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ispartof: JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM vol:107 issue:8 pages:E3532-E3533 ispartof: location:United States status: published

Background Renal hyperparathyroidism is a disease entity that is complex and poorly understood. Although there are guidelines regarding how to manage this patient group, evidence is scarce. Therefore, this survey-based study aims to map the physicians’ attitude in terms of preference for management of renal hyperparathyroidism and the influence of patient and respondent factors. Methods A survey was sent to Dutch societies of nephrology, endocrinology, and surgeons with interest in endocrine surgery. The survey consisted of eight case vignettes of renal hyperparathyroidism patients who were on hemodialysis and suitable for kidney transplantation, and varied in one of three patient variables import for decision making: age (40 vs. 65 years), parathyroid hormone (40 vs. 90 pmol/L), and serum calcium level (2.25 vs. 2.8 mmol/L). For each case, respondents could choose between maintaining conservative treatment (active vitamin D metabolites), calcimimetics, or subtotal parathyroidectomy as their treatment of choice. Categorical multilevel logistic models were used to investigate the association of patient and respondent variables with treatment preference. The influence of patient variables was determined independently of each other and by means of logistic regression the probabilities of treatment choice were calculated. Results In total, 115 surveys were included in the analysis. In 6 out of 8 cases, less than two-thirds of respondents agreed on the most favoured treatment. Among patient characteristics, the main disincentive for respondents not to choose conservative therapy was an elevated serum calcium level (subtotal parathyroidectomy vs conservative OR 93.1, 95%-CI: 48.39–179.07 and calcimimetics vs conservative OR 31.2 95%-CI: 18.58–52.30). Additionally, the most significant treatment differences were found between medical specialties and the experience of the respondents, expressed as the amount of cases the physician was involved in during the past year. Conclusions Elevated serum calcium levels were widely recognized and the prime reason for respondents to abandon conservative treatment. However, considerable disagreement in treatment preferences remained throughout the cases, demonstrating the current literature available being inconclusive in guiding physicians. Therefore, a high-quality trial comparing subtotal parathyroidectomy to medical treatment is needed to determine optimal treatment.

Background Etelcalcetide is a second-generation calcimimetic for the management of secondary hyperparathyroidism (SHPT) in patients on dialysis. We performed a post-marketing surveillance (PMS) to obtain information on the safety and efficacy of etelcalcetide in clinical practice in Japan. Methods This PMS enrolled SHPT patients who started initial treatment with etelcalcetide between April 1, 2017 and February 28, 2018 in Japan. Safety [adverse drug reactions (ADRs)] and efficacy [serum intact parathyroid hormone (iPTH), corrected calcium (cCa), phosphorous (P), and alkaline phosphatase (ALP)] were recorded for up to 52 weeks or until treatment discontinuation. Treatment decisions were at the physician’s discretion. Results Of 1226 patients enrolled across 282 centers, safety and efficacy data were available for 1195 and 1192, respectively, while 933 continued treatment to Week 52. The starting dose was 5 mg in 82.0% of patients. There were 218 ADRs in 169 patients (14.1%). Metabolism and nutrition disorders (8.8%), adverse laboratory test results (1.8%), and gastrointestinal disorders (1.6%) were the most frequent classes of ADRs. Hypocalcemia-related ADRs occurred in 104 patients (8.7%). The percentage of patients with iPTH levels within the target range (60–240 pg/mL) steadily increased from 19.5% at Week 0 to 64.1% at Week 52 or last dose. cCa, P, and ALP levels remained well controlled. Conclusion This was the first real-world, large-scale, long-term observational PMS of etelcalcetide in Japan. We did not observe any new safety concerns. Etelcalcetide was associated with clinically relevant improvements in serum iPTH and maintenance of serum cCa, P, and ALP levels.

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.

BACKGROUND: Phosphorus levels in the range seen clinically among patients undergoing dialysis have been reported to attenuate calcium receptor activation and modify parathyroid hormone (PTH) release from isolated parathyroid glands in vitro. Some clinicians and providers of dialysis thus have suggested that calcimimetic agents are ineffective and should not be used to manage secondary hyperparathyroidism among those undergoing dialysis when serum phosphorus concentrations exceed certain threshold levels.METHODS: To determine whether hyperphosphatemia diminishes the therapeutic response to calcimimetic agents, we used data from large clinical trials to analyze the effects of etelcalcetide and cinacalcet to lower plasma PTH levels in individuals on hemodialysis who had secondary hyperparathyroidism and varying degrees of hyperphosphatemia.RESULTS: Plasma PTH levels declined progressively during 26 weeks of treatment with either etelcalcetide or cinacalcet without regard to the degree of hyperphosphatemia at baseline. However, with each calcimimetic agent, the decreases in PTH from baseline were less at each interval of follow-up during the trials among participants with serum phosphorus levels above one of three prespecified threshold values compared with those with serum phosphorus levels below these thresholds.CONCLUSIONS: These in vivo findings are the first in humans to support the idea that hyperphosphatemia attenuates calcium receptor activation by calcium ions and by calcimimetic agents. The effect of hyperphosphatemia on the responsiveness to calcimimetic agents appears relatively modest, however, and unlikely to be significant therapeutically. The efficacy of treatment with calcimimetic agents for lowering plasma PTH levels among those with secondary hyperparathyroidism remains robust despite substantial elevations in serum phosphorus.

