Comparative Effects of Etelcalcetide and Maxacalcitol on Serum Calcification Propensity in Secondary Hyperparathyroidism: A Randomized Clinical Trial.

BACKGROUND AND OBJECTIVES: Vitamin D receptor activators and calcimimetics (calcium-sensing receptor agonists) are two major options for medical treatment of secondary hyperparathyroidism. A higher serum calcification propensity (a shorter T50 value) is a novel surrogate marker of calcification stress and mortality in patients with CKD. We tested a hypothesis that a calcimimetic agent etelcalcetide is more effective in increasing T50 value than a vitamin D receptor activator maxacalcitol. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: A randomized, multicenter, open-label, blinded end point trial with active control was conducted in patients with secondary hyperparathyroidism undergoing hemodialysis in Japan. Patients were randomly assigned to receive intravenous etelcalcetide 5 mg thrice weekly (etelcalcetide group) or intravenous maxacalcitol 5 or 10 µg thrice weekly (maxacalcitol group). The primary, secondary, and tertiary outcomes were changes in T50 value, handgrip strength, and score of the Dementia Assessment Sheet for Community-Based Integrated Care System from baseline to 12 months, respectively. RESULTS: In total, 425 patients from 23 dialysis centers were screened for eligibility, 326 patients were randomized (etelcalcetide, n=167; control, n=159), and 321 were included in the intention-to-treat analysis (median age, 66 years; 113 women [35%]). The median (interquartile range) of T50 value was changed from 116 minutes (interquartile range, 90-151) to 131 minutes (interquartile range, 102-176) in the maxacalcitol group, whereas it was changed from 123 minutes (interquartile range, 98-174) to 166 minutes (interquartile range, 127-218) in the etelcalcetide group. The increase in T50 value was significantly greater in the etelcalcetide group (difference in change, 20 minutes; 95% confidence interval, 7 to 34 minutes; P=0.004). No significant between-group difference was found in the change in handgrip strength or in the Dementia Assessment Sheet for Community-Based Integrated Care System score. CONCLUSIONS: Etelcalcetide was more effective in increasing T50 value than maxacalcitol among patients on hemodialysis with secondary hyperparathyroidism. There was no difference in handgrip strength or cognition between the two drugs. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: VICTORY; UMIN000030636 and jRCTs051180156.

Effect of cholecalciferol on serum hepcidin and parameters of anaemia and CKD-MBD among haemodialysis patients: a randomized clinical trial.

In this multicentre double-blind randomized clinical trial, we investigated the effects of oral cholecalciferol supplementation on serum hepcidin and parameters related to anaemia and CKD-MBD among haemodialysis patients. Participants were assigned in a 2:2:1:1 ratio to either (1) thrice-weekly 3,000-IU cholecalciferol, (2) once-monthly cholecalciferol (equivalent to 9,000 IU/week), (3) thrice-weekly placebo, or (4) once-monthly placebo. We also examined the effect modifications by selected single nucleotide polymorphisms in vitamin D-related genes. Out of 96 participants, 94 were available at Month 3, and 88 completed the 6-month study. After adjustment for baseline values, serum hepcidin levels were higher at Day 3 in the combined cholecalciferol (vs. placebo) group, but were lower at Month 6 with increased erythropoietin resistance. Cholecalciferol increased serum 1,25(OH)2D levels, resulting in a greater proportion of patients who reduced the dose of active vitamin D at Month 6 (31% vs. 10% in the placebo group). Cholecalciferol also suppressed intact PTH only among patients with severe vitamin D deficiency. In conclusion, cholecalciferol supplementation increases serum hepcidin-25 levels in the short term and may increase erythropoietin resistance in the long term among haemodialysis patients. Both thrice-weekly and once-monthly supplementation effectively increases serum 1,25(OH)2D levels, and hence, reduces active vitamin D drugs.Clinical Trial Registry: This study was registered at ClinicalTrials.gov and University Hospital Medical Information Network Clinical Trials Registry (UMIN-CTR) as NCT02214563 (registration date: 12/08/2014) and UMIN000011786 (registration date: 15/08/2014), respectively (please refer to the links below). ClinicalTrials.gov: https://clinicaltrials.gov/ct2/show/record/NCT02214563 . UMIN-CTR: https://upload.umin.ac.jp/cgi-open-bin/ctr/ctr.cgi?function=brows&action=brows&type=summary&recptno=R000017152&language=E .

Anion Gap as a Determinant of Ionized Fraction of Divalent Cations in Hemodialysis Patients.

