Effects of active vitamin D analogs and calcimimetic agents on PTH and bone mineral biomarkers in hemodialysis patients with SHPT: a network meta-analysis.

OBJECTIVE: Active vitamin D analogs and calcimimetic agents are primary drugs for patients with secondary hyperparathyroidism. Due to the different pharmacological mechanisms, they have different effects on the level of parathyroid hormone, serum calcium, phosphorus, and bone turnover biomarkers. This study aimed to evaluate the active vitamin D analogs and calcimimetic agents in hemodialysis patients with secondary hyperparathyroidism. METHODS: We included randomized clinical trials of hemodialysis patients with secondary hyperparathyroidism, comparing active vitamin D analogs to calcimimetic agents or placebo/control. The primary outcome was the change of PTH level from baseline to end-up. The secondary outcome was the change in serum calcium, phosphorus, calcium-phosphorus product, and bone turnover biomarkers. A network meta-analysis method was applied to complete this study. The forest plots reflected statistical differences in the outcomes between active vitamin D analogs and calcimimetic agents. The SUCRA result presented the ranking of impact on the outcomes. RESULTS: Twenty-one randomized clinical trials with 4653 patients were included in this network meta-analysis. Global and splitting-node inconsistencies provided no evidence of inconsistency in this study. There was no statistical difference between two active vitamin D analogs and three calcimimetic agents in the PTH, and phosphorus levels changed. Considering serum calcium level, compared with placebo, calcitriol (9.73, 3.09 to 16.38) and paricalcitol (9.74, 3.87 to 15.60) increase serum calcium. However, cinacalcet (- 1.94, - 3.72 to - 0.15) and etelcalcetide (- 7.80, - 11.80 to - 3.80) reduced the serum calcium, even a joint use of cinacalcet with active vitamin D analogs (- 5.83, - 9.73 to - 1.93). Three calcimimetic agents decreased calcium levels much more than calcitriol and paricalcitol. The same type of drugs was not distinct, with each one affecting the change in calcium level. Cinacalcet reduced calcium-phosphorus product much more than paricalcitol (- 3.66, - 6.72 to - 0.60). Evocalcet decreased calcium-phosphorus product more than cinacalcet (- 5.64, - 8.91 to - 2.37), calcitriol (- 9.36, - 14.81 to - 3.92), and paricalcitol (- 9.30, - 13.78 to - 4.82). Compared with paricalcitol, cinacalcet significantly increases the level of ALP (24.50, 23.05 to 25.95) and bALP (0.67, 0.03 to 1.31). The incidence of gastrointestinal disorders in cinacacet (29.35, 1.71 to 504.98) and etelcalcetide (20.92, 1.20 to 365.68) was notably higher than in paricalcitol. Etelcalcetide (0.71, 0.53 to 0.96) and evocalcet (0.46, 0.33 to 0.64) presented a lower rate of gastrointestinal disorders than cinacalcet. Cinacalcet ranked first in adverse gastrointestinal, nervous, and respiratory reactions. CONCLUSION: The same kinds of agents perform similar efficacy on the level of PTH, serum calcium, phosphorus, and calcium-phosphorus product. Paricalcitol did not lead to more hypercalcemia than calcitriol. The calcium decrease induced by cinacalcet was not settled even by associating it with active vitamin D analogs. Cinacalcet and evocalcet were superior to calcitriol and paricacitol in reducing calcium-phosphorus product. Calcimimetics induced more gastrointestinal disorders than active vitamin D analogs, especially cinacalcet.

Secondary hyperparathyroidism in chronic kidney disease: pathophysiology, current treatments and investigational drugs.

