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: 9930836
• 负责人: Muktar Hassan Aliyu
• 金额: $ 16万
• 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 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9930836
• 关键词: AIDS-Associated Nephropathy; Acquired Immunodeficiency Syndrome; Address; Adult; Adverse event; Africa; African; African Trypanosomiasis; 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; Diagnostic; Dialysis procedure; Disease Progression; Effectiveness; 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; 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; arm; base; cardiovascular risk factor; diabetic; diabetic patient; experience; falls; follow-up; genetic variant; hazard; high risk; macroalbuminuria; mortality; nephrogenesis; open label; outcome forecast; 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.

项目摘要：非洲人后裔患多种形式肾脏病的风险不成比例 疾病包括糖尿病肾病、动脉肾硬化（高血压引起的肾病）、局灶性肾病 节段性肾小球硬化症 (FSGS) 和 HIV 相关肾病 (HIVAN)，这是 FSGS 的一种独特形式。 Kopp 和 Winkler 等人表明，载脂蛋白 1 (APOL1) 基因的变异具有相当大的几率 FSGS（OR = 17）、HIVAN（美国 OR = 29；南非 89）和高血压所致的比率 (OR) 肾脏疾病（OR = 7）。这些变异仅存在于非洲起源的染色体上，代表一种 针对非洲锥虫病的进化保护机制 这些风险基因型的存在是。 在西非，特别是尼日利亚，豪萨族、富拉尼族、伊博族和阿桑特族后裔中这一比例最高。 肾脏疾病的标志包括微量白蛋白尿、蛋白尿和/或估计肾小球滤过减少 率（eGFR），这三者都与艾滋病毒感染者的死亡率增加有关。 白蛋白排泄对于肾病的初步识别和确认具有诊断和预后价值 疾病和蛋白尿的变化可用于评估治疗的有效性以及 肾素-血管紧张素醛固酮系统（RAAS）被认为是疾病进展的中枢。 基于糖尿病的大量临床试验，在 CKD 病理生理学方面发挥着重要作用。 联合使用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 醛固酮与血管紧张素 II 一起，已被证明可以促进患有 CKD 的糖尿病患者的病情进展。 因此，通过更积极地阻断 RAAS 来介导氧化应激、炎症和组织纤维化。 在 ACE-I 中添加醛固酮受体拮抗剂，可能能够引发更有效且更有效的作用。 持久的反应改变，从而改变他们发展为潜在严重肾病的风险轨迹 更深入地评估这一高危人群并确定减少并发症的最佳方法。 为了降低肾脏并发症的风险，我们计划对 2,200 名接受抑制性 ART 的 HIV 感染成年人进行筛查（≥ 6 月）在阿米努卡诺教学医院；实现以下具体目标： 1) 确定 APOL1 变异的流行率并评估它们的存在是否与 普遍的蛋白尿、中位 eGFR 和/或 CKD。 2) 评估与安慰剂相比，RAAS 抑制（使用 ACE-I 赖诺普利）是否会显着 降低肾脏并发症的风险；以及 3) 评估是否通过添加更积极地阻止 RAAS 系统 盐皮质激素拮抗剂螺内酯（除了赖诺普利）是一种更有效的方法 持续降低该人群肾脏并发症的风险。