Influence of dialysate Ca concentrations on the therapeutic effects of etelcalcetide with concomitant drugs in patients with secondary hyperparathyroidism.

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.

Pharmacodynamics of evocalcet for secondary hyperparathyroidism in Japanese hemodialysis patients.

BACKGROUND: This study investigated the pharmacokinetics, pharmacodynamics, and safety of multiple doses of evocalcet in Japanese secondary hyperparathyroidism (SHPT) patients receiving hemodialysis. METHODS: In this multicenter, open-label study, conducted between August 2013 and March 2014, 27 patients received multiple doses of 1 and 4 mg evocalcet for 14 days, followed by an extension period of multiple doses of 8 and 12 mg evocalcet for 7 days using an intra-patient dose escalation protocol. Pharmacodynamic parameters consisted of measurement of intact parathyroid hormone (PTH), serum-corrected calcium, serum phosphorus and intact fibroblast growth factor 23 concentrations. Safety was assessed by analysis of adverse events. RESULTS: Plasma evocalcet levels reached steady state 3 days after the first day of administration. Pharmacodynamic analyses showed that evocalcet effectively reduced intact PTH and serum-corrected calcium levels. Adverse events (AEs) occurred in 29.6 and 62.5% of patients receiving multiple doses of 1 or 4 mg, respectively. The AE 'blood calcium decreased' occurred in eight patients (33.0%) after multiple doses of 4 mg. All events were mild, except for one patient with a moderate AE (abnormal liver function) and one patient with a severe adverse drug reaction (blood calcium decreased). CONCLUSION: Multiple doses of evocalcet reduced intact PTH levels with a concomitant decrease in serum calcium levels. Evocalcet was well tolerated in SHPT patients receiving hemodialysis.

Long-term effects of etelcalcetide as intravenous calcimimetic therapy in hemodialysis patients with secondary hyperparathyroidism.

BACKGROUND: Secondary hyperparathyroidism (SHPT) is a serious major complication in hemodialysis patients with chronic kidney disease. Long-term maintenance of serum phosphate, calcium, and parathyroid hormone (PTH) levels in appropriate ranges in these patients is a major challenge. We investigated the efficacy and safety of long-term treatment with etelcalcetide, a novel intravenous calcimimetic, in Japanese SHPT patients on long-term hemodialysis. METHODS: This study was a multicenter open-label study. A total of 191 hemodialysis patients with serum intact PTH (iPTH) > 240 pg/mL were enrolled. Etelcalcetide was administered thrice weekly for 52 weeks, with an initial dose of 5 mg and flexibility to adjust the dose between 2.5 and 15 mg and to adjust the dosing of concomitant medications for SHPT. The efficacy endpoint was the proportion of patients with serum iPTH decreased to the target range (60-240 pg/mL). RESULTS: Serum iPTH levels decreased immediately after etelcalcetide was started. At the end of the study, 87.5% (95% confidence interval 81.4-92.2; 140/160 patients) of patients achieved target serum iPTH levels, with control of serum calcium and phosphate levels. Adverse events, mostly mild to moderate, were reported by 96.8% of patients and led to study discontinuation in 7.4% of patients. Nausea, vomiting, and symptomatic hypocalcemia were found in 4.7, 9.5, and 1.1%, with 0.5, 1.1, and 1.1% considered treatment-related. CONCLUSIONS: Etelcalcetide effectively maintained serum iPTH, calcium, and phosphate levels in appropriate ranges with concomitant medications for SHPT for 52 weeks in Japanese hemodialysis patients, and was safe and well tolerated. REGISTRATION NUMBER: JapicCTI-142665.

Microwave ablation: an effective treatment for mild-to-moderate secondary hyperparathyroidism in patients undergoing haemodialysis.

