Use of nicotinamide to treat hyperphosphatemia in dialysis patients

Abstract

Hyperphosphatemia in chronic kidney disease (CKD) has been associated with elevated cardiovascular morbidity and mortality. Serum phosphate control remains a cornerstone of the clinical management of patients with CKD, in order to both attenuate the progression of secondary hyperparathyroidism or bone disease and (possibly) reduce the risk of vascular calcification. Despite technical improvements in dialysis and the use of dietary restrictions, drug therapy is often required to control phosphate levels in patients with end-stage renal disease (ESRD). Currently available medications for hyperphosphatemia in ESRD are very expensive and not always well tolerated. The discovery and development of new drugs in this indication is therefore a priority for both medical and health-economic reasons. Nicotinamide (an amide derivative of the water-soluble vitamin B3) is a potentially interesting alternative to phosphate binders. In vitro and in vivo data show that nicotinamide reduces hyperphosphatemia by inhibiting sodium-dependent phosphate co-transport in the renal proximal tubule and in the intestine. Accordingly, targeting the sodium-dependent phosphate co-transporter 2b by using nicotinamide as an alternative or adjunct to classical phosphate binders may be a therapeutic option for modulating serum phosphate in CKD. Several recent clinical studies have explored the potential value of nicotinamide in phosphate control (as well as its effects on lipid levels) in dialysis patients. However, we consider that more data on pharmacodynamics, pharmacokinetics and safety are needed before this compound can be recommended as a treatment for hyperphosphatemia in ESRD patients.

Fig. 1

Nicotinamide’s mechanism of action at the brush border membrane of the enterocyte in the intestine. ADP adenosine diphosphate, ATP adenosine triphosphate

Fig. 2

Schematic description of nicotinamide metabolism. In summary, nicotinamide is metabolized to N-methylnicotinamide (MNA) by nicotinamide-N-methyltransferase, and MNA is further metabolized to N-methyl-2-pyridone-5-carboxamide (2PY) or N-methyl-4-pyridone-5-carboxamide (4PY) by aldehyde oxidase (for more details, please refer to the body of the text). 6HN 6 hydroxynicotinamide, ADP adenosine diphosphate, NA nicotinic acid, NAAD nicotinic acid adenine dinucleotide, NAD nicotinamide adenine dinucleotide, NAMN nicotinamide acid mononucleotide, NMN nicotinamide mononucleotide, NNO nicotinamide N oxide. Enzymes: 1 nicotinamide-N-methyltransferase, 2 aldehyde oxidase, 3–5 nicotinamide deamidase, 6 nicotinamide phosphoribosyltransferase, 7 NAMN adenylyltransferase, 8 nicotinamide synthetase, 9 poly(ADP-ribose) synthetase, 10 nicotinamide glycohydrolase, 11 nicotinamide phosphoribosyltransferase

Fig. 3

Nicotinamide metabolites as inhibitors of poly(ADP-ribose) [pADPr] polymerase 1 (PARP-1). Nicotinamide derivatives such as N-methyl-2-pyridone-5-carboxamide (2PY) and N-methyl-4-pyridone-5-carboxamide (4PY) may disturb cellular repair processes via inhibition of PARP-1 activity. PARP-1 catalyzes the formation of adenosine diphosphate (ADP)-ribose polymers on a variety of protein acceptors in a nicotinamide adenine dinucleotide (NAD+-dependent manner. The enzyme plays a key role in DNA damage repair in general and base excision repair in particular. Over-activation of PARP1 leads to a depletion of NAD+/adenosine triphosphate (ATP) energy stores and, ultimately, to necrotic cell death