INTRODUCTION: Secondary hyperparathyroidism (SHPT) is a common complication of chronic kidney disease (CKD). It begins as an adaptive increase in parathyroid hormone levels to prevent calcium and phosphate derangements. Over time, this condition becomes maladaptive and is associated with increased morbidity and mortality. Current therapies encompass phosphate-lowering strategies, vitamin D analogues, calcimimetics and parathyroidectomy. These approaches harbor inherent limitations, stimulating interest in the development of new drugs for SHPT to overcome these limitations and improve survival and quality of life among CKD patients. AREAS COVERED: This review delves into the main pathophysiological mechanisms involved in SHPT, alongside the treatment options that are currently available and under active investigation. Data presented herein stem from a comprehensive search conducted across PubMed, Web of Science, ClinicalTrials.gov and International Clinical Trials Registry Platform (ICTRP) spanning from 2000 onwards. EXPERT OPINION: The advancements in investigational drugs for SHPT hold significant promise for enhancing treatment efficacy while minimizing side effects associated with conventional therapies. Although several challenges still hinder their adoption in clinical practice, ongoing research will likely continue to expand the available therapeutic options, refine treatment strategies, and tailor them to individual patient profiles.

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

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

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

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

Oral cinacalcet administration decreases serum ionized calcium and parathyroid hormone concentrations in healthy dogs.

Cinacalcet is an oral calcimimetic that has potential to non-invasively treat primary hyperparathyroidism in dogs (Canis lupis familiaris). There is minimal data assessing its efficacy in dogs. This study aimed to determine whether a single dose of cinacalcet decreases serum ionized calcium (iCa), total calcium (tCa), and parathyroid hormone (PTH) concentrations. Twelve dogs received a median dose of 0.49 mg/kg (range 0.30-0.69 mg/kg) cinacalcet per os. Venous blood samples were collected at time 0 (before cinacalcet administration), 3, 8, and 24 h following cinacalcet administration. PTH, iCa, and tCa concentrations were measured at each time point and compared to 0 hour concentrations. A significant (50%) decrease in serum PTH occurred at 3 h with a median PTH of 4.6 pmol/L (range 2.7-10.8) at baseline and 1.65 pmol/L (range 0.5-14.7) at 3 h; p = .005. A significant, but not clinically relevant, decrease in serum iCa from a median baseline of 1.340 mmol/L (range 1.32-1.41) to a 3 h median of 1.325 mmol/L (range 1.26-1.39), p = .043, was also observed. tCa concentrations were not different. This study showed that a single dose of cinacalcet leads to transient decreases in iCa and PTH concentrations in healthy dogs.

Surgical outcomes of parathyroidectomy for secondary hyperparathyroidism resistant to calcimimetic treatment: A retrospective single-center cohort study.

To evaluate the surgical outcomes of parathyroidectomy (PTx) for secondary hyperparathyroidism (SHPT) resistant to calcimimetic treatment, we retrospectively studied 187 patients with SHPT who had no history of calcimimetic treatment (NCMT) (NCMT group) and 186 patients with SHPT who were resistant to calcimimetic treatment (RCMT) (RCMT group). Success rate and operative time of PTx were compared among the two groups. Operative time was significantly longer in the RCMT group than in the NCMT group (180 vs 158 minutes, P < .001), but the difference was attenuated after multivariate adjustment including the weight of the largest parathyroid gland. No significant differences were observed in success rate of PTx (90.9% vs 91.4%, P = 1.000) between the two groups. In patients with SHPT who are resistant to calcimimetic treatment, operative time could be elongated but success rate of PTx remains unchanged.

Therapeutic Effect of Calcimimetics on Osteoclast-Osteoblast Crosslink in Chronic Kidney Disease and Mineral Bone Disease.