Aim Secondary hyperparathyroidism (SHPT), a complication of haemodialysis, is commonly treated with calcimimetics. The impact of dialysates containing different calcium (Ca) concentrations on clinical efficacy of calcimimetics are unclear. We examined whether dialysate Ca concentrations influence the efficacy and dosing of etelcalcetide with concomitant drugs. Methods We performed post hoc analyses of a 52‐week, open‐label, multicentre study of etelcalcetide in Japanese SHPT patients to determine whether dialysate Ca influences the therapeutic effects of etelcalcetide with concomitant drugs. We evaluated the differences in serum intact parathyroid hormone (iPTH), corrected Ca (cCa) and phosphate levels among three dialysate Ca concentration groups (2.5, 2.75 or 3.0 mEq/L Ca). Tartrate‐resistant acid phosphatase 5b (TRACP‐5b) and bone alkaline phosphatase (BAP) levels were also compared. Since the dialysate Ca concentration may influence dose adjustment, we assessed the etelcalcetide and concomitant drug doses. Results There were no clinically meaningful differences in iPTH, cCa and phosphate levels among the 2.5, 2.75 and 3.0 mEq/L groups (n = 34, 64 and 35, respectively) over 52 weeks. At Week 52, more than 82%, 71% and 67% of patients had iPTH, cCa and phosphate levels within target ranges (60‐240 pg/mL, 8.4‐10.0 mg/dL and 3.5‐6.0 mg/dL, respectively) across the three groups. TRACP‐5b and BAP levels decreased by Week 52 regardless of dialysate Ca. Changes in etelcalcetide and concomitant drug doses were generally similar in each group. Conclusion The efficacy and dosing of etelcalcetide with concomitant drugs were essentially unaffected by the dialysate Ca concentration. Patients showed improvements in bone hypermetabolism during treatment., SUMMARY AT A GLANCE This is a small observational study of the effect of dialysate calcium concentrations on etelcalcetide with concomitant drugs in secondary hyperparathyroidism. No statistically significant differences were found between the different dialysate calcium groups suggesting that calcium concentrations in the dialysate do not modulate the effect of etelcalcetide.

In 2012, the Japanese Society for Dialysis Therapy (JSDT) established the order of correction of P, corrected Ca (cCa), and whole PTH (w-PTH) in the treatment of Chronic Kidney Disease-Metabolic Bone Disorder (CKD-MBD) as P-first. However, there is no report that analyzes whether this rule is in line with reality and what the adequate rate of P is. Therefore, we analyzed the test values of our 48 patients during the year of 2019 and examined the validity of the results. The results showed that the adequate range rates were 70.8% for P, 100% for cCa, and 89.6% for w-PTH. This result is better than the JSDT Web-based Analysis of Dialysis Data Archives (WADDA) P adequacy rate of 66.2%. Although the guideline is P-first, it is often the case that we cannot reach the adequate level; therefore, healthcare professionals and patients often blame each other. We believe that this is due to the mismatch between the modern era of processed foods covered with P additives and treatment methods (P intake restriction and P-binders). The development of processed foods with P additives has brought light and darkness to mankind. The light side is freedom from starvation, and the dark side is a new condition caused by P burden: P burden disease including CKD-MBD.

The calcium‐sensing receptor (CaS receptor) plays a pivotal role in extracellular calcium homeostasis, and germline loss‐of‐function and gain‐of‐function mutations cause familial hypocalciuric hypercalcaemia (FHH) and autosomal dominant hypocalcaemia (ADH), respectively. CaS receptor signal transduction in the parathyroid glands is probably regulated by G‐protein subunit α(11) (Gα(11)) and adaptor‐related protein complex‐2 σ‐subunit (AP2σ), and recent studies have identified germline mutations of these proteins as a cause of FHH and/or ADH. Calcimimetics and calcilytics are positive and negative allosteric modulators of the CaS receptor that have potential efficacy for symptomatic forms of FHH and ADH. Cellular studies have demonstrated that these compounds correct signalling and/or trafficking defects caused by mutant CaS receptor, Gα(11) or AP2σ proteins. Moreover, mouse model studies indicate that calcilytics can rectify the hypocalcaemia and hypercalciuria associated with ADH, and patient‐based studies reveal calcimimetics to ameliorate symptomatic hypercalcaemia caused by FHH. Thus, calcimimetics and calcilytics represent targeted therapies for inherited disorders of the CaS receptor signalling pathway. LINKED ARTICLES: This article is part of a themed section on Molecular Pharmacology of GPCRs. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.21/issuetoc