BACKGROUND: Microwave ablation (MWA) is an effective treatment for severe secondary hyperparathyroidism (SHPT), but it can also be used for mild-to-moderate secondary hyperparathyroidism (SHPT). In this randomised, controlled study, the efficacy of MWA in the treatment of mild-to-moderate hyperparathyroidism is investigated. MATERIALS AND METHODS: We assessed outcomes 12 months after the randomisation of 28 patients with mild-to-moderate SHPT. The subjects received either MWA plus calcitriol or calcitriol alone. The primary end-points were the rate of achieving target levels of intact parathyroid hormone (iPTH), changes in iPTH levels and the rate of patients developing severe SHPT. RESULTS: Primary end points: the overall rates of achieving target levels of iPTH were comparable between the MWA and calcitriol alone groups (24% vs. 22%, p = 0.85). However, the rate of iPTH <150 pg/mL (lower limit of the target range) in the MWA group was higher than that in the calcitriol alone group (23% vs. 8%, p = 0.02). The mean iPTH level in the MWA group after MWA was lower than that in the calcitriol alone group (373.09 ± 322.31 vs. 552.28 ± 361.87 pg/mL, p < 0.001). There was a significant difference in the change in iPTH levels over time within the MWA group (p < 0.001) but not in the calcitriol alone group. Only one patient developed severe SHPT in the MWA group, while six patients in the calcitriol alone group developed severe SHPT (p = 0.04). CONCLUSIONS: Compared with calcitriol alone, MWA plus calcitriol decreases iPTH levels and prevents the progression of mild-to-moderate SHPT.

Efficacy and its predictor in microwave ablation for severe secondary hyperparathyroidism in patients undergoing haemodialysis.

BACKGROUND: Microwave ablation (MWA) can be used to treat severe secondary hyperparathyroidism; however, its efficacy and the predictor of its efficacy are unclear. In this retrospective study we determined the predictor of efficacy of MWA and compared the efficacy of MWA and parathyroidectomy. MATERIALS AND METHODS: Patients with severe secondary hyperparathyroidism who had received MWA or parathyroidectomy were enrolled in the study. Participants with MWA were divided into response and no response groups based on efficacy. Possible predictors were analysed using logistic regression to determine efficacy predictors. The participants were divided into MWA and parathyroidectomy groups, and the efficacy (including rates of achieving recommended goals for intact parathyroid hormone (iPTH), calcium, and phosphorus levels) were compared between the two groups. RESULTS: Thirty-one participants were enrolled for predictor analysis. Only baseline iPTH level predicted efficacy (OR 0.997, P = 0.018). The optimal threshold value of iPTH for predicting efficacy was 1493.5 pg/mL. To compare efficacy, 30 patients were enrolled in MWA (18/30) and parathyroidectomy (12/30) groups. The rates of achieving recommended goals for iPTH levels varied between 0 and 60%; a significant difference was found between the groups at 5 months (P = 0.01). However, in the parathyroidectomy group, the iPTH level and rate of iPTH <124 pg/mL (lower limit of target range) were significantly lower than in the MWA group after treatment (40-75% versus 0-16.7%). CONCLUSION: Baseline iPTH level is a good predictor of MWA efficacy for severe secondary hyperparathyroidism; parathyroidectomy is more effective for severe secondary hyperparathyroidism than MWA.

[Treatment of secondary hyperparathyroidism in hemodialysed patients--paricalcitol with or without cinacalcet]. / Leczenie wtórnej nadczynnosci przytarczyc u chorych hemodializowanych--parykalcytol razem z cynakalcetem czy osobno?

