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.

Public Health Relevance

Chronic kidney disease is common and strongly linked with risk of fractures, cardiovascular disease, and end stage renal disease. Kidney disease patients have higher serum phosphate levels, and higher phosphate may be causing the higher risk of these outcomes. Leading international consensus guidelines recommend lowering phosphate, but existing therapies are minimally effective. We have identified that the lipid drug niacin lower serum phosphate through a unique mechanism. In a randomized clinical trial among patients with CKD, this study will test whether niacin lowers serum phosphate and other markers of mineral metabolism, and slows progression of CKD over 3 years.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
1R01DK101720-01
Application #
8672765
Study Section
Special Emphasis Panel (ZRG1-PSE-D (02))
Program Officer
Flessner, Michael Francis
Project Start
2014-04-01
Project End
2017-02-28
Budget Start
2014-04-01
Budget End
2015-02-28
Support Year
1
Fiscal Year
2014
Total Cost
$585,059
Indirect Cost
$83,530
Name
Veterans Medical Research Fdn/San Diego
Department
Type
DUNS #
933863508
City
San Diego
State
CA
Country
United States
Zip Code
92161
Rao, Madhumathi; Steffes, Michael; Bostom, Andrew et al. (2014) Effect of niacin on FGF23 concentration in chronic kidney disease. Am J Nephrol 39:484-90