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

摘要 肾移植的需求和可用性之间不断扩大的差距仍然是一个主要问题， 这是对移植所有可能从中受益的人的目标的挑战。肾移植等待名单进一步 由于过早移植失败而寻求重复移植的患者的负担。考虑到这种安装方式 面对这一挑战，我们必须通过匹配受体和 移植器官的寿命，并通过尽量减少边缘肾脏的丢弃，可以更好地用于 患者肾脏捐献者概况指数提供了肾脏质量和非裔美国人（AA）捐献者的估计。 种族是与较差结果相关的变量。在一般人群中，AA更容易发展 慢性肾脏病（CKD）的发病率高于其他种族。最近的观察研究表明，高- 风险APOL 1基因型变异（HR-APOL 1），只在AA中发现，占70%的风险增加。 只有一部分携带HR-APOL 1的AA会发展为CKD。在移植方面，最近的研究和我们的初步研究 数据表明，与供体相比，来自具有HR-APOL 1的AA供体的肾脏具有更大的移植物丢失风险， 低风险APOL 1变体（LR-APOL 1）。与APOL 1相关的CKD相似，只有20-30%的HR-APOL 1 肾脏在移植后2到3年内衰竭。似乎HR-APOL 1基因型本身并不倾向于 移植物损失，但在存在“二次打击”的情况下，它们过早地失败。与此同时，最近的数据表明， AA活体肾脏捐赠者比非AA捐赠者更有可能发展CKD。有可能AA活肾 携带HR-APOL 1的供体患上捐献后CKD的风险增加。进一步阐明捐助者的作用 APOL 1对受体移植物和活体供体结局的影响我们建议建立一个肾移植队列， 接受者，从生活或已故捐助者与非洲血统，并解决以下具体目标：1）我们 将确定供体肾脏或受体中的HR-APOL 1基因型是否与较大的肾脏相关 与LR-APOL 1肾受体相比，移植功能下降和移植物丢失; 2）收集 来自AA供体肾移植受者的纵向临床数据和生物样本，以评估移植 相关的免疫和非免疫“第二次打击”的候选人，触发早期移植功能障碍和失败， HR-APOL 1供体肾脏的接受者;和3）前瞻性收集捐赠前和捐赠后的临床和 来自AA活体肾脏供体的实验室数据，以确定HR-APOL 1基因型是否与较低的前 捐赠肾功能和更大的捐赠后肾功能下降，蛋白尿相比LR- APOL 1供体。我们的联合体是进行这项研究的理想选择，因为它汇集了大量的队列 研究参与者，包括加勒比-拉丁美洲人，一组具有互补专业知识的研究人员， 最先进的研究设施。确定供体APOL 1基因变异对受体和供体的影响 这些成果将提高我们照顾这一群体的能力。

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.