Effect of Pitavastatin on Kidney Function in HIV-infected Persons

 描述(申请人提供)：匹伐他汀对艾滋病毒感染者肾功能的影响稳定抗逆转录病毒治疗(ART)尽管抗逆转录病毒治疗(ART)取得了进展，艾滋病相关的机会性感染也有所减少，但艾滋病毒感染者持续的全身性炎症导致包括慢性肾脏疾病(CKD)在内的终末期器官疾病。传统因素(高龄、黑人、高血压、糖尿病)和艾滋病毒相关因素(慢性病毒感染、免疫抑制、炎症、过度氧化应激、抗逆转录病毒药物毒性)都已被证明在艾滋病毒感染的背景下导致慢性肾脏病。HMG-CoA还原酶抑制剂(即他汀类药物)不仅可以降低低密度脂蛋白胆固醇，还可以发挥有效的抗炎作用，这可能与防止以炎症加剧为特征的艾滋病毒感染等疾病的肾脏疾病的发展有关。在这项提案中，我们将利用NIH资助的缓刑试验的基础设施，在该试验中，6,500名EGFR和GT；60ml/min/1.73m2的HIV感染者将被随机分配到4 mg匹伐他汀或安慰剂，以减少动脉粥样硬化性心血管事件的发生率。为了简化研究，肾功能的测量并不是常规的。通过增加2,500名参与者的年度访问的尿液和血液收集，我们建议评估匹伐他汀治疗是否可以防止≥下降30%，EGFR下降30%，这是慢性肾病的推荐替代终点，以及蛋白尿的发生(ACR&GT；30 mg/g)。我们还将评估Pitavastatin在感染艾滋病毒的参与者中的效果，这些参与者的CKD风险已被证明较高，包括年龄较大、黑人种族、高血压、CD4T细胞计数较低的人，以及使用替诺福韦的患者。最后，我们将评估匹伐他汀的保护作用是否通过炎症和氧化应激等机制介导。最终，这项研究的结果将提供纵向的 关于HIV感染背景下CKD的流行病学数据，提供了他汀类药物是否通过调节炎症和氧化应激来预防CKD的机械性见解，并可能改变在这一高危人群中预防CKD的指南。

 DESCRIPTION (provided by applicant): Effect of Pitavastatin on Renal Function in HIV-infected Persons on stable ART Despite advances in antiretroviral treatment (ART) and the reduction in AIDS-related opportunistic infections, HIV-infected persons have persistent systemic inflammation that contributes to end organ diseases, including chronic kidney disease (CKD). Both traditional (older age, black race, hypertension, diabetes) and HIV-related (chronic viral infection, immunosuppression, inflammation, excess oxidative stress, ART toxicities) factors have been demonstrated to contribute to CKD in the setting of HIV infection. HMG-coA reductase inhibitors (i.e. statins) not only reduce LDL cholesterol but also exert potent anti-inflammatory effects that may be relevant to prevent the progression of kidney disease in diseases like HIV infection which is characterized by heightened inflammation. In this proposal, we will leverage the infrastructure of the NIH-funded REPRIEVE trial in which 6,500 HIV-infected participants with eGFR >60ml/min/1.73m2 will be randomized to 4mg pitavastatin or placebo to reduce the incidence of atherosclerotic cardiovascular events. In an effort to streamline the study, measures of kidney function are not routinely performed. By adding collection of urine and blood from annual visits in 2,500 participants, we propose to assess whether pitavastatin therapy can prevent a ≥30% eGFR decline, a recommended surrogate endpoint for CKD, and the development of albuminuria (ACR >30mg/g). We will also evaluate the effect of pitavastatin in sub-groups of HIV-infected participants for whom the risk of CKD has been demonstrated to be higher, including persons of older age, black race, hypertension, lower CD4 T cell counts, and on tenofovir-containing regimens. Finally, we will assess whether the protective effect of pitavastatin is mediated through mechanistic pathways involving inflammation and oxidative stress. Ultimately, the findings of this study will provide longitudinal data on the epidemiology of CKD in the setting of HIV infection, provide mechanistic insights into whether statins prevent CKD by modulating inflammation and oxidative stress, and potentially change guidelines for the prevention of CKD in this at risk population.