Etiology of Persistent Microalbuminuria in Nigeria

摘要：微量白蛋白尿是心血管和肾脏疾病的独立危险因素， 在普通人群和艾滋病毒携带者(PLWH)中都是终末器官损害的预测因子。 微量白蛋白尿，定义为白蛋白与肌酐的比率(UACR)30-300毫克/克，可以表示早期 肾小球损害或微血管内皮细胞功能障碍，已被用于早期检测 肾脏疾病。微量白蛋白尿也是PLWH患者死亡的重要危险因素 抗逆转录病毒治疗(ART)，可能是炎症和内皮激活的标志。在正在进行的 在尼日利亚的肾脏风险降低(R3)研究中，36.9%的人有微量白蛋白尿，通过两项测量证实4- 间隔8周，2.8%有大量白蛋白尿(uACR&GT；300 mg/g)。接受抗逆转录病毒治疗的中位数为9年。 [IQR 6，12]，CD4细胞计数中值为482个/mm3[IQR 324-661]，95.7%受到病毒抑制，以及 12.7%有1期或2期高血压(22.1%有高血压前期)。相比之下，其他传统风险因素 蛋白尿和肾脏疾病，包括糖尿病(2.1%)、APOL1高危基因(6.2%)和吸烟 (5%)是罕见的。相当一部分人(~59%)目前正在接受潜在的肾毒性ARV 药物，特别是富马酸替诺福韦双丙酯。最后，地方性混合感染，包括病毒(例如 乙型和丙型肝炎、巨细胞病毒)、寄生虫(例如恶性疟原虫、血吸虫、 粪类圆线虫、螺旋体、Loa Loa、Wuchereria bancrofti)和细菌(分枝杆菌 合并感染，可能是蛋白尿的潜在诱因。为了更好地理解这一点，我们计划 测试以下压倒一切的假设：高血压，联合感染的免疫激活，以及 累积、长期接触潜在的肾毒性ARV药物导致了高 这些有艺术经验的成年人的微量白蛋白尿率。为了检验这一假设，我们提出了 以下是具体目标： 1)比较大量队列中蛋白尿和已确定的肾脏疾病危险因素的患病率 在Aminu接受常规医疗护理的年龄和性别匹配的HIV阴性成年人的PLWH 尼日利亚卡诺的卡诺教学医院。我们将利用2500 R3的数据和存储的样本 以前接受过微量白蛋白尿筛查并将在未来参加额外的 300PLWH最近开始接受抗逆转录病毒治疗(≤，12个月)，以及750名年龄和性别匹配的艾滋病毒阴性成年人。 2)确定高血压和其他共病疾病(例如，镰状细胞特性或 疾病、寄生虫感染和结核病引起的免疫激活/炎症，以及接触 潜在的肾毒性抗逆转录病毒药物)，有发生蛋白尿的风险。我们将招收 1000名艾滋病毒阳性、接受抗逆转录病毒治疗的正常白蛋白尿成年人和500名艾滋病毒阴性的正常白蛋白尿成年人 从目标1开始，纵向跟踪它们三年。

ABSTRACT: Microalbuminuria is an independent risk factor for cardiovascular and kidney disease and a predictor of end organ damage, both in the general population and in persons living with HIV (PLWH). Microalbuminuria, defined as an albumin-to-creatinine ratio (uACR) 30-300 mg/g, can signify either early glomerular damage or microvascular endothelial dysfunction and has been used in the early detection of kidney disease. Microalbuminuria is also an important risk factor for mortality in PLWH treated with antiretroviral therapy (ART), likely as a marker for inflammation and endothelial activation. In the ongoing Renal Risk Reduction (R3) study in Nigeria, 36.9% had microalbuminuria confirmed by two measurements 4- 8 weeks apart, and 2.8% had macroalbuminuria (uACR >300 mg/g). The median duration on ART was 9 years [IQR 6,12], median CD4 cell count was 482 cells/mm3 [IQR 324–661], 95.7% were virally suppressed, and 12.7% had stage 1 or 2 hypertension (22.1% with pre-hypertension). In contrast, other traditional risk factors for albuminuria and kidney disease, including diabetes (2.1%), APOL1 high-risk genotype (6.2%), and smoking (5%) were uncommon. A significant proportion (~59%) were currently receiving potentially nephrotoxic ARV medications, specifically tenofovir disoproxil fumarate. Lastly, endemic co-infections, including viral (e.g. hepatitis B and C, Cytomegalovirus), parasitic (e.g. Plasmodium falciparum, Schistosoma species, Strongyloides stercoralis, Onchocerca volvulus, Loa loa, Wuchereria bancrofti), and bacterial (Mycobacterium tuberculosis) co-infections, may be potential contributors to albuminuria. To better understand this, we plan to test the following overarching hypothesis: Hypertension, immune activation from co-infections, and cumulative, long-term exposure to potentially nephrotoxic ARV medications contribute to the high rates of microalbuminuria in these ART-experienced adults. To test this hypothesis, we propose the following Specific Aims: 1) To compare the prevalence of albuminuria and established kidney disease risk factors in a large cohort of PLWH to age- and sex-matched HIV-negative adults presenting for routine medical care at the Aminu Kano Teaching Hospital in Kano, Nigeria. We will leverage data and stored specimens from 2500 R3 participants who were previously screened for microalbuminuria and will prospectively enroll an additional 300 PLWH recently initiated on ART (≤ 12 months) and 750 age- and sex-matched HIV-negative adults. 2) To determine the role that hypertension and other comorbid medical conditions (e.g. sickle cell trait or disease, immune activation/inflammation from parasitic infestations and tuberculosis, and exposure to potentially nephrotoxic ARV medications), have on the risk for development of albuminuria. We will enroll 1000 HIV-positive, ART-treated normoalbuminuric adults and 500 HIV-negative normoalbuminuric adults from Aim 1 and follow them longitudinally for three years.