Etiology of Persistent Microalbuminuria in Nigeria

尼日利亚持续性微量白蛋白尿的病因学

• 批准号: 10617771
• 负责人: Muktar Hassan Aliyu
• 金额: $ 52.69万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10617771
• 关键词: APOL1 gene; Acquired Immunodeficiency Syndrome; Address; Adult; Age; Albumins; Albuminuria; Angiotensin Receptor; Angiotensin-Converting Enzyme Inhibitors; Bacterial Infections; Biological Markers; Blood Pressure; CD14 gene; CD4 Lymphocyte Count; Cardiovascular Diseases; Cardiovascular system; Caring; Cells; Creatinine; Cytomegalovirus; Data; Development; Diabetes Mellitus; Disease; Early Diagnosis; Endothelium; Enrollment; Etiology; Exposure to; Fibrin fragment D; Filaria bancrofti; Fumarates; General Population; HIV; HIV Seronegativity; HIV Seropositivity; Hepatitis B; Hepatitis C; Hepatitis C co-infection; High Prevalence; Hypertension; Inflammation; Inflammatory; Interleukin-6; Kidney; Kidney Diseases; Lisinopril; Loa loa; Low Prevalence; Measurement; Medical; Microalbuminuria; Monitor; Morbidity - disease rate; Mycobacterium tuberculosis; Nigeria; Onchocerca volvulus; Organ; Parasitic infection; Participant; Persons; Pharmaceutical Preparations; Phase; Plasmodium falciparum; Population; Prevalence; Regimen; Renin-Angiotensin-Aldosterone System; Risk; Risk Factors; Risk Reduction; Role; Schistosoma; Sickle Cell Trait; Site; Smoking; Specimen; Strongyloides stercoralis; T-Cell Activation; TNFR-Fc fusion protein; TNFRSF1A gene; Teaching Hospitals; Tenofovir; Testing; Tuberculosis; Viral; Virus Diseases; antiretroviral therapy; cardiovascular risk factor; cigarette smoking; co-infection; cohort; comorbidity; eligible participant; experience; high risk; immune activation; inflammatory marker; macroalbuminuria; mortality; nephrotoxicity; non-diabetic; normotensive; prehypertension; prospective; randomized placebo controlled trial; risk variant; screening; sex; therapy development; vascular endothelial dysfunction

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.

摘要：微量白蛋白尿是心血管和肾脏疾病的独立危险因素，也是心血管疾病和肾脏疾病的独立危险因素。 普通人群和艾滋病毒感染者 (PLWH) 中终末器官损伤的预测因子。 微量白蛋白尿定义为白蛋白与肌酐比值 (uACR) 30-300 mg/g，可能意味着早期 肾小球损伤或微血管内皮功能障碍，已用于早期检测 肾脏疾病。微量白蛋白尿也是接受治疗的感染者死亡的重要危险因素 抗逆转录病毒治疗（ART），可能作为炎症和内皮激活的标志。在正在进行的 尼日利亚的肾脏风险降低 (R3) 研究显示，36.9% 的人有微量白蛋白尿，经两次测量证实 4- 相隔 8 周，2.8% 出现大量白蛋白尿 (uACR >300 mg/g)。 ART 的中位持续时间为 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，并且 12.7% 患有 1 期或 2 期高血压（22.1% 患有高血压前期）。相比之下，其他传统风险因素 针对白蛋白尿和肾脏疾病，包括糖尿病 (2.1%)、APOL1 高危基因型 (6.2%) 和吸烟 (5%) 不常见。很大一部分人（~59%）目前正在接受具有潜在肾毒性的抗逆转录病毒药物 药物，特别是富马酸替诺福韦二吡呋酯。最后，地方性合并感染，包括病毒感染（例如病毒感染）。 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、盘尾丝虫、Loa loa、Wuchereria bancrofti）和细菌（分枝杆菌） 结核病）合并感染，可能是蛋白尿的潜在因素。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、合并感染引起的免疫激活，以及 累积、长期接触具有潜在肾毒性的抗逆转录病毒药物会导致高 这些经历过 ART 的成年人的微量白蛋白尿发生率。为了检验这个假设，我们提出 以下具体目标： 1) 比较大型队列中蛋白尿的患病率和已确定的肾脏疾病危险因素 的 PLWH 中年龄和性别匹配的 HIV 阴性成年人在 Aminu 接受常规医疗护理 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 之前接受过微量白蛋白尿筛查的参与者将前瞻性地招募额外的参与者 300 名 PLWH 最近开始接受 ART（≤ 12 个月）和 750 名年龄和性别匹配的 HIV 阴性成年人。 2) 确定高血压和其他合并症（例如镰状细胞性状或 疾病、寄生虫感染和结核病引起的免疫激活/炎症以及接触 潜在肾毒性的抗逆转录病毒药物），有发生白蛋白尿的风险。我们将报名 1000 名 HIV 阳性、接受 ART 治疗的白蛋白尿正常的成人和 500 名 HIV 阴性、白蛋白尿正常的成人 从目标 1 开始，纵向跟踪它们三年。