Comparative effects of calcitriol and calcimimetic on bone health in renal insufficiency.

Calcitriol and calcimimetics are used to treat hyperparathyroidism secondary to chronic kidney disease (CKD). Calcitriol administration and the subsequent increase in serum calcium concentration decrease parathyroid hormone (PTH) levels, which should reduce bone remodeling. We have previously reported that, when maintaining a given concentration of PTH, the addition of calcimimetics is associated with an increased bone cell activity. Whether calcitriol administration affects bone cell activity while PTH is maintained constant should be evaluated in an animal model of renal osteodystrophy. The aim of the present study was to compare in CKD PTH-clamped rats the bone effects of calcitriol and calcimimetic administration. The results show that the administration of calcitriol and calcimimetic at doses that induced a similar reduction in PTH secretion produced dissimilar effects on osteoblast activity in 5/6 nephrectomized (Nx) rats with secondary hyperparathyroidism and in Nx rats with clamped PTH. Remarkably, in both rat models, the administration of calcitriol decreased osteoblastic activity, whereas calcimimetic increased bone cell activity. In vitro, calcitriol supplementation inhibited nuclear translocation of ß-catenin and reduced proliferation, osteogenesis, and mineralization in mesenchymal stem cells differentiated into osteoblasts. In conclusion, besides the action of calcitriol and calcimimetics at parathyroid level, these treatments have specific effects on bone cells that are independent of the PTH level.

Pharmaceutical Management of Secondary Hyperparathyroidism and the Role of Surgery: A 5-Year Retrospective Study.

Background and Objectives: Secondary hyperparathyroidism (SHPT) poses a common condition among patients with chronic kidney disease (CKD) due to the chronic stimulation of the parathyroid glands as a result of persistently low calcium levels. As a first option for medical treatment, vitamin D receptor analogs (VDRAs) and calcimimetic agents are generally used. Apart from cinacalcet, which is orally taken, in recent years, another calcimimetic agent, etelcalcetide, is being administered intravenously during dialysis. Materials and Methods: In a 5-year retrospective study between 2018 and 2023, 52 patients undergoing dialysis were studied. The aim of this study is to highlight the possible effects and/or benefits that intravenously administered calcimimetic agents have on CKD patients. A total of 34 patients (65.4%) received cinacalcet and etelcalcetide while parathormone (PTH) and calcium serum levels were monitored on a monthly basis. Results: A total of 29 out of 33 patients (87.9%) that received treatment with etelcalcetide showed a significant decrease in PTH levels, which rose up to 57% compared to the initial values. None of the included patients needed to undergo parathyroidectomy (PTx) due to either extremely high and persistent PTH levels or severe side effects of the medications. It is generally strongly advised that parathyroidectomies should be performed by an expert surgical team. In recent years, a significant decrease in parathyroidectomies has been recorded globally, a fact that is mainly linked to the constantly wider use of new calcimimetic agents. This decrease in parathyroidectomies has resulted in an important decrease in complications occurring in cervical surgeries (e.g., perioperative hemorrhage and nerve damage). Conslusions: Despite the fact that these surgical complications cannot be easily compared to the pharmaceutical side effects, the recorded decrease in parathyroidectomies is considered to be notable, especially in cases of relapse where a difficult reoperation would be considered based on previously published guidelines.

Pre-Transplant Calcimimetic Use and Dose Information Improves the Accuracy of Prediction of Tertiary Hyperparathyroidism after Kidney Transplantation: A Retrospective Cohort Study.

Tertiary hyperparathyroidism (THPT) is characterized by elevated parathyroid hormone and serum calcium levels after kidney transplantation (KTx). To ascertain whether pre-transplant calcimimetic use and dose information would improve THPT prediction accuracy, this retrospective cohort study evaluated patients who underwent KTx between 2010 and 2022. The primary outcome was the development of clinically relevant THPT. Logistic regression analysis was used to evaluate pre-transplant calcimimetic use as a determinant of THPT development. Participants were categorized into four groups according to calcimimetic dose, developing two THPT prediction models (with or without calcimimetic information). Continuous net reclassification improvement (CNRI) and integrated discrimination improvement (IDI) were calculated to assess ability to reclassify the degree of THPT risk by adding pre-transplant calcimimetic information. Of the 554 patients, 87 (15.7%) developed THPT, whereas 139 (25.1%) received pre-transplant calcimimetic treatment. Multivariate logistic regression analysis revealed that pre-transplant calcimimetic use was significantly associated with THPT development. Pre-transplant calcimimetic information significantly improved the predicted probability accuracy of THPT (CNRI and IDI were 0.91 [p < 0.001], and 0.09 [p < 0.001], respectively). The THPT prediction model including pre-transplant calcimimetic information as a predictive factor can contribute to the prevention and early treatment of THPT in the era of calcimimetics.

