Efficacy and safety of nicotinamide in haemodialysis patients: the NICOREN study.

BACKGROUND: Nicotinamide (NAM) has been proposed as an alternative treatment to phosphate binders for hyperphosphataemia in chronic kidney disease. METHODS: The NICOREN multicentre, open-label and randomized study was designed to examine non-inferiority and safety of NAM when compared with sevelamer (SEV) in chronic haemodialysis patients. One hundred patients were randomized to either NAM or SEV treatment for 24 weeks. Serum biochemistry and NAM's main metabolite, N -methyl-2-pyridone-5-carboxamide (2PY), were measured to assess compliance, efficacy and safety. RESULTS: After 24 weeks, we observed a comparable decrease in serum phosphorus in the NAM and SEV treatment arms, from 2.1 ± 0.4 to 1.8 ± 0.5 and 2.3 ± 0.5 to 1.7 ± 0.5 mM (P = not significant), respectively. The criterion for non-inferiority was, however, not met due to a more limited number of patients being included than planned. Treatment discontinuation due to adverse events was 1.6 times higher in the NAM than in the SEV group with only 55% of study completers in the NAM arm versus 90% in the SEV arm. Thrombocytopenia was observed in four NAM-treated patients. Serum 2PY levels were comparable at baseline, but increased markedly in the NAM group, but not in the SEV group, at 24 weeks (P < 0.0001). CONCLUSIONS: Thus, both drugs are equally effective in lowering serum phosphorus, but patients' tolerance of NAM was largely inferior to that of SEV. Extremely high 2PY levels may contribute to NAM's side effects.

How do calcimimetics fit into the management of parathyroid hormone, calcium, and phosphate disturbances in dialysis patients?

As suggested by its American brand name (Sensipar), the calcimimetic cinacalcet sensitizes the parathyroid cells to the extracellular calcium signal, suppressing parathyroid hormone (PTH) release and synthesis and preventing parathyroid cell proliferation. This primary PTH suppression decreases the release of calcium and phosphate from bone without increasing intestinal absorption of calcium and phosphate. Therefore cinacalcet decreases the risk of hypercalcemia and hyperphosphatemia in contrast to 1alpha-OH vitamin D derivatives. Compared with calcium-containing oral phosphate binder (OPB), it increases the risk of hypocalcemia and may decrease the PTH-mediated phosphaturia in predialysis patients. This justifies its combined use with calcium-containing OPB in order to prevent hypocalcemia and enhance the hypophosphatemic effect of the latter, while improving PTH suppression. The National Kidney Foundation (NKF) Kidney Disease Outcomes Quality Initiative (K/DOQI) has recommended restriction of supplemental elemental calcium to 1.5 g/day, a recommendation that we believe should be revised. No pathophysiologic or randomized trial data have yet evidenced the absolute necessity for systematically using 1alpha-OH vitamin D derivatives and noncalcium-containing OPB rather than higher doses of calcium-containing OPB alone in uremic patients without vitamin D insufficiency. In patients with hyperparathyroidism as severe as in the "Treat to Goal Study," the Durham study showed that a calcium carbonate dose more than three times the K/DOQI limit could decrease PTH into the recommended range, with the advantage of a lower calcium-phosphate product compared with the combination of calcitriol and noncalcium OPB. Besides the efficient PTH suppression associated with lower calcium-phosphate product and a good gastrointestinal tolerance, long-term data suggest that cinacalcet may decrease the risk of parathyroidectomy and fracture, while high bone turnover lesions are improved. However, no long-term data on bone mineral density and cardiovascular calcification and complications are yet available. Such studies, along with those comparing cinacalcet and 1alpha-OH vitamin D-based approaches to hyperparathyroidism, are needed.

Cinacalcet for secondary hyperparathyroidism in patients receiving hemodialysis.

BACKGROUND: Treatment of secondary hyperparathyroidism with vitamin D and calcium in patients receiving dialysis is often complicated by hypercalcemia and hyperphosphatemia, which may contribute to cardiovascular disease and adverse clinical outcomes. Calcimimetics target the calcium-sensing receptor and lower parathyroid hormone levels without increasing calcium and phosphorus levels. We report the results of two identical randomized, double-blind, placebo-controlled trials evaluating the safety and effectiveness of the calcimimetic agent cinacalcet hydrochloride. METHODS: Patients who were receiving hemodialysis and who had inadequately controlled secondary hyperparathyroidism despite standard treatment were randomly assigned to receive cinacalcet (371 patients) or placebo (370 patients) for 26 weeks. Once-daily doses were increased from 30 mg to 180 mg to achieve intact parathyroid hormone levels of 250 pg per milliliter or less. The primary end point was the percentage of patients with values in this range during a 14-week efficacy-assessment phase. RESULTS: Forty-three percent of the cinacalcet group reached the primary end point, as compared with 5 percent of the placebo group (P<0.001). Overall, mean parathyroid hormone values decreased 43 percent in those receiving cinacalcet but increased 9 percent in the placebo group (P<0.001). The serum calcium-phosphorus product declined by 15 percent in the cinacalcet group and remained unchanged in the placebo group (P<0.001). Cinacalcet effectively reduced parathyroid hormone levels independently of disease severity or changes in vitamin D sterol dose. CONCLUSIONS: Cinacalcet lowers parathyroid hormone levels and improves calcium-phosphorus homeostasis in patients receiving hemodialysis who have uncontrolled secondary hyperparathyroidism.

Sevelamer hydrochloride with or without alphacalcidol or higher dialysate calcium vs calcium carbonate in dialysis patients: an open-label, randomized study.

BACKGROUND: Sevelamer hydrochloride was recently proposed as a phosphate binder to prevent hypercalcaemia in place of calcium alkaline salts in dialysis patients. So far, it has been evaluated only in patients receiving calcitriol, without comparison with CaCO(3) alone, although the latter was found to be as effective as the combination of calcitriol and Al(OH)(3) in suppressing parathyroid hormone (PTH) without inducing hypercalcaemia and to have a better lowering effect on serum phosphate. Moreover, this bile salt binder may decrease serum 25-OH vitamin D. Therefore, we compared for 5 months two strategies for controlling moderate hyperparathyroidism: CaCO(3) alone vs sevelamer in conjunction with measures to increase calcium balance. METHODS: Forty-two patients were randomized: 21 continued their treatment with 4.8 g/day CaCO(3) and 21 were switched to sevelamer (initial dose: 2.4 g/day, increased to 4.4 g/day). Each month, when serum-corrected calcium decreased below 2.30 mmol/l, dialysate calcium was increased or alphacalcidol was given at each dialysis session, according to serum PO(4) levels. The following parameters were monitored: serum Ca, PO(4), bicarbonate and protein, weekly; and serum PTH, 25-OH vitamin D and total, LDL and HDL cholesterol monthly. RESULTS: Except for higher serum phosphate at month 1, lower serum bicarbonate at month 2 and lower LDL cholesterol at month 5 in the sevelamer group, no difference was found between the two groups. Compared with baseline levels, PTH increased and 25-OH vitamin D decreased significantly in both groups, these two parameters being inversely correlated. CONCLUSIONS: Given comparable control of plasma calcium, phosphate and 25-OH vitamin D, PTH control is comparable in both strategies. Sevelamer does not induce greater vitamin D depletion than CaCO(3). The transient decrease of serum bicarbonate after discontinuation of CaCO(3) in the sevelamer group suggests a less optimal prevention of acidosis. The sevelamer-induced decrease in LDL cholesterol gives this drug a potential advantage in cardiovascular prevention.