COMMENTARY

Niacin and Niacinamide for Hyperphosphatemia in Patients Undergoing Dialysis

Steven C. Cheng, MD; Daniel W. Coyne, MD

Disclosures

December 10, 2008

Introduction

Phosphorus is increased in most patients undergoing dialysis, and phosphorus control usually requires dietary restrictions and the use of several phosphate binder pills. Binders must be taken with each meal to create insoluble phosphate complexes, which may cause constipation, and the large pill burden can be both inconvenient and quite expensive. For these reasons, inhibition of intestinal transport of phosphorus has been an appealing alternative. In theory, inhibition of cellular uptake of phosphorus would decrease intestinal absorption and reduce phosphorus accumulation in patients with kidney disease. In vitro studies have shown that niacinamide decreases phosphate uptake, offering the possibility that niacinamide and niacin might be effective agents for phosphorus control.

Recent human clinical trials studies have shown that niacinamide and niacin inhibit intestinal transport of phosphorus and achieve clinically significant reductions in serum phosphate in patients undergoing dialysis. This article reviews the preclinical and clinical trials of these agents, and the potential benefits and risks of using one of these agents in patients undergoing dialysis.

 

Properties and Actions of Niacinamide and Niacin

 

The 2 major forms of vitamin B3 are niacin (or nicotinic acid) and its amide, niacinamide, also known as nicotinamide. Niacin undergoes amidation as the major metabolic pathway, resulting in niacinamide. Niacinamide is a central molecule in nicotinamide adenine dinucleotide and nicotinamide adenine dinucleotide phosphate, and therefore is essential for several crucial metabolic processes. Niacinamide can be converted to niacin through bacterial nicotinamidase, although not through normal human metabolic pathways.[1]

Although niacinamide and niacin are nutritionally equivalent, the 2 forms of vitamin B3 have distinct pharmacologic properties. Niacin has been more extensively studied and has been used since it was first reported to decrease plasma cholesterol in 1955.[2] The major clinical use of niacin has been to increase high-density lipoprotein (HDL) cholesterol and reduce triglyceride levels. Its major side effects are vasodilation and flushing, which appear to be mediated through prostaglandin production, and thus can be attenuated by premedication with aspirin.[3,4] Because niacinamide is not normally converted back to niacin and does not activate G-protein receptors specific for niacin, niacinamide does not cause flushing and has been reported to lack the lipid benefits of niacin in normal individuals.[5,6] However, both agents have dose-related gastrointestinal side effects, including diarrhea and cramping. Niacinamide does possess properties not demonstrated by niacin, such as anxiolysis and inhibition of poly(adenosine diphosphate-ribose) polymerase-1, resulting in anti-inflammatory effects.[7,8,9,10,11] As a result, the potential benefit of niacinamide administration is being studied in a variety of conditions, including diabetes, arthritis, psoriasis, and dementia, as well as hyperphosphatemia in patients undergoing dialysis.[12,13,14,15,16]

In the United States, niacin is available as an over-the-counter food supplement and prescription medication and is usually taken twice daily. A slow-release formulation of niacin (Niaspan®) can be taken once daily. Niacinamide is available only as an over-the-counter food supplement; therefore, the cost is low, although there is no standardization of dose and content.

 

Control of Serum Phosphorus in Dialysis Patients with Niacinamide and Niacin

 

Serum phosphorus in patients with chronic kidney disease is usually controlled by a combination of dietary restriction of phosphorus intake and the use of phosphate binders. These treatments reduce the phosphate available for intestinal absorption, thus reducing serum phosphorus. However, dietary restrictions can be complicated, and patients' understanding of the restrictions and adherence to them varies. Dietary limitations may also compromise nutrition if misapplied. Adherence to use of phosphate binders can also vary because of the number of pills, gastrointestinal side effects, and costs. Patients undergoing dialysis in particular often do not achieve adequate phosphorus control. About 50% of such patients have phosphorus levels > 5.5 mg/dL, and some experts have proposed even more aggressive targets.[17,18,19]

Phosphate is absorbed from the gastrointestinal tract via sodium-dependent and -independent transport pathways. Sodium-dependent phosphorus cotransport in the duodenum and jejunum appears to account for at least 50% of intestinal phosphorus absorption.[20,21] Niacinamide reduces intestinal phosphate absorption by inhibiting the sodium-phosphate 2b transporter in the gastrointestinal tract, although sodium-independent absorptive pathways remain intact.[22,23] As niacin is converted largely to niacinamide, it also inhibits intestinal phosphate absorption. Animal studies have shown that niacinamide prevents an increase in serum phosphate observed in control animals with renal failure by reducing sodium-phosphate 2b transporter expression in the jejunum and inhibiting intestinal phosphorus absorption.[21]

The first clinical trial demonstrating the phosphate-lowering effect of niacinamide in patients undergoing dialysis was by Takahashi and colleagues in Japan.[24] In an open-label design, 65 patients with hyperphosphatemia undergoing hemodialysis had their traditional binder therapy stopped. Patients then started niacinamide at 500 mg/d (as 250 mg twice daily), which was titrated to a maximum dose of 1750 mg/d if tolerated. During the 12-week treatment, phosphorus levels fell 6.9 mg/dL to 5.4 mg/dL (P < .001), intact parathormone decreased from 230 pg/mL to 150 pg/mL (P < .05), while calcium levels did not change.