The impact of accessibility to non-calcium-based phosphate binders and calcimimetics on mineral outcomes in patients receiving maintenance hemodialysis: A 10-year retrospective analysis of real-world data.

INTRODUCTION: Hyperphosphatemia and hyperparathyroidism are common in end-stage kidney disease and are associated with poor outcomes. In addition to adequate dialysis, medications are usually required for optimum control of serum phosphate and parathyroid hormone (PTH) levels. The use of calcium-based phosphate binders (CBPBs) and active vitamin D is associated with an increase in serum calcium and worsening vascular calcification. To overcome these limitations, non-calcium-based phosphate binders (NCBPBs) and calcimimetics have been developed. However, the coverage for these new medications remains limited in several parts of the world due to the lack of patient-level outcome data and cost. The present study examined the differences in mineral outcomes between two main categories of healthcare programs that provided different coverage for medications used to control mineral and bone disorders (MBD). The Social Security/Universal Coverage (SS/UC) program covered only CBPBs and active vitamin D, whereas the Civil Servant/State Enterprise (CS/SE) program provided coverage of CBPBs, active vitamin D, NCBPBs, and calcimimetics. METHODS: This 10-year retrospective cohort study examined the differences in mineral outcomes between two healthcare programs in maintenance hemodialysis patients. The differences in serum calcium, phosphate, and PTH levels, as well as the aortic arch calcification score, were analyzed according to dialysis vintage by linear mixed-effects regression analyses. The difference in the composite outcome of severe hyperparathyroidism and parathyroidectomy was analyzed by the Cox-proportional hazard regression model. RESULTS: 714 patients were included in the analyses (full cohort). Of these patients, 563 required at least one type of medication to control MBD (MBD medication subgroup). Serum calcium, phosphate, and the proportions of patients with hypercalcemia and hyperphosphatemia were substantially higher in the SS/UC group compared with the CS/SE group after appropriate adjustments for confounders in both the full cohort and the MBD medication subgroup. These findings were confirmed in propensity-score matched analyses. Higher parathyroid hormone levels and a higher rate of the composite endpoint of severe hyperparathyroidism and parathyroidectomy were also observed in the SS/UC group. A more rapid progression of aortic arch calcification was suggested in the SS/UC group, but between-group changes were not significant. CONCLUSION: Patients under the healthcare program that did not cover the use of NCBPBs and calcimimetics showed higher serum calcium and phosphate levels and a more rapid progression of hyperparathyroidism. The difference in the progression of vascular calcification could not be confirmed in the present study.

Multiscale effects of the calcimimetic drug, etelcalcetide on bone health of rats with secondary hyperparathyroidism induced by chronic kidney disease.

Chronic kidney disease-induced secondary hyperparathyroidism (CKD-SHPT) heightens fracture risk through impaired mineral homeostasis and elevated levels of uremic toxins (UTs), which in turn enhance bone remodeling. Etelcalcetide (Etel), a calcium-sensing receptor (CaSR) agonist, suppresses parathyroid hormone (PTH) in hyperparathyroidism to reduce excessive bone resorption, leading to increased bone mass. However, Etel's effect on bone quality, chemical composition, and strength is not well understood. To address these gaps, we established a CKD-SHPT rat model and administered Etel at a human-equivalent dose concurrently with disease induction. The effects on bone and mineral homeostasis were compared with a CKD-SHPT (vehicle-treated group) and a control group (rats without SHPT). Compared with vehicle-treated CKD-SHPT rats, Etel treatment improved renal function, reduced circulating UT levels, improved mineral homeostasis parameters, decreased PTH levels, and prevented mineralization defects. The upregulation of mineralization-promoting genes by Etel in CKD-SHPT rats might explain its ability to prevent mineralization defects. Etel preserved both trabecular and cortical bones with attendant suppression of osteoclast function, besides increasing mineralization. Etel maintained the number of viable osteocytes to the control level, which could also contribute to its beneficial effects on bone. CKD-SHPT rats displayed increased carbonate substitution of matrix and mineral, decreased crystallinity, mineral-to-matrix ratio, and collagen maturity, and these changes were mitigated by Etel. Further, Etel treatment prevented CKD-SHPT-induced deterioration in bone strength and mechanical behavior. Based on these findings, we conclude that in CKD-SHPT rats, Etel has multiscale beneficial effects on bone that involve remodeling suppression, mineralization gene upregulation, and preservation of osteocytes.

