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: 9440911
• 负责人: Kelly A Birdwell
• 金额: $ 28.28万
• 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/9440911
• 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; Institution; Kentucky; Kidney; Kidney Diseases; Kidney Transplantation; Knowledge; Link; Living Donors; Methods; Minority; Organ; Organ Procurements; Outcome; Participant; Patients; Pharmacogenomics; Population; Protocols documentation; Quality of life; Recruitment Activity; Renal function; Request for Applications; Research; Research Infrastructure; 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; multidisciplinary; nephrogenesis; non-diabetic; novel; personalized medicine; preference; response; risk variant; social; socioeconomics; targeted treatment; tool

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.

非裔美国人承受了慢性肾脏和终末期肾脏疾病的额外负担。风险 载脂蛋白 1 (APOL1) 基因的变异几乎只在非洲血统的个体中发现， 与非裔美国人的多种非糖尿病肾病相关，包括局灶性节段性肾病 肾小球硬化症、HIV 相关肾病和高血压相关肾病。这些 APOL1 风险 变异解释了非洲裔美国人患这些肾脏疾病的额外风险高达 70%。 然而，这些风险变异的存在并不能保证发展为继发性肾脏疾病。 需要基因或环境打击。再加上缺乏靶向治疗，基因疗法的价值就凸显出来了。 筛查 APOL1 风险变异未知。 APOL1 风险变异对肾移植的影响 捐助者和接受者都没有得到充分研究。肾移植是终末期的首选治疗方法 与慢性肾病相比，具有显着的生存率、生活质量和健康经济优势 透析。目前尚不清楚携带 APOL1 风险变异的活体肾捐献者患以下疾病的风险是否增加： 捐赠后肾脏疾病。对于受赠者来说，初步研究表明，接受捐赠者的受赠者 具有两个 APOL1 风险变异的肾脏可能具有更差的移植结果。由于生物和社会因素 由于经济因素，非裔美国人历来在接受肾移植方面处于不利地位，并且 APOL1 基因筛查和排除具有风险变异的捐献者的理论实践可以进一步 使该人群处于不利地位。这些多重问题凸显了彻底审查其影响的必要性。 APOL1 风险等位基因对移植结果的影响。 NIH 资助的 APOL1 长期肾移植 结果网络 (APOLLO) 将通过联合移植中心、器官移植中心来解决这一重要问题 采购组织 (OPO) 和器官共享联合网络 (UNOS) 来招募这些捐赠者 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 通过实现几个目标来应用。在目标 1 中，我们将招募并保留 200 个供体-受体肾脏 用于 APOL1 基因检测的移植对，捐赠者是非裔美国人或非洲混血血统，并且 对活体捐赠者和接受者进行纵向临床随访，以更好地了解 APOL1 的影响 捐献者状况影响移植结果。在目标 2 中，我们将进一步丰富 APOLLO 的目标： 通过评估当地的态度、优先事项和偏好，有意义地吸引患者参与 使用社区参与工作室的新颖方法招募参与者并进行 APOL1 基因检测。 这种方法对于招募和保留少数参与者是有效的。在目标 3 中，我们将确定 基因组“第二次打击”使用先进的基因组分析来确定哪些额外的遗传变异 APOL1 基因型以外的基因型与肾功能相关。一旦完成，这些目标将推进我们 APOL1在肾移植中的知识。