Patients with chronic kidney disease often develop secondary hyperparathyroidism (SHPT), marked by high levels of circulating parathyroid hormone (PTH) and increased risk of morbidity and mortality. Patients with SHPT are treated with a therapeutic combination that commonly includes calcimimetics, which have recently become popular in clinical settings, and other agents such as vitamin D preparations. Calcimimetics are a drug class that reduces PTH levels by targeting the calcium‐sensing receptor. Cinacalcet, a representative calcimimetic, is widely used; however, a high incidence of upper gastrointestinal (GI) tract‐related adverse events (AEs) can result in insufficient dosage and poor long‐term compliance. The newly approved evocalcet has equivalent efficacy to cinacalcet at a lower clinical dose, with improved bioavailability, fewer upper GI tract‐related AEs, and fewer safety concerns. This review gives an overview of calcimimetic agents, with a special focus on evocalcet, and describes the clinical advantages of evocalcet in the treatment of dialysis patients with SHPT.

Significant advances in immunosuppressive therapies have been made in renal transplantation, leading to increased allograft and patient survival. Despite improvement in overall patient survival, patients continue to require management of persistent post-transplant hyperparathyroidism. Medications that treat persistent hyperparathyroidism include vitamin D, vitamin D analogues, and calcimimetics. Medication side effects such as hypocalcemia or hypercalcemia, and adynamic bone disease, may lead to a decrease in the drugs. When medical management fails to control persistent post-transplant hyperparathyroidism, treatment is a parathyroidectomy. Surgical techniques are not uniform between centers and surgeons. Undergoing the surgery may include a subtotal technique or a technique including total parathyroid gland resection with partial heterotopic gland reimplantation. In addition, there are possible post-surgical complications. The ideal treatment for persistent post-transplant hyperparathyroidism is the treatment and prevention of the condition while patients are being managed for their late-stage chronic kidney disease and end-stage renal disease.

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

We have previously demonstrated calcimimetics optimize the balance between osteoclastic bone resorption and osteoblastic mineralization through upregulating Wingless and int-1 (Wnt) signaling pathways in the mouse and cell model. Nonetheless, definitive human data are unavailable concerning therapeutic effects of Cinacalcet on chronic kidney disease and mineral bone disease (CKD-MBD) and osteoclast&ndash, osteoblast interaction. We aim to investigate whether Cinacalcet therapy improves bone mineral density (BMD) through optimizing osteocytic homeostasis in a human model. Hemodialysis patients with persistently high intact parathyroid hormone (iPTH) levels &gt, 300 pg/mL for more than 3 months were included and received fixed dose Cinacalcet (25 mg/day, orally) for 6 months. Bone markers presenting osteoclast&ndash, osteoblast communication were evaluated at baseline, the 3rd and the 6th month. Eighty percent of study patients were responding to Cinacalcet treatment, capable of improving BMD, T score and Z score (16.4%, 20.7% and 11.1%, respectively). A significant correlation between BMD improvement and iPTH changes was noted (r = &minus, 0.26, p &lt, 0.01). Nonetheless, baseline lower iPTH level was associated with better responsiveness to Cinacalcet therapy. Sclerostin, an inhibitor of canonical Wnt/&beta, catenin signaling, was decreased from 127.3 &plusmn, 102.3 pg/mL to 57.9 &plusmn, 33.6 pg/mL. Furthermore, Wnt-10b/Wnt 16 expressions were increased from 12.4 &plusmn, 24.2/166.6 &plusmn, 73.3 pg/mL to 33.8 &plusmn, 2.1/217.3 &plusmn, 62.6 pg/mL. Notably, procollagen type I amino-terminal propeptide (PINP), a marker of bone formation and osteoblastic activity, was increased from baseline 0.9 &plusmn, 0.4 pg/mL to 91.4 &plusmn, 42.3 pg/mL. In contrast, tartrate-resistant acid phosphatase isoform 5b (TRACP-5b), a marker of osteoclast activity, was decreased from baseline 16.5 &plusmn, 0.4 mIU/mL to 7.7 &plusmn, 2.2 mIU/mL. Moreover, C-reactive protein levels were suppressed from 2.5 &plusmn, 0.6 to 0.8 &plusmn, 0.5 mg/L, suggesting the systemic inflammatory burden may be benefited after optimizing the parathyroid&ndash, bone axis. In conclusion, beyond iPTH suppression, our human model suggests Cinacalcet intensifies BMD through inhibiting sclerostin expression and upregulating Wnt-10b/Wnt 16 signaling that activates osteoblastic bone formation and inhibits osteoclastic bone resorption and inflammation. From the perspective of translation to humans, this research trial brings a meaningful insight into the osteoblast&ndash, osteoclast homeostasis in Cinacalcet therapy for CKD-MBD.

