Cinacalcet Group Research Articles

Treatment of Persistent Hyperparathyroidism after Renal Transplant

Background Hyperparathyroidism is a frequent complication in chronic kidney disease and may persist after transplant in 20 to 50% of cases, manifest by hypercalcemia and hypophosphatemia. Persistent disease is associated with an increase in the incidence of cardiovascular events, fracture and death. Therapeutic options currently available are parathyroidectomy (PTX) and therapy with calcimimetic agent cinacalcet. Methods Single-center retrospective study including adult renal transplant recipients who developed hipercalcemia due to persistent hyperparathyroidism. Criteria for treatment: Elevated PTH with serum calcium > 11 mg/dL at any time after transplantation or serum calcium persistently higher than 10.2 mg/dl one year after transplantation. Patients treated with cinacalcet (n = 46) were compared to patients treated with parathyroidectomy (n = 30). The follow up period was 1 year. Demographic and laboratory data were analyzed. In the cinacalcet group, episodes of rejection and medication tolerance were also analyzed. Results PTX controlled the calcemia faster and reached significantly lower levels in the long term (p = 0.0073); PTX showed significantly higher levels of serum phosphate (p = 0.0012) and returned PTH to normal levels (p <0.0001). Cinacalcet, despite of controlling calcium and phosphorus in the long term, did not correct PTH. There was no difference in response to cinacalcet when subgroups were stratified by PTH (≤700 pg/ml vs. > 700 pg/ml). Patients treated with cinacalcet had better renal function (p = 0.0002). The drug was well tolerated and no rejection episode was detected. Conclusions The surgical treatment was superior to cinacalcet to correct the metabolic disorders of hyperparathyroidism; however, it was associated with worse renal function in the long term. Cinacalcet proved to be a safe and well tolerated drug.

Incidence, predictors and therapeutic consequences of hypocalcemia in patients treated with cinacalcet in the EVOLVE trial

The calcimimetic cinacalcet is used to treat secondary hyperparathyroidism in patients receiving dialysis, and asymptomatic hypocalcemia is often observed following its initiation. Here we investigated the incidence, predictors and therapeutic consequences of hypocalcemia by a post hoc analysis of the randomized, double-blind, placebo-controlled EValuation Of Cinacalcet Hydrochloride Therapy to Lower CardioVascular Events (EVOLVE) trial. Hypocalcemia was classified as mild (total serum calcium 8.0-8.39 mg/dL), moderate (7.5-7.99 mg/dL) or severe (under 7.5 mg/dL). At least one episode of hypocalcemia developed within 16 weeks after the first administered dose among 58.3% of 1938 patients randomized to cinacalcet versus 14.9% of 1923 patients randomized to placebo. Hypocalcemia in the cinacalcet group was severe in 18.4% of the patients versus 4.4% in the placebo group. Severe hypocalcemia following administration of cinacalcet was associated with higher baseline plasma parathyroid hormone, lower corrected total serum calcium, higher serum alkaline phosphatase, geographic region (patients from Latin America and Russia had a higher risk relative to the United States) and higher body mass index. The median cinacalcet dose immediately prior to the first hypocalcemic episode was 54-58 mg/day and similar in the three hypocalcemia categories. In the majority of patients, hypocalcemia resolved spontaneously within 14 days without modification of background therapy. Among patients who received an intervention, the most common was an increase in the active vitamin D sterol dose. Thus, the occurrence of hypocalcemia is frequent following initiation of cinacalcet and the likelihood of developing hypocalcemia was related to the severity of secondary hyperparathyroidism. Hypocalcemia was generally asymptomatic and self-limited.

Prospective cohort study: Cinacalcet-mediated lowering of PTH level and cardiovascular disease mortality in younger Korean patients with stage 5 CKD at a Korean secondary hospital.

Cinacalcet may reduce cardiovascular disease (CVD) mortality in elderly patients with chronic kidney disease (CKD). However, previous studies of the clinical responses to cinacalcet have exhibited discrepancies due to highly variable baseline levels of parathyroid hormone (PTH), kidney function and age. Little is known about the true effect of cinacalcet on stage 5 CKD. The objective of the current observational study was to evaluate whether cinacalcet-mediated lowering of PTH levels improves all-cause mortality and cardiovascular disease mortality in younger stage 5 CKD patients (mean age <55years). This prospective, cohort study reviewed the electronic medical records (EMRs) of CKD patients (n=540) with secondary hyperparathyroidism (SHPT) for a period of 36months. Of 540 patients, 104 subjects met the inclusion criteria and were included in the final evaluation (mean serum iPTH 688.7pg/mL). Patients were divided into a cinacalcet group (n=43) and a non-cinacalcet group (n=61). Comparing the cinacalcet group to the non-cinacalcet group, Cox proportional hazard modelling found that all-cause mortality was five (31.3%) in the cinacalcet group and three (15.8%) in the non-cinacalcet group for patients with serum levels of PTH>600pg/mL [P=.277, hazard ratio 2.213, 95% confidence interval (CI): 0.529-9.262]. Cardiovascular disease mortality (CVD: heart disease) occurred in two (5.3%) in the cinacalcet group and one (2.1%) in the non-cinacalcet group [P=.425, HR 2.611, 95% CI: 0.228-9.939]. Overall, there were no significant differences in CVD mortality between the two groups. Cinacalcet was not associated with decreases in all-cause mortality or CVD mortality in younger stage 5 CKD patients with high PTH levels (>600pg/mL). This could be explained by the diversity of the population in terms of the patient's age, health insurance policies, target serum level of biochemical and PTH, and glomerular filtration rate (GFR) at admission. These data, although based on an observational study, indicate that adding cinacalcet to the current standard care for younger stage 5 CKD patients should be re-evaluated.

