APOL1 and Kidney Transplantation Outcomes Vanderbilt Clinical Center

APOL1 和肾移植结果范德比尔特临床中心

• 批准号: 9768574
• 负责人: Kelly A Birdwell
• 金额: $ 34.61万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 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/9768574
• 关键词: AIDS-Associated Nephropathy; Academic Medical Centers; Address; African; African American; American; Apolipoproteins; Attitude; Biological; Catchment Area; Chronic; Clinical; Clinical Data; Collaborations; Communities; Computerized Medical Record; Coupled; DNA Databases; Data; Dialysis procedure; Disadvantaged; Donor Selection; Economic Factors; End stage renal failure; Enrollment; Environment; Epidemiologist; Ethics; European; Focal Segmental Glomerulosclerosis; Foundations; Funding; Genes; Genetic; Genetic Risk; Genetic Screening; Genetic Variation; Genetic screening method; Genomics; Genotype; Health; Hypertension; Individual; Informed Consent; Infrastructure; Institution; Kentucky; Kidney; Kidney Diseases; Kidney Transplantation; Knowledge; Link; Living Donors; Methods; Minority; Organ; Organ Procurements; Outcome; Participant; Patient Recruitments; Patients; Pharmacogenomics; Population; Protocols documentation; Quality of life; Renal function; Request for Applications; Research; Resources; Risk; Sampling; Southeastern United States; Standardization; Tennessee; Transplant Surgeon; Transplantation; Trust; Underrepresented Minority; Underrepresented Populations; United Network for Organ Sharing; United States; United States National Institutes of Health; Variant; Virginia; Waiting Lists; Work; base; clinical care; cohort; disadvantaged population; experience; follow-up; genetic variant; graft function; health economics; high risk; improved; living kidney donor; multidisciplinary; nephrogenesis; non-diabetic; novel; patient engagement; personalized medicine; preference; recruit; response; risk variant; social; socioeconomics; targeted treatment; tool; transplant centers

An excess burden of chronic kidney and end stage renal disease is born by African Americans. Risk variants in the apolipoprotein-1 (APOL1) gene, found almost exclusively in individuals of African ancestry, are associated with several forms of non-diabetic kidney disease in African Americans, including focal segmental glomerulosclerosis, HIV-associated nephropathy, and hypertension-related kidney disease. These APOL1 risk variants explain up to 70% of the excess risk in African Americans developing these kidney diseases. However, presence of these risk variants does not guarantee development of kidney disease, with secondary genetic or environmental hits required. This along with lack of targeted therapies makes the value of genetic screening for APOL1 risk variants unknown. The impact of APOL1 risk variants in kidney transplantation, for both donors and recipients, is understudied. Kidney transplantation is the preferred treatment for end stage renal disease, affording significant survival, quality of life, and health economic advantages over chronic dialysis. It is unknown if living kidney donors with APOL1 risk variants are at increased risk for development of kidney disease post donation. For recipients, initial studies have suggested that recipients who receive donor kidneys with two APOL1 risk variants may have worse graft outcomes. Due to both biological and social- economic factors, African Americans have been historically disadvantaged in receiving kidney transplants, and the theoretical practice of APOL1 genetic screening and excluding donors with risk variants could further disadvantage this population. These multiple questions highlight the need to thoroughly examine the impact of APOL1 risk alleles on transplant outcomes. The NIH- sponsored APOL1 Long-term Kidney Transplantation Outcomes Network (APOLLO) will address this important question by uniting transplant centers, organ procurement organizations (OPOs), and the United Network for Organ Sharing (UNOS) to enroll these donors and follow transplant outcomes. We propose to be an ideal clinical center in direct response to this request for application by accomplishing several aims. In Aim 1, we will recruit and retain 200 donor-recipient kidney transplant pairs for APOL1 genetic testing where donors are African American or mixed African ancestry and perform longitudinal clinical follow up of living donors and recipients to better understand the impact APOL1 donor status has on transplant outcomes. In Aim 2, we will further enrich the APOLLO objectives by meaningfully engaging patients through assessing local attitudes, priorities, and preferences regarding participant recruitment and APOL1 genetic testing using the novel method of Community Engagement Studios. This method is effective in recruitment and retention of minority participants. In Aim 3, we will determine genomic “second hits” using advanced genomic analyses to determine what additional genetic variation beyond APOL1 genotype is associated with kidney function. Once completed, these Aims will advance our knowledge of APOL1 in kidney transplantation.

非裔美国人的慢性肾脏和终末期肾脏疾病负担过重。风险 载脂蛋白-1（APOL 1）基因的变异，几乎只在非洲血统的个体中发现， 与非裔美国人的几种形式的非糖尿病肾病相关，包括局灶性节段性肾病 肾小球硬化、HIV相关肾病和高血压相关肾病。APOL 1风险 变异解释了非洲裔美国人患这些肾脏疾病的70%的额外风险。 然而，这些风险变体的存在并不能保证发生肾脏疾病， 需要遗传或环境的打击。这沿着缺乏靶向治疗，使得基因治疗的价值 筛查未知的APOL 1风险变体。APOL 1风险变异对肾移植的影响， 捐助者和受援者都没有得到充分的研究。肾移植是终末期肾病的首选治疗方法 与慢性肾脏疾病相比， 透析目前尚不清楚携带APOL 1风险变体的活体肾脏供体是否会增加发生以下疾病的风险： 肾脏疾病捐赠后。对于接受者，初步研究表明，接受捐赠者 具有两个APOL 1风险变体的肾脏可能具有更差的移植结果。由于生物和社会的原因- 经济因素，非洲裔美国人在接受肾脏移植方面历来处于不利地位， APOL 1基因筛查和排除具有风险变体的供体的理论实践可以进一步 这对人口不利。这些多重问题突出表明，需要彻底审查 APOL 1风险等位基因对移植结果的影响美国国立卫生研究院资助的APOL 1长期肾移植 结果网络（APOLLO）将通过联合移植中心、器官移植中心和器官移植中心来解决这一重要问题。 器官采购组织（OPO）和器官共享联合网络（UNOS）来登记这些捐赠者 并跟踪移植结果。我们建议成为一个理想的临床中心，直接响应这一要求， 通过实现几个目标。在目标1中，我们将招募并保留200名供受肾者 用于APOL 1基因检测的移植对，其中供体是非洲裔美国人或非洲混血血统， 对活体供体和受体进行纵向临床随访，以更好地了解APOL 1的影响 捐献者身份对移植结果的影响在目标2中，我们将进一步丰富阿波罗计划的目标， 通过评估当地的态度、优先事项和偏好， 参与者招募和APOL 1基因测试使用社区参与工作室的新方法。 这种方法在征聘和留住少数族裔参与者方面是有效的。在目标3中，我们将确定 基因组“第二次命中”使用先进的基因组分析，以确定哪些额外的遗传变异， APOL 1基因型与肾功能相关。一旦完成，这些目标将推进我们的 APOL 1在肾移植中应用