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Vitamin D Analogues and Coronary Calcification in CKD Stages 3 and 4: A Randomized Controlled Trial of Calcitriol Versus Paricalcitol.

ABSTRACT: Rationale & Objective:Mineral and bone disorder in chronic kidney disease (CKD) is associated with progression of coronary artery calcification (CAC). Mineral and bone disorder often is treated with calcitriol and other vitamin D receptor activators, including paricalcitol, agents that may have differential effects on calcium, phosphate, and parathyroid hormone levels. Accordingly, we investigated whether these agents have differential effects on CAC progression in patients with CKD. Study Design:Randomized, double-concealed, 48-week clinical trial. Setting & Participants:CKD stage 3 or 4 with secondary hyperparathyroidism with CAC score > 0 and no prior treatment with activated vitamin D. Intervention:Calcitriol versus paricalcitol. Outcomes:The primary outcome was log-transformed CAC change. Secondary outcomes included percent change in CAC volume, valvular calcifications, and bone mineral metabolism markers. Results:Among 44 individuals randomly assigned, mean age was 65 years and mean estimated glomerular filtration rate was 27 mL/min/1.73 m2. Median CAC score was 140 (IQR, 55-277) Agatston units at baseline. There was no significant difference in CAC progression between treatment arms (P = 0.06). After adjustment for baseline CAC score (log), treatment group remains nonsignificant (P = 0.08). Further adjustment for creatinine level and/or CKD stage did not change the association. In secondary analyses adjusting for dose level of activated vitamin D, treatment group was significant (P = 0.01), and when dose level was also included in the model, the coefficient for individuals in the paricalcitol group was significantly associated with CAC progression (P = 0.02). An interaction term between dosing level and CKD stage was significant at the highest dosing level (P = 0.04). Limitations:Pilot single-center study. Conclusions:In patients with CKD with secondary hyperparathyroidism naive to activated vitamin D therapy, there was no difference in CAC or valvular progression in participants receiving calcitriol compared with paricalcitol during a 48-week period. Funding:Abbvie, Inc. Trial Registration:NCT00752102.

SUBMITTER: Anis KH

PROVIDER: S-EPMC7406841 | biostudies-literature | 2020 Jul-Aug

REPOSITORIES: biostudies-literature

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Vitamin D Analogues and Coronary Calcification in CKD Stages 3 and 4: A Randomized Controlled Trial of Calcitriol Versus Paricalcitol.

Anis Karim H KH Pober David D Rosas Sylvia E SE

Kidney medicine 20200617 4

<h4>Rationale & objective</h4>Mineral and bone disorder in chronic kidney disease (CKD) is associated with progression of coronary artery calcification (CAC). Mineral and bone disorder often is treated with calcitriol and other vitamin D receptor activators, including paricalcitol, agents that may have differential effects on calcium, phosphate, and parathyroid hormone levels. Accordingly, we investigated whether these agents have differential effects on CAC progression in patients with CKD.<h4> ...[more]

PMID: 32775985

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Project description:Background and objectivesCalcitriol is used to treat secondary hyperparathyroidism in patients with CKD. Paricalcitol is less calcemic and phosphatemic in preclinical studies and in some trials in dialysis patients, but head-to-head comparisons in nondialysis patients are lacking. A large meta-analysis of trials concluded that these agents did not consistently reduce parathyroid hormone (PTH) and increased the risk of hypercalcemia and hyperphosphatemia. Therefore, the objective of this multicenter trial was to compare the rate of hypercalcemia between calcitriol and paricalcitol, while suppressing PTH 40%-60%.Design, setting, participants, & measurementsPatients with stages 3-4 CKD (n=110) with a PTH level >120 pg/ml were recruited and randomized to 0.25 μg/d of calcitriol or 1 μg/d of paricalcitol between April 2009 and July 2011. Subsequent dose adjustments were by protocol to achieve 40%-60% PTH suppression below baseline. The primary endpoint was the rate of confirmed hypercalcemia of >10.5 mg/dl between groups.ResultsForty-five patients in each group completed the 24 weeks of treatment. Both agents suppressed PTH effectively (-52% with paricalcitol and -46% with calcitriol; P=0.17), although the paricalcitol group reached a 40% reduction in PTH sooner at a median 8 weeks (interquartile range [IQR], 4, 12) versus 12 weeks (IQR, 8, 18; P=0.02) and had a lower pill burden of 240 (IQR, 180, 298) versus 292 (IQR, 231, 405; P=0.01). Confirmed hypercalcemia was very low in both groups (three with paricalcitol and one with calcitriol) and was not significantly different (P=0.36). Both groups had small increases in calcium and phosphorus levels (0.3-0.4 mg/dl in each electrolyte) and significant decreases in alkaline phosphatase, a marker of high bone turnover, with no significant differences between groups.ConclusionsThese results show that both calcitriol and paricalcitol achieved sustained PTH and alkaline phosphatase suppression in stages 3-4 CKD, with small effects on serum calcium and phosphorus and a low incidence of hypercalcemia.

