APOL1 studies in kidney transplantation consortium clinical centers (ASK-CCC)

肾移植联盟临床中心 (ASK-CCC) 的 APOL1 研究

• 批准号: 9441096
• 负责人: Mona Doshi
• 金额: $ 27.68万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-25 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9441096
• 关键词: APOL1 gene; Acute; Address; Adult; Affect; African; African American; African Caribbean; Age; Albuminuria; Allografting; American; Area; Biological; Biopsy; Blood; Caribbean region; Caring; Caucasians; Childhood; Chronic Kidney Failure; Clinical; Clinical Data; Cohort Studies; DNA; Data; Data Coordinating Center; Diagnosis; Donor person; Early treatment; End stage renal failure; Failure; Florida; Functional disorder; Future; Gender; General Population; Genotype; Geographic Locations; Glomerular Filtration Rate; Goals; Graft Survival; Health; Histologic; Immune; Incidence; Individual; Infection; Injury; Investigation; Kentucky; Kidney; Kidney Diseases; Kidney Transplantation; Laboratories; Latino; Link; Living Donors; Longevity; Mediating; Michigan; Mission; Modeling; New Jersey; Observational Study; Ohio; Organ; Organ Procurements; Organ Transplantation; Outcome; Participant; Pathogenicity; Pathway interactions; Patients; Penetrance; Phenotype; Population; Positioning Attribute; Prospective cohort; RNA; Race; Recruitment Activity; Renal function; Reperfusion Injury; Reporting; Research; Research Personnel; Research Project Grants; Retrospective Studies; Risk; Role; Sampling; Time; Tissues; Transplant Recipients; Transplantation; Urine; Variant; Waiting Lists; West Virginia; Work; base; biobank; cohort; disorder risk; experience; follow-up; genetic variant; high risk; improved; indexing; innovation; kidney allograft; member; outcome forecast; premature; prospective; research facility; risk variant; stressor

ABSTRACT The ever-widening gap between the need and availability of kidneys for transplantation remains a major challenge to the goal of transplanting all whom may benefit from it. The kidney transplant waiting list is further burdened by patients seeking a repeat transplant due to premature transplant loss. Given this mounting challenge, it is imperative that we use the limited available kidneys more efficiently by matching recipient and transplant organ longevity and by minimizing discard of marginal kidneys that could be used in better suited patients. The Kidney Donor Profile Index provides an estimate of kidney quality and African American (AA) donor race is a variable associated with poorer outcomes. In the general population, AAs are more likely to develop chronic kidney disease (CKD) than individuals of other races. Recent observational studies suggest that high- risk APOL1 genotype variants (HR-APOL1), found exclusively in AA, accounts for 70% of this increased risk. Only a subset of AAs carrying HR-APOL1 develop CKD. In transplantation, recent studies and our preliminary data suggest that kidneys from AA donors with HR-APOL1 are at a greater risk for graft loss compared to donors with low risk APOL1 variants (LR-APOL1). Similar to APOL1-asscoiated CKD, only 20-30% of HR-APOL1 kidneys fail within 2 to 3 years of transplant. It appears that HR-APOL1 genotype alone does not predispose to graft loss but in the presence of a “second hit” they fail prematurely. At the same time, recent data suggests that AA live kidney donors are more likely to develop CKD than non-AA donors. It is possible that AA living kidney donors carrying HR-APOL1 are at increased risk for post-donation CKD. To further elucidate the role of donor APOL1 on recipient graft and living donor outcomes we propose to assemble a cohort of kidney transplant recipients, from living or deceased donors with African ancestry and address the following specific aims: 1) We will determine if either HR-APOL1 genotype in the donor kidney or the recipient associates with greater kidney transplant function decline and graft loss when compared to recipients of LR-APOL1 kidneys; 2) To collect longitudinal clinical data and biological samples from AA donor kidney transplant recipients to evaluate transplant related immune- and non-immune “second hit(s)” candidates that trigger early graft dysfunction and failure in recipients of kidneys from HR-APOL1 donors; and 3) To prospectively collect pre- and post-donation clinical and laboratory data from AA living kidney donors to determine if HR-APOL1 genotype associates with lower pre- donation kidney function and greater post-donation kidney function decline, and albuminuria compared to LR- APOL1 donors. Our consortium is ideally positioned to undertake this study as it brings together a large cohort of study participants, including Caribbean-Latinos, a group of investigators with complementary expertise, and state-of-art research facilities. Determining the impact of donor APOL1 gene variants on recipient and donor outcomes will improve our ability to care for this population.

摘要 肾脏移植的需求和可获得性之间不断扩大的差距仍然是一个主要问题。 对移植所有可能从中受益的人的目标提出挑战。肾移植等待名单上还有更多 由于过早失去移植而寻求重复移植的患者的负担。鉴于这种不断增加的趋势 挑战，我们当务之急是更有效地利用有限的可用肾脏，将受者和 移植器官的寿命和最大限度地减少边缘肾脏的丢弃，这些肾脏本来可以更适合 病人。肾脏捐赠者概况指数提供了对肾脏质量和非裔美国人(AA)捐赠者的估计 种族是一个与较差的结果相关的变量。在普通人群中，AA更有可能发展为 慢性肾脏疾病(CKD)比其他种族的人更容易患上。最近的观察研究表明，高- 仅在再生障碍性贫血中发现的风险APOL1基因变异(HR-APOL1)占增加的风险的70%。 只有携带HR-APOL1的AA子集才会发生CKD。在移植方面，最近的研究和我们的初步 数据表明，与捐赠者相比，携带HR-APOL1的AA捐赠者的肾脏移植丢失的风险更大 低风险的APOL1变异体(LR-APOL1)。与APOL1相关的CKD相似，HR-APOL1只有20%-30% 移植后的2到3年内，肾脏会衰竭。看来，仅有HR-APOL1基因型并不容易患上 贪污损失，但在“二次打击”的情况下，他们过早地失败了。与此同时，最近的数据表明， AA活体肾捐献者比非AA活体肾捐献者更容易发生CKD。AA活体肾脏有可能 携带HR-APOL1的捐献者患捐献后慢性肾脏病的风险增加。为了进一步阐明捐赠者的作用 关于受者移植和活体供者预后的APOL1我们建议组建一个肾移植队列 接受者，来自非洲血统的在世或已故捐赠者，并解决以下具体目标：1)我们 将确定供体肾脏或受者肾脏中的HR-APOL1基因是否与更大的肾脏相关 与LR-APOL1肾脏的受者相比，移植功能下降和移植物丢失；2)收集 AA供体肾移植受者的纵向临床数据和生物样本评估移植 相关免疫和非免疫“二次命中(S)”候选人引发早期移植物功能障碍和衰竭 接受来自HR-APOL1捐赠者的肾脏；以及3)前瞻性地收集捐献前和捐献后的临床和 来自AA活体肾脏捐赠者的实验室数据，以确定HR-APOL1基因型是否与较低的Pre-Pre 捐献肾功能与捐献后肾功能下降较大，且蛋白尿较LR- APOL1捐赠者。我们的财团非常适合进行这项研究，因为它汇集了一大群人 研究参与者，包括加勒比裔拉美人，一组具有互补专业知识的调查人员，以及 最先进的研究设施。确定供体APOL1基因变异对受体和供体的影响 结果将提高我们照顾这一人群的能力。