Cinacalcet versus Parathyroidectomy in the Treatment of Secondary Hyperparathyroidism Post Renal Transplantation

Persistent hyperparathyroidism (HPT) with hypercalcemia is prevalent after transplant and is considered a risk factor for progressive bone loss and fractures and vascular calcification, as well as the development of tubulointerstitial calcifications of renal allografts and graft dysfunction. The subtotal parathyroidectomy is the standard treatment, although currently it has been replaced by the calcimimetic cinacalcet. The hypothesis of this study is that subtotal parathyroidectomy is superior to cinacalcet for treatment of persistent secondary parathyroidectomy post renal transplant, with minimal morbidity and significantly it reduces the cost of treatment after transplantation. We report our long-term clinical experience with either cinacalcet or parathyroidectomy in 59 kidney transplant recipients with hyperparathyroidism. Group one included medical treatment with cinacalcet and had 45 patients while parathyroidectomy patients (group 2) were 16 patients with two of them excluded because of surgical failure. No difference was found between groups for any parameter. A greater short-term change of calcium and phosphorus homeostasis obtained by surgery than by cinacalcet, and in long term change, no significant difference between the two groups. The main findings of this study are that correction of severe hyperparathyroidism was similar in both surgical and cinacalcet groups with the absence of a difference of long-term serum iPTH 1-84 levels between the two groups.

Cinacalcet, dialysate calcium concentration, and cardiovascular events in the EVOLVE trial.

Among patients receiving hemodialysis, abnormalities in calcium regulation have been linked to an increased risk of cardiovascular events. Cinacalcet lowers serum calcium concentrations through its effect on parathyroid hormone secretion and has been hypothesized to reduce the risk of cardiovascular events. In observational cohort studies, prescriptions of low dialysate calcium concentration and larger observed serum-dialysate calcium gradients have been associated with higher risks of in-dialysis facility or peri-dialytic sudden cardiac arrest. We performed this study to examine the risks associated with dialysate calcium and serum-dialysate gradients among participants in the Evaluation of Cinacalcet Hydrochloride Therapy to Lower Cardiovascular Events (EVOLVE) trial. In EVOLVE, 3883 hemodialysis patients were randomized 1:1 to cinacalcet or placebo. Dialysate calcium was administered at the discretion of treating physicians. We examined whether baseline dialysate calcium concentration or the serum-dialysate calcium gradient modified the effect of cinacalcet on the following adjudicated endpoints: (1) primary composite endpoint (death or first non-fatal myocardial infarction, hospitalization for unstable angina, heart failure, or peripheral vascular event); (2) cardiovascular death; and (3) sudden death. In EVOLVE, use of higher dialysate calcium concentrations was more prevalent in Europe and Latin America compared with North America. There was a significant fall in serum calcium concentration in the cinacalcet group; dialysate calcium concentrations were changed infrequently in both groups. There was no association between baseline dialysate calcium concentration or serum-dialysate calcium gradient and the endpoints examined. Neither the baseline dialysate calcium nor the serum-dialysate calcium gradient significantly modified the effects of cinacalcet on the outcomes examined. The effects of cinacalcet on cardiovascular death and major cardiovascular events are not altered by the dialysate calcium prescription and serum-dialysate calcium gradient.

Effect of cinacalcet cessation on hyperparathyroidism in kidney transcaplant patients after long-term dialysis therapy.

Cinacalcet is a promising therapy widely used in dialysis patients with hyperparathyroidism resistant to conventional therapy. However, reports regarding the influence of cinacalcet cessation after long-term use on kidney transplantation patients are few. This retrospective observational study included 40 dialysis patients who underwent kidney transplantation. Creatinine, corrected calcium, phosphorus, alkaline phosphatase, and intact parathyroid hormone levels were assessed before and after kidney transplantation according to pretransplant treatment of chronic kidney disease-mineral and bone disorder. Ultrasonography revealed enlargement of the parathyroid in all patients treated with cinacalcet. Although the data at the time of kidney transplantation were comparable, the serum levels of calcium, alkaline phosphatase, and intact parathyroid hormone after kidney transplantation were higher in patients treated with cinacalcet than in those treated without. However, serum phosphate levels in the cinacalcet group were slightly higher at the time of kidney transplantation and significantly lower 3months later. Mineral abnormalities persisted in kidney transplant patients with enlarged parathyroid glands after discontinuation of cinacalcet treatment. Parathyroidectomy should be considered in kidney transplant candidates with the risk of developing refractory hyperparathyroidism after transplantation.

