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Long-Term Efficacy and Safety of Evocalcet in Japanese Patients with Secondary Hyperparathyroidism Receiving Hemodialysis.
Yokoyama, K, Shimazaki, R, Fukagawa, M, Akizawa, T, ,
Scientific reports. 2019;(1):6410
Abstract
Secondary hyperparathyroidism (SHPT) is a common complication of chronic kidney disease (CKD), and as the disease progresses SHPT is associated with systemic consequences, termed CKD-mineral and bone disorder. Currently, cinacalcet is indicated for the treatment of SHPT; however, cinacalcet is associated with upper gastrointestinal adverse events. Evocalcet has been developed to address these issues, but the long-term safety and efficacy of evocalcet need to be evaluated. To more accurately reflect clinical practice, this phase 3, multicenter, open-label study was specifically designed without a cinacalcet washout period, and focused on those patients who switched from cinacalcet to evocalcet. A total of 137 SHPT patients undergoing hemodialysis were enrolled, of whom 113 switched from cinacalcet to evocalcet. The most frequent type of adverse drug reaction was decreased adjusted calcium. The incidence of gastrointestinal-related adverse events did not increase in a dose-dependent manner as the dose of evocalcet was increased. The percentage of patients achieving the target intact parathyroid hormone concentration increased from 40.9% to 72.3% with 52-week treatment. The corrected serum calcium and phosphorus levels remained largely unchanged throughout the study. The long-term safety and efficacy of evocalcet was confirmed using a clinically relevant intra-subject dose-adjustment strategy in SHPT patients undergoing hemodialysis.
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Effectiveness and safety of a 6-month treatment with paricalcitol in patients on hemodialysis with secondary hyperparathyroidism.
Olaizola, I, Caorsi, H, Fajardo, L, Ferreiro, A, Campistrus, N, Dolinsky, D, Petraglia, A, Ambrosoni, P
Jornal brasileiro de nefrologia. 2016;(3):302-312
Abstract
INTRODUCTION The mineral bone disorder, particularly secondary hyperparathyroidism, in chronic kidney disease (CKD) has a systemic impact affecting not only bone metabolism. Therefore its correction is important to prevent cardiovascular, inflammatory and immune diseases. OBJECTIVE To assess the effectiveness and safety of intravenous paricalcitol administered over a 6 month period for the treatment of secondary hyperparathyroidism (SHPT) in patients undergoing conventional hemodialysis, with close follow-up of treatment response. METHODS A phase 4 clinical trial was performed comparing clinical and laboratory data before and after 6 months of treatment. SHPT patients undergoing hemodialysis who were naïve to vitamin D metabolites or had failed to current therapy were included. Clinical and laboratory characteristics were analyzed. Efficacy analyses were based on intact parathyroid hormone (iPTH) levels and were performed using data from patients who completed 6 months of treatment. RESULTS Nineteen of the 26 patients enrolled completed 6 months of treatment. All patients exhibited reduced baseline iPTH levels (mean reduction, 371.8 pg/mL; 95% CI, 273.3-470.2 pg/mL]; 17 patients (89.5%) had reductions exceeding 30%. Twelve patients (63%) achieved therapeutic success (defined as iPTH serum levels 150-300 pg/mL), with a median time of 2 months from the beginning of treatment. All reported episodes of hypercalcemia (n = 2) and hyperphosphatemia (n = 34) were asymptomatic. No major therapy-related serious AEs were reported. CONCLUSION Paricalcitol was safely administered and was associated with significant decreases in iPTH levels over the study period.
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Treatment of Secondary Hyperparathyroidism: Results of a Phase 2 Trial Evaluating an Intravenous Peptide Agonist of the Calcium-Sensing Receptor.
Bushinsky, DA, Block, GA, Martin, KJ, Bell, G, Huang, S, Sun, Y, Spiegel, DM, Walsh, L, Mix, TC, Kewalramani, R
American journal of nephrology. 2015;(5):379-88
Abstract
BACKGROUND/AIMS: This study evaluated the efficacy and safety of AMG416 (etelcalcitide), a novel peptide agonist of the calcium (Ca)-sensing receptor given intravenously (IV) after each hemodialysis session for the treatment of secondary hyperparathyroidism (SHPT). METHODS Adult subjects with SHPT on hemodialysis enrolled in a 12-week, dose titration (parent) study followed by an open-label extension phase. AMG416 was administered IV, thrice weekly starting at 5 mg/session and titrated based on the subject's parathyroid hormone (PTH) and albumin-corrected Ca (cCa) to target a PTH of 150-300 pg/ml. Efficacy (percent PTH change from baseline to the efficacy analysis period during the parent study) and safety (open-label extension phase) endpoints were evaluated. RESULTS Baseline (n = 37) mean (standard error [SE]) PTH was 853 (106 pg/ml). The mean (95% CI) percent change from baseline to the efficacy analysis period in PTH concentration was -53.6% (-60.8, -46.4). The proportion of subjects with ≥30% reduction in PTH from baseline to the efficacy assessment period (EAP) was 89% (32/36; 95% CI 73.9, 96.9). Results by the baseline PTH subgroup (≤700 vs. >700 pg/ml) were comparable for both analyses. The proportion of subjects achieving a PTH ≤300 pg/ml was 56% (n = 20/36) at the efficacy assessment period. The mean (SE) percent changes from baseline to EAP were observed for cCa -15% (1.0%) and phosphorus -10% (3.3%). Adverse events were mild to moderate in severity. The PTH reductions achieved in the parent study were maintained in the open-label extension phase. CONCLUSION AMG416 was well tolerated and appears to be an effective agent for the treatment of SHPT in patients on hemodialysis.