Effectiveness of calcimimetics on fractures in dialysis patients with secondary hyperparathyroidism: meta-analysis of randomized trials.

INTRODUCTION: This study aimed to assess the effectiveness of calcimimetics in reducing the risk of fractures in dialysis patients with secondary hyperparathyroidism (SHPT). MATERIAL AND METHODS: A comprehensive literature search was conducted using PubMed, Embase, and Cochrane Library for articles published through December 9, 2023. The quality of each trial was evaluated using the Cochrane Collaboration tool. Meta-analysis was performed using a random-effects model, and effect measures across studies were synthesized. The risk ratio (RR) and 95% confidence interval (CI) were used to quantify the risk of fracture. RESULTS: We identified seven studies involving 6481 dialysis patients with SHPT. The administration of calcimimetics reduced fracture incidence compared to placebo or conventional treatment (RR: 0.50, 95% CI 0.29-0.88, p = 0.02). Calcimimetics demonstrated a low number needed to treat (NNT) to prevent an incident fracture (NNT: 47). CONCLUSION: The use of calcimimetics offers a significant benefit in reducing the risk of fractures in patients undergoing dialysis with SHPT.

Pharmacokinetics, Pharmacodynamics, and Safety of Evocalcet (KHK7580), a Novel Calcimimetic Agent: An Open-Label, Single- and Multiple-Dose, Phase I Trial in Healthy Chinese Subjects.

Purpose: This study explored the pharmacokinetics (PK), pharmacodynamics (PD), and safety of evocalcet (KHK7580), a new calcimimetic agent, in healthy Chinese subjects following single and multiple doses. Methods: This was a single-center, open-label phase I trial conducted in China. The study started from the single-dose cohorts (1, 3, 6, 12 mg evocalcet, step-by-step administration) and proceeded to the multiple-dose cohort (6 mg evocalcet once daily for eight days). Blood and urine samples were collected at the designated time points for pharmacokinetic and pharmacodynamic analysis. Safety was evaluated by treatment-emergent adverse events (TEAEs), clinical laboratory tests, vital signs, electrocardiograms (ECGs), and ophthalmological examination. Results: Among 42 enrolled subjects, eight in each single-dose cohort and 10 in multiple-dose cohort, 40 subjects completed the study. In single-dose cohorts, tmax was 1.00-2.00 h and declined biphasically. The mean t1/2 was 15.99-20.84 h. Evocalcet exposure in AUC0-inf, AUC0-t, and Cmax showed a dose-proportional increase. In the multiple-dose cohort, tmax was 2.00 h and declined biphasically after multiple administrations. The accumulation was negligible. Ctrough levels were similar across days and steady from 24 hours after the first administration. The mean t1/2 was 15.59 h. PD analysis showed that evocalcet decreased intact parathyroid hormone and corrected calcium levels in a dose-dependent manner. Seventeen (40.5%) subjects reported TEAEs. No serious or severe TEAE occurred. Conclusion: In healthy Chinese subjects, evocalcet demonstrated dose-dependent PK and PD properties and was well-tolerated.

Chronic Cinacalcet improves skin flap survival in rats: the suggested role of the nitric oxide pathway.

