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CVD风险因素并不能完全解释这些风险，并且在一般人群中已确定获益的疗法并没有一致地证明对CKD有效。动物研究表明，较高的血清磷可能是CKD患者这些结局的因果风险因素。类似的发现得到了人类观察数据的支持。领先的国际指南建议CKD患者使用结合剂和饮食磷酸盐限制降低血清磷酸盐。然而，我们最近在CKD患者中进行的随机临床试验（RCT）表明，这些方法的疗效最低，患者难以依从，并可能造成伤害。需要新的方法，我们已经确定了脂质药物烟酸作为一种潜在的治疗剂，降低磷酸盐。动物研究表明，烟酸阻断肠道磷酸盐吸收。在ESRD患者中的研究以及我们在CKD患者中的初步研究表明，烟酸可显著降低磷酸盐水平，比结合剂或磷酸盐限制剂高约2至10倍。此外，初步数据表明，烟酸可能会减缓CKD的进展。因此，通过扩展，烟酸可能最终改善CKD患者的骨折，CVD和ESRD风险。由NHLBI资助，AIM-HIGH是一项最近完成的烟酸在普遍CVD患者中的大型RCT，12%的AIM-HIGH患者在基线时患有CKD。我们建议在患有CKD的AIM-HIGH受试者中进行一项辅助研究，检查烟酸对（1）血清磷酸盐水平，（2）其他矿物质代谢指标和（3）3年内肾功能变化的随机治疗效果。这种有效的设计将为CKD中矿物质骨疾病的治疗提供大量新的见解，同时将患者风险降至最低，并有可能迅速改变美国2700万CKD患者的临床实践，以及全球更多患者的临床实践。

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.