Optimal Management of HIV Infected Adults at Risk for Kidney Disease in Nigeria

尼日利亚有肾病风险的艾滋病毒感染者的最佳管理

• 批准号: 10255513
• 负责人: Muktar Hassan Aliyu
• 金额: $ 58.44万
• 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: 2017-09-15 至 2025-03-01
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10255513
• 关键词: AIDS-Associated Nephropathy; Acquired Immunodeficiency Syndrome; Address; Adult; Adverse event; Africa; African; African Trypanosomiasis; African ancestry; Albumins; Albuminuria; Aldosterone; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Apolipoproteins; Cardiovascular Diseases; Chromosomes; Chronic Kidney Failure; Clinical Trials; Consent; Creatinine; Data; Development; Diabetes Mellitus; Diabetic Nephropathy; Dialysis procedure; Disease Progression; End stage renal failure; Excretory function; Fibrosis; Focal Segmental Glomerulosclerosis; Functional disorder; Genes; Glomerular Filtration Rate; HIV; HIV Infections; HIV Seronegativity; Hypertension; Individual; Inflammation; Kidney; Kidney Diseases; Kidney Transplantation; Lisinopril; Literature; Mediating; Microalbuminuria; Mineralocorticoid Receptor; Mineralocorticoids; Nigeria; Nigerian; Odds Ratio; Organ; Oxidative Stress; Participant; Pathogenesis; Patients; Persons; Pharmaceutical Preparations; Placebos; Population; Populations at Risk; Prevalence; Prognosis; Proteinuria; Randomized; Reactive Oxygen Species; Regimen; Renal glomerular disease; Renin-Angiotensin-Aldosterone System; Risk; South Africa; Spironolactone; System; T-Cell Activation; Teaching Hospitals; Testing; Tissues; Variant; antagonist; arm; base; cardiovascular risk factor; diabetic; diabetic patient; diagnostic value; effectiveness evaluation; experience; falls; follow-up; genetic variant; hazard; high risk; macroalbuminuria; mortality; nephrogenesis; open label; prognostic value; protective effect; response; risk variant; screening; standard of care; treatment arm; urinary

PROJECT SUMMARY: Persons of African descent have a disproportionate risk for several forms of kidney disease including diabetic nephropathy, arterionephrosclerosis (hypertension-attributed kidney disease), focal segmental glomerulosclerosis (FSGS) and HIV-associated nephropathy (HIVAN), a distinct form of FSGS. Kopp and Winkler et al have shown that variants in the apolipoprotein-1 (APOL1) gene confer sizeable odds ratios (OR) for FSGS (OR = 17), HIVAN (OR = 29 in the US; 89 in South Africa), and hypertension-attributed kidney disease (OR = 7). These variants are present only on African-origin chromosomes and represent an evolutionary protective mechanism against African trypanosomiasis. The presence of these risk genotypes is highest in West Africa, and specifically in Nigeria among persons of Hausa, Fulani, Igbo, and Asante descent. Markers of kidney disease include microalbuminuria, proteinuria, and/or reduced estimated glomerular filtration rate (eGFR). All three have been associated with increased mortality in HIV-infected adults. Increased urinary albumin excretion has diagnostic and prognostic value in the initial identification and confirmation of renal disease, and changes in albuminuria can be useful in assessing the effectiveness of therapy as well as the progression of the disease. The renin-angiotensin aldosterone system (RAAS) is recognized as the central player in the pathophysiology of CKD based on numerous clinical trials in diabetics. The blockade of RAAS with angiotensin converting enzyme inhibitors (ACE-I) is a well-recognized strategy to slow down renal disease progression in diabetic patients with CKD. Aldosterone, together with angiotensin II, has been shown to mediate oxidative stress, inflammation and tissue fibrosis. Therefore by more aggressively blocking RAAS via the addition of an aldosterone receptor antagonist to an ACE-I, one may be able to elicit a more potent and durable response thereby altering their risk trajectory for the development of potentially serious kidney complications. To evaluate this at-risk population more in-depth and to determine the optimal means to reduce their risk for renal complications, we plan to screen 2,200 HIV-infected adults receiving suppressive ART (≥ 6 months) at the Aminu Kano Teaching Hospital; to conduct the following Specific Aims: 1) To determine the prevalence of APOL1 variants and assess whether their presence correlates with prevalent albuminuria, median eGFR, and/or CKD. 2) To assess whether RAAS inhibition (with the ACE-I lisinopril) compared to placebo will significantly reduce the risk of kidney complications; and 3) To evaluate whether more aggressively blocking the RAAS system via the addition of the mineralocorticoid antagonist spironolactone (in addition to lisinopril) is an even more potent means of sustainably reducing the risk of kidney complications in this population.