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-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 > 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-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 = -0.26, p < 0.01). Nonetheless, baseline lower iPTH level was associated with better responsiveness to Cinacalcet therapy. Sclerostin, an inhibitor of canonical Wnt/ß-catenin signaling, was decreased from 127.3 ± 102.3 pg/mL to 57.9 ± 33.6 pg/mL. Furthermore, Wnt-10b/Wnt 16 expressions were increased from 12.4 ± 24.2/166.6 ± 73.3 pg/mL to 33.8 ± 2.1/217.3 ± 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 ± 0.4 pg/mL to 91.4 ± 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 ± 0.4 mIU/mL to 7.7 ± 2.2 mIU/mL. Moreover, C-reactive protein levels were suppressed from 2.5 ± 0.6 to 0.8 ± 0.5 mg/L, suggesting the systemic inflammatory burden may be benefited after optimizing the parathyroid-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-osteoclast homeostasis in Cinacalcet therapy for CKD-MBD.

Cinacalcet as a First-Line Treatment in Neonatal Severe Hyperparathyroidism Secondary to Calcium Sensing Receptor (CaSR) Mutation.

INTRODUCTION: Neonatal severe hyperparathyroidism (NSHPT) is a rare cause of neonatal hypercalcemia caused by a loss of function mutation in the calcium-sensing receptor (CaSR). Hypercalcemia in NSHPT can be life-threatening. Maintenance of serum calcium within a safe range is the primary goal of treatment through hydration, forced diuresis, and bisphosphonate treatment, nevertheless most cases require parathyroidectomy. We report a case with NSHPT diagnosed on the first day of life (DoL) and successfully treated with cinacalcet as the first-line treatment from the 2nd DoL up to the age of 18 months. CASE REPORT: A full-term baby evaluated for weight loss at postnatal 14th hour and found to have hypercalcemia (14.4 mg/dL, reference range [RR]: 8.0-11.3). Despite hydration and diuresis, hypercalcemia persisted. Further evaluation revealed a parathyroid hormone (PTH) level of 1,493 pg/mL (RR: 15-65) and urine Ca/Cr of 0.09 mg/mg (RR: 0.03-0.81). Cinacalcet treatment was initiated on the 2nd DoL with the diagnosis of NSHPT due to hypocalciuric hypercalcemia and elevated PTH level. Ca levels decreased to normal levels on the 7th DoL. She was discharged from hospital at postnatal day 15 on cinacalcet treatment and still continued at 18 months of age. Sequencing of CaSR revealed a novel homozygous c.1836G>A (p.G613E) mutation in the patient, for which the parents and sister were heterozygous. CONCLUSION: This case represents the youngest age at cinacalcet initiation and the longest duration without parathyroidectomy in a homozygous NSHPT and demonstrates that cinacalcet is an effective first-line treatment in patients who are responsive to this treatment modality and allows avoiding/delay in surgical intervention in NSHPT.

Real World Use and Effects of Calcimimetics in Treating Mineral and Bone Disorder in Hemodialysis Patients.

BACKGROUND: Calcimimetics are used to treat mineral and bone disorder by reducing parathyroid hormone (PTH), calcium (Ca), and phosphorus (Phos). The study objectives were to assess the control of PTH, Ca, and Phos over time in patients receiving cinacalcet or etelcalcetide as well as dosing and time to discontinuation for etelcalcetide. METHODS: This was a retrospective cohort study using electronic medical records from small and independent dialysis centers. Adults ≥18 years of age were identified as cinacalcet or etelcalcetide users based on the first calcimimetic received in 2018 (index date). Patients were followed from the index date until parathyroidectomy, kidney transplant, death, or end of data (December 31, 2018). Analyses of mean PTH, Ca, and Phos, as well as target achievement of PTH, Ca, and Phos were conducted over a 9-month period. Discontinuation with etelcalcetide was measured with the Kaplan-Meier estimator. RESULTS: There were 1,346 cinacalcet patients (mean age 60.5 years, 43.5% female, and 47.1% Black) and 1,255 etelcalcetide patients (mean age 63.4 years, 46.6% female, and 38.5% Black). At baseline, the proportions in target were similar for etelcalcetide versus cinacalcet: 36 versus 38% for PTH, 79 versus 80% for Ca, and 43 versus 44% for Phos. Overall, 40-47% of cinacalcet users and 48-62% of etelcalcetide users were observed to be in target for PTH over 9 months. The proportion in target for Phos ranged from 41 to 46% for cinacalcet and 46-51% for etelcalcetide. The proportion in target for Ca ranged from 74 to 78% for cinacalcet and 60-73% for etelcalcetide. Etelcalcetide 12-month discontinuation was 37.4%. CONCLUSION: Both calcimimetics were effective in keeping PTH, Ca, and Phos levels within target. Patients receiving etelcalcetide tended to have lower laboratory values for PTH, Ca, and Phos over time, while patients receiving cinacalcet tended to be more likely to be in target for Ca over time.

