Polyomavirus and Mentoring in Renal Transplantation

描述(由申请人提供)： 我这次续签申请的近期和长期目标与我最初的申请相同。我的目标是继续并改进肾移植中的以患者为导向的研究，并改善对华盛顿大学以患者为导向研究的学生、住院医生、研究员和初级教员的培训和指导。我相信我过去的指导和研究努力促进了合作，跨越了部门和部门的障碍，提供了多学科的研究和指导。重要的是，我们实现了最初应用程序的所有三个具体目标：“肾移植中的多瘤病毒和指导”。我们发现，在随机接受他克莫司或环孢素治疗的患者中，尿液和血液中多瘤病毒(BK)的发生率是相同的。我们发现BK在血液之前出现在尿液中，尿液中的BK水平远远高于血液中的水平--尿液中的BK含量为10亿拷贝/毫升，而血液中的拷贝数为10-100,000拷贝/毫升。我们发现，随着移植后早期的频繁监测，当血液中检测到BK时，停用霉酚酸酯或硫唑嘌呤会导致BK的清除，并防止进展为BK肾病。我们还发现另外3种病毒CMV、HHV-6和HHV-7不是多瘤病毒感染的辅助因素，反之亦然。因此，我们报告了几个重要的发现，这些发现改变了移植社区对这种令人烦恼的病毒的态度，目前还没有有效的抗病毒治疗。 拟议研究的具体目标是： 具体目的1.确定肾移植患者中是否存在BK病毒变异，以及这些变异是否为促进BK病毒感染进展的危险因素。我们将通过分析最初研究中存储的尿液和血浆中的DNA来完成这项工作。具体目的2.确定肾移植受者移植前对多瘤病毒BK和JC抗体状态的作用，以及对感染或非感染的抗体反应。我们将通过分析最初研究中储存的血浆来完成这项工作。具体目的3：在随机接受他克莫司或环孢菌素作为免疫抑制的钙调神经磷酸酶成分的患者中，确定监测BK的策略和在检测到BK病毒血症后先行停用免疫抑制的抗代谢成分的长期结果。为此，我们将分析从电子病历、临床记录和医院图表中提取的数据。

DESCRIPTION (provided by applicant): 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.