Project description:BackgroundOral calcitriol decreases parathyroid hormone (PTH) concentrations in patients who have chronic kidney disease (CKD); however, treatment response is highly variable. We evaluated whether patient characteristics affect the PTH response to oral calcitriol in nondialysis patients with CKD in a clinic-based setting.Study designCohort study.Setting & participantsThis study included 379 new oral calcitriol users in the Veterans' Affairs Northwest Health Network. All had stages 3-4 CKD, hyperparathyroidism, and a serum PTH measurement before and 1-6 months after initiating oral calcitriol therapy.PredictorsPatient-level characteristics hypothesized to affect calcitriol response: race, body size, concurrent medications, and kidney function.OutcomesRelative decrease in serum PTH concentration after starting oral calcitriol therapy.MeasurementsData were abstracted from the Veterans' Affairs Northwest Health Network (VISN 20) Data Warehouse, which includes electronic pharmacy and laboratory records.ResultsMean estimated glomerular filtration rate was 30 mL/min/1.73 m(2) and mean initial PTH concentration was 199 pg/mL. Regular- (0.25 μg/d) and low-dose (<0.25 μg/d) oral calcitriol were associated with on average 23% and 13% relative decreases in serum PTH concentrations, respectively. After adjustment for calcitriol dosage, initial PTH concentration, and time to follow-up measurement, African American race was associated with a blunted calcitriol response (geometric mean final PTH value, 26% higher; 95% CI, 8%-47%). Serum albumin concentration <3.5 g/dL also was associated with a diminished calcitriol response (geometric mean final PTH, 19% higher; 95% CI, 6%-35%). Although numbers were small, concurrent use of benzodiazepines and nonactivated vitamin D supplements was associated with a significantly greater PTH response.LimitationsClinic-based study is limited by the availability of PTH measurements after starting calcitriol therapy. Study of a predominantly older male population.ConclusionsIn patients with stages 3-4 CKD, African American race and low serum albumin level are associated with a diminished PTH response to oral calcitriol.

Project description:RATIONALE & OBJECTIVE:Coronary artery calcification (CAC) is prevalent among patients with chronic kidney disease (CKD) and increases risks for cardiovascular disease events and mortality. We hypothesized that a novel serum measure of calcification propensity is associated with CAC among patients with CKD stages 2 to 4. STUDY DESIGN:Prospective cohort study. SETTING & PARTICIPANTS:Participants from the Chronic Renal Insufficiency Cohort (CRIC) Study with baseline (n=1,274) and follow-up (n=780) CAC measurements. PREDICTORS:Calcification propensity, quantified as transformation time (T50) from primary to secondary calciprotein particles, with lower T50 corresponding to higher calcification propensity. Covariates included age, sex, race/ethnicity, clinical site, estimated glomerular filtration rate, proteinuria, diabetes, systolic blood pressure, number of antihypertensive medications, current smoking, history of cardiovascular disease, total cholesterol level, and use of statin medications. OUTCOMES:CAC prevalence, severity, incidence, and progression. ANALYTICAL APPROACH:Multivariable-adjusted generalized linear models. RESULTS:At baseline, 824 (65%) participants had prevalent CAC. After multivariable adjustment, T50 was not associated with CAC prevalence but was significantly associated with greater CAC severity among participants with prevalent CAC: 1-SD lower T50 was associated with 21% (95% CI, 6%-38%) greater CAC severity. Among 780 participants followed up an average of 3 years later, 65 (20%) without baseline CAC developed incident CAC, while 89 (19%) with baseline CAC had progression, defined as annual increase≥100 Agatston units. After multivariable adjustment, T50 was not associated with incident CAC but was significantly associated with CAC progression: 1-SD lower T50 was associated with 28% (95% CI, 7%-53%) higher risk for CAC progression. LIMITATIONS:Potential selection bias in follow-up analyses; inability to distinguish intimal from medial calcification. CONCLUSIONS:Among patients with CKD stages 2 to 4, higher serum calcification propensity is associated with more severe CAC and CAC progression.

