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

项目摘要：非洲人后裔患多种肾脏疾病的风险不成比例 疾病包括糖尿病肾病、动脉硬化症(高血压引起的肾脏疾病)、 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等人已经证明，载脂蛋白-1(APOL1)基因的变异会带来相当大的几率 FSGS(OR=17)、HIVAN(OR=29；南非为89)和高血压的比值(OR) 肾脏疾病(OR=7)。这些变异只存在于非洲起源的染色体上，代表着一种 非洲锥虫病的进化保护机制。这些危险基因的存在是 在西非最高，特别是在尼日利亚豪萨族、富拉尼族、伊博族和阿桑特族人中。 肾脏疾病的标志包括微量白蛋白尿、蛋白尿和/或估计的肾小球滤过率降低。 率(EGFR)。所有这三个因素都与感染艾滋病毒的成年人死亡率增加有关。尿量增加 白蛋白排泄物对肾脏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 疾病的发展。肾素-血管紧张素-醛固酮系统(RAAS)是公认的中枢 在糖尿病患者的大量临床试验的基础上，参与了慢性肾脏病的病理生理学研究。封锁RAAS 血管紧张素转换酶抑制剂(ACE-I)是公认的延缓肾脏疾病的策略 糖尿病合并慢性肾脏病患者的进展。醛固酮和血管紧张素II一起被证明可以 调节氧化应激、炎症和组织纤维化。因此，通过更积极地阻止RAAS 在ACE-I中加入醛固酮受体拮抗剂，可能能够诱导出更有效和 持久的反应，从而改变了他们发生潜在严重肾脏的风险轨迹 并发症。更深入地评估这一高危人群，并确定减少 他们肾脏并发症的风险，我们计划筛查2,200名接受抑制性ART(≥6)的艾滋病毒感染的成年人 几个月)在阿米努·卡诺教学医院；执行以下具体目标： 1)确定APOL1变异体的流行情况，并评估它们的存在是否与 普遍的蛋白尿、中位数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)评估是否通过添加 盐皮质激素拮抗剂螺内酯(除了赖诺普利外)是一种更有效的治疗方法 可持续地降低这一人群中肾脏并发症的风险。

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.