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The impact of CASR A990G polymorphism in response to cinacalcet treatment in hemodialysis patients with secondary hyperparathyroidism.

ABSTRACT: The objective of this study was to determine the impact of calcium sensing receptor (CASR) A990G genetic polymorphism on parathyroid hormone (PTH) lowering response to cinacalcet treatment when controlling for significant influencing clinical factors. This retrospective study was conducted on 135 Thai hemodialysis (HD) patients with secondary hyperparathyroidism (SHPT). CASR A990G genotypes were determined. The patients were identified as either G carriers (heterozygous or homozygous CASR 990G allele carriers) or noncarriers (homozygous CASR 990A carriers). Tested covariates were baseline PTH level (bPTH), baseline serum phosphate (bPhos), baseline serum calcium (bCa), baseline calcitriol equivalent dose (bCtriol), baseline ergocalciferol dose (bErgo), and age. The ANCOVA showed that intact PTH levels after 12 weeks of cinacalcet treatment (PTHw12) was significantly lower among G carriers compared with noncarriers after controlling for bPTH, bPhos, bCtriol, and bErgo (F(1, 127) = 15.472, p < 0.001), with the adjusted mean difference of 253.7 pg/mL. The logistic regression analysis revealed that the odds of a G carrier achieving 30% PTH reduction after 12-week cinacalcet treatment were 3.968 times greater than the odds for a noncarrier after adjusting for bPhos, bCtriol, and age. In conclusion, the CASR A990G polymorphism significantly influences cinacalcet response in HD patients with SHPT.

SUBMITTER: Ngamkam J

PROVIDER: S-EPMC8429569 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Pharmacogenetic analysis of cinacalcet response in secondary hyperparathyroidism patients.

Project description:Secondary hyperparathyroidism (SHPT) is one of the major risk factors of morbidity and mortality in end-stage renal disease. Cinacalcet effectively controls SHPT without causing hypercalcemia and hyperphosphatemia. However, there is significant inter-individual response variance to cinacalcet treatment. Therefore, we aimed to evaluate the genetic effects related with parathyroid hormone regulation as factors for cinacalcet response variance.Patients with a diagnosis of SHPT based on intact parathyroid hormone (iPTH) >300 pg/mL on dialysis were included in this study. They were over 18 years and have been treated by cinacalcet for more than 3 months. Responders and nonresponders were grouped by the serum iPTH changes. Twenty-four single nucleotide polymorphisms of CASR, VDR, FGFR1, KL, ALPL, RGS14, NR4A2, and PTHLH genes were selected for the pharmacogenetic analysis.After adjusting for age, sex, and calcium level, CASR rs1042636 (odds ratio [OR]: 0.066, P=0.027) and rs1802757 (OR: 10.532, P=0.042) were associated with cinacalcet response. The association of haplotypes of CASR rs1042636, rs10190, and rs1802757; GCC (OR: 0.355, P=0.015); and ATT (OR: 2.769, P=0.014) with cinacalcet response was also significant.We obtained supporting information of the associations between cinacalcet response and CASR polymorphisms. CASR single nucleotide polymorphisms (SNPs) rs1802757, rs1042636, and haplotypes of rs1042636, rs10190, and rs1802757 were significantly associated with cinacalcet response variance.

| S-EPMC4944925 | biostudies-literature

PTH-dependence of the effectiveness of cinacalcet in hemodialysis patients with secondary hyperparathyroidism.

Project description:Cinacalcet lowers parathyroid hormone levels. Whether it can prolong survival of people with chronic kidney disease (CKD) complicated by secondary hyperparathyroidism (SHPT) remains controversial, in part because a recent randomized trial excluded patients with iPTH <300 pg/ml. We examined cinacalcet's effects at different iPTH levels. This was a prospective case-cohort and cohort study involving 8229 patients with CKD stage 5D requiring maintenance hemodialysis who had SHPT. We studied relationships between cinacalcet initiation and important clinical outcomes. To avoid confounding by treatment selection, we used marginal structural models, adjusting for time-dependent confounders. Over a mean of 33 months, cinacalcet was more effective in patients with more severe SHPT. In patients with iPTH ≥ 500 pg/ml, the reduction in the risk of death from any cause was about 50% (Incidence Rate Ratio [IRR] = 0.49; 95% Confidence Interval [95% CI]: 0.29-0.82). For a composite of cardiovascular hospitalization and mortality, the association was not statistically significant, but the IRR was 0.67 (95% CI: 0.43-1.06). These findings indicate that decisions about using cinacalcet should take into account the severity of SHPT.

| S-EPMC4829837 | biostudies-literature

Comparison of the Oral Calcimimetics Evocalcet and Cinacalcet in East Asian Patients on Hemodialysis with Secondary Hyperparathyroidism.