Background: Secondary hyperparathyroidism (SHPT) have been associated with poor health outcomes in hemodialysis patients. The cinacalcet has popularized in clinic which has efficacy but more adverse events; the novel oral calcimimetic agents evocalcet has appeared in recent years. However, it is currently unknown whether evocalcet produces more beneficial effects and fewer adverse events in patients with SHPT. The aim of this systematic review is to estimate the safety and efficacy of evocacelt. Methods: Only randomized controlled trials (RCT) will be included in MEDLINE, EMBASE, the Cochrane Register of Controlled Trials, and PUBMED from July 2010 to July 2020. Two reviewers will screen, select studies, extract data, and assess quality independently. The methodological quality including the risk of bias of the included studies will be evaluated using a modified assessment form, which is based on Cochrane assessment tool. Review Manager 5.3 software will be used for heterogeneity assessment, generating funnel-plots, data synthesis, subgroup analysis, and sensitivity analysis. We will use GRADE system to evaluate the quality of our evidence. Results: We will provide some more practical and targeted results investigating the effect and safety of evocalcet for SHPT on hemodialysis in the current meta-analysis. Conclusion: The stronger evidence about evocalcet effect and safety will be provided for clinicians and policymakers. Ethics and dissemination: Ethical approval will be unnecessary because the data being included in this systematic review come from published literature and there will be no concerns regarding privacy. Findings of this research will be disseminated in a peer-reviewed journal or conference presentations. OSF Registration number: DOI 10.17605/OSF.IO/N59RB.

Secondary hyperparathyroidism (SHPT) is an important complication of advanced chronic kidney disease (CKD) in children, which is often difficult to treat with conventional therapy. The calcimimetic cinacalcet is an allosteric modulator of the calcium-sensing receptor. It has proven to be effective and safe in adults to suppress parathyroid hormone (PTH), but data on its use in children are limited. To date, studies in children only consist of two randomized controlled trials, nine uncontrolled interventional or observational studies, and case reports that report the efficacy of cinacalcet as a PTH-lowering compound. In 2017, the European Medical Agency approved the use of cinacalcet for the treatment of SHPT in children on dialysis in whom SHPT is not adequately controlled with standard therapy. Since evidence-based guidelines are so far lacking, we present a position statement on the use of cinacalcet in paediatric dialysis patients based on the available evidence and opinion of experts from the European Society for Paediatric Nephrology, Chronic Kidney Disease-Mineral and Bone Disorder and Dialysis Working Groups, and the ERA-EDTA. Given the limited available evidence the strength of these statements are weak to moderate, and must be carefully considered by the treating physician and adapted to individual patient needs as appropriate. Audit and research recommendations to study key outcome measures in paediatric dialysis patients receiving cinacalcet are suggested.

Background The calcimimetic agent cinacalcet is effective for the management of secondary hyperparathyroidism (SHPT) in dialysis patients. Changes to reimbursement of cinacalcet in Australia provided an opportunity to assess effects of medication cessation on biochemical and clinical outcomes in dialysis patients, including changes to novel biomarkers such as calciprotein particles (CPP). CPP are nanoparticles of mineral and protein in the circulation associated with increased vascular calcification in patients with chronic kidney disease. Methods Dialysis patients from a single center who ceased cinacalcet between August 2015 and March 2016 were included in a prospective observational study. Bloods were taken at the time of cessation of cinacalcet and at 1, 6 and 12 months. Clinical and biochemical outcomes were compared with an age- and gender-matched cohort of cinacalcet-naïve dialysis patients. Results Sixty-two patients participated in the study. Mean age was 69.6 ± 13.2 years. Biochemical changes over 12 months following cessation of cinacalcet included an increase in serum parathyroid hormone (PTH) (42.2 [IQR 27.8–94.6] pmol/L to 114.8 [83.9–159.1] pmol/L [p

This study aimed to investigate the association of gastrointestinal (GI) adverse events of cinacalcet with gallstones in the hemodialysis (HD) patients with secondary hyperparathyroidism (SHPT). A total of 23 HD patients under the treatment with cinacalcet and 101 control patients were enrolled in this cross-sectional study. We investigated the prevalence of gallstones and the association of GI adverse events of cinacalcet with gallstones. The prevalence of gallstones was significantly higher in the HD patients with cinacalcet compared with the controls (47.8% vs. 15.8%). The longer time on HD, hypercalcemia, hyperphosphatemia and elevated parathyroid hormone level were observed in the HD patients with cinacalcet. Besides, GI adverse events of cinacalcet were observed more frequently in the HD patients with gallstones compared with those without gallstones (odds ratio 13.5, 95% CI: 1.80–101). Therefore, screening for gallstones before dosing cinacalcet may reduce the risk of GI adverse events in SHPT patients.