Characteristics of Patients Who Achieve Serum Phosphorus Control on Sucroferric Oxyhydroxide or Sevelamer Carbonate: A post hoc Analysis of a Phase 3 Study.

INTRODUCTION: Control of hyperphosphatemia in patients on dialysis remains a major challenge. OBJECTIVE: This study evaluated predictors of serum phosphorus (sP) control among dialysis patients treated with noncalcium, oral phosphate binder therapy in a phase 3 clinical trial. METHODS: Post hoc analyses were performed using data for patients with hyperphosphatemia who received 52 weeks of treatment with sucroferric oxyhydroxide (SFOH) or sevelamer carbonate (sevelamer). Patients were categorized into those who achieved sP control (n = 302; defined as sP ≤ 5.5 mg/dL at week 52), and those with uncontrolled sP (n = 195; sP >5.5 mg/dL at week 52). Because SFOH and sevelamer have previously demonstrated similar effects on chronic kidney disease-mineral-bone disorder parameters in this study, the treatment groups were pooled. RESULTS: Average age at baseline was higher among sP-controlled versus sP-uncontrolled patients (56.9 vs. 53.4 years; p = 0.005). Baseline sP levels were significantly lower among sP-controlled versus sP-uncontrolled patients (7.30 vs. 7.85 mg/dL; p < 0.001), and sP reductions from baseline were significantly greater in the sP-controlled group (-2.89 vs. -0.99 mg/dL at week 52; p < 0.001). Logistic regression analysis identified higher baseline sP levels (odds ratio [OR] = 0.86, 95% confidence interval [CI]: 0.765-0.960), no concomitant active vitamin D therapy use (OR = 0.51, 95% CI: 0.328-0.804), and higher body mass index at baseline (OR = 0.96, 95% CI: 0.937-0.992) as significant predictors of uncontrolled sP. CONCLUSION: This analysis indicates that sP control may be more challenging in younger patients with high sP levels. Closer monitoring and management of serum phosphorus levels may be required in this population.

Cinacalcet studies in pediatric subjects with secondary hyperparathyroidism receiving dialysis.

BACKGROUND: Secondary hyperparathyroidism (sHPT), a complication of chronic kidney disease (CKD) characterized by persistently elevated parathyroid hormone (PTH), alterations in calcium-phosphorus homeostasis, and vitamin D metabolism, affects 50% of children receiving dialysis. A significant proportion of these children develop CKD-mineral and bone disorder (CKD-MBD), associated with an increased risk of fractures and vascular calcification. The standard of care for sHPT in children includes vitamin D sterols, calcium supplementation, and phosphate binders. Several agents are approved for sHPT treatment in adults undergoing dialysis, including vitamin D analogs and calcimimetics, with limited information on their safety and efficacy in children. The calcimimetic cinacalcet is approved for use in adults with sHPT on dialysis, but is not approved for pediatric use outside Europe. METHODS: This review provides dosing, safety, and efficacy information from Amgen-sponsored cinacalcet pediatric trials and data from non-Amgen sponsored clinical studies. RESULTS: The Amgen cinacalcet pediatric clinical development program consisted of two Phase 3 randomized studies, one Phase 3 single arm extension study, one open-label Phase 2 study, and two open-label Phase 1 studies. Effects of cinacalcet on PTH varied across studies. Overall, 7.4 to 57.1% of subjects who received cinacalcet in an Amgen clinical trial attained PTH levels within recommended target ranges and 22.2 to 70.6% observed a ≥ 30% reduction in PTH. In addition, significant reductions in PTH were demonstrated in all non-Amgen-supported studies. CONCLUSIONS: To help inform the pediatric nephrology community, this manuscript contains the most comprehensive review of cinacalcet usage in pediatric CKD patients to date.

