo; Lentine, Krista L; Salvalaggio, Paolo R et al. (2011) Three-year post-transplant Medicare payments in kidney transplant recipients: associations with pre-transplant comorbidities. Saudi J Kidney Dis Transpl 22:24-39|
|Boothpur, Raghavender; Brennan, Daniel C (2010) Human polyoma viruses and disease with emphasis on clinical BK and JC. J Clin Virol 47:306-12|
|Spinner, Michael L; Saab, Georges; Casabar, Ed et al. (2010) Impact of prophylactic versus preemptive valganciclovir on long-term renal allograft outcomes. Transplantation 90:412-8|
|Hardinger, K L; Koch, M J; Bohl, D J et al. (2010) BK-virus and the impact of pre-emptive immunosuppression reduction: 5-year results. Am J Transplant 10:407-15|
|Lentine, Krista L; Schnitzler, Mark A; Xiao, Huiling et al. (2010) Racial variation in medical outcomes among living kidney donors. N Engl J Med 363:724-32|
|Israni, A K; Snyder, J J; Skeans, M A et al. (2010) Predicting coronary heart disease after kidney transplantation: Patient Outcomes in Renal Transplantation (PORT) Study. Am J Transplant 10:338-53|
|Machnicki, G; Pinsky, B; Takemoto, S et al. (2009) Predictive ability of pretransplant comorbidities to predict long-term graft loss and death. Am J Transplant 9:494-505|
|Randhawa, P; Bohl, D; Brennan, D et al. (2008) longitudinal analysis of levels of immunoglobulins against BK virus capsid proteins in kidney transplant recipients. Clin Vaccine Immunol 15:1564-71|
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