Comparison of AMG 416 and cinacalcet in rodent models of uremia

BackgroundAMG 416 is a novel peptide agonist of the calcium-sensing receptor (CaSR). This report describes the activity of AMG 416 in two different rodent models of uremia, compared in each case to cinacalcet, an approved therapeutic for secondary hyperparathyroidism (SHPT) in patients with chronic kidney disease on dialysis.MethodsAMG 416 was administered as a single intravenous (IV) bolus in a severe, acute model of renal insufficiency (the “1K1C” model) and plasma parathyroid hormone (PTH) and serum calcium levels were monitored for 24 hours. In a chronic, less severe model of renal dysfunction, the 5/6 nephrectomy (5/6 Nx) model, AMG 416 was administered as a once-daily IV bolus for 28 days. Both studies included a control (vehicle) group and a comparison cinacalcet group (po dosing at 30 mg/kg and 10 mg/kg for the 1K1C and 5/6 Nx studies, respectively).ResultsAdministration of AMG 416 by IV bolus injection into rats with acute renal dysfunction (1K1C model) resulted in a sustained reduction in plasma PTH from the initial elevated values. Following a single IV bolus (0.5 mg/kg), AMG 416 caused a substantial drop in PTH levels which remained approximately 50% below their initial level at 24 hrs. In the same model, oral treatment with cinacalcet (30 mg/kg) resulted in an acute drop in PTH which almost returned to the starting level by 24 hours after dosing. In the 5/6 Nx chronic uremia model, daily IV dosing of AMG 416 over 4 weeks (1 mg/kg) resulted in a sustained reduction in PTH, with approximately 50% of the initial level observed 48 hours post treatment throughout the study. Cinacalcet treatment (10 mg/kg) in the same model resulted in acutely lowered plasma PTH levels which returned to placebo levels by 24 hours post-dose. Consistent with the reductions in plasma PTH, reductions in serum calcium were observed in both AMG 416- and cinacalcet-treated animals.ConclusionsAs a long-acting CaSR agonist suitable for administration by the IV route, AMG 416 is a potential new therapy for the treatment of CKD patients with SHPT receiving hemodialysis.

Cinacalcet Induces Apoptosis in Parathyroid Cells in Patients with Secondary Hyperparathyroidism: Histological and Cytological Analyses

Background/Aims: Previous studies reported a reduction in parathyroid gland volume during treatment with cinacalcet in patients with secondary hyperparathyroidism (SHPT). However, it remains to be determined whether cinacalcet accelerates apoptosis of hyperplastic parathyroid cells in these patients. Methods: The study subjects were 16 hemodialysis patients who had undergone parathyroidectomy for severe SHPT. We compared the expression of the apoptotic marker TUNEL and the proliferative marker Ki67 by immunohistochemistry and the expression of CYP27B1 by quantitative real-time PCR in hyperplastic parathyroid glands from patients treated with cinacalcet (cinacalcet group; n = 8) and those not treated with cinacalcet (non-cinacalcet group; n = 8). We also examined the effect of cinacalcet on parathyroid cell death in in vitro cell culture with TUNEL staining, using parathyroid cells from SHPT patients. Results: Compared with the non-cinacalcet group, the expression of TUNEL was significantly increased but was accompanied with significantly increased Ki67 expression in the parathyroid glands from the cinacalcet group. In vitro examination showed dose- and time-dependent increases of apoptotic cells by adding cinacalcet into culture medium. We also found that the expression of CYP27B1 showed a three-fold increase in glands from the cinacalcet group compared to that of the non-cinacalcet group. Conclusion: Our data suggest that cinacalcet induces apoptosis of human parathyroid cells, but this effect may be overcome by more aggressive proliferation of parathyroid cells in patients with severe, cinacalcet-resistant SHPT.

Before the Jury Is out on Cinacalcet’s Cardiovascular Effects in Hemodialysis Patients: Is Troponin a Missing Link?