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| S-EPMC10658267 | biostudies-literature

The effectiveness of cinacalcet: a randomized, open label study in chronic hemodialysis patients with severe secondary hyperparathyroidism.

Project description:BackgroundSecondary hyperparathyroidism (SHPT) is associated with high incidences of cardiovascular disease, bone fracture, and mortality. This study was conducted to demonstrate the effectiveness of cinacalcet treatment on chronic kidney disease-mineral bone disorder (CKD-MBD) markers in chronic hemodialysis patients with severe SHPT.MethodsIn phase 1, 30 adult HD patients were randomized to cinacalcet or control groups for 12 weeks to explore the achievement of >30% reduction of iPTH. In phase 2, 45 patients were participated to further explore the effect of cinacalcet on CKD-MBD parameters for 24-week follow up and 12 additional weeks after cinacalcet discontinuation.ResultsIn phase 1, the baseline serum iPTH levels were not different [1374 (955, 1639) pg/mL in the control group vs. 1191 (1005, 1884) pg/mL in the cinacalcet group], the percentage of patients achieving iPTH target were significantly higher in the treatment group [80% vs. 13%, p = .001]. In phase 2, the significant reductions of iPTH, FGF-23, tartrate-resistant acid phosphatase 5b, and slightly decreased size of parathyroid gland and stabilized vascular calcification were observed at 24-week follow up and markedly rebounded after discontinuation of cinacalcet.ConclusionsThe effectiveness of cinacalcet were still obviously demonstrated even in chronic HD patients with severe SHPT. In addition, the improvements of bone markers and FGF-23, and stabilization of vascular calcification were observed. Therefore, cinacalcet can provide salutary effects on CKD-MBD in severe SHPT and might be an initially effective PTH-lowering therapy prior to surgical parathyroidectomy as well as an alternative treatment in the patients unsuitable for surgery.Clinical trial registrationClinicalTrials.gov: NCT02056730. Date of registration: February 4, 2014.

| S-EPMC6493313 | biostudies-literature

Efficacy of Evocalcet in Previously Cinacalcet-Treated Secondary Hyperparathyroidism Patients.

Project description:IntroductionEvocalcet is a recently approved calcimimetic agent for secondary hyperparathyroidism (SHPT). In this study, the efficacy and safety of once-daily oral evocalcet were evaluated in patients without prior cinacalcet use (nonusers) and previously treated patients (users).MethodsThis post hoc analysis of a previous phase III head-to-head comparison study included SHPT patients treated with evocalcet with or without prior cinacalcet use. Endpoints included trends in the median intact and whole parathyroid hormone (PTH), mean corrected calcium, phosphate, and bone metabolic markers, and whole-to-intact PTH ratios throughout the 30-week study period; proportions of patients achieving target intact PTH, corrected calcium, and phosphate at weeks 28 to 30; and adverse drug reactions (ADRs).ResultsThis study included 127 nonusers and 190 users with significant differences in age; duration of dialysis; use of intravenous vitamin D receptor activators; levels of intact PTH, corrected calcium, tartrate-resistant acid phosphatase 5b, procollagen type 1 N-terminal-propeptide; and largest parathyroid gland volume (P < 0.05 for all characteristics) between 2 groups at baseline. Users required higher evocalcet dosages than nonusers. Similar efficacy results were found in the 2 groups except for a significantly higher proportion of nonusers achieving the intact PTH target (81.6% vs 67.1%, difference [95% confidence interval], -14.5% [-24.59, -3.34]), and a significant reduction in largest parathyroid gland volume from week 0 to week 30 (-120.6 [567.2] mm3, P = 0.043). No difference was found in ADRs between the 2 groups.ConclusionTreatment with evocalcet is effective and safe irrespective of prior cinacalcet treatment in SHPT patients.

| S-EPMC8589700 | biostudies-literature

Bone histomorphometry before and after long-term treatment with cinacalcet in dialysis patients with secondary hyperparathyroidism.

