A Novel Approach to Phosphorus Lowering in Patients with Chronic Kidney Disease

Veterans Medical Research Fdn/San Diego, San Diego CA

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Abstract

DESCRIPTION (provided by applicant): Chronic kidney disease (CKD) is highly prevalent and strongly associated with cardiovascular disease (CVD). Because traditional CVD risk factors do not fully explain the link between CKD and CVD, it is likely that non-traditional risk factors that are altered in CKD may be involved. Among such factors, higher serum phosphorus (Pi) levels represent a causal candidate, and may be modifiable. Higher serum Pi induces arterial calcification, arterial stiffness, and left ventricular hypertrophy in animals. Similar fidings are observed in humans, and higher Pi levels are also associated with the development and progression of CKD, CVD events and mortality in humans. The KDIGO international clinical practice guidelines recommend targeting Pi within the normal range and recommends using oral phosphorus binders (OPBs) to do so. However, since the recommendations were published, studies have consistently shown that OPBs have minimal efficacy for Pi lowering in CKD stage 3-4, even with very high doses and pill burden, and may be associated with harm. In contrast, animal studies and pilot studies in humans show that nicotinamide (vitamin B3) substantially lowers serum Pi levels, and can do so with only 1-2 pills/day. Nicotinamide reduces Pi through a different mechanism. Rather than binding Pi, it blocks intestinal Pi absorption by down-regulating a key intestinal Pi transporter. The lipid drug niacin contains both nicotinamide and nicotinic acid, and we have shown that it lowers Pi in CKD patients. However, nicotinamide alone may have advantages. Unlike niacin, it does not cause flushing, liver test abnormalities, hyperuricemia, or insulin resistance. Nicotinamide has considerable long-term safety data in the general population, is available over the counter as a dietary supplement in the US, and would cost about $2/patient/month. Thus, nicotinamide may provide a readily available, well-tolerated, inexpensive, and convenient method to lower serum Pi levels in patients with CKD. However, the efficacy of nicotinamide for Pi lowering in CKD stage 3-4 is unknown. Moreover, the effects of nicotinamide on other components of mineral metabolism including urine phosphorus excretion and counter- regulatory hormones FGF23, PTH, and calcitriol are unknown. Changes in these factors may have their own influences on CVD, CKD progression, and bone health. Thus, nicotinamide is not yet ready for widespread clinical use in CKD patients. The efficacy for Pi lowering and effects on other components of mineral metabolism must first be established. We propose a phase 2, randomized double blind placebo controlled study among 150 patients with eGFR 20-45ml/min/1.73m2 treated with nicotinamide or placebo for 6 months. Our primary aims are to determine (1) the Pi lowering efficacy, (2) the effects of nicotinamide on other components of mineral metabolism including urine phosphorus excretion and Pi regulatory hormones. If effective and well tolerated, this study will rapidly alter the standard of care by introducing icotinamide for Pi lowering in CKD stage 3-4.