Raised levels of the cardiac biomarker, Troponin I, are frequently encountered in hemodialysis patients and appear to be prognostic indicators for cardiovascular risk. Though evidence suggests that control of secondary hyperparathyroidism may reduce cardiac endpoints, the effect of the calcimimetic agent, cinacalcet, remains controversial. This retrospective study aimed at evaluating troponin levels in hemodialysis patients with severe secondary hyper parathyroidism (SHPT) who are on cinacalcet vs controls on conventional treatment. In addition, clinical outcomes including all-cause, cardiovascular morbidity and mortality were compared among both groups. A decline in Troponin I levels was observed in the cinacalcet group, this however was not translated clinically into improved survival. In fact, all-cause and cardiac mortality was similar in the two groups. Conversely, comparison of the incidence of cardiovascular events revealed lower rates in the cinacalcet group including cardiac, cerebral and peripheral vascular complications. Given some of our study limitations, further long-term, placebo-controlled trials are necessary to definitively establish the effect of cinacalet on cardiac biomarkers and ultimately its impact on clinical outcomes.

Cinacalcet ameliorates cardiac fibrosis in uremic hearts through suppression of endothelial-to-mesenchymal transition

Cardiac fibrosis is a common feature in patients with chronic kidney disease (CKD). Increasing evidence has shown that elevated parathyroid hormone (PTH) is causally involved in cardiac fibrosis [1–4]. Cinacalcet (CINA), a calcimimetic agent, reduces PTH levels without increasing circulating levels of calcium and phosphorus [5,6]. Recent studies have shown that CINA treatment markedly attenuated myocardial fibrosis and vascular remodeling [6,7]. However, the underlying mechanisms of this action are still unknown. Endothelial-to-mesenchymal transition (EndMT) plays an important role in the development of cardiac fibrosis [8,9]. The purpose of this study was to investigate whether CINA ameliorated cardiac fibrosis in rats with uremia was mediated by suppression of EndMT. Study protocols were approved by the Ethical Committee of Southeast University. The rat model of uremia and secondary hyperparathyroidism was established as previously described [10]. Briefly, 8-week-old male Wistar rats were randomly divided into three groups: the control group (CTL, n = 6), the uremia group (U, n = 8) and the CINA-treated uremia group (U + CINA, n = 8). Uremia was induced by feeding rats a 0.75% adenine diet for 4 weeks. After adenine withdrawal, all animals were maintained on a 1.03% phosphorus diet for next 8 weeks. At initiation of the adenine diet, rats in the U + CINA group were orally treated with CINA (Santa Cruz Biotechnology, USA) once daily (10 mg/kg) until the end of experiment. The effect of elevated PTH on EndMT was also studied in primary aortic endothelial cells (ECs). It was demonstrated that the area of cardiac fibrosis in the U group was significantly increased compared to controls, and it was significantly attenuated by the administration of CINA (Fig. 1A–B). And CINA also inhibited the expression of the extracellular matrix elements type I collagen and fibronectin in uremic hearts (Fig. 1C–E). Furthermore, there was significant up-regulation of mesenchymal markers FSP1 and α-SMA, and down-regulation of the endothelial marker CD31, while CINA markedly abrogated expression of EndMT-associated markers in uremic hearts (Fig. 2). Compared with the U group, serum PTH concentrations were significantly lower in uremic rats treated with CINA (440.64 ± 43.25 vs 326.54 ± 47.86, p < 0.05). To further confirm the causal effect of elevated PTH on induction of EndMT, an in vitro experiment with primary aortic ECs was performed. The results showed that PTH incubation increased expression of FSP1 and α-SMA and decreased expression of CD31 at mRNA and protein levels in a concentration and time dependent manner (p < 0.05). Fig. 1 Effect of CINA on fibrotic lesions in uremic hearts. (A) Cardiac fibrosis was assessed by Masson’s trichrome staining. Images with different magnifications are shown. (B) Quantitative determination of cardiac fibrosis in the different groups. ... Fig. 2 Effect of CINA on the expression of EndMT-related markers in uremic hearts. (A) Representative micrographs showing immunohistochemical staining for cardiac expression of CD31 and FSP1 (original magnification is ×200). (B) Representative micrographs ... In conclusion, our data demonstrated that elevation of PTH induces EndMT and contributes to cardiac fibrosis in uremic rats, which could be prevented by CINA treatment. These results suggest that strategies aiming at lowering PTH levels might exert cardiac protective effects through an anti-EndMT mechanism.

Cost Effectiveness of Paricalcitol Versus Cinacalcet with Low-Dose Vitamin D for Management of Secondary Hyperparathyroidism in Haemodialysis Patients in the USA