Project description:The multicenter, single-arm BONAFIDE study characterized the skeletal response to cinacalcet in adult dialysis patients with plasma parathyroid hormone (PTH) levels of 300?pg/ml or more, serum calcium of 8.4?mg/dl or more, bone-specific alkaline phosphatase over 20.9?ng/ml and biopsy-proven high-turnover bone disease. Of 110 enrolled patients, 77 underwent a second bone biopsy with quantitative histomorphometry after 6-12 months of cinacalcet treatment. The median PTH decreased from 985?pg/ml at baseline to 480?pg/ml at the end of study (weeks 44-52). Bone formation rate/tissue area decreased from 728 to 336??m(2)/mm(2)/day, osteoblast perimeter/osteoid perimeter decreased from 17.4 to 13.9%, and eroded perimeter/bone perimeter decreased from 12.7 to 8.3%. The number of patients with normal bone histology increased from none at baseline to 20 at 12 months. Two patients had adynamic bone at the end of study with a PTH under 150?pg/ml, and one patient with overt hypophosphatemia at baseline that reoccurred during follow-up developed osteomalacia. Thus, long-term treatment with cinacalcet substantially reduced PTH, diminished the elevated bone formation rate/tissue area, lowered several biochemical markers of high-turnover bone disease toward normal, and generally improved bone histology. Twenty patients had normal bone histology at follow-up, whereas most had mild hyperparathyroidism or mixed uremic osteodystrophy.

| S-EPMC4382689 | biostudies-literature

Cinacalcet studies in pediatric subjects with secondary hyperparathyroidism receiving dialysis.

Project description:BackgroundSecondary hyperparathyroidism (sHPT), a complication of chronic kidney disease (CKD) characterized by persistently elevated parathyroid hormone (PTH), alterations in calcium-phosphorus homeostasis, and vitamin D metabolism, affects 50% of children receiving dialysis. A significant proportion of these children develop CKD-mineral and bone disorder (CKD-MBD), associated with an increased risk of fractures and vascular calcification. The standard of care for sHPT in children includes vitamin D sterols, calcium supplementation, and phosphate binders. Several agents are approved for sHPT treatment in adults undergoing dialysis, including vitamin D analogs and calcimimetics, with limited information on their safety and efficacy in children. The calcimimetic cinacalcet is approved for use in adults with sHPT on dialysis, but is not approved for pediatric use outside Europe.MethodsThis review provides dosing, safety, and efficacy information from Amgen-sponsored cinacalcet pediatric trials and data from non-Amgen sponsored clinical studies.ResultsThe Amgen cinacalcet pediatric clinical development program consisted of two Phase 3 randomized studies, one Phase 3 single arm extension study, one open-label Phase 2 study, and two open-label Phase 1 studies. Effects of cinacalcet on PTH varied across studies. Overall, 7.4 to 57.1% of subjects who received cinacalcet in an Amgen clinical trial attained PTH levels within recommended target ranges and 22.2 to 70.6% observed a ≥ 30% reduction in PTH. In addition, significant reductions in PTH were demonstrated in all non-Amgen-supported studies.ConclusionsTo help inform the pediatric nephrology community, this manuscript contains the most comprehensive review of cinacalcet usage in pediatric CKD patients to date.

| S-EPMC7385021 | biostudies-literature

Effectiveness of cinacalcet treatment for secondary hyperparathyroidism on hospitalization: Results from the MBD-5D study.

Project description:ObjectivesTo elucidate the effect of cinacalcet use on all-cause and cause-specific hospitalization outcomes using a prospective cohort of maintenance hemodialysis patients.MethodsWe used data from a prospective cohort of Japanese hemodialysis patients with secondary hyperparathyroidism and examined baseline characteristics as well as longitudinal changes. All patients were cinacalcet-naïve at study enrollment. Further, we used a marginal structural model to account for time-varying confounders on cinacalcet initiation and hospitalization outcomes, and an Andersen-Gill-type recurrent event model to account for any recurring events of hospitalization in the outcome analysis using the weighted dataset.ResultsAmong the 3,276 patients, cinacalcet treatment was initiated in 1,384 patients during the entire follow-up. Cinacalcet users were slightly younger, included more patients with chronic glomerulonephritis and fewer patients with diabetes, were more likely to have a history of parathyroidectomy, and were more often used receiving vitamin D receptor activator, phosphate binders, and iron supplements. The overall hospitalization analysis yielded a hazard ratio (HR) of 0.97 (95% confidence interval [CI]: 0.80, 1.18). A trend toward a mild protective association was observed for cardiovascular-related hospitalizations (HR: 0.85; 95% CI: 0.64, 1.14). In the subgroup analysis, a protective association was seen due to cinacalcet use for infection-related hospitalizations in the lowest intact parathyroid hormone group (HR: 0.36; 95% CI: 0.14, 0.95).ConclusionsCinacalcet initiation in patients on maintenance hemodialysis had no effect on all-cause and cause-specific hospitalizations. Although the overall association was statistically not significant, cinacalcet may have a protective association on cardiovascular-related hospitalization in all patients and infection-related hospitalization in patient with low intact parathyroid hormone.

