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， 终末器官损伤的预测因子，无论是在一般人群和艾滋病毒感染者（PLWH）。 微量白蛋白尿，定义为白蛋白与肌酐比值（uACR）30 - 300 mg/g，可表示早期 肾小球损伤或微血管内皮功能障碍，并已用于早期检测 肾病微量白蛋白尿也是PLWH患者死亡的一个重要危险因素， 抗逆转录病毒治疗（ART），可能作为炎症和内皮激活的标志物。正在进行的 在尼日利亚进行的肾脏风险降低（R3）研究中，36.9%的患者经两次测量证实存在微量白蛋白尿4- 间隔8周，2.8%有大量白蛋白尿（uACR> 300 mg/g）。接受抗逆转录病毒治疗的中位时间为9年 [IQR 6，12]，中位CD4细胞计数为482个细胞/mm3 [IQR 324 - 661]，95.7%的病毒受到抑制， 12.7%有1或2期高血压（22.1%有高血压前期）。其他传统风险因素 蛋白尿和肾脏疾病，包括糖尿病（2.1%），APOL 1高风险基因型（6.2%）和吸烟 （5%）不常见。很大一部分人（约59%）目前正在接受可能具有肾毒性的抗逆转录病毒治疗 药物，特别是富马酸替诺福韦酯。最后，地方性合并感染，包括病毒性（例如， B和C型肝炎，巨细胞病毒），寄生虫（例如恶性疟原虫，血吸虫属， 粪类圆线虫、盘尾丝虫、Loa loa、班氏吴策线虫）和细菌（分枝杆菌 结核病）合并感染，可能是蛋白尿的潜在贡献者。为了更好地理解这一点，我们计划 测试以下总体假设：高血压，合并感染的免疫激活， 累积的，长期暴露于潜在的肾毒性抗逆转录病毒药物有助于高 这些ART经验丰富的成人中微量白蛋白尿的发生率。为了验证这一假设，我们提出了 具体目标： 1)在一个大型队列中比较蛋白尿的患病率和已确定的肾脏疾病危险因素 在阿米努医院接受常规医疗护理的年龄和性别匹配的HIV阴性成年人中， 位于尼日利亚卡诺的卡诺教学医院。我们将利用来自2500 R3的数据和储存的标本 既往接受过微量白蛋白尿筛查的受试者， 300名最近开始接受抗逆转录病毒治疗（≤ 12个月）的艾滋病毒感染者和750名年龄和性别匹配的艾滋病毒阴性成人。 2)确定高血压和其他共病疾病（如镰状细胞性状或 疾病、寄生虫感染和结核病引起的免疫激活/炎症，以及暴露于 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例HIV阳性、ART治疗的正常白蛋白尿成人和500例HIV阴性的正常白蛋白尿成人 从目标1开始，纵向跟踪他们三年。

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.