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Cinacalcet treatment decreases plasma fibroblast growth factor 23 concentration in haemodialysed patients with chronic kidney disease and secondary hyperparathyroidism.
Kuczera, P, Adamczak, M, Wiecek, A
Clinical endocrinology. 2014;(4):607-12
Abstract
OBJECTIVE Recent clinical studies suggest that fibroblast growth factor 23 (FGF23) is important in the pathogenesis of calcium-phosphate abnormalities in patients with chronic kidney disease and that increased plasma FGF23 concentration is a cardiovascular risk factor in these patients. The aim of this prospective, single-arm, open-label clinical study was to assess the influence of 6-month cinacalcet treatment on plasma FGF23 concentration in haemodialysed patients with secondary hyperparathyroidism (sHPT). DESIGN, PATIENTS AND MEASUREMENTS In 58 haemodialysed patients with sHPT (parathormone PTH > 300 ng/l), serum PTH, FGF23, calcium and phosphate concentrations were assessed before the first dose of cinacalcet and after 3 and 6 months of treatment. RESULTS Serum PTH concentration decreased significantly after 3 and 6 months of treatment, and the mean serum calcium and phosphate concentrations remained stable during the treatment period. Plasma FGF23 concentration (geometric mean with 95% confidence index) decreased after 3 and 6 months of treatment from 354 (261-481) ng/l to 295 (204-428) ng/l; P = 0·099 and to 183 (117-285) ng/l; P = 0·015, respectively. FGF23 concentration decreased in 52% of patients. In multivariate regression analysis, plasma FGF23 concentration changes were explained by the changes in serum phosphate, but not by serum PTH or calcium changes or by the dose of cinacalcet. CONCLUSIONS 1. Cinacalcet treatment decreases plasma FGF23 concentration in haemodialysed patients with secondary hyperparathyroidism. 2. The decrease in plasma FGF23 concentration seems to be related to the decrease in serum phosphate concentration.
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Parathyroidectomy improves cardiovascular outcome in nondiabetic dialysis patients with secondary hyperparathyroidism.
Lin, HC, Chen, CL, Lin, HS, Chou, KJ, Fang, HC, Liu, SI, Hsu, CY, Huang, WC, Huang, CW, Huang, CK, et al
Clinical endocrinology. 2014;(4):508-15
Abstract
OBJECTIVE Secondary hyperparathyroidism and its associated abnormalities in mineral metabolism and haemodynamic changes increase the cardiovascular risk in patients with end-stage renal disease (ESRD). Our objective was to determine the association of parathyroidectomy (PTX) with major cardiovascular events in nondiabetic dialysis patients with severe secondary hyperparathyroidism (SHPTH). DESIGN AND PATIENTS We performed a cohort study with fifty-three nondiabetic ESRD patients who were treated with maintenance haemodialysis and who had intact parathyroid hormone (PTH) levels > 800 pg/ml. Participants received either only medical therapy or medical therapy and total PTX with autotransplantation for SHPTH. MEASUREMENTS We evaluated the associations between PTX and major cardiovascular events including death, cerebrovascular accident and myocardial infarction. The biochemical and haemodynamic changes associated with PTX were measured. RESULTS During the mean follow-up of 72 months, twenty-three patients received only medical treatment (medical group) while thirty patients underwent PTX in addition to medical treatment (PTX group). The two groups were comparable in respect of baseline characteristics. PTX group was found to be associated with a reduced incidence of major cardiovascular events (P = 0·021). A multiple Cox regression analysis showed that the variable significantly associated with major cardiovascular events was treatment modality (medical therapy vs medical therapy and parathyroidectomy, hazard ratio = 26·12, 95% CI = 1·30-526·27, P = 0·033). Blood pressure, haemoglobin, alkaline phosphatase, calcium, phosphate and calcium × phosphate product significantly improved after PTX. CONCLUSIONS PTX was associated with better cardiovascular outcome in nondiabetic dialysis patients with severe SHPTH.
