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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Midcareer Investigator Award in Patient-Oriented Research (K24)
Project #
5K24DK002886-10
Application #
8261838
Study Section
Diabetes, Endocrinology and Metabolic Diseases B Subcommittee (DDK)
Program Officer
Rankin, Tracy L
Project Start
2000-07-01
Project End
2014-02-28
Budget Start
2012-03-01
Budget End
2014-02-28
Support Year
10
Fiscal Year
2012
Total Cost
$172,633
Indirect Cost
$12,195
Name
Washington University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Rani, Asha; Ranjan, Ravi; McGee, Halvor S et al. (2016) A diverse virome in kidney transplant patients contains multiple viral subtypes with distinct polymorphisms. Sci Rep 6:33327
Anwar, Siddiq; Larson, Derek S; Naimi, Nima et al. (2015) A case report of adrenocorticotropic hormone to treat recurrent focal segmental glomerular sclerosis post-transplantation and biomarker monitoring. Front Med (Lausanne) 2:13
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
Java, Anuja; Gaut, Joseph P; Brennan, Daniel C (2012) De novo membranoproliferative glomerulonephritis III in a renal transplant patient: case report and review of the literature. Transpl Int 25:e58-61
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
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
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
Boothpur, Raghavender; Brennan, Daniel C (2010) Human polyoma viruses and disease with emphasis on clinical BK and JC. J Clin Virol 47:306-12
Hardinger, Karen L; Rasu, Rafia S; Skelton, Rebecca et al. (2010) Thymoglobulin induction dosing strategies in a low-risk kidney transplant population: three or four days? J Transplant 2010:957549

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