Background Secondary hyperparathyroidism (SHPT) is a common complication in patients receiving chronic dialysis therapy. Although cinacalcet can control parathyroid function and bone turnover, preventing ectopic calcification remains challenging. Cinacalcet can also suppress PTH secretion due to parathyroid carcinoma in the same way as it does for parathyroid hyperplasia in the uremic condition. We present a case of parathyroid carcinoma partially controlled by cinacalcet, in which tumorous calcinosis was successfully resolved by total parathyroidectomy. Case presentation A female patient in her forties who had received dialysis for 12 years was referred to our hospital for painful ectopic calcifications on her right hip joint and both knees. Although she had been treated with alfacalcidol and cinacalcet for 2 years, this therapy had been discontinued 6 months earlier as a result of hypercalcemia. The patient exhibited normocalcemia (2.37 mmol/L) and hyperphosphatemia (2.42 mmol/L) with elevated intact parathyroid hormone (707,000 μg/L). Ultrasonography revealed an enlarged parathyroid gland on the left lower side of the thyroid gland. The otolaryngologist surgeons had to perform an en bloc excision to remove this parathyroid gland because of tight adhesions. Histological examination revealed that parathyroid cells had invaded the surrounding skeletal muscle through fibrous capsules, consistent with parathyroid carcinoma. Her joint pain disappeared 2 weeks after parathyroidectomy, and the tumorous calcinosis had largely resolved after 1 year. Conclusions Parathyroid carcinoma is a rare cause of hyperparathyroidism in end-stage kidney disease. Our case indicates that the use of cinacalcet hinders the diagnosis of parathyroid carcinoma in a chronic dialysis patient. When uncontrolled hypercalcemia and/or hyperphosphathemia develop during cinacalcet administration, parathyroidectomy should be considered to prevent a vicious exacerbation of ectopic calcification.

O hiperparatireoidismo persistente em pacientes transplantados renais tem sido associado a aumento da mortalidade, maior risco de perda de aloenxerto e maior risco de o paciente desenvolver fraturas e doencas osseas.1,2 O tratamento do hiperparatireoidismo persistente apos transplante renal permanece controverso para os especialistas em transplante. Existem opinioes divergentes quanto a se o cinacalcet ou a paratireoidectomia levam a melhores resultados para o paciente. Assim, o objetivo de qualquer tratamento seria nao apenas melhorar os resultados laboratoriais, mas tambem aprimorar ou [...]

Introduction: Treating secondary hyperparathyroidism (SHPT), a common condition associated with death in patients with chronic kidney disease, is a challenge for nephrologists. Calcimimetics have allowed the introduction of drug therapies no longer based on phosphate binders and active vitamin D. This study aimed to assess the safety and effectiveness of cinacalcet in managing chronic dialysis patients with severe SHPT. Methods: This retrospective study included 26 patients [age: 52 ± 12 years; 55% females; time on dialysis: 54 (4-236) months] on hemodialysis (N = 18) or peritoneal dialysis (N = 8) with severe SHPT (intact parathyroid hormone (iPTH) level > 600 pg/mL) and hyperphosphatemia and/or persistent hypercalcemia treated with cinacalcet. The patients were followed for 12 months. Their serum calcium (Ca), phosphorus (P), alkaline phosphatase (ALP), and iPTH levels were measured at baseline and on days 30, 60, 90, 180, and 365. Results: Patients with hyperphosphatemia (57.7%), hypercalcemia (23%), or both (19.3%) with iPTH > 600 pg/mL were prescribed cinacalcet. At the end of the study, decreases were observed in iPTH (1348 ± 422 vs. 440 ± 210 pg/mL; p < 0.001), Ca (9.5 ± 1.0 vs. 9.1 ± 0.6 mg/dl; p = 0.004), P (6.0 ± 1.3 vs. 4.9 ± 1.1 mg/dl; p < 0.001), and ALP (202 ± 135 vs. 155 ± 109 IU/L; p = 0.006) levels. Adverse events included hypocalcemia (26%) and digestive problems (23%). At the end of the study, 73% of the patients were on active vitamin D and cinacalcet. Three (11.5%) patients on peritoneal dialysis did not respond to therapy with cinacalcet, and their iPTH levels were never below 800 pg/mL. Conclusion: Cinacalcet combined with traditional therapy proved safe and effective and helped manage the mineral metabolism of patients with severe SHPT. Resumo Introdução: O tratamento do hiperparatireoidismo secundário (HPTs), patologia comum e associada à mortalidade na doença renal crônica, é um desafio para o nefrologista. Advento dos calcimiméticos propiciou terapêutica medicamentosa diferente da usual, baseada em quelantes de fósforo e vitamina D ativa. O objetivo deste estudo foi avaliar segurança e efetividade de cinacalcete no controle do HPTs grave de pacientes em diálise crônica. Métodos: Estudo retrospectivo 26 pacientes [idade: 52 ± 12 anos; 55% mulheres; tempo em diálise: 54 (4-236) meses], em hemodiálise (N = 18) ou diálise peritoneal (N = 8), com HPTs grave (nível de paratormônio intacto (PTHi) > 600 pg/mL), com hiperfosfatemia e/ou hipercalcemia persistentes, em tratamento com cinacalcete. Período de seguimento de 12 meses. Avaliados níveis séricos de cálcio (Ca), fósforo (P), fosfatase alcalina (FA) e PTHi no início do seguimento, 30, 60, 90, 180 e 365 dias. Resultados: Indicações para início do cinacalcete: hiperfosfatemia (57,7%), hipercalcemia (23%), ou ambos (19,3%) com PTH > 600 pg/mL. Ao final do seguimento, observada redução dos níveis PTHi (1348 ± 422 vs. 440 ± 210 pg/mL; p < 0,001), Ca (9,5 ± 1,0 vs. 9,1 ± 0,6 mg/dl; p = 0,004), P (6,0 ± 1,3 vs. 4,9 ± 1,1 mg/dl; p < 0,001) e FA (202 ± 135 vs. 155 ± 109 UI/L; p = 0,006). Eventos adversos: hipocalcemia (26%) e queixas digestivas (23%). No fim do estudo, 73% pacientes utilizavam vitamina D ativada associada ao cinacalcete. Três (11,5%) pacientes, todos em DP, não responderam ao cinacalcete, mantendo níveis PTHi > 800 pg/mL. Conclusão: Utilização de cinacalcete, associado à terapia tradicional, em pacientes com HPTs grave foi segura, eficiente e associada a melhor controle do metabolismo mineral.

