Safety concerns with erythropoietin analogues and intravenous (IV) iron for treatment of anemia in CKD necessitate development of safer therapies. Roxadustat (FG-4592) is an orally bioavailable hypoxia-inducible factor (HIF) prolyl hydroxylase inhibitor that promotes coordinated erythropoiesis through HIF-mediated transcription. We performed an open-label, randomized hemoglobin (Hb) correction study in anemic (Hb#10.0 g/dl) patients incident to hemodialysis (HD) or peritoneal dialysis (PD). Sixty patients received no iron, oral iron, or IV iron while treated with roxadustat for 12 weeks. Mean6SD baseline Hb was 8.361.0 g/dl in enrolled patients. Roxadustat at titrated doses increased mean Hb by $2.0 g/dl within 7 weeks regardless of baseline iron repletion status, C-reactive protein level, iron regimen, or dialysis modality. Mean6SEM maximal change in Hb from baseline (DHb max ), the primary endpoint, was 3.160.2 g/dl over 12 weeks in efficacy-evaluable patients (n=55). In groups receiving oral or IV iron, DHb max was similar and larger than in the no-iron group. Hb response (increase in Hb of $1.0 g/dl from baseline) was achieved in 96% of efficacy-evaluable patients. Mean serum hepcidin decreased significantly 4 weeks into study: by 80% in HD patients receiving no iron (n=22), 52% in HD and PD patients receiving oral iron (n=21), and 41% in HD patients receiving IV iron (n=9). In summary, roxadustat was well tolerated and corrected anemia in incident HD and PD patients, regardless of baseline iron repletion status or C-reactive protein level and with oral or IV iron supplementation; it also reduced serum hepcidin levels.

Background and objectives The calcimimetic cinacalcet reduced the risk of death or cardiovascular (CV) events in older, but not younger, patients with moderate to severe secondary hyperparathyroidism (HPT) who were receiving hemodialysis. To determine whether the lower risk in younger patients might be due to lower baseline CV risk and more frequent use of cointerventions that reduce parathyroid hormone (kidney transplantation, parathyroidectomy, and commercial cinacalcet use), this study examined the effects of cinacalcet in older ($65 years, n=1005) and younger (,65 years, n=2878) patients.Design, setting, participants, & measurements Evaluation of Cinacalcet HCl Therapy to Lower Cardiovascular Events (EVOLVE) was a global, multicenter, randomized placebo-controlled trial in 3883 prevalent patients on hemodialysis, whose outcomes included death, major CV events, and development of severe unremitting HPT. The age subgroup analysis was prespecified.Results Older patients had higher baseline prevalence of diabetes mellitus and CV comorbidity. Annualized rates of kidney transplantation and parathyroidectomy were .3-fold higher in younger relative to older patients and were more frequent in patients randomized to placebo. In older patients, the adjusted relative hazard (95% confidence interval) for the primary composite (CV) end point (cinacalcet versus placebo) was 0.70 (0.60 to 0.81); in younger patients, the relative hazard was 0.97 (0.86 to 1.09). Corresponding adjusted relative hazards for mortality were 0.68 (0.51 to 0.81) and 0.99 (0.86 to 1.13). Reduction in the risk of severe unremitting HPT was similar in both groups. ConclusionsIn the EVOLVE trial, cinacalcet decreased the risk of death and of major CV events in older, but not younger, patients with moderate to severe HPT who were receiving hemodialysis. Effect modification by age may be partly explained by differences in underlying CV risk and differential application of cointerventions that reduce parathyroid hormone.

