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.

抽象的 肾脏对移植的需求与可用性之间的越来越大的差距仍然是主要的 挑战将所有可能从中受益的人移植的目标。肾脏移植等待名单进一步 由于过早的移植损失而寻求重复移植的患者燃烧。考虑到这个安装 挑战，我们必须通过匹配收件人和 移植器官的寿命并通过最大程度地减少可用于更好适合的边缘肾脏的丢弃 患者。肾脏捐赠者个人资料指数提供了肾脏质量和非裔美国人（AA）捐助者的估计 种族是与较差的结果相关的变量。在一般人群中，AA更有可能发展 慢性肾脏疾病（CKD）比其他种族的个人。最近的观察性研究表明，高 仅在AA中发现的风险APOL1基因型变体（HR-APOL1）占风险增加的70％。 只有携带HR-APOL1的AAS的子集发展为CKD。在移植中，最近的研究和我们的初步 数据表明，与捐助者相比 具有低风险APOL1变体（LR-APOL1）。与Apol1固定的CKD相似，只有20-30％的HR-APOL1 肾脏在移植2至3年内失败。看来HR-APOL1基因型仅易于 嫁接损失，但在“第二次命中”的情况下，他们过早失败了。同时，最近的数据表明 与非AA捐助者相比，AA现场肾脏捐献者更有可能发展CKD。活着的肾脏可能 携带HR-APOL1的供体的捐赠后CKD风险增加。进一步阐明捐助者的作用 Apol1在接受者草和生物捐助者成果上，我们建议组装一批肾脏移植 接收者，来自非洲血统的生物或已故捐助者，并针对以下特定目的：1）我们 将确定供体肾脏中的HR-APOL1基因型是 与LR-APOL1肾脏的接受者相比，移植功能下降和谷物丧失； 2）收集 来自AA供体肾脏移植受者的纵向临床数据和生物样品，以评估移植 相关的免疫和非免疫性“第二击（S）”候选者，触发早期移植功能障碍和失败 HR-APOL1捐助者的孩子的接收者； 3）前瞻性收集临床前后的临床和 来自AA活肾脏供体的实验室数据确定HR-APOL1基因型是否与较低的前相关 与LR-相比 Apol1捐赠者。我们的联盟理想地进行了这项研究，因为它汇集了大型队列 研究参与者，包括一群具有完整专业知识的调查员，包括 最先进的研究设施。确定供体APOL1基因变体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。