BackgroundThe IMPACT SHPT [Improved Management of Intact Parathyroid Hormone (iPTH) with Paricalcitol-Centered Therapy Versus Cinacalcet Therapy with Low-Dose Vitamin D in Hemodialysis Patients with Secondary Hyperparathyroidism] study compared the effectiveness of paricalcitol and cinacalcet in the management of secondary hyperparathyroidism in haemodialysis patients but did not report the costs or cost effectiveness of these treatments.AimThe aim of this study was to compare the cost effectiveness of a paricalcitol-based regimen versus cinacalcet with low-dose vitamin D for management of secondary hyperparathyroidism in haemodialysis patients from a US payer perspective, using a 1-year time horizon.MethodsThis was a post hoc cost-effectiveness analysis of data collected for US patients enrolled in the IMPACT SHPT study—a 28-week, randomized, open-label, phase 4, multinational study (ClinicalTrials.gov identifier: NCT00977080). Patients eligible for the IMPACT SHPT study were aged ≥18 years with stage 5 chronic kidney disease, had been receiving maintenance haemodialysis three times weekly for at least 3 months before screening and were to continue haemodialysis during the study. Only US patients who reached the evaluation period (weeks 21–28) were included in this secondary analysis. US subjects in the IMPACT SHPT study were randomly assigned to receive intravenous paricalcitol, or oral cinacalcet plus fixed-dose intravenous doxercalciferol, for 28 weeks. Patients in the paricalcitol group could also receive supplemental cinacalcet for hypercalcaemia. The primary effectiveness endpoint in the IMPACT SHPT study was the proportion of subjects who achieved a mean intact parathyroid hormone (iPTH) level of 150–300 pg/mL during the evaluation period. In this secondary analysis, we estimated the incremental cost-effectiveness ratio (ICER), comparing paricalcitol-treated patients with cinacalcet-treated patients on the basis of this primary endpoint and several secondary endpoints. Costs were estimated by examining the dosage of the study drug (paricalcitol or cinacalcet) and phosphate binders used by each participant during the trial. Nonparametric bootstrap analysis was used to examine the accuracy of the ICER point estimates.ResultsThe percentages of patients achieving the treatment goal of a mean iPTH level between 150–300 pg/mL during weeks 21–28 of therapy were 56.9 % in the paricalcitol group and 34.0 % in the cinacalcet group (a difference of 23 %, p = 0.0235). Paricalcitol was also more effective for each of the secondary endpoints. When annualized, the total drug costs were US$10,153 in the paricalcitol group and US$15,967 in the cinacalcet group, a difference of US$5,814 (57.3 %, p = 0.0053). Because the paricalcitol-based treatment was less expensive and more effective, it was ‘dominant’, compared with cinacalcet, in this cost-effectiveness analyses. In our bootstrap analysis, 99.1 % of bootstrap replicates for the ICER of the primary endpoint fell within the lower right quadrant of the cost-effectiveness plane—where paricalcitol is considered dominant. For all of the other endpoints, paricalcitol was dominant in 100 % of replicates.ConclusionOn the basis of dosing and effectiveness data from US patients in the IMPACT SHPT study, we found that a regimen of intravenous paricalcitol was more cost effective than cinacalcet plus low-dose vitamin D in the management of iPTH in patients with SHPT requiring haemodialysis.

Role of cinacalcet in the treatment of secondary hyperparathyroidism in chronic kidney disease

Introduction — Secondary hyperparathyroidism (SHPT) is common in patients with chronic kidney disease (CKD) affecting most of the patients in end stage renal disease. Materials and Methods — This prospective case control study was conducted on 50 adult patients of CKD, having individual parathyroid hormone (iPTH) levels >300 pg/ml. These patients were divided into two groups: Group I (n=25) received calcitriol in dosage of 0.5 µg/day. Group II (n=25) received cinacalcet in dosage of 30 mg/day and calcitriol 0.5 µg/day. The study was carried out for 6 month duration. Results — The mean basal value of iPTH decreased to 246.40±219.99 pg/ml at the end of the study from basal value of 482.80±229.86 in group II. There was a 43% decrease in serum iPTH values in group II as opposed to the 14% decrease in group I (P<0.05). Serum Ca×P decreased by 9% in group I and by 13% in group II and there was statistically significant difference at the end of 3rd month as well as at the end of study in cinacalcet group. Conclusion — Cinacalcet is unique in its ability to simultaneously lower PTH, calcium, phosphorus and Ca×P in patients with SHPT and thus could become an important component in treatment of CKD patients.

Comparative cost analysis of management of secondary hyperparathyroidism with paricalcitol or cinacalcet with low-dose vitamin D in hemodialysis patients