BACKGROUND AND OBJECTIVES: Circulating levels of anions that bind to magnesium and calcium are often altered in patients with CKD. However, it is unknown how these alterations affect the ionized fraction of magnesium and calcium. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This cross-sectional study involved patients on maintenance hemodialysis and patients not on dialysis who visited the outpatient department of nephrology. We collected whole-blood samples to measure ionized magnesium and calcium concentrations. Adjusted anion gap was calculated as an integrative index of unmeasured anions. RESULTS: A total of 118 patients on hemodialysis and 112 patients not on dialysis were included. Although the prevalence of hypermagnesemia defined by total magnesium was much higher in patients on hemodialysis than in patients not on dialysis (69% versus 12%; P<0.001), the prevalence of hypermagnesemia defined by ionized magnesium did not differ significantly (13% versus 18%; P=0.28). Among patients on hemodialysis with high total magnesium, 83% had normal or low ionized magnesium. Consequently, the mean ionized fraction of magnesium in patients on hemodialysis was significantly lower than that in patients not on dialysis (51% versus 63%; P<0.001). Similarly, the mean ionized fraction of calcium in patients on hemodialysis was lower than that in patients not on dialysis (55% versus 56%; P<0.001). In patients on hemodialysis who had a higher adjusted anion gap than patients not on dialysis (mean [SD]: 14.1 [2.2] versus 5.1 [3.1]), the ionized fractions of magnesium and calcium were inversely associated with the adjusted anion gap. Furthermore, the anion gap significantly improved predictions of ionized magnesium and calcium in patients on hemodialysis. CONCLUSIONS: Anions that accumulate in patients on hemodialysis contribute to the lower ionized fraction of magnesium and calcium. Equations that incorporate the anion gap provide better predictions of ionized magnesium and calcium in patients on hemodialysis.

Intravenous Vitamin B6 Increases Resistance to Erythropoiesis-Stimulating Agents in Hemodialysis Patients: A Randomized Controlled Trial.

OBJECTIVE: Vitamin B6 deficiency is common in hemodialysis patients and may contribute to anemia and abnormal bone metabolism in this population. DESIGN: 6-month, open-label, randomized controlled parallel-group study in hemodialysis centers. SUBJECTS: Fifty-six maintenance hemodialysis patients with relatively high resistance to erythropoiesis-stimulating agents (ESA). INTERVENTION: Intravenous vitamin B6 (60 mg of intravenous pyridoxal 5'-phosphate after each thrice-weekly hemodialysis session). MAIN OUTCOME MEASURE: The primary and secondary outcomes were changes over time in ESA resistance index and bone turnover markers, respectively. RESULTS: The prevalence of vitamin B6 deficiency was 40% overall. Compared with the control group, the B6 group showed an upward change in ESA resistance index over time (Pinteraction = .038). At week 13 (a priori-defined time point), pyridoxal 5'-phosphate administration was associated with higher ESA resistance index by 0.97 (95% confidence interval, 0.02-1.92) ×10-2 µg ⋅darbepoetin-α/kg per g/dL⋅hemoglobin after baseline adjustment, which was not modified by baseline vitamin B6 status. There was a trend toward increase in serum erythropoietin concentrations in the B6 group after adjustment for baseline values, hemoglobin, and weekly ESA dose (Pinteraction = .06). The downward changes of bone-specific alkaline phosphatase and tartrate-resistant acid phosphatase 5b in the B6 group relative to the control group were pronounced in patients without vitamin B6 deficiency (Pinteraction < .001 and .017, respectively), despite nonsignificant between-group difference in 1-84 parathyroid hormone. CONCLUSIONS: Thrice-weekly intravenous vitamin B6 (60 mg pyridoxal 5'-phosphate hydrate) worsens the response to ESA and may blunt the response of bone to parathyroid hormone in hemodialysis patients.

[Low dose estrogen replacement therapy (ERT) for postmenopausal hemodialysis (HD) patients].

We studied the short-time effects of low dose estradiol (E2) on bone metabolism in hemodialysis (HD) patients. We prescribed transdermal E2 (0.36 mg every other day) to 17 non-diabetic postmenopausal osteoporotic HD patients and measured intact parathyroid hormone (iPTH), serum NTX (sNTX), intact osteocalcin (iOC), and bone resorptive cytokines including IL-6 and TNF-alpha. Serum E2 increased from 20 to approximately 40 pg/mL, which is comparable to that of male HD patients. Three-month treatment decreased serum calcium by 0.7 mg/dL followed by a significant elevation of iPTH and iOC. Despite the increase of iPTH, collagen breakdown product, sNTX did not change significantly, implying decreased skeletal sensitivity to PTH resorbing effect. IL-6 and TNF-alpha decreased, but this trend was not statistically significant. Bone pain and/or pain from carpal tunnel syndrome resolved by ERT. We needed to dose-up active vitamin D to control enhanced iPTH. Our data suggests that E2 attenuates the resorbing effect of PTH and stimulates bone formation, also in HD patients.