Calcimimetic Agent Research Articles

Etelcalcetide for the treatment of secondary hyperparathyroidism

ABSTRACTIntroduction: Calcium sensing receptor is an important target for the treatment of secondary hyperparathyroidism (SHPT). Etelcalcetide hydrochloride is a novel peptide calcimimetic agent that has a similar mechanism of action as cinacalcet hydrochloride. Clinical trials of etelcalcetide have been performed in the US, Europe, and Japan, and these trials demonstrated the safety and efficacy of etelcalcetide in dialysis patients. Etelcalcetide has recently been approved in Europe, the US and Japan.Areas covered: We review the development, pharmacokinetics, and clinical efficacy and safety of etelcalcetide for the treatment of SHPT in hemodialysis patients. We also summarize the clinical evidence regarding cinacalcet to forecast the potential clinical benefit of etelcalcetide.Expert opinion: Etelcalcetide is an injectable calcimimetic with a longer elimination half-life than cinacalcet. The injectable formulation improves adherence and reduces pill burden, while the frequency of gastrointestinal adverse events has been comparable between cinacalcet and etelcalcetide. The longer half-life of etelcalcetide reduces the fluctuation of biochemical markers of mineral and bone metabolism, but it remains to be determined whether such a sustained effect results in improved outcomes. Further studies are needed to determine the impact of etelcalcetide on clinical outcomes, particularly in comparison with the conventional calcimimetic cinacalcet.

Cinacalcet Hydrochloride.

Cinacalcet hydrochloride is a calcimimetic agent that increases the sensitivity to the extracellular calcium of the calcium-sensing receptors of the parathyroid gland which regulates parathyroid hormone secretion. This comprehensive profile on cinacalcet hydrochloride starts with a description: nomenclature, formulae, chemical structure, elemental composition, and appearance. The uses and applications of the drug are included. The methods of preparation of cinacalcet hydrochloride are described and their respective schemes are outlined. The physical characterization of the drug is: ionization constant, solubility, X-ray powder diffraction (XRPD) pattern, crystal polymorphs, melting point, and differential scanning calorimetry. The spectral characteristics of the drug include: ultraviolet spectrum, vibrational spectrum, 1H and 13C nuclear magnetic resonance spectra, and the mass spectrum. The methods of analysis of the drug include: spectrophotometry, electrophoresis, fluorimetry, and high-performance liquid chromatography alone or with mass spectrometry. The stability of the drug in various media and storage conditions are reported. Biological studies on the drug include: the metabolism pharmacokinetics and pharmacodynamics. More than 100 references are listed at the end of the chapter.

Etelcalcetide: A New Intravenous Calcimimetic for the Treatment of Secondary Hyperparathyroidism in Haemodialysis Patients

Etelcalcetide hydrochloride (also known as AMG 416) is a new, second generation, long-acting calcimimetic agent that is administered intravenously. In November 2016 it received its first approval i...

Kronik böbrek hastalıklı hastalarda sekonder hiperparatiroidizm: Tanı, medikal ve cerrahi tedavi

