Effects of Niacin on Mineral Metabolism in Chronic Kidney Disease

描述(由申请人提供)：慢性肾脏疾病(CKD)很常见，与骨折、心血管疾病(CVD)和终末期肾脏疾病(ESRD)的风险密切相关。传统的心血管疾病风险因素并不能完全解释这些风险，而且在普通人群中已确定受益的治疗方法并不总是被证明对慢性肾脏病有效。动物研究表明，较高的血磷可能是CKD患者这些结果的一个原因危险因素。类似的发现也得到了人类观察数据的支持。领先的国际指南建议在CKD患者中使用粘合剂和限制饮食磷来降低血磷。然而，我们最近在CKD患者中进行的随机临床试验(RCT)表明，这些方法最低限度有效，患者难以坚持，并且可能造成伤害。需要新的方法，我们已经确定了脂类药物烟酸作为一种潜在的降磷治疗剂。动物研究表明，烟酸可以阻止肠道磷酸盐的吸收。对终末期肾病患者的研究以及我们对CKD患者的初步研究表明，烟酸可以显著降低磷酸盐水平，其降幅约为粘结剂或磷酸盐限制的2-10倍。此外，初步数据表明，烟酸可以减缓慢性肾脏病的进展。因此，烟酸可能最终改善CKD患者的骨折、心血管疾病和终末期肾病的风险。在NHLBI的资助下，AIM-HIGH是一项最近完成的针对流行的CVD患者的大规模烟酸随机对照试验，12%的AIM-HIGH患者在基线时患有CKD。我们建议对患有慢性肾脏病的AIM-HIGH参与者进行一项辅助研究，考察烟酸对(1)血磷水平、(2)其他矿物质代谢指标以及(3)3年来肾功能变化的随机治疗效果。这一高效的设计将为治疗慢性肾脏病的矿物质骨病提供实质性的新见解，将患者风险降至最低，并有可能迅速改变美国2700万慢性肾脏病患者以及世界各地更多人的临床实践。

DESCRIPTION (provided by applicant): Chronic kidney disease (CKD) is common, and strongly associated with risk of fractures, cardiovascular disease (CVD), and end stage renal disease (ESRD). Traditional CVD risk factors do not completely explain these risks, and therapies with established benefit in the general population have not consistently proven effective in CKD. Animal studies suggest that higher serum phosphate may be a causal risk factor for these outcomes in CKD patients. Similar findings are supported by observational data in humans. Leading international guidelines recommend lowering serum phosphate using binders and dietary phosphate restriction in CKD patients. However, we have recently conducted randomized clinical trials (RCTs) in CKD patients demonstrating that these approaches are minimally effective, difficult for patients adherence, and may cause harm. Novel approaches are needed, and we have identified the lipid drug niacin as a potential therapeutic agent for phosphate lowering. Animal studies demonstrate that niacin blocks intestinal phosphate absorption. Studies in ESRD patients, and our pilot studies in CKD patients, suggest that niacin may substantially lower phosphate levels by approximately 2 to 10 fold more than binders or phosphate restriction. In addition, preliminary data suggest that niacin may slow progression of CKD. Thus, by extension, niacin may ultimately improve fracture, CVD, and ESRD risk in CKD patients. Funded by the NHLBI, AIM-HIGH is a recently completed large RCT of niacin in patients with prevalent CVD, and 12% of AIM-HIGH patients had CKD at baseline. We propose an ancillary study in AIM-HIGH participants with CKD examining the randomized treatment effect of niacin on (1) serum phosphate levels, (2) other measures of mineral metabolism, and (3) change in kidney function over 3 years. This efficient design will provide substantial new insights to treatment of mineral bone disorder in CKD with minimal patient risk, and has the potential to rapidly change clinical practice for the 27 million persons with CKD in the US, and many more worldwide.