Geoffrey A. Block

Introduction and Aims: Etelcalcetide is a novel IV calcimimetic agent shown to significantly decrease circulating parathyroid hormone (PTH) levels in 3, 26-week (wk) phase 3 trials for the treatment of sHPT in uremic subjects with CKD who were receiving HD. This 52-wk, phase 3, multicenter, open-label, single-arm extension study was designed to characterize the long-term safety and efficacy of etelcalcetide.

Background/Aims: Serum phosphate (P) has been linked to adverse events in patients with chronic kidney disease. Salivary phosphate (Psal) has been proposed as a potential target of therapy with a chitosan-containing chewing gum. Methods: We conducted several pilot studies to characterize Psal and its relationship with kidney function and subsequently conducted two clinical efficacy studies: a double-blind placebo-controlled trial in patients with end-stage renal disease (ESRD) and an open-label trial in those with stage 3-4 CKD. Results: Pilot studies demonstrated no relationship between the level of kidney function and Psal. Mean Psal was approximately 6.46 mmol/l across the entire spectrum of kidney function. Passive saliva collection demonstrated higher Psal concentration as compared to active collection. There was no evidence of diurnal variation in Psal. Twice daily 20 mg chitosan gum over 4 weeks reduced serum P by 0.065 mmol/l in the double-blind, placebo-controlled trial in ESRD (p = NS vs. placebo). In an open-label extension in these subjects, 40 mg chitosan gum three times daily reduced serum P by 0.065 mmol/l (p = 0.03 vs. end of washout). In a 2-week open-label trial in patients with CKD not on dialysis, 20 mg chitosan gum given three times daily reduced serum P by 0.05 mmol/l (p = 0.003 vs. day 1). Neither trial demonstrated any significant change in Psal with chitosan gum. Conclusions: Psal concentration is approximately 4-5 times that of serum P and is not related to glomerular filtration rate. Chitosan chewing gum resulted in a reduction of serum P by approximately 0.05-0.065 mmol/l but had no effect on Psal concentration.

Some propose using phosphate binders in the CKD population given the association between higher levels of phosphorus and mortality, but their safety and efficacy in this population are not well understood. Here, we aimed to determine the effects of phosphate binders on parameters of mineral metabolism and vascular calcification among patients with moderate to advanced CKD. We randomly assigned 148 patients with estimated GFR=20–45 ml/min per 1.73 m² to calcium acetate, lanthanum carbonate, sevelamer carbonate, or placebo. The primary endpoint was change in mean serum phosphorus from baseline to the average of months 3, 6, and 9. Serum phosphorus decreased from a baseline mean of 4.2 mg/dl in both active and placebo arms to 3.9 mg/dl with active therapy and 4.1 mg/dl with placebo (P=0.03). Phosphate binders, but not placebo, decreased mean 24-hour urine phosphorus by 22%. Median serum intact parathyroid hormone remained stable with active therapy and increased with placebo (P=0.002). Active therapy did not significantly affect plasma C-terminal fibroblast growth factor 23 levels. Active therapy did, however, significantly increase calcification of the coronary arteries and abdominal aorta (coronary: median increases of 18.1% versus 0.6%, P=0.05; abdominal aorta: median increases of 15.4% versus 3.4%, P=0.03). In conclusion, phosphate binders significantly lower serum and urinary phosphorus and attenuate progression of secondary hyperparathyroidism among patients with CKD who have normal or near-normal levels of serum phosphorus; however, they also promote the progression of vascular calcification. The safety and efficacy of phosphate binders in CKD remain uncertain.

Chronic kidney disease-mineral and bone disorder (CKD-MBD) encompasses a broad spectrum of abnormalities related to bone and cardiovascular health. Many reports related to therapeutic interventions specifically aimed at these disorders describe an effect only on surrogate outcomes. This review will focus on recent literature pertaining to interventions directed at CKD-MBDs that emphasize the clinical outcome of mortality. Higher levels of serum phosphorus (including those within the normal range) and its regulatory hormone, fibroblast growth factor 23 (FGF-23), are associated with increased mortality in patients with all stages of CKD. Reports investigating specific interventions that affect dietary intake of phosphorus, as well as serum levels of phosphorus, FGF-23, calcium, and parathyroid hormone have recently been published which support the hypothesis that abnormal mineral metabolism is directly linked to increased mortality. Unfortunately, with the exception of altered dialysis prescription, no intervention has been subject to the scrutiny of placebo-controlled randomized clinical trials. Observational evidence continues to accumulate relating specific therapeutic interventions to improved survival in patients with kidney disease including phosphate binders, calcimimetics, and altered dietary and dialysis prescription patterns. It is time for randomized clinical trials to definitively establish whether or not interventions directed at CKD-MBD effect improvement in hard clinical outcomes in patients with kidney disease.

Introduction. The risk of death after coronary revascularization is markedly higher for dialysis patients than for the general population and the cause is inadequately explained. We analyzed cause-specific mortality of dialysis patients after coronary revascularization.