Cinacalcet is a calcimimetic medicine that has been used to treat secondary hyperparathyroidism and parathyroid cancer. Various studies have proposed the positive role of calcium and its receptor in skin wound healing. Furthermore, Cinacalcet interacts with other skin repair-related mechanisms, including inflammation and nitric oxide pathways. The present study evaluated the effect of Cinacalcet on the random-pattern skin flap survival. Eighty-four Wistar male rats were used. Multiple doses of Cinacalcet (30, 3, 1, 0.3, and 0.05 mg/kg) were used in 3 different routes of administration before the surgery. Histopathological evaluations, quantitative assessment of IL-6, TNF-α, and nitric oxide (NO), and the expression of calcium-sensing receptor (CaSR) and E-cadherin were evaluated in the skin tissue. To assess the role of NO, a NO synthase inhibitor, N-nitro-L-arginine methyl ester hydrochloride (L-NAME), was used, and histopathological effects were investigated. Cinacalcet pretreatment at the IP chronic 1 mg/kg dose significantly increased the skin flap survival rate and enhanced the NO tissue level compared to the control. However, the administration of L-NAME abolished its protective effects. IP Chronic 1 mg/kg of Cinacalcet could also decline the levels of IL-6 and TNF-α and also increase the expression of CaSR and E-cadherin in the flap tissue compared with the control group. Chronic Cinacalcet at 1 mg/kg could improve skin flap survival, probably mediated by the CaSR, NO, and inflammation-related pathways.

Safety of cinacalcet in children and adolescents with chronic kidney disease-mineral bone disorder: systematic review and proportional meta-analysis of case series.

BACKGROUND: Mineral and bone disease in children with chronic kidney disease can cause abnormalities in calcium, phosphorus, parathyroid hormone, and vitamin D and when left untreated can result in impaired growth, bone deformities, fractures, and vascular calcification. Cinacalcet is a calcimimetic widely used as a therapy to reduce parathyroid hormone levels in the adult population, with hypocalcemia among its side effects. The analysis of safety in the pediatric population is questioned due to the scarcity of randomized clinical trials in this group. OBJECTIVE: To assess the onset of symptomatic hypocalcemia or other adverse events (serious or non-serious) with the use of cinacalcet in children and adolescents with mineral and bone disorder in chronic kidney disease. DATA SOURCES AND STUDY ELIGIBILITY CRITERIA: The bibliographic search identified 2699 references from 1927 to August/2023 (57 LILACS, 44 Web of Science, 686 PubMed, 131 Cochrane, 1246 Scopus, 535 Embase). Four references were added from the bibliography of articles found and 12 references from the gray literature (Clinical Trials). Of the 77 studies analyzed in full, 68 were excluded because they did not meet the following criteria: population, types of studies, medication, publication types and 1 article that did not present results (gray literature). PARTICIPANTS AND INTERVENTIONS: There were 149 patients aged 0-18 years old with Chronic Kidney Disease and mineral bone disorder who received cinacalcet. STUDY APPRAISAL AND SYNTHESIS METHODS: Nine eligible studies were examined for study type, size, intervention, and reported outcomes. RESULTS: There was an incidence of 0.2% of fatal adverse events and 16% of serious adverse events (p < 0.01 and I2 = 69%), in addition to 10.7% of hypocalcemia, totaling 45.7% of total adverse events. LIMITATIONS: There was a bias in demographic information and clinical characteristics of patients in about 50% of the studies and the majority of the studies were case series. CONCLUSIONS AND IMPLICATIONS OF KEY FINDINGS: If used in the pediatric population, the calcimimetic cinacalcet should be carefully monitored for serum calcium levels and attention to possible adverse events, especially in children under 50 months. SYSTEMATIC REVIEW REGISTRATION NUMBER (PROSPERO REGISTER): CRD42019132809.

Hypocalcemia and cardiovascular mortality in cinacalcet users.

BACKGROUND: Calcimimetics are widely used in hemodialysis patients and influence serum calcium levels. Although the Kidney Disease: Improving Global Outcomes guidelines argued that low calcium levels induced by calcimimetics may be harmless, large observational studies investigating the association between hypocalcemia and mortality are scarce. We investigated the association between serum calcium levels and cardiovascular mortality in calcimimetics users using the nationwide Japanese registry for dialysis patients. METHODS: In this 9-year prospective cohort study, the baseline data were collected at the end of 2009. We enrolled patients on maintenance hemodialysis or hemodiafiltration. We employed three models (baseline, time-dependent and time-averaged) to conduct Cox proportional hazard regression analyses. RESULTS: Cinacalcet was prescribed to 12.7% (N = 22 853) at baseline. The median observation period was 98 (interquartile range 40-108) months and 108 (interquartile range 59-108) months in the whole cohort (N = 180 136) and in cinacalcet users, respectively. Three-quarters of survivors at the end of 2019 had continued calcimimetic therapy for 10 years, corresponding to a mean annual dropout rate of 2.9%. Hypocalcemia was not associated with cardiovascular mortality in the baseline or time-averaged model. In the time-dependent model, however, the lowest calcium decile (corrected calcium <8.4 mg/dL) was significantly associated with higher cardiovascular mortality than the reference (corrected calcium 8.7-8.9 mg/dL) in both cinacalcet users and all patients [hazard ratio (95% confidence interval) 1.32 (1.00, 1.75) and 1.15 (1.05, 1.26), respectively]. Hypocalcemia was especially associated with sudden death and death due to hemorrhagic stroke, heart failure and ischemic heart disease. Higher rate of fatal and non-fatal cardiovascular events was observed in hypocalcemic patients regardless of cinacalcet usage. CONCLUSIONS: Our findings suggest that transient hypocalcemia was associated with an increased risk of cardiovascular death independent of cinacalcet usage. We should pay attention to hypocalcemia transiently induced by cinacalcet.