项目总结：非洲裔人患几种肾脏疾病的风险不成比例 疾病，包括糖尿病肾病、动脉肾硬化（高血压引起的肾病）、局灶性 节段性肾小球硬化（FSGS）和HIV相关肾病（HIVAN），FSGS的一种不同形式。 Kopp和Winkler等人已经表明，载脂蛋白-1（APOL 1）基因的变异赋予了相当大的几率， FSGS（OR = 17）、HIVAN（OR = 29，美国; 89，南非）和高血压归因的 肾脏疾病（OR = 7）。这些变异只存在于非洲起源的染色体上，代表了一种 对非洲锥虫的进化保护机制。这些风险基因型的存在是 在西非，特别是在尼日利亚，豪萨人、富拉尼人、伊博人和阿桑特人后裔中的死亡率最高。 肾脏疾病的标志物包括微量白蛋白尿、蛋白尿和/或估计肾小球滤过率降低 发生率（eGFR）。所有这三种疾病都与艾滋病毒感染成年人死亡率的增加有关。尿量增加 白蛋白排泄对肾性高血压的初始识别和确认具有诊断和预后价值。 蛋白尿的变化可用于评估治疗的有效性以及 疾病的进展。肾素-血管紧张素醛固酮系统（RAAS）被认为是 根据糖尿病患者的大量临床试验，对RAAS的封锁 血管紧张素转换酶抑制剂（ACE-I）是一种公认的减缓肾脏疾病的策略 CKD糖尿病患者的病情进展。醛固酮与血管紧张素II一起，已被证明 介导氧化应激、炎症和组织纤维化。因此，通过更积极地阻断RAAS， 在ACE-I中加入醛固酮受体拮抗剂，可以引起更有效且 从而改变其发生潜在严重肾脏疾病的风险轨迹 并发症为了更深入地评估这一高危人群，并确定减少 他们的肾脏并发症的风险，我们计划筛选2,200名接受抑制性ART（≥ 6 月）在阿米努卡诺教学医院;进行以下具体目标： 1)确定APOL 1变异的患病率，并评估其存在是否与 普遍性白蛋白尿、中位eGFR和/或CKD。 2)评估RAAS抑制（使用ACE-I赖诺普利）与安慰剂相比是否显著 降低肾脏并发症的风险;以及 3)为了评估是否通过添加 盐皮质激素拮抗剂螺内酯（除赖诺普利外）是一种更有效的手段， 可持续地降低这一人群中肾脏并发症的风险。

项目成果

Kidney disease and APOL1.

肾脏疾病和 APOL1。

• DOI: 10.1093/hmg/ddab024
• 发表时间: 2021
• 期刊: Human molecular genetics
• 影响因子: 3.5
• 作者: Yusuf,AminuAbba;Govender,MelanieA;Brandenburg,Jean-Tristan;Winkler,CherylA
• 通讯作者: Winkler,CherylA

The Vanderbilt Nigeria Biostatistics Training Program (VN-BioStat): Results from a Skills Workshop.

范德比尔特尼日利亚生物统计学培训计划 (VN-BioStat)：技能研讨会的结果。

• DOI: 10.5539/ijsp.v12n6p66
• 发表时间: 2023
• 期刊: International journal of statistics and probability
• 作者: Shepherd,BryanE;Hussaini,Nafiu;Huang,Alex;VanWyk,Chelsea;Kowalski,MeiraS;Ingles,DonnaJ;Wester,CWilliam;Li,Chun;Aliyu,MuktarH
• 通讯作者: Aliyu,MuktarH

HIV-associated nephropathy: Protocol and rationale for an exploratory genotype-phenotype study in a sub-Saharan African population.

• DOI: 10.1371/journal.pone.0249567
• 发表时间: 2021
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Yusuf AA;Musa BM;Galadanci NA;Babashani M;Mohammed AZ;Ingles DJ;Fogo AB;Wester CW;Aliyu MH
• 通讯作者: Aliyu MH

Apolipoprotein-1 risk variants and associated kidney phenotypes in an adult HIV cohort in Nigeria.

• DOI: 10.1016/j.kint.2021.03.038
• 发表时间: 2021-07
• 期刊: Kidney international
• 影响因子: 19.6
• 作者: Wudil UJ;Aliyu MH;Prigmore HL;Ingles DJ;Ahonkhai AA;Musa BM;Muhammad H;Sani MU;Nalado AM;Abdu A;Abdussalam K;Shepherd BE;Dankishiya FS;Burgner AM;Ikizler TA;Wyatt CM;Kopp JB;Kimmel PL;Winkler CA;Wester CW
• 通讯作者: Wester CW