Etelcalcetide: injectable calcimimetic for the treatment of secondary hyperparathyroidism in hemodialysis-dependent patients.

Chronic kidney disease is associated with mineral and bone disorders that are now considered as a syndrome. One of the major complications of this syndrome is secondary hyperparathyroidism (SHPT). SHPT increases bone turnover and the risk of fracture. SHPT is also associated with cardiovascular calcification and high mortality risk. The classical medical therapies of SHPT lack long-term efficacy and have undesirable effects on serum calcium and phosphate levels. Surgical parathyroidectomy is a radical therapeutic solution potentially exposing patients to a permanent state of hypoparathyroidism among other complications. Oral cinacalcet revolutionized the treatment of SHPT because of its great efficacy; however, more than one-third of patients do not respond appropriately to cinacalcet, mostly because of intolerance and lack of compliance. Intravenous etelcalcetide improves medical adherence and reduces pill burden. It is 10-15% superior than cinacalcet in controlling parathyroid hormone, but also leads to more frequent episodes of hypocalcemia.

Integral pharmacological management of bone mineral disorders in chronic kidney disease (part I): from treatment of phosphate imbalance to control of PTH and prevention of progression of cardiovascular calcification.

INTRODUCTION: Chronic kidney disease-mineral and bone disorders (CKD-MBD), involving a triad of laboratory and bone abnormalities, and tissue calcifications, are associated with dismal hard-outcomes. AREAS COVERED: In two comprehensive articles, we review contemporary and future pharmacological options for treatment of phosphate (P) imbalance (this part 1) and hyperparathyroidism (part 2), taking into account CKD-accelerated atheromatosis/atherosclerosis and/or cardiovascular calcification (CVC) processes. EXPERT OPINION: Improvements in CKD-MBD require an integral approach, addressing all three components of the CKD-MBD triad. Individualization of treatment with P-binders and combinations of anti-parathyroid agents may improve biochemical control with lower incidence of undesirable effects. Isolated biochemical parameters do not accurately reflect calcium or P load or bone activity and do not stratify high cardiovascular risk patients with CKD. Initial guidance is provided on reasonable therapeutic strategies which consider the presence of CVC. This part reflects that although there is not an absolute evidence, many studies point to the need to improve P imbalance while trying to, at least, avoid progression of CVC by restriction of Ca-based P-binders if economically feasible. The availability of new drugs (i.e. inhibitors of intestinal transporters), and studies including early CKD should ultimately lead to clearer and more cost/effective clinical targets for CKD-MBD.

Integral pharmacological management of bone mineral disorders in chronic kidney disease (part II): from treatment of phosphate imbalance to control of PTH and prevention of progression of cardiovascular calcification.

INTRODUCTION: Chronic kidney disease-mineral and bone disorders (CKD-MBD) are associated with costly complications and dismal hard-outcomes. AREAS COVERED: In two comprehensive articles we review contemporary and future pharmacological options for treatment of phosphate (P) imbalance (part 1) and hyperparathyroidism (this part 2), taking into account CKD-accelerated cardiovascular calcification (CVC) processes. EXPERT OPINION: Improvements in CKD-MBD require an integral approach, addressing all three components of the CKD-MBD triad. Here, initial guidance to control hyperparathyroidism is provided, taking into account the presence/absence of CVC. We include also measures for patients at risk of adynamic bone disease or suffering from calciphylaxis. Many epidemiological studies (relating to vitamin D) and thorough analyses of recent randomized clinical trials (of cinacalcet) point towards benefits of attempting to improve biochemical parameters while trying to, at least, avoid progression of CVC by more rational use of intestinal P-binders and low-dose vitamin D derivatives and/or calcimimetics. This approach does not seem to be far away from significantly improving hard-outcomes, at least in the dialysis population. The availability of new drugs and the performance of randomized clinical trials should ultimately lead to define earlier, clearer, and more cost-effective patient stratification and biochemical targets with consequent significant clinical improvements.

[Incidence and characteristics of calciphylaxis in Martinique (2006-2012)]. / Incidence et caractéristiques de la calciphylaxie en Martinique (2006-2012).