Objective:The objective of this analysis was to compare costs of paricalcitol or cinacalcet plus low dose vitamin D, and of phosphate binders, in patients in the IMPACT SHPT study; and to extrapolate those to estimate expected annual maintenance costs.Methods:IMPACT SHPT was a 28-week, randomized, open-label trial. Subjects from 12 countries received intravenous (IV) or oral paricalcitol, or oral cinacalcet plus fixed IV doxercalciferol or oral alfacalcidol. The primary end-point was the proportion of subjects who achieved a mean intact parathyroid hormone (iPTH) value of 150–300 pg/mL during weeks 21–28 (evaluation period). This study compares the costs of study drugs and phosphate binders among participants during the study and annualized. This analysis includes only those subjects that reached the evaluation period (134 in each group).Results:The mean total drug costs over the study period were €2606 (SD = €2000) in the paricalcitol group and €3034 (SD = €3006) in the cinacalcet group (difference €428, p = 0.1712). The estimated annualized costs were €5387 (SD = €4139) in the paricalcitol group and €6870 (SD = €6256) in the cinacalcet group (difference €1492, p = 0.0395). In addition, a significantly greater proportion (p = 0.010) of subjects in the paricalcitol arm (56.0%) achieved an iPTH of 150–300 pg/mL during the evaluation period compared to the cinacalcet arm (38.2%).Limitations:This was a secondary analysis of the IMPACT SHPT study which was not designed or powered for costs as an outcome. The dosing of study drugs and phosphate binders in the IMPACT study may not reflect actual practice, and patients were followed for 28 weeks, while the treatment of SHPT is long-term.Conclusion:Patients with SHPT requiring hemodialysis who were treated with a paricalcitol-based regimen for iPTH control had lower estimated annual drug costs compared to those treated with cinacalcet plus low-dose vitamin D.

Cinacalcet lowering of serum fibroblast growth factor-23 concentration may be independent from serum Ca, P, PTH and dose of active vitamin D in peritoneal dialysis patients: a randomized controlled study

BackgroundElevated serum level of fibroblast growth factor-23 (FGF23) is associated with adverse outcomes in dialyzed patients.ObjectivesThe CUPID study compared the efficacy of a cinacalcet-based regimen with conventional care (vitamin D and P binders) for achieving the stringent NKF-K/DOQI targets for peritoneal dialysis (PD) patients. Additionally, we analyzed change in FGF23 levels between two treatments to explore the cinacalcet effect in lowering FGF23.DesignMulticenter, open-labeled, randomized controlled study.SettingSeven university-affiliated hospitals in Korea.ParticipantsOverall, 66 peritoneal dialysis patients were enrolled.InterventionSixty six patients were randomly assigned to treatment with either cinacalcet + oral vitamin D (cinacalcet group, n = 33) or oral vitamin D alone (control group, n = 33) to achieve K/DOQI targets. CUPID included a 4-week screening for vitamin D washout, a 12-week dose-titration, and a 4-week assessment phases. We calculated mean values of iPTH, Ca, P, Ca x P, during assessment phase and final FGF23 to assess the outcome.Main outcome measuresAchievement of >30% reduction of iPTH from baseline (primary) and FGF23 reduction (secondary).Results72.7% (n = 24) of the cinacalcet group and 93.9% (n = 31) of the control group completed the study. Cinacalcet group received 30.2 ± 18.0 mg/day of cinacalcet and 0.13 ± 0.32 μg/d oral vitamin D (P < 0.001 vs. control with 0.27 ± 0.18 μg/d vitamin D). The proportion of patients who reached the primary endpoint was not statistically different (48.5% vs. 51.5%, cinacalcet vs. control, P = 1.000). After treatment, cinacalcet group experienced a significant reduction in FGF23 levels (median value from 3,960 to 2,325 RU/ml, P = 0.002), while an insignificant change was shown for control group (from 2,085 to 2,415 RU/ml). The percent change of FGF23 after treatment was also significantly different between the two groups (− 42.54% vs. 15.83%, P = 0.008). After adjustment, cinacalcet treatment was independently associated with the serum FGF23 reduction.ConclusionCinacalcet treatment was independently associated with the reduction of FGF23 in our PD patients.Trial registrationControlled trials NCT01101113

Cinacalcet Upregulates Calcium-Sensing Receptors of Parathyroid Glands in Hemodialysis Patients

Background: Cinacalcet hydrochloride (cinacalcet), a calcimimetic, has been shown to upregulate calcium-sensing receptor (CaSR) expression in parathyroid glands of rats with chronic renal insufficiency. However, the effect of cinacalcet on the reduced CaSR expression in human parathyroid glands remains to be elucidated. Methods: Four normal parathyroid glands and 71 hyperplastic parathyroid glands from 18 hemodialysis patients with refractory secondary hyperparathyroidism (SHPT) treated with (n = 10; cinacalcet group) or without (n = 8; conventional group) cinacalcet were examined immunohistochemically with a specific antibody against CaSR. The expression level of CaSR was analyzed semiquantitatively. Results: Compared with normal glands, the immunohistochemical expression of CaSR was decreased significantly in both the cinacalcet and conventional groups. In the cinacalcet group, the expression of CaSR was increased significantly compared with that in the conventional group (1.83 ± 0.14 vs. 0.87 ± 0.15, p < 0.001), even though the proportion of patients using vitamin D sterols and the mean administered dose of calcitriol equivalents were not significantly different between the two groups. The expression of CaSR was significantly decreased in the larger glands (>500 mg) compared with that in the smaller glands (<500 mg) in both groups; furthermore, it was markedly decreased in areas of nodular hyperplasia compared with diffuse hyperplasia in the cinacalcet group. Conclusions: Our results indicate that cinacalcet upregulates the depressed expression of CaSR in hemodialysis patients with SHPT, and that insufficient expression of CaSR, especially in larger glands with advanced nodular hyperplasia, underlies the pathogenesis of SHPT in patients who are resistant to cinacalcet.