Secondary hyperparathyroidism (SHPT) is a secondary adaptive response to maintain calcium homeostasis and caused by any condition associated with chronically reduced serum calcium (Ca) levels, and low serum Ca levels lead to compensatory overactivity of the parathyroid gland. It is a common complication of chronic kidney disease (CKD) and is part of the CKD-mineral bone disorder (CKD-MBD). SHPT is associated with increased risk of morbidity and mortality; thus, SHPT control is recommended. SHPT develops in patients with CKD due to a variety of mechanisms including increased phosphorus and fibroblast growth factor 23 (FGF23), and decreased calcium and 1.25-dihydroxyvitamin D levels. Patients present with various bone disorders, cardiovascular disease, and certain patterns of biochemical abnormalities. The diagnosis of patients with SHPT require a combination of clinical investigation and laboratory findings. Many patients with this disease are asymptomatic and only have abnormalities detectable by laboratory and radiologic studies. Laboratory tests may reveal hypocalcemia, normocalcemia or hypercalcemia and hyperphosphatemia. In addition, patients wirh SHPT have extremely elevated parathyroid hormone (PTH) levels, elevated or normal alkaline phosphatase (ALP) levels and decereased vitamin D (vit D) levels. Patients also can become symptomatic. Untreated SHPT leads to progressive bone disease, osteitis fibrosa cystica, and soft tissue calcifications. Patients may experience intractable bone pain, fractures, pruritis, soft tissue or vascular calcifications, calciphylaxis, erythropoietin resistant anemia, and mental status changes. Medical treatment consists of controlling hyperphosphatemia, vit D analogs and Ca administration, and calcimimetic agents. The majority of patients with SHPT can be managed by medical treatment. Despite improvements in medical therapy, it does not always provide control of the SHPT. Some patients require surgical treatment. The surgical indications include PTH levels >500-800 pg/ml associated with hypercalcemia and/or hyperphosphatemia despite medical therapy. Other indications include calciphylaxis, fractures, bone pain or pruritis. Pre-operative imaging is only occasionally helpful except in re-operative parathyroidectomy (PTX). Operative approaches include subtotal PTX, total PTX (TPTX) with or without autotransplantation, and possible thymectomy. Each approach has its own proponents, advantages and disadvantages which are discussed. Hypocalcemia is the most common postoperative complication requiring aggressive calcium administration. Benefits of surgical treatment may include improved survival, bone mineral density and alleviation of symptoms.

Etelcalcetide: First Global Approval.

Etelcalcetide (Parsabiv™) is a novel second generation calcimimetic agent developed by Amgen for the treatment of secondary hyperparathyroidism (SHPT), a complication of chronic kidney disease (CKD). Etelcalcetide reduces circulating levels of parathyroid hormone and calcium by binding directly to the calcium-sensing receptor. Intravenous etelcalcetide has been approved in the EU for the treatment of SHPT in adult patients with CKD on haemodialysis therapy. Regulatory applications for etelcalcetide in SHPT are also under review in the USA and Japan. This article summarizes the milestones in the development of etelcalcetide leading to this first global approval for the treatment of SHPT.

A model of calcium homeostasis in the rat.

We developed a model of calcium homeostasis in the rat to better understand the impact of dysfunctions such as primary hyperparathyroidism and vitamin D deficiency on calcium balance. The model accounts for the regulation of calcium intestinal uptake, bone resorption, and renal reabsorption by parathyroid hormone (PTH), vitamin D3, and Ca2+ itself. It is the first such model to incorporate recent findings regarding the role of the calcium-sensing receptor (CaSR) in the kidney, the presence of a rapidly exchangeable pool in bone, and the delayed response of vitamin D3 synthesis. Accounting for two (fast and slow) calcium storage compartments in bone allows the model to properly predict the effects of bisphophonates on the plasma levels of Ca2+ ([Ca2+]p), PTH, and vitamin D3 Our model also suggests that Ca2+ exchange rates between plasma and the fast pool vary with both sex and age, allowing [Ca2+]p to remain constant in spite of sex- and age-based hormonal and other differences. Our results suggest that the inconstant hypercalciuria that is observed in primary hyperparathyroidism can be attributed in part to counterbalancing effects of PTH and CaSR in the kidney. Our model also correctly predicts that calcimimetic agents such as cinacalcet bring down [Ca2+]p to within its normal range in primary hyperparathyroidism. In addition, the model provides a simulation of CYP24A1 inactivation that leads to a situation reminiscent of infantile hypercalcemia. In summary, our model of calcium handling can be used to decipher the complex regulation of calcium homeostasis.

Rhodium-Catalyzed Enantioselective Arylation of Aliphatic Imines.

Chiral rhodium(I)-catalyzed highly enantioselective arylation of aliphatic N-sulfonyl aldimines with arylboronic acids has been developed. This transformation is achieved by the use of a rhodium/bis(phosphoramidite) catalyst to give enantiomerically enriched α-branched amines (up to 99 % ee). In addition, this system enables efficient synthesis of (+)-NPS R-568 and Cinacalcet which are calcimimetic agents.