BACKGROUND: Calciphylaxis is a rare and severe disease with an annual incidence of around 1 % in dialysis patients. The main study aim was to determine its incidence in Martinique, where there is a significant population of patients on dialysis. PATIENTS AND METHODS: All patients diagnosed with calciphylaxis between 2006 and 2012 and living in Martinique were included, retrospectively. Social, demographic, biological, anatomic, pathological, histological and outcome data were analysed. RESULTS: Fifteen patients were included (8 women, 7 men). The incidence of calciphylaxis in this population was about 4.62/1,000,000 inhabitants per year. All patients presented very painful skin ulcerations and necrosis, chiefly on the lower extremities in 53.3 % of cases. All patients were on haemodialysis and two had undergone renal transplantation. Fourteen of the 15 patients were presenting secondary hyperparathyroidism, 12 had hypertension, 9 peripheral arterial disease, 8 obesity and 8 diabetes mellitus. Raised calcium and phosphorus were noted in 8 patients, with hypoalbuminaemia in 9 patients. Treatment with sodium thiosulfate was given for 8 patients, and was beneficial for all after a mean duration of 3.4 months. After 6 months of follow-up, 8 of the 15 patients were cured, 1 showed improvement and 6 had died. CONCLUSION: To our knowledge, this is the first study to examine the incidence of calciphylaxis in the general population. The relatively large number of patients could be accounted for by the high number of comorbidities in end-stage renal disease patients in Martinique, including obesity, diabetes, hypertension and arteritis. Treatment with sodium thiosulfate was beneficial for 8 patients.

Calcium-mediated parathyroid hormone suppression to assess progression of secondary hyperparathyroidism during treatment among incident dialysis patients.

CONTEXT: Parathyroid gland function is affected adversely by tissue hyperplasia and gland enlargement in hyperparathyroidism. OBJECTIVE: We examined the effects of 2 treatment strategies on the progression of secondary hyperparathyroidism using measurements of the nonsuppressible component of calcium-regulated PTH secretion as an index of parathyroid mass. DESIGN, SUBJECTS, AND INTERVENTION: In this randomized, open-label study, subjects managed with hemodialysis for >3 but <12 months before entering the trial (mean, 7.2 months) who had baseline plasma PTH levels >300 pg/mL received cinacalcet and low-dose vitamin D sterols (Cin-D, n = 153) or larger, varying doses of calcitriol, or other vitamin D analogs (Flex-D, n = 151). Study drug doses were adjusted periodically based on PTH and serum total calcium determinations. MAIN OUTCOME MEASURES: The exploratory endpoint was calcium-regulated PTH release, assessed using a standardized PTH suppression test before and after 52 weeks of treatment and 4 weeks after withdrawing treatment. PTH and serum total calcium were measured before hemodialysis using high-calcium (3.5 mEq/L or 1.75 mmol/L) dialysate and after 150 and 180 minutes. RESULTS: Mean (95% confidence interval) nonsuppressible calcium-regulated PTH release at baseline did not differ between Cin-D, 33.4% (25.9%, 40.9%), and Flex-D, 28.1% (23.2%, 32.9%). Corresponding values after 52 weeks of treatment were 34.3% (29.7%, 38.9%) and 42.0% (32.7%, 51.3%), not significant, and did not change measurably in either group when reevaluated 4 weeks after treatments were withdrawn. CONCLUSION: Disease progression over 12 months was not documented using a PTH suppression test in this population. Calcium-mediated PTH suppression was maintained fully, however, in Cin-D despite reductions in serum total calcium concentration, whereas values did not increase in Flex-D despite substantial increases in serum calcium.

Bone mass does not correlate with the serum fibroblast growth factor 23 in hemodialysis patients.

Circulating fibroblast growth factor 23 (FGF23) increases renal phosphate excretion, decreases bone mineralization and is markedly increased in hemodialysis patients. Bone cells express fibroblast growth receptor 1, suggesting that FGF23 could alter bone mineralization by means of a direct effect on the skeleton and/or secondarily due to hypophosphatemia. To distinguish between these possibilities we measured serum concentrations of FGF23, parathyroid hormone, phosphate, calcium, and markers of bone remodeling, and assessed bone mineral density in 99 hemodialysis patients. FGF23 concentrations were increased in all hemodialysis patients, even in those without hyperphosphatemia, and positively correlated with serum phosphate but not with parathyroid hormone. Hemodialysis did not decrease the serum FGF23 concentration. We found no significant correlation between serum FGF23 levels and bone mineral density. Further analysis by gender or T-score did not modify these results. Serum markers of bone remodeling significantly correlated with parathyroid hormone but not with FGF23 levels. The increase in serum FGF23 concentration in hemodialysis patients cannot be solely ascribed to hyperphosphatemia. Our study suggests that the effects of FGF23 on bone mineralization are mainly due to hypophosphatemia and not a direct effect on bone.