Calcimimetics decrease parathyroid hormone (PTH) secretion in patients with secondary hyperparathyroidism. The decrease in PTH should cause a reduction in bone turnover; however, the direct effect of calcimimetics on bone cells, which express the calcium-sensing receptor (CaSR), has not been defined. In this study, we evaluated the direct bone effects of CaSR activation by a calcimimetic (AMG 641) in vitro and in vivo. To create a PTH "clamp," total parathyroidectomy was performed in rats with and without uremia induced by 5/6 nephrectomy, followed by a continuous subcutaneous infusion of PTH. Animals were then treated with either the calcimimetic or vehicle. Calcimimetic administration increased osteoblast number and osteoid volume in normal rats under a PTH clamp. In uremic rats, the elevated PTH concentration led to reduced bone volume and increased bone turnover, and calcimimetic administration decreased plasma PTH. In uremic rats exposed to PTH at 6-fold the usual replacement dose, calcimimetic administration increased osteoblast number, osteoid surface, and bone formation. A 9-fold higher dose of PTH caused an increase in bone turnover that was not altered by the administration of calcimimetic. In an osteosarcoma cell line, the calcimimetic induced Erk1/2 phosphorylation and the expression of osteoblast genes. The addition of a calcilytic resulted in the opposite effect. Moreover, the calcimimetic promoted the osteogenic differentiation and mineralization of human bone marrow mesenchymal stem cells in vitro. Thus, calcimimetic administration has a direct anabolic effect on bone that counteracts the decrease in PTH levels.

Since 2011, the Centers for Medicare and Medicaid Services has provided reimbursement for renal dialysis services furnished to Medicare beneficiaries through a bundled payment system known as the Prospective Payment System. Medications that have no injectable equivalent, known as “oral-only medications,” are currently excluded from the bundle and are paid separately through Medicare Part D. Thus, prior to the development of etelcalcetide, the first injectable calcimimetic, calcimimetics were reimbursed outside the bundle. Etelcalcetide’s introduction and approval for use in Medicare triggered a transition payment for a minimum of two years that will eventually result in the incorporation of calcimimetics into the dialysis bundle. Consequently, providers may face incentives to reduce calcimimetic use once the transition period has expired. The complexity of bone-mineral management in conjunction with the paucity of evidence-based recommendations in this area makes it difficult to predict the impact of this transition. Because these medications are expensive, a poor transition could have financial ramifications for dialysis organizations and, potentially, patient health. To ensure that patients are not adversely affected, it is critical that Medicare incorporate these medications into the bundle carefully, with close monitoring of outcomes.