Effect of Cinacalcet on Cardiovascular Disease in Patients Undergoing Dialysis

BackgroundDisorders of mineral metabolism, including secondary hyperparathyroidism, are thought to contribute to extraskeletal (including vascular) calcification among patients with chronic kidney disease. It has been hypothesized that treatment with the calcimimetic agent cinacalcet might reduce the risk of death or nonfatal cardiovascular events in such patients.MethodsIn this clinical trial, we randomly assigned 3883 patients with moderate-to-severe secondary hyperparathyroidism (median level of intact parathyroid hormone, 693 pg per milliliter [10th to 90th percentile, 363 to 1694]) who were undergoing hemodialysis to receive either cinacalcet or placebo. All patients were eligible to receive conventional therapy, including phosphate binders, vitamin D sterols, or both. The patients were followed for up to 64 months. The primary composite end point was the time until death, myocardial infarction, hospitalization for unstable angina, heart failure, or a peripheral vascular event. The primary analysis was performed on the basis of the intention-to-treat principle.ResultsThe median duration of study-drug exposure was 21.2 months in the cinacalcet group, versus 17.5 months in the placebo group. The primary composite end point was reached in 938 of 1948 patients (48.2%) in the cinacalcet group and 952 of 1935 patients (49.2%) in the placebo group (relative hazard in the cinacalcet group vs. the placebo group, 0.93; 95% confidence interval, 0.85 to 1.02; P=0.11). Hypocalcemia and gastrointestinal adverse events were significantly more frequent in patients receiving cinacalcet.ConclusionsIn an unadjusted intention-to-treat analysis, cinacalcet did not significantly reduce the risk of death or major cardiovascular events in patients with moderate-to-severe secondary hyperparathyroidism who were undergoing dialysis. (Funded by Amgen; EVOLVE ClinicalTrials.gov number, NCT00345839.)

Effects and Safety of Calcimimetics in End Stage Renal Disease Patients with Secondary Hyperparathyroidism: A Meta-Analysis

PurposeSecondary hyperparathyroidism (SHPT) is one of the most common abnormalities of mineral metabolism in patients with chronic kidney disease. We performed a meta-analysis to determine the effect and safety of cinacalcet in SHPT patients receiving dialysis.MethodsThe meta-analysis was performed to determine the effect and safety of cinacalcet in SHPT patients receiving dialysis by using the search terms ‘cinacalcet’ or ‘mimpara’ or ‘sensipar’ or ‘calcimimetic’ or ‘R586’ on MEDLINE and EMBASE (January 1990 to February 2012).ResultsFifteen trials were included, all of which were performed between 2000 and 2011 enrolling a total of 3387 dialysis patients. Our study showed that calcimimetic agents effectively ameliorated iPTH levels(WMD, −294.36 pg/mL; 95% CI, −322.76 to −265.95, P<0.001) in SHPT patients and reduced serum calcium (WMD, −0.81 mg/dL; 95% CI, −0.89 to −0.72, P<0.001) and phosphorus disturbances(WMD, −0.29 mg/dL; 95% CI, −0.41 to −0.17, P<0.001). The percentage of patients in whom there was a 30% decrease in serum iPTH levels by the end of the dosing was higher in cinacalcet group than that in control group(OR = 10.75, 95% CI: 6.65–17.37, P<0.001). However, no significant difference was found in all-cause mortality and all adverse events between calcimimetics and control groups(OR = 0.86, 95% CI: 0.46–1.60, P = 0.630; OR = 1.30, 95% CI: 0.78–2.18, P = 0.320, respectively). Compared with the control therapy, there was a significant increase in the episodes of hypocalcemia (OR = 2.46, 95% CI: 1.58–3.82, P<0.001), nausea (OR = 2.45, 95% CI: 1.29–4.66, P = 0.006), vomiting(OR = 2.78, 95% CI: 2.14–3.62, P<0.001), diarrhea(OR = 1.51, 95% CI: 1.04–2.20, P = 0.030) and upper respiratory tract infection (OR = 1.79, 95% CI: 1.20–2.66, P = 0.004)in calcimimetics group.ConclusionsCalcimimetic treatment effectively improved biochemical parameters of SHPT patients receiving dialysis without increasing all-cause mortality and all adverse events.