Cinacalcet use in secondary hyperparathyroidism: a machine learning-based systematic review.

Introduction: This study aimed to systematically review research on cinacalcet and secondary hyperparathyroidism (SHPT) using machine learning-based statistical analyses. Methods: Publications indexed in the Web of Science Core Collection database on Cinacalcet and SHPT published between 2000 and 2022 were retrieved. The R package "Bibliometrix," VOSviewer, CiteSpace, meta, and latent Dirichlet allocation (LDA) in Python were used to generate bibliometric and meta-analytical results. Results: A total of 959 articles were included in our bibliometric analysis. In total, 3753 scholars from 54 countries contributed to this field of research. The United States, Japan, and China were found to be among the three most productive countries worldwide. Three Japanese institutions (Showa University, Tokai University, and Kobe University) published the most articles on Cinacalcet and SHPT. Fukagawa, M.; Chertow, G.M.; Goodman W.G. were the three authors who published the most articles in this field. Most articles were published in Nephrology Dialysis Transplantation, Kidney International, and Therapeutic Apheresis and Dialysis. Research on Cinacalcet and SHPT has mainly included three topics: 1) comparative effects of various treatments, 2) the safety and efficacy of cinacalcet, and 3) fibroblast growth factor-23 (FGF-23). Integrated treatments, cinacalcet use in pediatric chronic kidney disease, and new therapeutic targets are emerging research hotspots. Through a meta-analysis, we confirmed the effects of Cinacalcet on reducing serum PTH (SMD = -0.56, 95% CI = -0.76 to -0.37, p = 0.001) and calcium (SMD = -0.93, 95% CI = -1.21to -0.64, p = 0.001) and improving phosphate (SMD = 0.17, 95% CI = -0.33 to -0.01, p = 0.033) and calcium-phosphate product levels (SMD = -0.49, 95% CI = -0.71 to -0.28, p = 0.001); we found no difference in all-cause mortality (RR = 0.97, 95% CI = 0.90 to 1.05, p = 0.47), cardiovascular mortality (RR = 0.69, 95% CI = 0.36 to 1.31, p = 0.25), and parathyroidectomy (RR = 0.36, 95% CI = 0.09 to 1.35, p = 0.13) between the Cinacalcet and non-Cinacalcet users. Moreover, Cinacalcet was associated with an increased risk of nausea (RR = 2.29, 95% CI = 1.73 to 3.05, p = 0.001), hypocalcemia (RR = 4.05, 95% CI = 2.33 to 7.04, p = 0.001), and vomiting (RR = 1.90, 95% CI = 1.70 to 2.11, p = 0.001). Discussion: The number of publications indexed to Cinacalcet and SHPT has increased rapidly over the past 22 years. Literature distribution, research topics, and emerging trends in publications on Cinacalcet and SHPT were analyzed using a machine learning-based bibliometric review. The findings of this meta-analysis provide valuable insights into the efficacy and safety of cinacalcet for the treatment of SHPT, which will be of interest to both clinical and researchers.

Pharmacological profile of upacicalcet, a novel positive allosteric modulator of calcium-sensing receptor, in vitro and in vivo.