ChemInform Abstract: A Two‐Step, One Pot Preparation of Amines via Acyl Succinimides. Synthesis of the Calcimimetic Agents Cinacalcet, NPS R‐467, and NPS R‐568.

Abstract A method has been developed for the preparation of amines through a process of coupling acyl succinimides derived from commercially available carboxylic acids with amines to afford the corresponding amides. These amides are then reduced in situ with either diisobutylaluminum hydride or lithium aluminum hydride. The reaction tandem of the coupling reaction followed by the reduction affords the amine in fair to good yields after purification by flash chromatography. This one-pot, two reaction tandem process has been successfully applied to the synthesis of the calcimimetic agents cinacalcet, NPS R-467, and NPS R-568.

A two-step, one pot preparation of amines via acyl succinimides. Synthesis of the calcimimetic agents cinacalcet, NPS R-467, and NPS R-568

A method has been developed for the preparation of amines through a process of coupling acyl succinimides derived from commercially available carboxylic acids with amines to afford the corresponding amides. These amides are then reduced in situ with either diisobutylaluminum hydride or lithium aluminum hydride. The reaction tandem of the coupling reaction followed by the reduction affords the amine in fair to good yields after purification by flash chromatography. This one-pot, two reaction tandem process has been successfully applied to the synthesis of the calcimimetic agents cinacalcet, NPS R-467, and NPS R-568.

The Emerging Role of Denosumab in the Long-Term Management of Parathyroid Carcinoma-Related Refractory Hypercalcemia

The main cause of death in patients with parathyroid carcinoma is parathyroid hormone (PTH)-induced hypercalcemia. To date, the management of hypercalcemia has been based on the use of bisphosphonates and calcimimetic agents. In recent reports, the use of denosumab has shown encouraging results in cases of refractory hypercalcemia of malignancy. Our objective is to present a case of successful management of resistant hypercalcemia due to parathyroid carcinoma with denosumab, to review similar cases from the literature, and to propose denosumab's use in the clinical management of PTH-induced refractory hypercalcemia. Presentation of a case report and review of the literature for cases of parathyroid carcinoma-mediated hypercalcemia successfully treated with denosumab. A 71-year-old man with metastatic parathyroid carcinoma was referred to our department for uncontrolled hypercalcemia, resistant to treatment with bisphosphonates and cinacalcet. Treatment with denosumab (120 mg per month) in addition to cinacalcet (180 mg per day) resulted in normalization of calcium levels and maintenance within the normal range for an observation period of 11 months. Review of the literature revealed 4 case reports and a letter to the editor, all of which reported the successful treatment of resistant hypercalcemia associated with parathyroid carcinoma. Based on the above findings of the effectiveness of denosumab in controlling refractory hypercalcemia, its safety in renal failure and the fact that denosumab may reduce PTH-induced bone loss, we endorse its use in the management of hypercalcemia in patients with parathyroid carcinoma and perhaps other conditions with PTH-induced hypercalcemia.

CALCIFILAXIA URÉMICA SOB O EFEITO DO CALCIMIMÉTICO CINACALCET

A calcifilaxia urémica é uma complicação rara mas grave dos doentes dialisados. A patogenia não está claramente estabelecida, sendo os principais factores de risco o hiperparatiroidismo e a consequente elevação do produto fosfo-cálcico. Uma doente do sexo feminino de 72 anos de idade, sob hemodiálise há 15 anos, com hiperfosfatémia, normocalcémia e hiperparatiroidismo grave apesar da terapêutica com cinacalcet e sevelâmero, foi observada com lesões ulceradas dolorosas, de configuração geográfica, superfície necrótica central e bordos hemorrágicos na perna direita com 6 semanas de evolução. A biópsia cutânea revelou deposição de cálcio na parede de múltiplos vasos da derme profunda e hipoderme, confirmando a hipótese clínica evocada de calcifilaxia. Com o aumento das doses do cinacalcet e sevelâmero houve melhoria discreta das lesões ulceradas. Porém, a doente faleceu devido a múltiplas co-morbilidades. Relata-se um caso de ineficácia do cinacalcet no controlo dos parâmetros laboratoriais e nas consequentes lesões cutâneas.