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Paricalcitol reduces proteinuria in non-dialysis chronic kidney disease patients.
Hojs, N, Bevc, S, Balon, BP, Hojs, R, Ekart, R
Therapeutic apheresis and dialysis : official peer-reviewed journal of the International Society for Apheresis, the Japanese Society for Apheresis, the Japanese Society for Dialysis Therapy. 2013;(4):368-72
Abstract
Existing treatment of proteinuria is not sufficient to halt the chronic kidney disease (CKD) epidemic. Therefore the aim of our study was to evaluate the effect of paricalcitol on proteinuria in non-dialysis CKD patients with secondary hyperparathyroidism treated according to Kidney Disease: Improving Global Outcomes (KDIGO) guidelines. Forty-one non-dialysis CKD patients with secondary hyperparathyroidism (iPTH >65 pg/mL), serum calcium <2.6 mmol/L, serum phosphate <1.8 mmol/L and proteinuria (>150 mg/day) were treated with paricalcitol 1 μg/day. Most were treated for 6 months, with the exception of three patients having iPTH <30 pg/mL after 3 months, in whom therapy was stopped. All patients were followed for 6 months. 24-h ambulatory blood pressure (24hABP) monitoring was performed at 0 and 6 months. Fixed doses of ACE inhibitors and/or ARBs and/or statins were kept for 3 months before and during the study. Forty-one patients (30 men, 11 women; age 62.44 ± 11.93 years) with different primary causes of CKD were enrolled in the study. Urinary albumin/creatinine ratio (UACR), 24-h urinary albuminuria (24hUA) and 24-h urinary quantitative proteinuria (24hUQP) were measured. Values at 0 and 6 months of these parameters were log-transformed for statistical analysis. After treatment with paricalcitol, statistically significant reduction (paired t-test) in 24hUA (P < 0.011) and 24hUQP (P < 0.0001) were found. The reduction of UACR was not significant (P = 0.074). In the observational period no statistically significant reduction in 24hABP was found. Treatment with 1 μg paricalcitol daily according to clinical practice in non-dialysis CKD patients with secondary hyperparathyroidism and proteinuria significantly reduces 24hUA and 24hUQP without significant change in 24hABP.
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Cinacalcet improves endothelial dysfunction and cardiac hypertrophy in patients on hemodialysis with secondary hyperparathyroidism.
Choi, SR, Lim, JH, Kim, MY, Hong, YA, Chung, BH, Chung, S, Choi, BS, Yang, CW, Kim, YS, Chang, YS, et al
Nephron. Clinical practice. 2012;(1-2):1-8
Abstract
BACKGROUND Secondary hyperparathyroidism (SHPT) in patients on hemodialysis is strongly associated with cardio-vascular morbidity and mortality. Treatment of SHPT with cinacalcet decreases circulating parathyroid hormone (PTH) concentrations and lowers serum calcium and phosphorus concentrations. Therefore, we investigated the cardiovascular effects of cinacalcet in hemodialysis patients with SHPT. METHODS We studied 12 hemodialysis patients with SPHT [serum intact PTH (iPTH) >300 pg/ml]. The study consisted of three phases: an initial run-in period of 16 weeks, including a wash-out period of 4 weeks (pretreatment), a cinacalcet treatment period of 20 weeks (treatment), and 20-week follow-up after suspension of cinacalcet treatment (posttreatment). In this study, vitamin D sterols were not prescribed to all the study subjects for at least 1 year during the pretreatment period. RESULTS Cinacalcet significantly decreased serum iPTH (pretreatment vs. treatment; 628.2 ± 250.8 vs. 251.7 ± 237.4 pg/ml, p < 0.01), calcium, phosphorus, and calcium × phosphorus product (p < 0.01), all of which returned to baseline levels after treatment. There was no change in C-reactive protein during the study period. There was significantly improvement in brachial flow-mediated dilatation (p < 0.01) and enhanced cardio-ankle vascular index (p < 0.01) with cinacalcet treatment. Moreover, cinacalcet significantly improved diastolic function (E/e' ratio, p < 0.05) and the left ventricular mass index (p < 0.05). Cinacalcet also increased serum NO x (p < 0.05) and decreased serum isoprostane (p < 0.05) and soluble intercellular adhesion molecule-1 concentrations (p < 0.05). All of these biochemical parameters returned to their pretreatment concentrations after withdrawal of cinacalcet. CONCLUSIONS Cinacalcet hydrochloride without vitamin D might ameliorate endothelial dysfunction, diastolic dysfunction, and cardiac hypertrophy by decreasing oxidative stress and increasing the serum nitric oxide production in hemodialysis patients with SHPT.
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Secondary hyperparathyroidism but stable bone-mineral density in patients with chronic myeloid leukemia treated with imatinib.