Background The putative benefits of cinacalcet therapy for management of secondary hyperparathyroidism (SHPT) are thought to be most manifested when patients are taking it consistently and as prescribed. Real-world descriptions of cinacalcet prescription discontinuation and reinitiation in European hemodialysis patients are lacking. To address this knowledge gap, we used Dialysis Outcomes and Practice Patterns Study (DOPPS) data, based on dialysis facility medical records, from seven European countries to estimate rates and predictors of cinacalcet prescription discontinuation and reinitiation in hemodialysis patients and to describe the trajectories of CKD-MBD laboratory values after discontinuation. Methods Cox regression analyses were used to predict (1) cinacalcet discontinuation among 613 patients with ≥3 consecutive months without cinacalcet prescription immediately prior to a new cinacalcet prescription and (2) cinacalcet reinitiation among 415 patients with a newly discontinued cinacalcet prescription immediately after ≥3 consecutive months of prescribed use. Results Cinacalcet was discontinued in 21 and 35% of new users after 6 and 12 months, respectively. Cinacalcet was reinitiated in 38 and 49% of newly-discontinued users after 6 and 12 months, respectively. Predictors of discontinuation included lower parathyroid hormone (PTH) in the previous month (

Background: Since 2004, end-stage renal disease related hyperparathyroidism patients are treated mainly with cinacalcet, which ceased to be subsidized through the Australian Pharmaceutical Benefits Scheme in 2015. We aimed to investigate the impact of these changes on the treatment strategy in the Australian end-stage renal disease population.Methods: The following groups were formed according to the date of parathyroidectomy: A, before calcimimetics; B, during the era of calcimimetics; and C, after cinacalcet removal by the Australian Pharmaceutical Benefits Scheme. The primary outcome was time from start of dialysis to parathyroidectomy. Regression analysis was used to examine trends in parathyroidectomy rates.Results: Between 1998 and 2016, 195 parathyroidectomies were performed. Median time to referral was 69 (33-123), 67 (31-110) and 44 (23-102) months for groups A, B, and C, respectively (P=.55). Parathyroidectomy rates increased throughout the years (CI 0.09-1.13, R-2=0.27, P=.02). A trend toward a dip in parathyroidectomy rates was seen during the era of cinacalcet (P=.08). Median preoperative parathyroid hormone levels increased significantly (842 [418-1,553] versus 1,040 [564-1,810] versus 1,350 [1,0371,923] pg/mL, for groups A, B, and C, respectively [P Conclusion: Parathyroidectomy rates seem to vary according to the availability of cinacalcet. This change in treatment strategy is accompanied with increased preoperative parathyroid hormone levels, reflecting delayed surgery and increased disease severity. (C) 2018 Elsevier Inc. All rights reserved.

Resumen Antecedentes: Los efectos de cinacalcet en el hiperparatiroidismo secundario (HPTS), persistente o asociado a hipercalcemia han sido descritos en pacientes en diálisis. Objetivos: Analizar la eficacia y seguridad de cinacalcet en HPTS no sometido a diálisis y sus efectos sobre marcadores de recambio óseo. Métodos: Estudio analítico observacional, no aleatorizado, longitudinal, de pacientes con enfermedad renal crónica (ERC) e HPTS (PTH > 80 pg/mL); con normohipercalcemia (≥8,5 mg/dL), tratados con cinacalcet. Resultados: La dosis media de cinacalcet fue de 30mg/día en un 66,7%. Estudiamos 15 pacientes (10 mujeres), con edad de 66,0 ± 17,93 años. Etiología desconocida en 20% de los casos. Registramos variables sociodemográficas y parámetros de función renal. Comparamos valores basales, tras 6 y 12 meses. Descendieron los niveles de iPTH (392,4 ± 317,65 vs. 141,8 ± 59,26) y calcio (10,3 ± 0,55 vs. 9,4 ± 1,04). Aumentaron los valores de fósforo (3,7 ± 1,06 vs. 3,9 ± 0,85) y ß-CTX (884,2 ± 797,22 vs. 1.053,6 ± 999,00), sin variaciones significativas del FG, calciuria y demás marcadores óseos. Registrados 2 abandonos (intolerancia digestiva y paratiroidectomía, respectivamente). Conclusiones: Cinacalcet a dosis bajas es eficaz en el manejo del HPTS del paciente con ERC no tratado mediante diálisis, al disminuir la iPTH y la calcemia, sin ocasionar efectos adversos graves ni variación significativa de la función renal. Abstract Background: The effects of cinacalcet in persistent and/or hypercalcaemia-associated secondary hyperparathyroidism (SHPT) have been described in patients on dialysis. Objectives: To evaluate the efficacy and safety of cinacalcet in SHPT not on dialysis and its effects on bone turnover markers. Methods: Non-randomised, longitudinal, observational, analytical study of patients with chronic kidney disease (CKD) and SHPT (PTH> 80 pg/mL) as well as normo- or hypercalcaemia (≥8.5 mg/dL), treated with cinacalcet. Results: Mean cinacalcet dose was 30mg/day in 66.7%. We studied 15 patients (10 women), aged 66.0 ± 17.93years. The aetiology was unknown in 20% of cases. Sociodemographic variables and renal function parameters were recorded. We compared values at baseline as well as after 6 and 12 months. Calcium (10.3 ± 0.55 vs. 9.4 ± 1.04) and iPTH (392.4 ± 317.65 vs. 141.8 ± 59.26) levels decreased. Increased levels of phosphorus (3.7 ± 1.06 vs. 3.9 ± 0.85) and ß-CTX (884.2 ± 797.22 vs. 1053.6 ± 999.00) were detected, although there were no significant changes in GFR, urinary calcium or other bone markers. Two patients withdrew from the study (gastrointestinal intolerance and parathyroidectomy, respectively). Conclusions: Cinacalcet at low doses is effective in the management of SHPT in CKD patients who are not on dialysis. Its use reduces iPTH and calcaemia, without causing serious side effects or significant changes in renal function.