The Use of Calcimimetics for the Treatment of Secondary Hyperparathyroidism: A 10 Year Evidence Review.

Until the discovery of calcimimetics, the management of secondary hyperparathyroidism (SHPT) relied exclusively on treatment with phosphate binders, vitamin D derivatives or surgical parathyroidectomy with limited success. The therapeutic use of calcimimetic agents, together with a better understanding of the pivotal role of the calcium-sensing receptor (CaSR) in the physiological regulation of parathyroid gland function, substantially advanced the management of hyperparathyroidism in dialysis practice. Calcimimetics bind selectively to the CaSR receptor in parathyroid tissue and enhance the inhibitory effect of extracellular calcium ions on parathyroid hormone (PTH) secretion, thereby reducing PTH levels even when serum calcium concentrations are normal or low. The availability of calcimimetic agents for clinical use has opened a new era in the management of patients with SHPT. Indeed, calcimimetic compounds have been shown to reduce PTH levels and to lower serum calcium concentrations in all forms of hyperparathyroidism, including primary hyperparathyroidism (PHPT) and parathyroid carcinoma. Such findings underscore the critical importance of the CaSR as a therapeutic target in this family of clinical disorders. New calcimimetic agents are being developed that have the potential to offer improved efficacy and safety compared with currently available calcimimetic compounds.

Pathophysiology and treatment of nonfamilial hyperparathyroidism.

Primary hyperparathyroidism (HPT) is the main cause of hypercalcemia and the most common parathyroid glands disease. The diagnosis is easy in patients with hypercalcemia and elevated PTH serum level. Minimally invasive parathyroidectomy (PTx) represents the treatment of choice for symptomatic patients, leading to several advantages, including immediate normalization of hypercalcemia and significant improvement of bone mineral density, cardiovascular dysfunctions, neuropsychological symptoms and quality of life. Secondary and tertiary HPT are relatively common complications in patients with chronic kidney disease (CKD) or advanced kidney failure, and in kidney transplant recipients who did not achieve complete calcium/phosphate metabolism normalization, respectively. The drugs available for patients with secondary HPT, and to treat hyperphosphatemia include non-calcium-containing phosphate binder, calcitriol analogues, calcimimetic agents, or a combination of two or more drugs. Although recent studies report that PTx significantly improves survival also in patients with CKD and severe secondary HPT, the indications for surgery are not yet well established. Subtotal or total PTx with or without autotransplantation are the surgical options for treating all patients with secondary HPT. Total PTx leads to a faster reduction in serum calcium level and normalization of PTH, but the risk of hypoparathyroidism is higher than after subtotal PTx. Further studies are needed to confirm the usefulness of the drugs currently recommended, and others will have to be tested in the near future.

Tolerance and efficacy of a low dose of the calcimimetic agent cinacalcet in controlling moderate to severe secondary hyperparathyroidism in hemodialysis patients.

Secondary hyperparathyroidism is almost a constant feature in chronic kidney disease (CKD) patients maintained on hemodialysis (HD). Calcimimetic agents appear to offer an alternative to surgery in controlling secondary hyperparathyroidism in these patients. Recent studies provide conflicting data on the benefits, efficacy and tolerance of cinacalcet as first-line therapy for the treatment of secondary hyperparathyroidism in CKD. This study was designed to investigate the efficacy and tolerance of a low dose of the calcimimetic agent cinacalcet in patients on long-term HD having moderate to severe secondary hyperparathyroidism. Twenty five adult male patients on HD for more than three years were included in the study. All had moderate to severe secondary hyperparathyroidism with serum intact parathyroid hormone (iPTH) >50 pmol/L, resistant to conventional treatment. We used the targets of Chronic Kidney Disease: Outcomes Quality Initiative (K/DOQI) clinical guidelines as optimal target of serum iPTH, calcium and phosphate. Patients were administered cinacalcet as a single oral daily dose of 30 mg and were followed-up for six months. Cinacalcet treatment for six months resulted in a significant reduction in the serum phosphate and iPTH levels while the serum calcium levels remained unchanged. Thirty-six percent of the patients attained the recommended serum iPTH levels, 40% achieved significant reduction of the serum iPTH levels and 24% showed no favorable response. Only one patient dropped out because of severe gastrointestinal symptoms. Our results suggest that treatment of CKD patients, having moderate to severe secondary hyperparathyroidism, with low-dose cinacalcet is effective and well tolerated.