Jönsson, S, Standal, T, Olsson, B, Mellström, D, Wadenvik, H
American journal of hematology. 2012;(5):550-2
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Abstract
Imatinib is currently the standard treatment for chronic myeloid leukemia(CML). Previous studies have shown that imatinib affects bone metabolism in CML patients. However, these effects are not well-studied prospectively. The authors studied bone-mineral density (BMD) and bone metabolism in 17 CML patients and matched controls in 2007 and now repeated the analyses prospectively in 2011. All CML patients were in complete cytogenetic remission during this 4-year period and treated with 400 mg imatinib q.d. (n 5 15) or 600 mg imatinib q.d. (n 5 2). Mean treatment duration was 102 months (range 69–129) in 2011. The authors found that serum levels of parathyroid hormone increased significantly in the patients between 2007 and 2011, and seven out of 17 patients had secondary hyperparathyroidism in 2011. However, the mean areal and volumetric BMDs were stable in the CML patients over the 4-year-observation period. Moreover, the CML patients had significantly higher volumetric BMD in the cortical compartment when compared with controls in 2011 and 2007. Thus, despite a high incidence of secondary hyperparathyroidism,there were no signs of osteoporosis or osteomalacia in imatinib-treated CML patients as suggested earlier.
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Vitamin D receptor activator reduces oxidative stress in hemodialysis patients with secondary hyperparathyroidism.
Tanaka, M, Tokunaga, K, Komaba, H, Itoh, K, Matsushita, K, Watanabe, H, Kadowaki, D, Maruyama, T, Otagiri, M, Fukagawa, M
Therapeutic apheresis and dialysis : official peer-reviewed journal of the International Society for Apheresis, the Japanese Society for Apheresis, the Japanese Society for Dialysis Therapy. 2011;(2):161-8
Abstract
Treatment with a vitamin D receptor activator (VDRA) has survival benefits probably related to its effects beyond the traditional role in mineral metabolism. We hypothesized that VDRA reduces oxidative stress in hemodialysis (HD) patients. To test this hypothesis, we investigated the effect of VDRA on the oxidative status of albumin in HD patients with secondary hyperparathyroidism. Eleven HD patients with secondary hyperparathyroidism were treated with calcitriol at an intravenous dose of 1.5 µg/week for four weeks. Serum intact parathyroid hormone, calcium and phosphorus were monitored and we measured the amount of oxidized albumin and albumin hydroperoxides form before and after calcitriol treatment. The ratio of oxidized to un-oxidized albumin was determined as a representative marker of oxidative stress. The radical scavenging activity of albumin was also evaluated. After four weeks of calcitriol therapy, there were no significant changes in serum intact parathyroid hormone, calcium, or phosphorus levels; however, the ratio of oxidized to un-oxidized albumin was markedly decreased and serum thiol content was significantly increased after calcitriol treatment. Furthermore, the radical scavenging activity of albumin was greater after calcitriol treatment compared with that of untreated albumin. Our data suggest that intravenous calcitriol treatment reduces oxidative stress and strengthens antioxidant defenses by inhibiting albumin oxidation in HD patients with secondary hyperparathyroidism.
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Local calcitriol injections as a suppressive treatment of secondary hyperparathyroidism in chronic dialysis patients.
Junik, R, Polaáska, M, Manitius, J, Doroszewski, W, Sypniewska, G, Gruszka, M
Renal failure. 2007;(8):941-5
Abstract
AIM: A prospective study was made of the effectiveness of repeatable local calcitriol injections therapy to suppress secondary hyperparathyroidism resistant to conventional therapy in chronic dialysis patients. METHODS Under ultrasonographic guidance, six injections at an interval of two days were performed in 14 chronic dialysis patients. The total amount of calcitriol to be injected each time was estimated as 100% of the calculated gland volume. Calcitriol was given in doses 1 mug of medicine per 1 cubic cm (as measured by USG) of parathyroid tissue. Parathormone concentration, total calcium, ionized calcium, phosphate, and alkaline phosphatase levels were assessed on the first and last day of the treatment period. RESULTS Prior to therapy, the mean gland volumes were 0.62 (0.15-3.0) ml, and they increased to 0.85 (0.2-3.9) after 14 days (NS). Seven patients were found to have decreased their PTH levels to 909 +/- 387 pg/mL after 14 days of treatment when compared with the first day mean values of 1588 +/- 440 pg/mL (p < 0.05). After completion of the therapy, four patients were reported to be free from any clinical symptoms of ostalgia or arthralgia. Others reported an alleviation of pain. CONCLUSIONS Parathyroid adenoma injection is an alternative method of treatment for some patients resistant to treatment by means of vitamin D3 pulses or intravenous administration of calcitriol. The success of treatment is to a great extent determined by proper selection of patients and the taking of decisions when the period of secondary hyperparathyroidism is not very advanced.