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

基本信息

批准号：
9241189
负责人：
Muktar Hassan Aliyu
金额：
$ 64.74万
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：
2017-09-15 至 2022-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9241189
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 Eligibility Determination End stage renal failure Excretory function Fibrosis Focal Segmental Glomerulosclerosis Functional disorder Genes Glomerular Filtration Rate HIV HIV Infections Hypertension Individual Inflammation Intervention 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 urinary

项目摘要

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：非洲血统的人对几种形式的肾脏有不成比例的风险包括糖尿病性肾病，动脉粥样硬化（高血压植入肾脏疾病），局灶性疾病节段性肾小球硬化（FSGS）和与HIV相关的肾病（Hivan），一种不同的FSG形式。 Kopp和Winkler等人表明，载脂蛋白-1（apol1）基因会议中的变体很大 FSGS（OR = 17），Hivan（OR = 29在美国；在南非89）和高血压分配的比率（OR = 17）肾脏疾病（OR = 7）。这些变体仅存在于非洲 - 原始染色体上，并代表进化保护的机制抗非洲锥虫病。这些风险基因型的存在是在西非，尤其是尼日利亚的豪萨，富拉尼，伊博和阿桑特血统中的最高。肾脏疾病的标志物包括微量白蛋白尿，蛋白尿和/或估计的肾小球滤过费率（EGFR）。这三个都与感染HIV的成年人死亡率增加有关。增加尿白蛋白排泄在肾脏的初始识别和确认中具有诊断和预后价值疾病和蛋白尿的变化对于评估治疗的有效性以及肾素 - 血管紧张素醛固酮系统（RAAS）被认为是中央基于众多糖尿病患者的临床试验，CKD病理生理学的参与者。 Raas的封锁使用血管紧张素转化酶抑制剂（ACE-I）是一种良好认可的策略，可减缓肾脏疾病 CKD糖尿病患者的进展。醛固酮与血管紧张素II一起已被证明介导氧化应激，感染和组织纤维化。因此，通过更积极地通过在ACE-I中添加了醛固酮受体拮抗剂，可能会引起更多潜力，并且持久的反应，从而改变了他们的风险轨迹，以发展潜在的严重肾脏并发症。评估这一高危人群的更深入，并确定减少的最佳手段它们的肾脏并发症风险，我们计划筛选2200名受到抑制作用的HIV感染的成年人（≥6）几个月）在Aminu Kano教学医院；执行以下特定目标： 1）确定apol1变体的患病率和评估是否与普遍的蛋白尿，中位EGFR和/或CKD。 2）评估与安慰剂相比的RAAS抑制（使用ACE-I Lisinopril）是否会显着降低肾脏并发症的风险；和 3）评估是否通过添加更积极地阻止RAAS系统矿物皮质激素拮抗剂螺内酯（除了赖诺普利）是更有潜力的手段可持续地降低了该人群中肾脏并发症的风险。