Calcimimetics for secondary hyperparathyroidism in chronic kidney disease patients.

Calcimimetic agents lower abnormal serum parathyroid hormone (PTH) levels in people who have chronic kidney disease (CKD), but the benefits and harms on patient-level outcomes are uncertain. Since this review was first published in 2006 showing that evidence for calcimimetics was largely restricted to biochemical outcomes, additional studies have been conducted. This is an update of a review first published in 2006. To evaluate the benefits and harms of cinacalcet on patient-level outcomes in adults with CKD. MEDLINE, EMBASE, CENTRAL and conference proceedings were searched for randomised controlled trials (RCTs) evaluating any calcimimetic against placebo or another agent in adults with CKD (persistent albuminuria > 30 mg/g with or without reduced glomerular filtration rate (GFR) (below 60 mL/min/1.73 m²)). We updated searches to 7 February 2013 including the Cochrane Renal Group's Specialised Register to complete this update. We included all RCTs of a calcimimetic administered to patients with CKD for the treatment of elevated serum PTH levels. Data were extracted on all relevant patient-centred and surrogate outcomes. We summarised treatment estimates using random effects and expressed treatment effects as a risk ratio (RR) or mean difference (MD) with 95% confidence intervals (CI). Eighteen studies (7446 participants) compared cinacalcet in addition to standard therapy with no treatment or placebo plus standard therapy. In adults with GFR category G5 (GFR below 15 mL/min/1.73 m²) treated with dialysis, routine cinacalcet treatment had little or no effect on all-cause mortality (RR 0.97, 95% CI 0.89 to 1.05), imprecise effects on cardiovascular mortality (RR 0.67, 95% CI 0.16 to 2.87), and prevented surgical parathyroidectomy (RR 0.49, 95% CI 0.40 to 0.59) and hypercalcaemia (RR 0.23, 95% CI 0.05 to 0.97), but increased hypocalcaemia (RR 6.98, 95% CI 5.10 to 9.53), nausea (RR 2.02, 95% CI 1.45 to 2.81) and vomiting (RR 1.97, 95% CI 95% CI 1.73 to 2.24). Cinacalcet decreased serum PTH (MD -281.39 pg/mL, 95% CI -325.84 to -234.94) and calcium (MD -0.87 mg/dL, 95% CI -0.96 to -0.77) levels, but had little or no effect on serum phosphorous levels (MD -0.23 mg/dL, 95% CI -0.58 to 0.12).Data were sparse for adults with GFR categories G3a to G4 (GFR 15 to 60 mL/min/1.73 m²) and kidney transplant recipients.Overall, based on GRADE criteria, evidence for cinacalcet in adults with GFR category G5 treated with dialysis (mortality, parathyroidectomy, hypocalcaemia, and nausea) is of high or moderate quality. High quality evidence suggests "further research is very unlikely to change our confidence in the estimate of treatment effect" and moderate quality evidence is "further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate". Information for adults with less severe CKD GFR category G3a to G4 is of low or very low quality. This means that further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate Routine cinacalcet therapy reduced the need for parathyroidectomy in adults treated with dialysis and elevated PTH levels but does not improve all-cause or cardiovascular mortality. Cinacalcet increases risks of nausea, vomiting and hypocalcaemia, suggesting harms may outweigh benefits in this population.

