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Background/aims: Vitamin D insufficiency and secondary hyperparathyroidism (SHPT) are associated with increased morbidity and mortality in chronic kidney disease (CKD) and are poorly addressed by current treatments. The present clinical studies evaluated extended-release (ER) calcifediol, a novel vitamin D prohormone repletion therapy designed to gradually correct low serum total 25-hydroxyvitamin D, improve SHPT control and minimize the induction of CYP24A1 and FGF23., Methods: Two identical multicenter, randomized, double-blind, placebo-controlled studies enrolled subjects from 89 US sites. A total of 429 subjects, balanced between studies, with stage 3 or 4 CKD, SHPT and vitamin D insufficiency were randomized 2:1 to receive oral ER calcifediol (30 or 60 µg) or placebo once daily at bedtime for 26 weeks. Most subjects (354 or 83%) completed dosing, and 298 (69%) entered a subsequent open-label extension study wherein ER calcifediol was administered without interruption for another 26 weeks., Results: ER calcifediol normalized serum total 25-hydroxyvitamin D concentrations (>30 ng/ml) in >95% of per-protocol subjects and reduced plasma intact parathyroid hormone (iPTH) by at least 10% in 72%. The proportion of subjects receiving ER calcifediol who achieved iPTH reductions of ≥30% increased progressively with treatment duration, reaching 22, 40 and 50% at 12, 26 and 52 weeks, respectively. iPTH lowering with ER calcifediol was independent of CKD stage and significantly greater than with placebo. ER calcifediol had inconsequential impact on serum calcium, phosphorus, FGF23 and adverse events., Conclusion: Oral ER calcifediol is safe and effective in treating SHPT and vitamin D insufficiency in CKD., (© 2016 S. Karger AG, Basel.)

Background/aims: Is cholecalciferol (D3) superior to ergocalciferol (D2) in treating nutritional vitamin D deficiency in chronic kidney disease (CKD)? The answer to this question has not been fully explored., Methods: A retrospective analysis of 57 patients with non-dialysis-requiring CKD was conducted to assess the relative effectiveness of D2 versus D3 replacement on circulating 25(OH)D levels. Levels of 25(OH) D were assessed at baseline, after attempted repletion with D2, and then after attempted repletion with D3. The relative paired differences of the drug treatment effects were tested using t-tests. Multiple regression modeling was used to determine the factors significantly associated with differential responsiveness to the drugs., Results: The mean (SEM) age was 66.4 ± 1.4 and mean eGFR was 40.5 ± 2.2 ml/min/1.73 m(2). The baseline 25(OH)D level was 15.3 ± 0.8 ng/ml. After standardizing to 100,000 units of drug, increases after cholecalciferol (2.7 ± 0.3 ng/ml) were more than twice as great as those from ergocalciferol (1.1 ± 0.3 ng/ml) (p < 0.0001). A sensitivity analysis, which pooled the results of an additional 109 individuals treated with ergocalciferol alone, revealed similar findings (standardized change 2.7 ± 0.3 vs. 1.6 ± 0.3 ng/ml, p = 0.0025). Factors associated with a superior response to cholecalciferol were lower baseline 25(OH) D level at the start of therapy (p = 0.015) and the interaction of sex and age (p = 0.0048), with younger females tending to benefit relatively more from cholecalciferol than older males did., Conclusion: Cholecalciferol may be superior to ergocalciferol in treating nutritional vitamin D deficiency in non-dialysis CKD., (© 2015 S. Karger AG, Basel.)

Background: Iron-deficiency anemia in non-dialysis-dependent chronic kidney disease (NDD-CKD) frequently requires parenteral iron replacement, but existing therapies often require multiple administrations. We evaluated the efficacy and cardiovascular safety of ferric carboxymaltose (FCM), a non-dextran parenteral iron permitting large single-dose infusions, versus iron sucrose in patients with iron-deficiency anemia and NDD-CKD., Methods: A total of 2584 participants were randomized to two doses of FCM 750 mg in one week, or iron sucrose 200 mg administered in up to five infusions in 14 days. The primary efficacy endpoint was the mean change to highest hemoglobin from baseline to Day 56. The primary composite safety endpoint included all-cause mortality, nonfatal myocardial infarction, nonfatal stroke, unstable angina, congestive heart failure, arrhythmias and hyper- and hypotensive events., Results: The mean hemoglobin increase was 1.13 g/dL in the FCM group and 0.92 g/dL in the iron sucrose group (95% CI, 0.13-0.28). Similar results were observed across all subgroups, except Stage 2 CKD. More subjects in the FCM group achieved a hemoglobin increase of ≥ 1.0 g/dL between baseline and Day 56 (48.6 versus 41.0%; 95% CI, 3.6-11.6%). There was no significant difference between FCM and iron sucrose recipients with respect to the primary composite safety endpoint, including the major adverse cardiac events of death, myocardial infarction, or stroke. A significant difference in the number of protocol-defined, predominantly transient hypertensive episodes was observed in the FCM group., Conclusions: Two 750-mg infusions of FCM are a safe and effective alternative to multiple lower dose iron sucrose infusions in NDD-CKD patients with iron-deficiency anemia.