Project description:BACKGROUND:Vascular calcification is common among patients with chronic kidney disease (CKD), and it is associated with all-cause and cardiovascular disease mortality. Deoxycholic acid, a metabolite of circulating bile acids, is elevated in CKD and induces vascular mineralization and osteogenic differentiation in animal models. STUDY DESIGN:Cohort analysis of clinical trial participants. SETTING & PARTICIPANTS:112 patients with moderate to severe CKD (estimated glomerular filtration rate, 20-45mL/min/1.73m2) who participated in a randomized controlled study to examine the effects of phosphate binders on vascular calcification. PREDICTOR:Serum deoxycholic acid concentration. OUTCOMES:Baseline coronary artery calcification (CAC) volume score and bone mineral density (BMD) and change in CAC volume score and BMD after 9 months. MEASUREMENTS:Deoxycholic acid was assayed in stored baseline serum samples using liquid chromatography-tandem mass spectrometry, CAC was measured using a GE-Imitron C150 scanner, and BMD was determined using computed tomographic scans of the abdomen with calibrated phantom of known density. RESULTS:Higher serum deoxycholic acid concentrations were significantly correlated with greater baseline CAC volume and lower baseline BMD. After adjusting for demographics, coexisting illness, body mass index, estimated glomerular filtration rate, and concentrations of circulating markers of mineral metabolism, including serum calcium, phosphorus, vitamin D, parathyroid hormone, and fibroblast growth factor 23, a serum deoxycholic acid concentration > 58ng/mL (the median) was positively associated with baseline CAC volume (?=0.71; 95% CI, 0.26-1.16; P=0.003) and negatively associated with baseline BMD (? = -20.3; 95% CI, -1.5 to -39.1; P=0.04). Serum deoxycholic acid concentration > 58ng/mL was not significantly associated with change in CAC volume score after 9 months (?=0.06; 95% CI, -0.09 to 0.21; P=0.4). The analysis for the relationship between baseline deoxycholic acid concentrations and change in BMD after 9 months was not statistically significant, but was underpowered. LIMITATIONS:The use of nonfasting serum samples is a limitation because deoxycholic acid concentrations may vary based on time of day and dietary intake. Few trial participants with complete data to evaluate the change in CAC volume score (n=75) and BMD (n=59). No data for changes in deoxycholic acid concentrations over time. CONCLUSIONS:Among patients with moderate to severe CKD, higher serum deoxycholic acid concentrations were independently associated with greater baseline CAC volume score and lower baseline BMD.

Project description:BackgroundRecent studies suggest that vitamin D deficiency represents an additional cofactor of renal anemia, with several mechanisms accounting for this relationship. In line with it, the administration of vitamin D or its analogues has been associated with an improvement of anemia. There are no data, however, about a direct effect of paricalcitol on hemoglobin (Hb) levels. Therefore, we conducted a study to determine whether paricalcitol, compared to calcitriol, improves anemia in patients with chronic kidney disease (CKD).MethodsIn this randomized trial 60 CKD patients stage 3b-5 and anemia (Hb levels: 10-12.5 g/dL) were assigned (1:1) to receive low doses of calcitriol (Group Calcitriol) or paricalcitol (Group Paricalcitol) for 6 months. All the patients had normal values of plasma calcium, phosphorus and PTH, a stable iron balance, and normal values of C-Reactive Protein. The primary endpoint was to evaluate the effects of the two treatments on Hb levels; the modifications in 24hr-proteinuria (UProt) were also evaluated.ResultsA significant Group x Time interaction effect was observed in the longitudinal analysis of Hb levels (F(1,172)=31.4, p<0.001). Subjects in Paricalcitol experienced a significant monthly increase of Hb levels equal to +0.16 g/dL [95% C.I. 0.10 to +0.22, p<0.001) while in Group Calcitriol, Hb decrease throughout the follow-up with an average monthly rate of -0.10 g/dL (95% C.I.: -0.17 to -0.04, p<0.001). In Group Paricalcitol, UProt was significantly reduced after 6 months [0.35 (0.1-1.2) vs 0.59 (0.2-1.6), p<0.01], whereas no significant difference emerged in Group Calcitriol. Plasma levels of calcium, phosphate, PTH and of inflammation markers remained in the normal range in both groups throughout the study.ConclusionsShort-term exposure to paricalcitol results in an independent increase in Hb levels, which occurred with no modification of iron balance, inflammatory markers, and PTH plasma concentrations, and was associated with a decrease in UProt.Trial registrationClinicalTrials.gov NCT01768351.

Dataset Information

Vitamin D Analogues and Coronary Calcification in CKD Stages 3 and 4: A Randomized Controlled Trial of Calcitriol Versus Paricalcitol.

Publications

Vitamin D Analogues and Coronary Calcification in CKD Stages 3 and 4: A Randomized Controlled Trial of Calcitriol Versus Paricalcitol.

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