Secondary hyperparathyroidism (sHPT) is a common complication being a consequence of metabolic disorders associated with chronic kidney disease (CKD). Treatment of the sHPT should lead to calcium-phosphate management stabilization and parathyroid hormone levels reduction. The phosphate binders, synthetic vitamin D analogs and calcimimetics are used in sHPT treatment. In this paper we analyzed the results of three month paricalcitol treatment of 36 hemodialysis patients with sHPT (serum iPTH> 500 pg/ml). 11 patients have additionally received cinacalcet. Analysis of the results showes a statistically significant reduction in iPTH and alkaline phosphatase. Paricalcitol is effecitve in the tratment of SHPT with favourable profile of side effects. Alcaline phosphatase reduction may be a desirable additional therapeuctic effect. However, it appears that combined therapy with paricalcitol and cinacalcet shoud be offered to selected population of patients i.e. with hypocalcemia after calcimimetics.

[Diagnostics and treatment of primary and secondary hyperparathyroidism].

The experience of treatment of 41 patients (aged 32-67 years) was presented in the article. The duration of disease was 2-5 years. Primary hyperparathyroidism was diagnosed in 16 patients and secondary--in 25. Diagnostics of the disease included clinical methods of treatment; studying levels of general and ionized calcium, phosphorus, parathormone; an ultrasound of thyroid and parathyroid glands, the substratum scintigraphy. All patients were undergone the operation. Adenomas of parathyroid glands were removed in the case of primary hyperparathyroidism including mini-access. Hyperplastic parathyroid glands (31/2) were disposed in the case of secondary hyperparathyroidism. Good immediate and long-term results were obtained.

Paricalcitol versus cinacalcet plus low-dose vitamin D therapy for the treatment of secondary hyperparathyroidism in patients receiving haemodialysis: results of the IMPACT SHPT study.

BACKGROUND: Optimal treatment for secondary hyperparathyroidism (SHPT) has not been defined. The IMPACT SHPT (ClinicalTrials.gov identifier: NCT00977080) study assessed whether dose-titrated paricalcitol plus supplemental cinacalcet only for hypercalcaemia is superior to cinacalcet plus low-dose vitamin D in controlling intact parathyroid hormone (iPTH) levels in patients with SHPT on haemodialysis. METHODS: In this 28-week, multicentre, open-label Phase 4 study, participants were randomly selected to receive paricalcitol or cinacalcet plus low-dose vitamin D. Randomization and analyses were stratified by mode of paricalcitol administration [intravenous (IV) or oral]. The primary efficacy end point was the proportion of subjects who achieved a mean iPTH value of 150-300 pg/mL during Weeks 21-28. RESULTS: Of 272 subjects randomized, 268 received one or more dose of study drug; 101 in the IV and 110 in the oral stratum with two or more values during Weeks 21-28 were included in the primary analysis. In the IV stratum, 57.7% of subjects in the paricalcitol versus 32.7% in the cinacalcet group (P = 0.016) achieved the primary end point. In the oral stratum, the corresponding proportions of subjects were 54.4% for paricalcitol and 43.4% for cinacalcet (P = 0.260). Cochran-Mantel-Haenszel analysis, controlling for stratum, revealed overall superiority of paricalcitol (56.0%) over cinacalcet (38.2%; P = 0.010) in achieving iPTH 150-300 pg/mL during Weeks 21-28. Hypercalcaemia occurred in 4 (7.7%) and 0 (0%) of paricalcitol-treated subjects in the IV and oral strata, respectively. Hypocalcaemia occurred in 46.9% and 54.7% of cinacalcet-treated subjects in the IV and oral strata, respectively. CONCLUSION: Paricalcitol versus cinacalcet plus low-dose vitamin D provided superior control of iPTH, with low incidence of hypercalcaemia.

Effects of pamidronate and calcitriol on the set point of the parathyroid gland in postmenopausal hemodialysis patients with secondary hyperparathyroidism.

