APOL1 and Kidney Transplantation Outcomes Vanderbilt Clinical Center

APOL1 和肾移植结果范德比尔特临床中心

基本信息

批准号：
9975007
负责人：
Kelly A Birdwell
金额：
$ 13.33万
依托单位：
VANDERBILT UNIVERSITY MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-25 至 2023-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9975007
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 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 clinical center cohort disadvantaged population experience follow-up genetic testing 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

项目摘要

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.

慢性肾脏和末期肾脏疾病的燃烧超出了非洲裔美国人的诞生。风险载脂蛋白-1（apol1）基因的变体几乎完全在非洲血统中发现与非洲裔美国人的几种形式的非糖尿病肾脏疾病相关，包括局灶性分段肾小球硬化，HIV相关肾病和与高血压相关的肾脏疾病。这些apol1风险变体解释了患有这些肾脏疾病的非裔美国人中多达70％的过量风险。但是，这些风险变异的存在并不能保证肾脏疾病的发展，需要遗传或环境打击。这与缺乏靶向疗法有关遗传的价值筛选APOL1风险变体未知。 apol1风险变异在肾脏移植中的影响，用于捐助者和接收者都被理解。肾脏移植是终阶段的首选治疗肾脏疾病，负担得起的大量生存，生活质量和健康经济优势比慢性透析。尚不清楚具有APOL1风险变体的活肾脏供体是否有增加的风险捐赠后肾脏疾病。对于接受者，初步研究表明，接收捐助者的接受者具有两个APOL1风险变体的肾脏可能会有更较差的移植结果。由于生物学和社会 - 经济因素，非洲裔美国人在接受肾脏移植方面一直处于不利地位，并且 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这一人群不利。这些多个问题强调了需要彻底检查的影响 APOL1有可能在移植结果上等位基因。 NIH赞助的APOL1长期肾脏移植成果网络（Apollo）将通过团结移植中心，器官来解决这个重要问题采购组织（OPO）和联合器官共享网络（UNOS）招募这些捐助者并遵循移植结果。我们建议在直接响应此请求的直接回应中成为理想的临床中心通过完成多个目标来申请。在AIM 1中，我们将招募并保留200个捐助者接收器肾脏供体是非洲裔美国人或非洲血统和混合的APOL1基因测试的移植对对活捐助者和接受者进行纵向临床随访，以更好地了解影响APOL1 捐助者身份对移植结果具有。在AIM 2中，我们将通过通过评估当地参加，优先级和偏好，使患者有意义地吸引患者参与者招募和APOL1基因测试使用了新型社区参与工作室的方法。此方法可有效招募和保留少数参与者。在AIM 3中，我们将确定基因组“第二击”使用高级基因组分析来确定哪些其他遗传变异除了APOL1基因型之外，与肾功能有关。完成后，这些目标将推动我们的肾脏移植中APOL1的知识。