Is There Still a Place for Niacin in the CKD Therapeutic Armamentarium?

In the May issue of AJKD, Streja et al reviewed the use of niacin in the progression of chronic kidney disease (CKD). The review explores the effects of niacin on lipid profile, oxidative stress, inflammation, endothelial function, and serum phosphate; all potential pathogenetic factors in CKD progression.

The lipid profile of patients with CKD is characterized by high levels of triglycerides (TAG) and low and dysfunctional high density lipoprotein concentration (HDL-C) levels. Low TAG and high HDL-C have been associated with CKD progression, but the pathogenic mechanism remains unknown. What is more, drugs that decrease TAG and increased HDL-C, such as fibrates and cholesterylester transfer protein (CETP) inhibitors, have a poor safety profile in CKD or failed in clinical trials of non-CKD patients, respectively. Nevertheless, in an experimental kidney disease model, niacin was shown to slow GFR decline and improve albuminuria. What is more, niacin derivatives have demonstrated some benefits on CKD progression in small clinical trials.

CKD is considered a state of high oxidative stress attributed to high levels of reactive oxygen species. A leukocyte enzyme, myeloperoxidase (MPO), is considered a primary mediator of tissue injury induced by oxygen reactive species in CKD. MPO is elevated in patients and animal models of CKD. A Cochrane analysis reported that antioxidant therapy reduced CKD progression. Niacin has not only been shown to decrease levels of mediators of oxidative stress but also inhibit MPO release from leukocytes, preventing HDL from becoming dysfunctional. This represents a theoretical benefit in CKD.

CKD is also regarded as an inflammatory state characterized by elevated levels of C-reactive protein (CRP), which is a predictor of GFR decline. Niacin has been shown to have anti-inflammatory potential by decreasing the levels of CRP and other inflammatory markers.

Endothelial dysfunction is a proposed mechanism for CKD progression. Elevated levels of asymmetric dimethylarginine (ADMA), which is a natural inhibitor of nitric oxide (NO) by the endothelium, is a reliable marker of endothelial dysfunction. ADMA and von Willebrand factor have been found to be elevated in CKD. Studies show that niacin can decrease ADMA levels by a clinically significant margin.

Hyperphosphatemia not only directly contributes to vascular calcification, but also CKD progression. Niacin is an effective phosphate binder by blocking the NaPi-IIb transporter in the intestine and therefore inhibiting phosphate absorption into the circulation.

In light of the recent 2013 American College of Cardiology/American Heart Association (ACC/AHA) Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults, where treatment targets shifted from LDL-C and non-HDL-C levels to statin intensity, the use of non-statin lipid medications has been relegated. However, it is still unclear whether targeting lipid levels in CKD patient is of any cardiovascular benefit. In the AIM-HIGH trial, a treated group of patients on statin background, niacin increases HDL-C and decreases TAG but did not affect cardiovascular outcomes. The AIM-HIGH trial found however a benefit in a subgroup analysis of patients with TAG ≥ 200 mg/dL and HDL ≤ 32 mg/dL. In the HPS2-THRIVE trial of patients with normal lipid levels on background statin, niacin did not have an effect on cardiovascular outcomes either. In both trials, niacin was associated with a non-specific risk of infection, and bleeding in the HPS2-THRIVE trial.

Based on the above data, the authors are currently exploring the safety of niacin by conducting a retrospective analysis of a VA database with more than 50,000 patients with incident CKD treated with niacin. Using this analysis they propose to soon undertake a randomized control trial of niacin versus placebo on statin background therapy in patients with non-dialysis dependent CKD, TAG levels > 200 mg/dL, and HDL-C levels ≤ 35 mg/dL. In order to identify suitable patients for this study, they are planning to use CRP levels, MPO levels, endothelial dysfunction surrogate marker levels, and dysfunctional HDL and/or reduced HDL particle number, as part of their inclusion criteria.

Given the fact that the current CKD therapeutic armamentarium is limited, we praise the authors’ efforts and hope we will soon have an answer to this question.

Helbert Rondon, MD, FACP, FASN
Assistant Professor of Medicine
Renal-Electrolyte Division
University of Pittsburgh School of Medicine
AJKD Blog Contributor

To view the article abstract or full-text (subscription required), please visit AJKD.org.

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