Upacicalcet (formerly SK-1403/AJT240) is a novel non-peptide calcimimetic agent that acts as a calcium-sensing receptor (CaSR) agonist for the treatment of secondary hyperparathyroidism (SHPT) in chronic kidney disease (CKD). We compared upacicalcet with other calcimimetics (etelcalcetide or cinacalcet) and examined its in vitro and in vivo characteristics in terms of its human CaSR agonistic activity, its efficacy in normal and CKD rats after a single administration, and its effect on gastric emptying in rats. Upacicalcet activated human CaSR depending on the extracellular calcium (Ca2+) concentration without exhibiting an agonistic action when the extracellular Ca2+ level was below the physiological level. On the other hand, etelcalcetide had an agonistic activity even in the absence of physiological levels of extracellular Ca2+. The intravenous administration of upacicalcet to normal and double-nephrectomized rats dose-dependently (0.03-3mg/kg and 0.3-30mg/kg, respectively) decreased the serum intact parathyroid hormone (iPTH) and serum Ca2+ levels; however, the effect of upacicalcet on the reduction in serum Ca2+ disappeared at extracellular Ca2+ levels below the physiologically range, even when administered at a dose higher (100-fold) than the effective dose. Furthermore, upacicalcet did not affect gastric emptying in normal rats when administered up to a dose of 10mg/kg (300-fold higher than the dose affecting serum iPTH levels), while the administration of cinacalcet significantly slowed gastric emptying by approximately 50%. These findings suggest that upacicalcet has potential as an alternative calcimimetic agent with good pharmacological properties and a lower risk of hypocalcemia and gastrointestinal complications.

Impact of Cinacalcet and Etelcalcetide on Bone Mineral and Cardiovascular Disease in Dialysis Patients.

PURPOSES OF REVIEW: With chronic kidney disease (CKD) progression, secondary hyperparathyroidism (sHPT) and mineral and bone metabolism disease (MBD) almost inevitably develop and result in renal osteodystrophy and cardiovascular disease (CVD). Together with active vitamin D, calcimimetics are the main therapy for sHPT in CKD. This review provides an overview of the therapeutic effects of oral cinacalcet and intravenous etelcalcetide on CKD-MBD and vascular disease, with a focus on pediatric dialysis patients. RECENT FINDINGS: Randomized controlled trials in adults and children demonstrate efficient lowering of parathyroid hormone (PTH) by the calcimimetics together with a reduction in serum calcium and phosphate when combined with low-dose active vitamin D, while therapy with active vitamin D analogs alone increases serum calcium and phosphate. Cinacalcet and etelcalcetide both improve bone formation and correct adynamic bone, i.e., have a direct bone anabolic effect. They decrease serum calciprotein particles, which are involved in endothelial dysfunction, atherogenesis, and vascular calcification. Clinical trials in adults suggest a modest slowing of the progression of cardiovascular calcification with cinacalcet. Calcimimetic agents represent a major pharmacological tool for improved control of CKD-MBD, by efficiently counteracting sHPT and allowing for better control of calcium/phosphate and bone homeostasis. Albeit definite evidence is lacking, the beneficial effects of calcimimetics on CVD are promising. Routine use of cinacalcet has been suggested in children.

Long-term use of etelcalcetide for the treatment of secondary hyperparathyroidism in patients undergoing hemodialysis for end-stage renal failure: a real-life retrospective observational study.

BACKGROUND: Patients with end-stage renal failure (ESRD) or dialysis frequently suffer from secondary hyperparathyroidism (sHPTH), a severe complication of mineral metabolism disorders. The calcimimetic etelcalcetide has been approved and shown efficacy in randomized controlled trials, however, data are limited from real-life studies. This study aimed to evaluate the long-term use etelcalcetide for the treatment of sHPTH (PTH > 600 pg/mL) in patients undergoing extracorporeal hemodialysis for ESRD for at least 2 years. METHODS: In 45 patients, we administered etelcalcetide for the treatment of sHPTH (PTH > 600 pg/mL); One group of patients (control group, Group A; N = 26) were previously treated with intravenous vitamin D analogues only (paricalcitol 5 µg/ml, three times/week) and then treated with etelcalcetide and a second group of patients already on cinacalcet therapy for at least six months in combination with iv paricalcitol were switched to etelcalcetide (Group B, N = 19). RESULTS: PTH levels decreased over time in both groups of patients, with higher values for patients previously treated with cinacalcet (Group B) compared to Group A for the entire study duration even if the final value of the two groups was comparable. After 12 months, the percentage of subjects who had PTH concentrations within the targets recommended by KDIGO guidelines was 87% in Group A and 58% in Group B. In seven patients, despite a parathyroid gland volume > 1000 mm3, an adequate response in the reduction of PTH was obtained. CONCLUSION: Findings from this study demonstrate that the efficacy of etelcalcetide is maintained over the long term.