Background: Hemodialysis patients are at increased risk of hepatitis B virus (HBV) infection and patients with chronic kidney disease (CKD) are commonly hyporesponsive to HBV vaccines. Current recommendations for CKD patients are to utilize 4 double-doses (2×20 mcg HBsAg) of a licensed hepatitis B vaccine (HBsAg-Eng)., Methods: An observer-blind, randomized, active-controlled, parallel group, multicenter trial was conducted among 521 patients 18-75 years of age with CKD, comparing 3 single doses of an investigational hepatitis B vaccine (20 mcg rHBsAg+3000 mcg 1018, a toll-like receptor 9 agonist) given at 0, 4, and 24 weeks to 4 double-doses of HBsAg-Eng (2×20 mcg rHBsAg+500 mcg alum) given at 0, 4, 8, and 24 weeks (total of 8 injections). Participants were followed for 1 year., Results: Among 467 participants in the modified intent-to-treat population, at the primary endpoint at week 28, the seroprotection rate (SPR: % with anti-HBs≥10mIU/mL) in the HBsAg-1018 group (89.9%) met criteria for noninferiority and superiority to the SPR in the HBsAg-Eng group (81.8%). At week 28, the percentage of participants with anti-HBs≥100mIU/mL in the HBsAg-1018 group (73.6%) was significantly higher than in the HBsAg-Eng group (63.2%). In addition, the geometric mean concentration of anti-HBs in the HBsAg-1018 group (587.1mIU/mL) was significantly higher than in the HBsAg-Eng group (156.5mIU/mL). At weeks 8 and 12 after the first study injection, SPRs in the HBsAg-1018 group were significantly higher than in the HBsAg-Eng group. At 52 weeks, the immune response to HBsAg-1018 remained higher than to HBsAg-Eng. HBsAg-1018 was generally well tolerated and had a similar safety profile to HBsAg-Eng., Conclusion: In CKD patients, 3 doses of HBsAg-1018 induced significantly higher seroprotection, earlier seroprotection, and more durable seroprotection than 4 double doses of HBsAg-Eng., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Aim: Nutritional vitamin D [25(OH)D] deficiency is common in patients with chronic kidney disease (CKD). No studies have specifically examined the differences between ethnic groups in response to ergocalciferol ("D2") therapy., Methods: A retrospective analysis was performed to evaluate the effectiveness of D2 therapy as recommended by the KDOQI guidelines in 184 Hispanic and Caucasian nondialysis CKD patients., Results: Low 25(OH)D levels (<75 nmol/L) were found in 89.4 % of Hispanics versus 61.4 % of Caucasians, despite similar degrees of CKD. Treatment per KDOQI guidelines resulted in 85.5 % of treated Hispanics and 66.7 % of treated Caucasians remaining vitamin D-deficient. Although both Hispanics and Caucasians had significant (P < 0.0001) changes in 25(OH)D levels, absolute changes were modest (12.5 ± 2.0 nmol/mL in Hispanics, 20.0 ± 3.5 nmol/L in Caucasians). The increase seen in Caucasians was significantly greater than in Hispanics (P < 0.0001). In multiple logistic regression modeling, Hispanic ethnicity remained independently associated with poorer response to therapy (P = 0.0055), even after adjustment for other factors., Conclusions: While both Hispanics and Caucasians demonstrated suboptimal response to the KDOQI-guided vitamin D repletion strategy, Hispanic ethnicity was significantly associated with poorer response. Our findings may have implications for other darker-skinned populations, even in solar-rich environments.