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.

慢性肾脏和终末期肾脏疾病的过重负担是由非裔美国人出生的。风险 几乎只在非洲血统的个体中发现的载脂蛋白-1(APOL1)基因的变体是 与非裔美国人的几种形式的非糖尿病肾病有关，包括局灶性节段性肾病 肾小球硬化、艾滋病毒相关肾病和高血压相关肾脏疾病。这些APOL1风险 变异可以解释非裔美国人患上这些肾脏疾病高达70%的额外风险。 然而，这些风险变异的存在并不保证肾脏疾病的发展，继发性肾脏疾病 需要基因或环境方面的打击。这一点，加上缺乏有针对性的治疗，使得基因治疗的价值 APOL1风险变异的筛查未知。载脂蛋白1风险变异对肾移植的影响 无论是捐赠者还是接受者，都没有得到充分的研究。肾移植是终末期患者的首选治疗方法 肾脏疾病，与慢性疾病相比，提供显著的生存、生活质量和健康经济优势 透析。目前尚不清楚具有APOL1风险变异的活体肾脏捐赠者是否有更高的风险发生 肾脏疾病捐献后。对于接受者，初步研究表明，接受捐赠者的接受者 具有两个APOL1风险变异体的肾脏移植结果可能更差。由于生物学和社会性的原因- 由于经济因素，非洲裔美国人在接受肾脏移植方面历来处于不利地位，而且 APOL1基因筛查和排除具有风险变异的捐赠者的理论实践可能会进一步 让这群人处于不利地位。这多个问题突出表明，有必要彻底检查 APOL1风险等位基因对移植结果的影响。美国国立卫生研究院赞助的APOL1长期肾移植 结果网络(Apollo)将通过联合移植中心、器官 采购组织(OPO)和器官共享联合网络(UNOS)招募这些捐助者 并跟踪移植结果。我们建议成为一个理想的临床中心，以直接响应这一要求 通过实现几个目标来应用。在目标1中，我们将招募和保留200个捐赠者-接受者的肾脏 用于APOL1基因检测的移植对，捐赠者为非洲裔美国人或非洲混血 对活体供者和受者进行纵向临床随访，以更好地了解APOL1的影响 捐赠者的身份对移植结果有影响。在目标2中，我们将通过以下方式进一步丰富阿波罗目标 通过评估当地对以下方面的态度、优先事项和偏好，有意义地吸引患者 参与者招募和APOL1基因测试使用社区参与工作室的新方法。 这种方法在招募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 使用先进的基因组分析来确定哪些额外的遗传变异 Beyond APOL1基因与肾功能相关。一旦完成，这些目标将推进我们的 肾移植患者对载脂蛋白1的认识