Parathyroidectomy and Cinacalcet Use in Medicare-Insured Kidney Transplant Recipients.

RATIONALE & OBJECTIVE: Posttransplant hyperparathyroidism is common, and treatment practices are poorly characterized. The goal of this study was to examine the incidence, associations, and outcomes of posttransplant parathyroidectomy and calcimimetic use in a cohort of Medicare-insured US kidney transplant recipients. STUDY DESIGN: Retrospective observational cohort study. SETTING & PARTICIPANTS: We used the US Renal Data System to extract demographic, clinical, and prescription data from Medicare Parts A, B, and D-insured patients who received their first kidney transplant in 2007-2013. We excluded patients with pretransplant parathyroidectomy. PREDICTORS: Calendar year of transplantation and pretransplant patient characteristics. OUTCOME: (1) Incidence of and secular trends in parathyroidectomy and cinacalcet use in the 3 years after transplant; (2) 90-day outcomes after posttransplant parathyroidectomy and cinacalcet initiation. ANALYTICAL APPROACH: Temporal trends and pretransplant correlates of parathyroidectomy and cinacalcet use were assessed using proportional hazards models and multivariable Poisson regression, respectively. RESULTS: The inclusion criteria were met by 30,127 patients, of whom 10,707 used cinacalcet before transplant, 551 underwent posttransplant parathyroidectomy, and 5,413 filled≥1 prescription for cinacalcet. The rate of posttransplant parathyroidectomy was stable over time. By contrast, cinacalcet use increased during the period studied. Long dialysis vintage and pretransplant cinacalcet use were strongly associated with posttransplant parathyroidectomy and cinacalcet use. Roughly 1 in 4 patients were hospitalized within 90 days of posttransplant parathyroidectomy, with hypocalcemia-related diagnoses being the most common complication. Parathyroidectomy (vs cinacalcet initiation) was not associated with an increase in acute kidney injury. LIMITATIONS: We lacked access to laboratory data to help assess the severity of secondary/tertiary hyperparathyroidism. The cohort was limited to Medicare beneficiaries. CONCLUSIONS: Almost one-fifth of our study cohort was treated with parathyroidectomy and/or cinacalcet. Further studies are needed to establish the optimal treatment for posttransplant hyperparathyroidism.

Implementation of a Nurse-Led Etelcalcetide Protocol at the Outpatient Dialysis Unit: A Quality Improvement Project.

This quality improvement project was implemented to improve renal hyperparathyroidism in patients with end stage kidney disease who are on hemodialysis through the implementation of a nurse-led etelcalcetide protocol. Results showed that the post-intervention group had a 16.7% increase of the intact parathyroid hormone (iPTH) range within the target goal compared to the 3-month pre-intervention assessment (95% CI; 20.3% to 48.1%). The odds of being in the PTH target range were 1.73 times higher after the 3-month intervention than measurements obtained before starting the intervention (95% CI for the odds ratio: 0.29 to 10.3). Despite the lack of statistical significance (p = 0.688) due to a small sample size, there was an improvement in reaching goal PTH levels. Further studies are needed to analyze the effectiveness of nurse-led protocols in treating renal hyperparathyroidism in dialysis patients.

Current therapeutic options for the treatment of secondary hyperparathyroidism in end-stage renal disease patients treated with hemodialysis: a 12-month comparative study.