The use of cinacalcet after pediatric renal transplantation: an international CERTAIN Registry analysis.

BACKGROUND: Secondary hyperparathyroidism (SHPT) may persist after renal transplantation (RTx), inducing hypophosphatemia and hypercalcemia that precludes the use of vitamin D analogs. The calcimimetic cinacalcet improved plasma calcium and parathyroid hormone (PTH) levels in randomized controlled trials in adults after RTx, but pediatric data are scarce. METHODS: In this retrospective study, we analyzed 20 pediatric patients from the Cooperative European Paediatric Renal TransplAnt Initiative (CERTAIN) Registry who received cinacalcet after RTx. The results are presented as median and interquartile range (25th-75th percentile). RESULTS: At 13.7 (11.0-16.5) years of age, 20 pediatric patients received a renal allograft. Cinacalcet was introduced at 0.4 (0.3-2.7) years post-transplant at an estimated glomerular filtration rate (eGFR) of 50 (34-66) mL/min/1.73 m2, plasma calcium of 2.58 (2.39-2.71) mmol/L, age-standardized (z score) phosphate of - 1.7 (- 2.7-- 0.4), and PTH of 136 (95-236) ng/L. The starting dose of cinacalcet was 0.5 (0.3-0.8) mg/kg per day, with a maximum dose of 1.1 (0.5-1.3) mg/kg per day. With a follow-up of 3.0 (1.5-3.6) years on cinacalcet therapy, eGFR remained stable; PTH levels decreased to 66 (56-124) ng/L at the last follow-up (p = 0.015). One patient displayed hypocalcemia (1.8 mmol/L). Cinacalcet was withdrawn in three patients (hypocalcemia, parathyroidectomy, incompliance). Nephrocalcinosis of the graft was not reported. CONCLUSIONS: This pilot study suggests that cinacalcet as off-label therapy for SHPT after pediatric RTx is efficacious in controlling post-transplant SHPT with acceptable tolerability. Continuing cinacalcet even with normal PTH can lead to dangerous life-threatening hypocalcemia. Therefore, at each subsequent visit, the need to continue cinacalcet must be assessed.

New Intravenous Calcimimetic Agents: New Options, New Problems. An Example on How Clinical, Economical and Ethical Considerations Affect Choice of Treatment.

BACKGROUND: Dialysis treatment is improving, but several long-term problems remain unsolved, including metabolic bone disease linked to chronic kidney disease (CKD-MBD). The availability of new, efficacious but expensive drugs (intravenous calcimimetic agents) poses ethical problems, especially in the setting of budget limitations. METHODS: Reasons of choice, side effects, biochemical trends were discussed in a cohort of 15 patients (13% of the dialysis population) who stared treatment with intravenous calcimimetics in a single center. All patients had previously been treated with oral calcimimetic agents; dialysis efficacy was at target in 14/15; hemodiafiltration was employed in 10/15. Median Charlson Comorbidity Index was 8. The indications were discussed according to the principlist ethics (beneficience, non maleficience, justice and autonomy). Biochemical results were analyzed to support the clinical-ethical choices. RESULTS: In the context of a strict clinical and biochemical surveillance, the lack of side effects ensured "non-maleficence"; efficacy was at least similar to oral calcimimetic agents, but tolerance was better. Autonomy was respected through a shared decision-making model; all patients appreciated the reduction of the drug burden, and most acknowledged better control of their biochemical data. The ethical conflict resides in the balance between the clinical "beneficience, non-maleficience" advantage and "justice" (economic impact of treatment, potentially in attrition with other resources, since the drug is expensive and included in the dialysis bundle). The dilemma is more relevant when a patient's life expectancy is short (economic impact without clear clinical advantages), or when non-compliance is an issue (unclear advantage if the whole treatment is not correctly taken). CONCLUSIONS: In a context of person-centered medicine, autonomy, beneficence and non-maleficence should weight more than economic justice. While ethical discussions are not aimed at finding "the right answer" but asking "the right questions", this example can raise awareness of the importance of including an ethical analysis in the choice of "economically relevant" drugs.