BACKGROUND/AIMS: Secondary hyperparathyroidism may worsen after the administration of pamidronate in postmenopausal hemodialysis (HD) patients. The aim of this study was to evaluate the short-term effect of coadministration of calcitriol and pamidronate on dynamic parathyroid hormone (PTH) secretion. METHODS: Fifteen postmenopausal women undergoing regular HD with serum intact PTH levels of >200 pg/ml were enrolled. The PTH-ionized calcium (iCa) curve was evaluated by the response to hypo- and hypercalcemia induced with 1 and 4 mEq/l of dialysate calcium, respectively. Parameters were compared after pamidronate was administered and after coadministration of pamidronate and calcitriol. Changes in serum levels of maximal serum PTH (PTHmax), basal PTH (PTHbase) and minimal PTH (PTHmin) were evaluated. RESULTS: Pamidronate therapy resulted in a decrease in predialysis basal plasma iCa (p < 0.05) and an increase in PTHmax (p < 0.01), PTHbase (p < 0.01) and PTHmin (p < 0.01). The change in serum iCa and PTH was reversed after the coadministration of calcitriol and pamidronate. CONCLUSION: Our study demonstrated that pamidronate therapy is associated with a reduced plasma iCa and increased PTH secretion. These adverse effects may be reversed by calcitriol. These findings suggest that in considering pamidronate treatment in postmenopausal patients with osteoporosis receiving HD, it might be safer to add calcitriol to prevent the increased PTH secretion.

Bone metabolism after cinacalcet administration in patients with secondary hyperparathyroidism.

Cinacalcet, an allosteric modulator of a calcium (Ca)-sensing receptor, significantly suppresses parathyroid hormone (PTH) secretion and bone turnover rate in chronic hemodialysis (HD) patients with secondary hyperparathyroidism (SHPT). In this study, bone metabolism after cinacalcet treatment was examined, because hungry bone syndrome is sometimes experienced after parathyroidectomy in severe SHPT. We conducted a prospective observational study in 17 HD patients with SHPT. Cinacalcet was started at 25 mg/day, and the dose was increased step by step based on serum calcium level. A significant decrease in serum Ca and intact PTH concentration was found within 2 weeks. Tartrate-resistant acid phosphatase 5b, a good bone resorption marker, was significantly decreased at week 2 of the study. Serum bone alkaline phosphatase, a marker of bone formation, was increased at week 2 compared with the basal level. It became, however, gradually decreased until week 14. Only one patient whose bone turnover was considerably high had a mild numbness feeling. These results suggest that cinacalcet treatment might transiently accelerate bone formation with rapid suppression of bone resorption. This uncoupling could be involved in a mechanism by which cinacalcet decreases serum Ca level.

[The role of the anesthesiologist in secondary hyperparathyroidism]. / Il ruolo dell'anestesista nell'iperparatiroidismo secondario.

In the last years the increasing of diabetes and hypertension has produced a considerable increase of patients with chronic renal failure; secondary hyperparathyroidism is one of the major complications. The resection of hyperfunctioning parathyroid tissue is the ultimate goal of the treatment. The preoperative examination by the anesthetist is the starting-point of the treatment. The anesthetist programs hemodialysis, the correction of fluid and electrolyte abnormalities and of the anaemia. In the operating room the anesthetist is involved in the careful monitoring of liquid infusion and anesthesiological procedure. The intraoperative parathyroid hormone (PTH) assay is an essential tool because the stress of orotracheal intubation elicits the raising of the catecholamine levels, and the catecholamines stimulates PTH secretion. Propofol can interfere with the intraoperative PTH assay causing an artificial reduction of PTH levels. This study highlights the difficulty in the application of anesthesiological protocol in the uremic patient.

Management of patients with secondary and tertiary hyperparathyroidism referred to surgical treatment.