AIM: The aim of the study was to investigate the effect of a new calcimimetic, Etelcalcetide, on secondary hyperparathyroidism and its effects in end-stage renal disease (ESRD) patients treated with hemodialysis (HD) compared with hemodialysis (HD) patients not treated with calcimimetics. MATERIALS AND METHODS: The cohort study included 203 ESRD patients with secondary hyperparathyroidism (SHPT) who received HD treatment. Total number patients were randomly to two groups. The main group (n=71) included HD patients treated by new calcimimetic Etelcalcetide. The historical group (n=132) was evaluated retrospectively and included patients who had SHPT but did not receive calcimimetic treatment. Serum levels of phosphorus, calcium and parathyroid hormone were compared for 12 months. The primary endpoint of the study was death from any cause, surrogates - cases of fractures, parathyroidectomy, death from cardiovascular (CV) events. RESULTS: The dose of Etelcalcetide changed monthly and averaged 8.58±1.79 mg. The dynamics of parathormone (PTH) indicators showed that the decrease in PTH levels by 30% from basal occurred after 3 months of treatment in 39 (54.9%) and 12 (9.1%) patients of the main group and historical group, respectively (p<0.0001). At the end of the study, the target PTH level reached in 52 (73.2%) patients in the main group and only 14 (10.6%) in the comparison group (p<0.0001). In addition to the decrease in serum PTH content, in the main group of patients, there was also a decrease in serum calcium and phosphorus levels. During the time to be analyzed, 36 deaths were reported, 61.1% of which were fatal CV events. The proportion of CV events in the mortality structure is more than 70% higher in the historical group than in the group of patients treated with Etelcalcetide, and is 69,2% vs 40,0%, respectively. The frequency of fractures is almost three times higher in the historical than in the main group of patients. The proportion of patients who required parathyroidectomy was significantly more than three times higher in the historical group than in the main group (p<0,05). CONCLUSIONS: In a prospective study, we demonstrated the high efficacy of Etelcalcetide in the treatment of SHPT in hemodialysis patients. Treatment of SHPT with the inclusion of Etelcalcetide is accompanied by improved clinical outcomes such as the incidence of bone fractures, cardiovascular morbidity and mortality.

A Systematic Review and Meta-analysis of Efficacy and Safety of Calcimimetic Agents in the Treatment of Secondary Hyperparathyroidism in Patients with Chronic Kidney Disease.

BACKGROUND: Some reports have pointed out that calcimimetics agents are effective in the treatment of secondary hyperparathyroidism (SHPT) in chronic kidney disease (CKD) patients, but there is no detailed description of the advantages and disadvantages of calcimimetics agents of SHPT in CKD patients. We tried to pool the published data to verify the effectiveness of calcimimetics agents and to compare the advantages and disadvantages of cinacalcet compared with control in the treatment of SHPT in CKD patients. METHODS: We included eligible studies of published papers from January 1st, 2000 to December 31st, 2020 in Medline, Pubmed and Web of science databases, and the data were extracted for this meta-analysis. RESULTS: Twenty-seven studies were eligible, and all the included studies were randomized controlled trials (RCT) including patients treated with long-term dialysis. The results indicated that calcimimetic agents can reduce the parathyroid hormone (PTH, pg/ml) level (WMD = -178.22, 95% CI: -238.57, -117.86, P < 0.00001), calcium (Ca, mg/dl) level (WMD = -0.71, 95% CI: -0.86, -0.55, P < 0.00001), phosphorus (P, mg/dl) level (WMD = -0.32, 95% CI: -0.55, -0.08, P = 0.008), calcium-phosphorus product level (WMD = -7.73, 95% CI: -9.64, -5.82, P < 0.00001). Calcimimetic agents increased the bone alkaline phosphatase (BSAP, ng/ml) levels and rate of achieving target PTH, and reduced osteocalcin levels and the rate of parathyroidectomy. Calcimimetic agents increased the total adverse events' rate, the rate of hypocalcemia and gastrointestinal side effects (nausea, vomiting, abdominal pain and diarrhea), but there was no significant difference in serious adverse events between the calcimimetic agent group and control group. CONCLUSION: Calcimimetic agents can reduce the PTH level, Ca level, P level, calcium-phosphorus product level and do not increase serious adverse events.

Mineral Bone Disorders in Kidney Disease Patients: The Ever-Current Topic.

Chronic kidney disease (CKD) is a complex and multifactorial disease, and one of the most prevalent worldwide. Chronic kidney disease-mineral bone disorders (CKD-MBD) with biochemical and hormonal alterations are part of the complications associated with the progression of CKD. Pathophysiology of CKD-MBD focused on abnormalities in serum levels of several biomarkers (such as FGF-23, klotho, phosphate, calcium, vitamin D, and PTH) which are discussed in this review. We therefore examine the prognostic association between CKD-MBD and the increased risk for cardiovascular events, mortality, and CKD progression to end-stage kidney disease (ESKD). Lastly, we present specific treatments acting on CKD to prevent and treat the complications associated with secondary hyperparathyroidism (SHPT): control of hyperphosphatemia (with dietary restriction, intestinal phosphate binders, and adequate dialysis), the use of calcimimetic agents, vitamin D, and analogues, and the use of bisphosphonates or denosumab in patients with osteoporosis.