Treatment of hyperphosphatemia: the dangers of high PTH levels.

The control of secondary hyperparathyroidism (SHPT) in pediatric chronic kidney disease is of utmost importance. Even though parathyroid hormone (PTH) is an important biomarker of mineral and bone disorders associated to CKD (CKD-MBD), calcium, phosphate, alkaline phosphatase, and vitamin D are also crucial and should be assessed together. In pediatric dialysis, high PTH levels have been associated with impaired longitudinal growth, bone disease, cardiovascular comorbidities, left ventricular hypertrophy, anemia, and even mortality (when PTH levels were above 500 pg/mL, i.e., 8.3-fold the upper normal limit (UNL)). As such, high PTH levels are for sure deleterious, but too low PTH levels have also been shown to impair growth and to promote vascular calcifications because of the underlying adynamic bone. This manuscript is part of a pros and cons debate for keeping PTH levels within the normal range in pediatric CKD, focusing on the pros. High bone turnover lesions can occur at lower PTH levels than "current" guidelines would suggest; thus, PTH alone is not a good predictor of the underlying osteodystrophy. PTH results can vary locally depending on the assay. Existing guidelines for PTH targets are conflicting and based on a very little evidence. However, the 120-180 pg/mL (2- to 3-fold the UNL) range is common to most of the guidelines; it seems to be a reasonable target in children undergoing dialysis, even though it does not correspond to "normal" PTH levels. As always, the philosophy of PTH levels in pediatric dialysis may be balanced, i.e., "not too low, not too high, and keep phosphate under control."

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.

Treatment of hyperphosphatemia: the dangers of aiming for normal PTH levels.

Secondary hyperparathyroidism is part of the complex of chronic kidney disease-associated mineral and bone disorders (CKD-MBD) and is linked with high bone turnover, ectopic calcification, and increased cardiovascular mortality. Therefore, measures for CKD-MBD aim at lowering PTH levels, but there is no general consensus on optimal PTH target values. This manuscript is part of a pros and cons debate for keeping PTH levels within the normal range in children with CKD, focusing on the cons. We conclude that a modest increase in PTH most likely represents an appropriate adaptive response to declining kidney function in patients with CKD stages 2-5D, due to phosphaturic effects and increasing bone resistance. There is no evidence for strictly keeping PTH levels within the normal range in CKD patients with respect to bone health and cardiovascular outcome. In addition, the potentially adverse effects of PTH-lowering measures, such as active vitamin D and calcimimetics, must be taken into account. We suggest that PTH values of 1-2 times the upper normal limit (ULN) may be acceptable in children with CKD stage 2-3, and that PTH levels of 1.7-5 times UNL may be optimal in patients with CKD stage 4-5D. However, standard care of CKD-MBD in children relies on a combination of different measures in which the observation of PTH levels is only a small part of, and trends in PTH levels rather than absolute target values should determine treatment decisions in patients with CKD as recommended by the 2017 KDIGO guidelines.

Short-term medical treatment of hypercalcaemia in primary hyperparathyroidism predicts symptomatic response after parathyroidectomy.