INTRODUCTION: Aim of the study was present personal observations connected with the management of patients referred to surgical treatment for secondary hyperparathyroidism (SHT) or tertiary hyperparathyroidism (THT), and to assess immediate results of such management. MATERIAL AND METHODS: A total of 175 patients aged 21-80 years were treated surgically for SHT, and 16 patients aged 36-64 years were treated surgically for THT, between 1 January 1996 and 31 December 2008. The patients were classified for surgical treatment in cooperation with a nephrologist, internist, and anaesthesiologist. Each patient underwent bilateral exploration of the neck and assessment of all identified parathyroid glands. Subtotal parathyroidectomy or resection of parathyroid glands combined with autotransplantation (the latter in two patients with recurrent SHT) were performed. Ionized calcium concentration in blood serum, water-electrolyte equilibrium, and cardiovascular system were monitored postoperatively. RESULTS: A fall in ionized calcium levels was obtained postoperatively in all patients. Successful surgical treatment was confirmed by intraoperative macroscopic and immunochemical examinations. Intensive bleeding from the wound was noted in 2 (1%) patients, and intensified stenocardial symptoms in 15 (7.9%) patients with SHT. No deaths were noted during the perioperative period. Five (2.8%) patients with SHT required emergency dialyses. CONCLUSIONS: 1. Surgical treatment of secondary or tertiary hyperparathyroidism requires close cooperation between the surgeon, nephrologist, internist, and anaesthesiologist. 2. Successful results of the treatment, including minimum cardiovascular complications, can only be obtained in integrated cooperation with a dialysis centre.

[Cinacalcet in the therapy of secondary hyperparathyroidism--own experiences]. / Doswiadczenia wlasne w stosowaniu cynakalcetu u chorych z wtónq nadczynnoscia przytarczyc.

UNLABELLED: Secondary hyperparathyroidism (sHPT) affects 20-25% dialysed patients and is related to the bone, mineral and cardiovascular complications. Cinacalcet, acts on the calcium-sensing receptor increasing its sensitivity to calcium, thereby reducing parathyroid hormone (PTH) secretion. The aim of this study was to evaluate the effect of cinacalcet in dialysed patients with sHPT Material and methods. We studied group of 12 patients on dialysis > 3 month with sHPT and baseline iPTH > 450 pg/ml (F = 6, M = 6; peritoneal dialysis 2 patients and HD 10 patients; mean age 56 +/- 14). Cinacalcet was titrated from 30 mg once daily during a 6 month period. The following parameters were determined in serum: iPTH, Ca, P, before onset of therapy and every 4 weeks during 6 months therapy. RESULTS: Serum iPTH significantly decreased after 4 weeks therapy compared to the start point (from 849 +/- 253 to 338 +/- 260 pg/ml) and after 24 weeks cinacalcet therapy to 298 +/- 153 pg/ml. (64% reduction). Serum calcium and phosphate decrease but not significantly 8.7 +/- 1.2 vs 8.6 +/- 1.1 mg/dl and 7.3 +/- 2.8 vs 6.3 +/- 1.7 mg/dl respectively. There weren't serious adverse events. CONCLUSIONS: Cinacalcet is effective and well tolerated nonsurgical management treatment of secondary hyperparathyroidism in dialysed patients.

[Experience of low calcium crisis after the operation in peritonea dialysis secondary].

We report a case of secondary hyperparathyroidism after peritoneal dialysis. After given the total parathyroidectomy and forearm autoplantation (PTX+AT), the patient presented with an acute low calcium crisis (tongue myoparalysis, tetany and ECG abnormalities). As the conventional calcium treatment was invalid, the calcium solution was then changed, and replaced by the standard calcium dialysate with monitoring calcium ions. At the last, the patient was rescued. After a long term followed up, the patient's clinical symptoms were improved, and the parathyroid hormone (iPTH) level basically kept within the scope of the KDIGO guidelines.

Multiple Osteosclerotic Lesions: ARare Presentation of Hyperparathyroidism Secondary to Hypovitaminosis D.

Hypovitaminosis D is an under-recongnised and important factor responsible for secondary hyperparathyroidism. Hyperparathyroidism mostly presents with osteolytic lesions, especially in secondary hyperparathyroidism with renal failure. There are some rare presentations of hyperparathyroidism as focal or generalized osteosclerotic lesions. The exact mechanism for the osteosclerosis is still unknown, but there are some theories suggesting an exaggerated response of osteoblasts in response to prolonged osteolytic activity in order to restore bone loss. Here, we report a case of secondary hyperparathyroidism secondary to severe Vitamin D deficiency presented as multiple osteosclerotic lesions.

