Effect of Pitavastatin on Kidney Function in HIV-infected Persons

 描述（由申请人提供）：匹伐他汀对接受稳定ART的HIV感染者肾功能的影响尽管抗逆转录病毒治疗（ART）取得了进展，艾滋病相关机会性感染也有所减少，但HIV感染者仍有持续的全身炎症，这会导致终末器官疾病，包括慢性肾病（CKD）。传统因素（老年、黑人、高血压、糖尿病）和HIV相关因素（慢性病毒感染、免疫抑制、炎症、过度氧化应激、ART毒性）均已被证明可导致HIV感染背景下的CKD。HMG-CoA还原酶抑制剂（即他汀类药物）不仅可降低LDL胆固醇，还可发挥强效抗炎作用，可能与预防以炎症加剧为特征的HIV感染等疾病中的肾脏疾病进展有关。在这项提案中，我们将利用NIH资助的REPRIEVE试验的基础设施，其中6，500名eGFR > 60 ml/min/1.73 m2的HIV感染参与者将被随机分配至4 mg匹伐他汀或安慰剂组，以降低动脉粥样硬化心血管事件的发生率。为了简化研究，未常规进行肾功能测量。通过增加2,500例参与者年度访视的尿液和血液采集，我们建议评估匹伐他汀治疗是否可以预防eGFR下降≥30%（推荐的CKD替代终点）和白蛋白尿（ACR > 30 mg/g）的发生。我们还将评估匹伐他汀在已证实CKD风险较高的HIV感染受试者亚组中的作用，包括老年人、黑人、高血压、CD 4 T细胞计数较低的人和含替诺福韦的方案。最后，我们将评估匹伐他汀的保护作用是否通过涉及炎症和氧化应激的机制途径介导。最终，这项研究的结果将提供纵向 在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的机制见解，并可能改变在该高危人群中预防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.