Our group has performed the only placebo-controlled trials of niacinamide in the dialysis population.[25] We selected patients who were hyperphosphatemic despite binder therapy, and continued binders at that fixed dose during 2 trials. In a randomized, double-blind, placebo-controlled crossover trial, 33 patients undergoing hemodialysis who had serum phosphorus levels > 5.0 mg/dL despite binder therapy were randomly assigned to placebo or niacinamide for 8 weeks. Concurrent binder therapy, vitamin D analogues, and calcimimetics were continued without any dosing adjustments during the study. Niacinamide and placebo were packaged in identical 250-mg capsules, and dosages were titrated from 500 mg/d (taken as 1 capsule twice a day) to 1500 mg/d (3 capsules twice a day) over 4 weeks. After 8 weeks, patients underwent a 2-week washout period, followed by 8 weeks of the alternative therapy (from niacinamide to placebo, and vice versa). Niacinamide treatment decreased serum phosphorus from 6.26 to 5.47 mg/dL (P = .02), and no significant changes occurred in the placebo group. Among patients who demonstrated more than 80% adherence based on routine pill counts, the fall in serum phosphorus was more pronounced, decreasing from 6.45 to 5.28 mg/dL (P = .002). Two patients developed diarrhea during niacinamide therapy, and 1 required a decrease in niacinamide dosage to alleviate symptoms. Patients receiving niacinamide also showed a trend toward lower platelet counts, with a mean reduction in platelet counts of 17,000 cells/mm3 (P = .07); no patients developed bleeding complications.

In our second double-blind trial, we randomly assigned hyperphosphatemic patients undergoing peritoneal dialysis to placebo or niacinamide treatment for 8 weeks, titrating the dose as we did in the hemodialysis trial.[26] Fifteen patients undergoing peritoneal dialysis were randomly assigned to placebo or niacinamide. In both groups, dosages were titrated from 500 mg/d to 1500 mg/d over the 8-week study period. Phosphorus levels decreased 10.9% in the niacinamide group, and there was a small (1.1 mg/dL) but statistically significant difference between treatment groups (P = .037).

Only 1 study has examined the effect of niacin on phosphorus levels in the dialysis population.[27] Twenty patients were enrolled in a nonrandomized trial using Niaspan®, a long-acting preparation of niacin. After a 2-week washout period from existing phosphorus binders, all patients began receiving Niaspan® at 375 mg/d, with titration up to a maximum dosage of 2000 mg/d over the 12-week study period. In the 17 patients who could tolerate the minimal dosage of 1000 mg/d, serum phosphorus levels decreased from 7.2 to 5.9 mg/dL (P < .015) while serum calcium and parathormone levels remained stable. Of note, 3 patients could not tolerate the minimal Niaspan® dosage, and 6, who were included in the analysis, stopped prematurely at 6 to 10 weeks. These patients cited flushing, weight loss, and intradialytic hypotension as causes for withdrawal.

 

Effect of Niacin and Niacinamide on Lipids in Dialysis Patients

 

For many years it has been thought that niacin, but not niacinamide, raises HDL cholesterol and reduces triglyceride levels. Recent studies of niacinamide in patients undergoing dialysis have challenged this viewpoint, however.

The first trial by Takahashi and colleagues found that niacinamide treatment increased HDL levels from 47 to 67 mg/dL (P < .001), whereas low-density lipoprotein (LDL) levels fell from 79 to 70 mg/dL (P < .01) over 12 weeks.[24] A placebo-controlled trial in patients undergoing hemodialysis showed that niacinamide, but not placebo, increased HDL levels from 40 to 51 mg/dL (P = .04).[25] LDL levels decreased, but the changes were not statistically significant.

In the trial with niaspan, Muller and colleagues found that HDL levels rose from 40 to 59 mg/dL, while LDL levels trended slightly downward.[27] In comparison, a meta-analysis of the effect of niacin in patients without chronic kidney disease showed that treatment with niacin is associated with a 6.7-mg/dL increase (16%) in HDL levels.[28]

 

Recommendations

 

On the basis of the available data, niacinamide and niacin decrease serum phosphorus, significantly raise HDL, and moderately reduce LDL levels in patients undergoing dialysis. Compared with phosphorus binders, both niacinamide and niacin have the advantage of being dosed once or twice each day and do not need to be taken with meals. There are insufficient long-term safety and efficacy data on niacinamide to supplant dietary phosphorus restrictions and phosphate-binding agents as first-line therapy. At this point, niacinamide should be considered adjunctive therapy for patients who have hyperphosphatemia despite management or who cannot tolerate phosphorus binders. Niacin, which is already FDA approved for lipid disorders, can be used in patients undergoing dialysis who have low HDL levels and may be particularly beneficial for those with coexisting hyperphosphatemia. More research is clearly needed.

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