Background and objectives Cinacalcet and vitamin D are often combined to treat secondary hyperparathyroidism (SHPT) in patients on dialysis. Independent effects on fibroblast growth factor-23 (FGF-23) concentrations in patients on hemodialysis administered cinacalcet or vitamin D analogs as monotherapies during treatment of SHPT are evaluated.Design, setting, participants, & measurements A multicenter, randomized, open-label study to compare the efficacy of cinacalcet versus traditional vitamin D therapy for management of secondary hyperparathyroidism among subjects undergoing hemodialysis (PARADIGM) was a prospective, phase 4, multicenter, randomized, open-label study conducted globally. Participants (n=312) were randomized 1:1 to cinacalcet (n=155) or vitamin D analog (n=157) for 52 weeks. Levels of FGF-23 were measured at baseline and weeks 20 and 52. The absolute and percentage changes from baseline in plasma FGF-23, parathyroid hormone (PTH), calcium (Ca), phosphorus (P), and calcium-phosphorus product (Ca3P) were assessed. Correlations and logistic regression were used to explore relationships between changes in FGF-23 and changes in PTH, Ca, P, and Ca3P from baseline to week 52 by treatment arm.Results Median (quartiles 1, 3) decrease in FGF-23 concentrations was observed in the cinacalcet arm (240%; 263%, 16%) compared with median increase in the vitamin D analog arm (47%; 0%, 132%) at week 52 (P,0.001). Changes in FGF-23 in both arms were unrelated to changes in PTH (cinacalcet: r=0.17, P=0.11; vitamin D analog: r=20.04, P=0.70). Changes in FGF-23 in the vitamin D analog but not the cinacalcet arm were correlated with changes in Ca (cinacalcet: r=0.11, P=0.30; vitamin D analog: r=0.32, P,0.01) and P (cinacalcet: r=0.19, P=0.07; vitamin D analog: r=0.49, P,0.001). Changes in FGF-23 were correlated with changes in Ca3P in both arms (cinacalcet: r=0.26, P=0.01; vitamin D analog: r=0.57, P,0.001). Independent of treatment arm, participants with reductions in P or Ca3P were significantly more likely to show reductions in FGF-23.Conclusions During treatment of SHPT, cinacalcet use was associated with a decrease in FGF-23 concentrations, whereas vitamin D analogs were associated with an increase. The divergent effects of these treatments on FGF-23 seem to be independent of modification of PTH. It is possible that effects of cinacalcet and vitamin D analogs on FGF-23 may be mediated indirectly by other effects on bone and mineral metabolism.

Background and objectives Direct comparison of cinacalcet and vitamin D analogs as monotherapies to lower parathyroid hormone (PTH) levels has not been undertaken.Design, setting, participants, & measurements This was a prospective, multicenter, phase 4, randomized, openlabel study that enrolled participants from 2010 to 2012. Adult participants (n=312) on hemodialysis with PTH .450 pg/ml were randomized 1:1 to 12 months of treatment with either cinacalcet (n=155) or vitamin D analogs (n=157) to evaluate the mean percentage change in plasma PTH level (primary end point) and the proportion of participants achieving plasma PTH ,300 pg/ml or a $30% decrease in PTH (secondary end points). A preplanned analysis to determine whether there were important region-by-treatment interactions was also undertaken.Results Baseline mean PTH was 846 pg/ml (n=155) for cinacalcet and 816 pg/ml (n=157) for vitamin D analog therapy. The mean (95% confidence interval) percentage change from baseline in PTH was 212.1% (220.0% to 24.1%) in the cinacalcet arm and 27.0% (214.9% to 0.8%) in the vitamin D analog arm, a difference of 25.0% (215.4% to 5.4%) (P=0.35). Similarly, there was no difference in achievement of secondary efficacy end points between arms (19.4% and 15.3% of participants with PTH#300 pg/ml and 42.6% and 33.8% of participants had a PTH reduction .30% in the cinacalcet and vitamin D analog arms, respectively). A prespecified analysis revealed a large treatment-by-region interaction, with nominally greater response to cinacalcet compared with vitamin D analogs in non-United States participants (US versus non-US participants, P,0.001). Hypocalcemia was more common in the cinacalcet arm, whereas hypercalcemia and hyperphosphatemia occurred more often in the vitamin D analog arm.Conclusions Participants had similar modest reductions in PTH with either cinacalcet or vitamin D analog monotherapy over 52 weeks of treatment, but effects varied by region. Treatments differed with regard to effect on calcium and phosphorus levels.

With the transition to hemodialysis, end-stage renal disease patients presented with distinctive changes in BC. These were mainly associated with gender, older age, presence of diabetes, low baseline FTI, and high baseline LTI. BMI increases did not fully represent the changes in BC.