| S-EPMC6541241 | biostudies-literature

Paricalcitol versus cinacalcet plus low-dose vitamin D therapy for the treatment of secondary hyperparathyroidism in patients receiving haemodialysis: results of the IMPACT SHPT study.

Project description:BackgroundOptimal treatment for secondary hyperparathyroidism (SHPT) has not been defined. The IMPACT SHPT (ClinicalTrials.gov identifier: NCT00977080) study assessed whether dose-titrated paricalcitol plus supplemental cinacalcet only for hypercalcaemia is superior to cinacalcet plus low-dose vitamin D in controlling intact parathyroid hormone (iPTH) levels in patients with SHPT on haemodialysis.MethodsIn this 28-week, multicentre, open-label Phase 4 study, participants were randomly selected to receive paricalcitol or cinacalcet plus low-dose vitamin D. Randomization and analyses were stratified by mode of paricalcitol administration [intravenous (IV) or oral]. The primary efficacy end point was the proportion of subjects who achieved a mean iPTH value of 150-300 pg/mL during Weeks 21-28.ResultsOf 272 subjects randomized, 268 received one or more dose of study drug; 101 in the IV and 110 in the oral stratum with two or more values during Weeks 21-28 were included in the primary analysis. In the IV stratum, 57.7% of subjects in the paricalcitol versus 32.7% in the cinacalcet group (P = 0.016) achieved the primary end point. In the oral stratum, the corresponding proportions of subjects were 54.4% for paricalcitol and 43.4% for cinacalcet (P = 0.260). Cochran-Mantel-Haenszel analysis, controlling for stratum, revealed overall superiority of paricalcitol (56.0%) over cinacalcet (38.2%; P = 0.010) in achieving iPTH 150-300 pg/mL during Weeks 21-28. Hypercalcaemia occurred in 4 (7.7%) and 0 (0%) of paricalcitol-treated subjects in the IV and oral strata, respectively. Hypocalcaemia occurred in 46.9% and 54.7% of cinacalcet-treated subjects in the IV and oral strata, respectively.ConclusionParicalcitol versus cinacalcet plus low-dose vitamin D provided superior control of iPTH, with low incidence of hypercalcaemia.

| S-EPMC3408938 | biostudies-literature

Pharmacodynamics of evocalcet for secondary hyperparathyroidism in Japanese hemodialysis patients.

Project description:BackgroundThis study investigated the pharmacokinetics, pharmacodynamics, and safety of multiple doses of evocalcet in Japanese secondary hyperparathyroidism (SHPT) patients receiving hemodialysis.MethodsIn this multicenter, open-label study, conducted between August 2013 and March 2014, 27 patients received multiple doses of 1 and 4 mg evocalcet for 14 days, followed by an extension period of multiple doses of 8 and 12 mg evocalcet for 7 days using an intra-patient dose escalation protocol. Pharmacodynamic parameters consisted of measurement of intact parathyroid hormone (PTH), serum-corrected calcium, serum phosphorus and intact fibroblast growth factor 23 concentrations. Safety was assessed by analysis of adverse events.ResultsPlasma evocalcet levels reached steady state 3 days after the first day of administration. Pharmacodynamic analyses showed that evocalcet effectively reduced intact PTH and serum-corrected calcium levels. Adverse events (AEs) occurred in 29.6 and 62.5% of patients receiving multiple doses of 1 or 4 mg, respectively. The AE 'blood calcium decreased' occurred in eight patients (33.0%) after multiple doses of 4 mg. All events were mild, except for one patient with a moderate AE (abnormal liver function) and one patient with a severe adverse drug reaction (blood calcium decreased).ConclusionMultiple doses of evocalcet reduced intact PTH levels with a concomitant decrease in serum calcium levels. Evocalcet was well tolerated in SHPT patients receiving hemodialysis.

| S-EPMC6510802 | biostudies-literature

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