Genetic, Environmental & Histologic Basis for Kidney Disease Risk among Persons Living with HIV

遗传、环境

• 批准号: 10186736
• 负责人: JAYME ELIZABETH LOCKE
• 金额: $ 79.57万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10186736
• 关键词: Acquired Immunodeficiency Syndrome; Address; Biological; CD4 Lymphocyte Count; Caring; Categories; Characteristics; Chronic Kidney Failure; Clinical; Complication; DNA; Data; Development; Dialysis procedure; Disease; Disease Progression; Donor Selection; End stage renal failure; Enrollment; Evaluation; Failure; Future; General Population; Genes; Genetic; Genetic Risk; Genetic Variation; Genotype; HIV; HIV Infections; HIV risk; Histologic; Histology; Incidence; Individual Differences; Intervention; Kidney; Kidney Diseases; Knowledge; Light; Living Donors; Measures; Mendelian randomization; Methods; Modification; Natural History; Nephrology; Outcome; Participant; Patient-Focused Outcomes; Pennsylvania; Persons; Phenotype; Population; Predictive Value; Process; Regimen; Research; Risk; Specimen; Structural Models; System; Time; Transplantation; United States; Universities; Update; Validation; Variant; Viral; Virus Diseases; antiretroviral therapy; base; care outcomes; clinical decision-making; cohort; comorbidity; disorder risk; follow-up; gene environment interaction; genetic association; genetic variant; hazard; high risk; improved; insight; kidney biopsy; living kidney donor; mortality; novel; predictive tools; prognostic; prospective; public health relevance; response; risk prediction; risk stratification; tool

SUMMARY More than 1.1 million people in the United States (US) are living with human immunodeficiency virus (HIV) infection, and an estimated 30% of people living with HIV (PLWH) have evidence of chronic kidney disease (CKD). Compared to the general population, the rate of end-stage renal disease (ESRD) among PLWH is tenfold greater and mortality on dialysis is 19-fold higher. Contributors to CKD in PLWH include comorbidities shared with the uninfected population, HIV-specific factors, and genetic variants; however, the interplay of these various determinants remains incompletely understood. Existing CKD risk prediction tools for PLWH have low sensitivity and insufficient positive predictive value for clinical decision-making. The ability to risk- stratify PLWH and distinguish those at highest risk for future development of CKD from those at low risk is critical to optimize care and patient outcomes. PLWH at high risk can be targeted for interventions to slow CKD progression and improve survival, including earlier establishment of nephrology care and referral for transplantation; while identification of those at low risk allows for the development of a living donor selection framework specific to PLWH, effectively expanding HIV+ to HIV+ transplantation to include living donors. We hypothesize that the impact of HIV on CKD risk varies by the interplay between comorbid conditions, HIV- related factors, and genetic variants, and distinct phenotypes of PLWH with high and low CKD risk exist. To better understand this relationship, we will leverage the Centers for AIDS Research Network of Integrated Clinical Systems (CNICS), a unique prospective clinical cohort with > 34,000 participants, and will address the following unique aims: (1) to explore the association of unique HIV-related processes and clinical characteristics with risk for CKD; (2) to explore the association of genetic variants with risk for CKD and correlate histologic findings with genetic risk; and (3) develop a tool for predicting CKD risk among PLWH. Stratification by risk for future development of CKD is critical for identifying those PLWH at highest risk that would benefit from early nephrology care and referral for transplantation and those at lowest risk that could be eligible for living kidney donation. Using an existing cohort of PLWH representative of the US HIV population, with time varying data and DNA for genotyping, to inform CKD risk prediction is necessary, practical, and novel. Our findings will contribute new insights into the relationship between HIV and risk for kidney disease.

总结 美国有超过110万人感染人类免疫缺陷病毒（HIV） 感染，估计30%的艾滋病毒感染者（PLWH）有慢性肾脏疾病的证据 （CKD）。与普通人群相比，艾滋病病毒携带者中终末期肾病（ESRD）的发病率为 透析死亡率高19倍。PLWH中CKD的促成因素包括合并症 与未感染人群，艾滋病毒特异性因素和遗传变异共享;然而， 这些不同的决定因素仍然不完全清楚。PLWH的现有CKD风险预测工具 敏感性低，对临床决策的阳性预测值不足。冒险的能力- 对PLWH进行分层并区分那些未来发展为CKD风险最高者和风险较低者， 对优化护理和患者结果至关重要。高风险的PLWH可以作为干预措施的目标，以减缓CKD 进展和提高生存率，包括早期建立肾病护理和转诊， 移植;而识别那些低风险的允许发展活体供体选择 艾滋病毒/艾滋病感染者艾滋病毒感染我们 假设HIV对CKD风险的影响因共病条件、HIV- 存在相关因素和遗传变异以及具有高和低CKD风险的PLWH的不同表型。到 为了更好地理解这种关系，我们将利用艾滋病研究中心综合网络， 临床系统（CNICS），一个独特的前瞻性临床队列，有超过34，000名参与者，并将解决 以下独特的目的：（1）探索独特的HIV相关过程和临床 （2）探索遗传变异与CKD风险的相关性， 将组织学发现与遗传风险相关联;和（3）开发一种预测PLWH中CKD风险的工具。 根据CKD未来发展的风险进行分层对于识别处于最高风险的PLWH至关重要， 将受益于早期肾脏病护理和转诊移植和那些风险最低的人， 符合活体肾脏捐赠的条件使用代表美国HIV人群的PLWH现有队列， 随着时间变化的数据和基因分型的DNA，告知CKD风险预测是必要的，实用的， 小说我们的研究结果将有助于对艾滋病毒与肾脏疾病风险之间的关系提出新的见解。