Multilevel brown tumors of the spine in a patient with severe secondary hyperparathyroidism A case report and review of the literature.

BACKGROUND: The brown tumour is an extreme form of osteitis fibrosa cystica, representing a serious complication of the advanced primary or secondary hyperparathyroidism. It occurs in settings of high levels parathyroid hormone, like in primary or secondary hyperparathyroidism, with a frequency of 3-4% and 1.5-13% respectively, usually affecting young people. CASE REPORT: The authors report a case of a 45 years old woman on long-term hemodialysis, with severe secondary hyperparathyroidism. The main clinical complaints were neck pain, lower thoraco-lumbar back pain, persistent left groin pain, and bilateral lower extremities weakness. The computed tomography scan revealed multiple spine brown tumors affecting the cervical, thoracic and lumbar level. After an initial partial response to the treatment of two years with Cinacalcet, a deterioration of the secondary hyperparathyroidism occurred (hypercalcemia, hyperphosphatemia) and the patient was referred for parathyroidectomy. The patient underwent total parathyroidectomy with auto-transplantation, with a positive postoperative result. CONCLUSIONS: Secondary hyperparathyroidism can lead, during its course, to osteolytic bone lesions called brown tumors. If the medical treatment fails, the surgical removal of the parathyroid glands with autotransplant remains the only treatment of the bone lesions progression. Reviewing the relevant literature in English (until March 2015), we found 24 cases of symptomatic vertebral brown tumors. To the authors' knowledge, this is the first case which describes a multilevel spine involvement (more than two), and the fifth describing a cervical localization. KEY WORDS: Hypocalcaemia, Secondary hyperparathyroidism, Spine brown tumors.

Kinetics of parathyroid hormone after parathyroidectomy in chronic hemodialysis patients.

Secondary hyperparathyroidism is a common complication in chronic renal failure. The treatment in some cases requires parathyroidectomy. The kinetics of the parathyroid hormone (PTH) levels after surgery helps to evaluate the efficacy of parathyroidectomy. Prospective analysis was made of the kinetics of intact PTH (iPTH) after parathyroidectomy in 10 chronic hemodialysis (HD) patients who had secondary hyperparathyroidism. We determined the levels of iPTH before surgery and its evolution after parathyroidectomy at regular intervals: Day 0, D7, D15, D30 and D90. The mean age of our patients was 40 ± 13 years, with a sex ratio of 1. The mean duration on HD was 122 ± 63 months. The duration of secondary hyperparathyroidism varied from one year to 12 years. All patients had received medical treatment for hyperparathyroidism. The indications for parathyroidectomy included resistance to medical treatment in seven cases, development of brown tumors in two cases and soft tissue calcifications in one case. All patients had radiographic evidence of hyperparathyroidism. The parathyroidectomy was sub-total in all patients, 6/8 in four cases and 7/8 in six cases. The mean iPTH level was 2341 ± 1946 pg/mL before surgery. A sharp drop in this level was noticed on D0, with a median of 92 pg/mL and, thereafter, the levels were 79 pg/mL on D7, 25 pg/mL on D15 and 36 pg/mL after 1 month. At 3 months post-surgery, the mean iPTH level was 302 pg/mL. Histological examination of the resected gland showed parathyroid hyperplasia in all patients. In our series, the efficacy of sub-total parathyroidectomy was satisfactory with rapid normalization of PTH, which is consistent with the literature data. Sub-total parathyroidectomy still has a place in the treatment of secondary hyperparathyroidism in chronic renal failure. Its indications should be limited to cases resistant to medical treatment and, in particular, in cases with occurrence of complications.