BACKGROUND: Primary hyperparathyroidism is often associated with non-disease-specific symptoms. The aim of this study was to evaluate whether normalization of hypercalcaemia with short-term medical treatment can be used to predict the effects of parathyroidectomy and guide in surgical decision-making. METHODS: This observational study included patients who received calcimimetic treatment for 4 weeks before parathyroidectomy (30-60 mg daily). A panel of tests was used to assess various aspects of quality of life (European Organisation and Treatment of Cancer QLQ-C30 core questionnaire, Hospital Anxiety and Depression Scale and Positive State of Mind questionnaire), cognitive function (Montreal Cognitive Assessment) and muscle strength (timed-stands test). The tests were carried out at baseline, after 4 weeks of calcimimetic treatment, and at 6 weeks and 6 months after parathyroidectomy. The predictive values of changes during calcimimetic treatment were determined for each test. RESULTS: The study included 110 patients of median age 62 years (91 women). Calcimimetic treatment resulted in normalization of calcium levels and improvements in quality-of-life parameters. The time spent on the timed-stands test was significantly shortened. Eleven of 38 participants with a baseline Montreal Cognitive Assessment score below 26, indicating mild cognitive impairment, reached scores of at least 26 during treatment with calcimimetic. Improvements during treatment with calcimimetic correlated well with postoperative outcomes (positive predictive values 74-96 per cent). CONCLUSION: The method described in this study may be used to aid surgical decision-making for patients with primary hyperparathyroidism and non-disease-specific symptoms by predicting the effects of normalization of hypercalcaemia.

ANTECEDENTES: El hiperparatiroidismo primario (pHPT) a menudo se asocia con síntomas no específicos de la enfermedad. El objetivo de este estudio fue evaluar si la normalización de la hipercalcemia a corto plazo con tratamiento médico se podría usar para predecir los efectos de la paratiroidectomía y guiar la toma de decisiones quirúrgicas. MÉTODOS: Estudio observacional (ClinicalTrials.gov, registro NCT02227264) que incluyó 110 pacientes programados para paratiroidectomía (mediana de edad 62 años; 91 mujeres). Intervención: tratamiento calcimimético, cuatro semanas, 30-60 mg al día. Medidas de resultado: Un panel de pruebas para evaluar los aspectos de la calidad de vida (cuestionario de calidad de vida core 30, QLQ-C30; escala hospitalaria de ansiedad y depresión (HAD) y estado mental positivo (PSOM); función cognitiva (evaluación cognitiva de Montreal, MoCa) y fuerza muscular (Timed-Stands Test, TST). Las pruebas se realizaron cuatro veces: al inicio del estudio (basal), después de cuatro semanas de tratamiento calcimimético, a las seis semanas y seis meses después de la paratiroidectomía. Para cada prueba se determinaron los valores predictivos de los cambios durante el tratamiento calcimimético. RESULTADOS: El tratamiento con fármacos calcimiméticos determinó una normalización en los niveles de calcio y una mejoría en los parámetros de calidad de vida. El tiempo del TST se redujo significativamente. Once de los 38 participantes con una puntuación MoCa basal < 26, definida como deterioro cognitivo leve, alcanzaron puntuaciones ≥ 26 durante el uso de la medicación. Las mejoras observadas durante el tratamiento mostraron una buena correlación con el resultado postoperatorio (valores predictivos positivos 74-96%). CONCLUSIÓN: Este estudio presenta un método basado en la predicción de los efectos de la normalización de la hipercalcemia para ayudar en la toma de decisiones quirúrgicas en pacientes con pHPT y síntomas no específicos de la enfermedad.

Cinacalcet plus vitamin D versus vitamin D alone for the treatment of secondary hyperparathyroidism in patients undergoing dialysis: a meta-analysis of randomized controlled trials.