Impact of Long-Term Cinacalcet, Ibandronate or Teriparatide Therapy on Bone Mineral Density of Hemodialysis Patients: A Pilot Study

Background: Insufficient evidenced-based information is available for the treatment of osteoporosis in hemodialysis (HD) patients. Methods: In 102 HD patients, bone mineral density (BMD) was measured twice 16 ± 3 months apart. In the second BMD measurement 66 of them had a femoral neck (FN) T-score <–2.5. Of these 66 patients, 38 consented to a bone biopsy. Depending on both the bone biopsy findings and parathyroid hormone levels, patients were assigned to treatment groups. Eleven patients with osteitis fibrosa and iPTH >300 pg/ml received cinacalcet, 11 with osteitis fibrosa and iPTH <300 pg/ml received ibandronate, 9 with adynamic bone disease received teriparatide, and 7 with mild abnormalities received no treatment. A third BMD measurement was done after an average treatment period of 13–16 months. We compared the annual percent change of FN and lumbar spine (LS) BMD before and during treatment. Results: FN and LS BMD decreased significantly in the cinacalcet group, with an annual change of 3.6 and 3.4% before treatment to –4.2% (p = 0.04) and –7.7% (p = 0.02) during treatment, respectively. In the teriparatide group, FN and LS BMD increased, although not significantly, with an annual change of –5.4 and –2.6% before treatment to 2.7 and 4.9% during treatment, respectively. In both the ibandronate and the no treatment groups, BMD change rate remained negative during the whole study. Conclusions: Teriparatide administration improved BMD in HD patients with adynamic bone disease, although these results did not reach statistical significance. In HD patients with osteitis fibrosa, ibandronate did not improve BMD while cinacalcet reduced BMD.

Effects of cinacalcet on bone mineral density and bone markers in hemodialysis patients with secondary hyperparathyroidism

Cinacalcet markedly reduces the serum intact parathyroid hormone (PTH) level of hemodialysis (HD) patients with secondary hyperparathyroidism. Parathyroidectomy also reduces the serum intact PTH level of HD patients and it increases their bone mineral density (BMD). However, there is little information about the effect of cinacalcet on BMD or on the associations between bone markers and BMD in HD patients. We performed a 1-year cohort study of 25 HD patients who had a serum intact PTH level above 300 pg/ml during treatment by conventional therapies, such as with active vitamin D, and cinacalcet was prescribed for 14 of them. BMD of the femoral neck and the serum levels of two circulating bone markers, alkaline phosphatase (ALP) and bone-specific alkaline phosphatase (BSAP), were measured before and after treatment. The other 11 HD patients without cinacalcet treatment were defined as control group. BMD significantly increased by 7.3 % during the 1 year of treatment in the cinacalcet group and decreased by 6.2 % during the same period in the control group, and cinacalcet therapy was independently associated with the changes in BMD after multiple regression analysis that included intact PTH (β = 7.57, P < 0.01). In the cinacalcet group, the serum ALP levels (R(2) = 0.315, P < 0.05) and BSAP levels (R(2) = 0.682, P < 0.01) levels were significantly negatively correlated with the changes in BMD, but the serum intact PTH levels were not significantly associated with the changes in BMD (R(2) = 0.011, P = 0.72). One year of treatment with cinacalcet increased the BMD of the femoral neck in the HD cohort, especially in the patients who had higher serum ALP and BSAP levels at baseline.

Tertiary Hyperparathyroidism in Kidney Transplant Recipients

Several treatment options exist for kidney transplant patients with tertiary hyperparathyroidism. However, the decision to endorse observation (OBS), medical therapy, or parathyroidectomy (PTX) remains controversial. We performed a retrospective cohort study of kidney transplant patients with tertiary hyperparathyroidism at a single institution over a 7-year period. Patients were classified by treatment mode: OBS, medical therapy with cinacalcet (CIN), or PTX. Descriptive statistics were performed. Serum calcium levels and change in serum creatinine level were compared using analysis of variance with comparisons between individual groups using the Student's t test with a Bonferroni correction. Time to treatment was compared between CIN and PTX groups using the Student's t test. Complication rates were compared using the Fisher exact test. We identified 83 patients: 52 were treated by OBS; 13 were treated with CIN, and 18 underwent PTX. Six weeks after treatment, PTX resulted in lower serum calcium level (9.28 mg/dL) compared with CIN (10.20 mg/dL) (P<0.01). There was no difference in the change in serum creatinine level 1 year after treatment initiation (P=0.98). Time to treatment was shorter (1.7 vs. 3.3 years, P<0.01), and the highest pretreatment calcium level was higher (12.2 vs. 11.7 mg/dL, P<0.01) in patients treated with PTX compared with CIN. Complication rates differed by treatment group (P<0.01). A quarter of OBS patients showed persistent hypercalcemic symptoms, compared with only 7.7% in the CIN group and 0% in the PTX group (P<0.01). PTX led to a greater reduction in serum calcium level and lower chance of persistent hypercalcemic symptoms, without any appreciable harm to the kidney allograft.