Background/Aims: Calcium sensing receptor (CaSR) is expressed, among others also in testis. Cinacalcet binds to the CaSR, increases sensitivity of CaSR to serum calcium and is used in the treatment of secondary hyperparathyroidism (sHPT) in chronic hemodialysis patients (HDP). In most of male HDP, serum testosterone concentration is lower than in healthy males. The aim of this study was to assess the influence of six-month treatment with cinacalcet on the serum total and free testosterone concentration in male HDP with sHPT. Methods: 38 male, hemodialysed CKD patients with sHPT (PTH>300 pg/ml) were enrolled into the study. In each patient serum PTH, total testosterone (TT) and free testosterone (FT) concentrations were assessed before the first dose of cinacalcet and then after 3 and 6 months of treatment. The results are presented as means with 95% confidence interval. Results: In 33 patients who completed the study cinacalcet treatment caused significant decrease of serum PTH from 1143 pg/ml (828 - 1458 pg/ml) at the baseline, to 809 pg/ml (487 - 1132pg/ml) after 3 month of treatment (p = 0.002), and to 607 pg/ml (281 - 934pg/ml; p < 0.0001) after 6 months of treatment. Serum TT concentration also decreased from 4.95ng/ml (4.23 - 5.67 ng/ml) to 4.45 ng/ml (3.85 - 5.06ng/ml) and to 4.39 ng/ml (3.75 - 5.03ng/ml), respectively (p for trend = 0.009). Moreover, serum FT concentration decreased from 6.95 pg/ml (5.54 - 8.36pg/ml) to 5.98 pg/ml (5.00-6.94 pg/ml); p = 0.14 and to 5.60 pg/ml (4.63 - 6.57 pg/ml); p = 0.034, respectively (p for trend = 0.012). Conclusion: Treatment with cinacalcet decreases serum total and free testosterone concentration in male hemodialysed patients with chronic kidney disease and secondary hyperparathyroidism.

Rationale: Calcium-sensing receptor (CaSR) mutations can cause life-threatening neonatal severe hyperparathyroidism (NSHPT). The medical management of NSHPT is often challenging and complex. Here, we present a case of NSHPT caused by a novel homozygous CaSR mutation. Patient concerns: A Chinese female infant presented with poor feeding, constipation, severe hypotonia, and periodic bradycardia. Biochemistry tests revealed markedly elevated serum levels of Ca2+ and parathyroid hormone (PTH). Diagnoses: Genetic sequencing revealed a previously undescribed CaSR mutation in exon 3 (c.242T>A; p.I81K). A diagnosis of NSHPT secondary to homozygously inherited familial hypocalciuric hypercalcemia syndrome was established. Interventions: Cinacalcet was administered after the common treatments (low-calcium intake, hydration, and furosemide), calcitonin, and pamidronate therapy all failed. Outcomes: Serum Ca2+ decreased and stabilized with cinacalcet therapy. During a 10-month follow-up, total calcium was maintained within the high-normal range and PTH was normalized. Lessons: A trial of cinacalcet therapy might be undertaken in cases of NSHPT while definitive results of the genetic analysis are awaited.

Cardiovascular disease has earned its place as one of the leading noncommunicable diseases that has become a modern-day global epidemic. The increasing incidence and prevalence of chronic kidney disease (CKD) has added to this enormous burden, given that CKD is now recognized as an established risk factor for accelerated cardiovascular disease. In fact, cardiovascular disease remains the leading cause of death in the CKD population, with significant prognostic implications. Alterations in vitamin D levels as renal function declines has been linked invariably to the development of cardiovascular disease beyond a mere epiphenomenon, and has become an important focus in recent years in our search for new therapies. Another compound, cinacalcet, which belongs to the calcimimetic class of agents, also has taken center stage over the past few years as a potential cardiovasculoprotective agent. However, given limited well-designed randomized trials to inform us, our clinical practice for the management of cardiovascular disease in CKD has not been adequately refined. This article considers the biological mechanisms, regulation, and current experimental, clinical, and trial data available to help guide the therapeutic use of vitamin D and calcimimetics in the setting of CKD and cardiovascular disease.