BACKGROUND: Secondary hyperparathyroidism (SHPT) is a common and serious complication of chronic kidney disease, particularly in end-stage renal disease. Currently, both cinacalcet and vitamin D are used to treat SHPT via two different mechanisms, but it is still unclear whether the combination use of these two drugs can be a safe and effective alternative to vitamin D alone. Therefore, the aim of this meta-analysis was to assess the efficacy and safety of cinacalcet plus vitamin D in the treatment of SHPT. METHODS: Four electronic databases, including PubMed, EMBASE, Cochrane Central Register of Controlled Trials (CENTRAL), and Web of Science, were searched for eligible publications. All randomized-controlled trials comparing cinacalcet plus vitamin D with vitamin D alone in SHPT patients undergoing dialysis were included. Mean difference (MD) with 95% confidence intervals (CIs) and risk ratios (RRs) with 95% CIs were calculated using a random-effects model or fixed-effects model. Sensitivity analysis was conducted by removing any one study successively to estimate the stability of the pooled results, and subgroup analysis was carried out to explore potential sources of heterogeneity, and funnel plots were used to test publication bias. RESULTS: A total of 8 randomized-controlled trials involving 1480 patients were included in the study. Compared with vitamin D treatment, the combination use of cinacalcet and vitamin D significantly lowered serum calcium (MD - 0.82, 95% CI - 1.02 to - 0.61, P < 0.001), phosphorus (MD - 0.57, 95% CI - 0.97 to - 0.18, P = 0.005), and calcium × phosphorus product (MD - 9.41, 95% CI - 10.00 to - 8.82, P < 0.001). However, there was no difference in serum parathyroid hormone (PTH, MD 43.99, 95% CI - 49.22 to 137.20, P = 0.35), ≥ 30% reduction in PTH (RR 1.02, 95% CI 0.69-1.52, P = 0.91), and PTH achieve 150-300 pg/ml (RR 0.88, 95% CI 0.68-1.15, P = 0.35). Moreover, the combination therapy did not increase the risk of all adverse events, all-cause mortality, diarrhea, muscle spasms, and headache (all P > 0.05), but had a higher risk of hypocalcemia (RR 17.98, 95% CI 5.68-56.99, P < 0.001), and nausea or vomiting (RR 3.47, 95% CI 2.25-5.35, P < 0.001). CONCLUSIONS: In comparison with vitamin D alone, the combination use of cinacalcet and vitamin D significantly lowered serum calcium, phosphorus, and the calcium × phosphorus product, and did not increase the risk of all adverse events, all-cause mortality, diarrhea, muscle spasms, and headache, whereas had no effect on serum PTH and increased the risk of hypocalcemia and nausea or vomiting. Future studies are needed to assess the effects of cinacalcet plus vitamin D on PTH level, cardiovascular events, and other clinical outcomes in larger samples with longer durations.

Predictors of cinacalcet discontinuation and reinitiation in hemodialysis patients: results from 7 European countries.

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 (< 150 pg/ml vs. 150-299, HR = 2.57 [95% CI: 1.52-4.33]) and lower serum calcium in the previous month (< 8.4 mg/dl vs. 8.4-10.19, HR = 1.67 [95% CI: 1.08-2.59]). Predictors of reinitiation included higher PTH in the previous month (300-599 pg/ml vs. 150-299, HR = 1.88 [95% CI = 1.19-2.97]; 600+ pg/ml, HR = 3.02 [95% CI = 1.92-4.76]). After cinacalcet discontinuation, mean serum PTH increased from 408 to 510 pg/ml, mean serum calcium briefly rose from 9.12 to 9.22 mg/dl before declining to 9.06 mg/dl, and mean serum phosphorus showed little change. CONCLUSIONS: Nephrologist discontinuation of cinacalcet therapy is common in European countries. Additional research is needed to identify optimal cinacalcet treatment strategies for SHPT management, including comparisons of intermittent cinacalcet therapy versus sustained treatment with reduced dose or frequency.