Highly Sensitive and Simple Validated Ultra-performance Liquid Chromatography/ Tandem Mass Spectrometry Method for the Determination of Cinacalcet in Human Plasma

With the objective of decreasing analysis time and retaining good efficiency (UPLC-MS/MS) is an outstanding analytical approach for speedy biomedical analysis. The aim of this study was to develop validate a simple, rapid, sensitive and specific UPLC-MS/MS method for quantification of cinacalcet, a calcimimetic agent, which acts on a calcium sensing receptor of the parathyroid gland in human plasma. After following a liquid–liquid extraction procedure with diethyl ether–dichloromethane (70:30, v/v), cinacalcet (CIN) and internal standard (IS) abiraterone with C18 Acquity UPLC BEHTM column. m/z 358.07 > 155.0 and m/z 350.1 > 156.0 where the ion transitions recorded in the positive ion multiple reaction monitoring mode for cinacalcet for IS. The mobile phase consisted of acetonitrile: 10 mM ammonium acetate: formic acid (90:10:0.1% v/v/v) with a flow rate of 0.4 mL/min. The assay exhibited a linear dynamic range of 0.2–100 ng/mL for cinacalcet in human plasma with good correlation coefficient (IQ 0.995) and with an LOQ of 1 ng/mL. The intra- and inter-assay precisions were satisfactory; the relative standard deviations did not exceed 6.98 %. This method was simple, rapid and highly sensitive, hence could be used for analysis of cinacalcet in human plasma. Keywords: Cinacalcet, UPLC, LC-MS/MS, pharmacokinetic study, human plasma.

Are there ways to attenuate arterial calcification and improve cardiovascular outcomes in chronic kidney disease?

The risk of cardiovascular mortality among patients with end-stage renal disease is several times higher than general population. Arterial calcification, a marker of atherosclerosis and a predictor of cardiovascular mortality, is common in chronic kidney disease (CKD). The presence of traditional cardiovascular risk factors such as diabetes, hypertension, hyperlipidemia, and advanced age cannot fully explain the high prevalence of atherosclerosis and arterial calcification. Other factors specific to CKD such as hyperphosphatemia, excess of calcium, high dose active vitamin D and prolonged dialysis vintage play important roles in the development of arterial calcification. Due to the significant health risk, it is prudent to attempt to lower arterial calcification burden in CKD. Treatment of hyperlipidemia with statin has failed to lower atherosclerotic and arterial calcification burden. Data on diabetes and blood pressure controls as well as smoking cessation on cardiovascular outcomes in CKD population are limited. Currently available treatment options include non-calcium containing phosphate binders, low dose active vitamin D, calcimimetic agent and perhaps bisphosphonates, vitamin K and sodium thiosulfate. Preliminary data on bisphosphonates, vitamin K and sodium thiosulfate are encouraging but larger studies on efficacy and outcomes are needed.

Three-Year Successful Cinacalcet Treatment of Secondary Hyperparathyroidism in a Patient with X-Linked Dominant Hypophosphatemic Rickets: A Case Report

Hypophosphatemic rickets (HR) is a rare inherited disorder characterized by a classic rickets phenotype with low plasma phosphate levels and resistance to treatment with vitamin D. Development of secondary hyperparathyroidism (SHPT) as a direct consequence of treatment is a frequent complication and a major clinical challenge, as this may increase risk of further comorbidity. Cinacalcet, a calcimimetic agent that reduces the secretion of PTH from the parathyroid glands, has been suggested as adjuvant treatment to SHPT in patients with HR. However, only two papers have previously been published and no data are available on effects of treatment for more than six months. We now report a case of 3-year treatment with cinacalcet in a patient with HR complicated by SHPT. A 53-year-old woman with genetically confirmed X-linked dominant hypophosphatemic rickets developed SHPT after 25 years of conventional treatment with alfacalcidol and phosphate supplements. Cinacalcet was added to her treatment, causing a sustained normalization of PTH. Ionized calcium decreased, requiring reduction of cinacalcet, though asymptomatical. Level of phosphate was unchanged, but alkaline phosphatase increased in response to treatment. Cinacalcet appeared to be efficient, safe, and well tolerated. We recommend close control of plasma calcium to avoid hypocalcemia.

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

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

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

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