Severe sHPT Research Articles

Pretransplant Parathyroidectomy in Patients with Severe Secondary Hyperparathyroidism and Long-Term Effectiveness After Kidney Transplantation.

Kidney transplantation (KT) is the best option for patients with end-stage renal disease, but recipients still have legacy bone mineral disease from the pretransplant period, especially patients with severe secondary hyperparathyroidism (sHPT). Patients who had severe sHPT and underwent KT were analyzed retrospectively. Two groups were identified (patients with severe sHPT who had parathyroidectomy or calcimimetic before KT). Bone mineral density (BMD) was measured in the first year and last follow-up at the femoral neck, total hip, and lumbar spine using the dual-energy X-ray absorptiometry (DXA). Persistent hyperparathyroidism (perHPT) incidence was significantly higher in the calcimimetic group (75% vs. 40%, p=0.007). In patients with parathyroidectomy, BMDs were higher at femoral neck (0.818±0.114 vs. 0.744±0.134, p=0.04) and lumbar spine (1.005±0.170 vs. 0.897±0.151, p=0.01) at the first assessment. The BMD comparison between patients treated with parathyroidectomy and calcimimetic found a significant difference only in the femoral neck at second evaluation (0.835±0.118 vs. 0.758±0.129; p=0.03). In multivariate, linear regression revealed a positive association between the last BMD of the femoral neck with body mass index (CC: 0.297, 95% CI, 0.002-0.017) and parathyroidectomy (CC: 0.319, 95% CI, 0.021-0.156). Parathyroidectomy is associated with a significantly better femoral neck BMD and a lower incidence of perHPT in patients with severe sHPT.

Safety and Efficacy of Cinacalcet in Children Aged Under 3 Years on Maintenance Dialysis

BackgroundSecondary hyperparathyroidism (sHPT) is particularly severe in rapidly growing infants in dialysis. While cinacalcet is effective and licensed in dialysis above 3 years, its efficacy and safety below 3 years is unknown. MethodsWe identified 26 children on dialysis below three years treated with cinacalcet between 2009 and 2021 in 8 European pediatric centers. ResultsMedian (IQR) age at start of cinacalcet was 18[IQR 11–27] months, serum parathyroid hormone (PTH) was 792[411–1397] pg/mL, corresponding to 11.6[5.9–19.8] times the upper limit of normal (ULN). Serum calcium was 2.56[2.43–2.75] mmol/L, and serum phosphate 1.47[1.16-1.71] mmol/L. Serum 25-OHD was 70[60–89] nmol/L, three children were vitamin D deficient (<50nmol/L). The initial cinacalcet dose was 0.4[0.2–0.8] mg/kg/day and the maximum dose was 1.1[0.6–1.2] mg/kg/day. The median follow-up under cinacalcet was 1.2[0.7-2.0] years. PTH decreased to 4.3[2.2–7.8] times the ULN after 6 months, to 2.0[1.0–5.3] times ULN after 12 months and to 1.6[0.5–3.4] times thereafter (p=0.017/ 0.003/<0.0001, log-transformed PTH). Seven of the 26 infants developed 10 hypocalcemic episodes <2.10 mmol/L. Oral calcium intake was 84[66-117] % of recommended nutrient intake at start, 100[64-142] % at 3 months and declined to 78[65-102] % at 12 months of therapy. Three children developed clinical signs of precocious puberty. ConclusionCinacalcet efficiently controlled severe sHPT in children below 3 years of age and was associated with hypocalcemic episodes (similarly, to what is observed in older children) and precious puberty, mandating meticulous control of calcium (taking into account nutrition, supplementation and dialysate) and endocrine changes.

#5922 CINACALCET IMPACT ON ESTIMATED GLOMERULAR FILTRATION RATE AMONG KIDNEY TRANSPLANT RECIPIENTS WITH SECONDARY HYPERPARATHYROIDISM: A CASE-CONTROL STUDY

Abstract Background and Aims Secondary hyperparathyroidism (sHPT) is common in kidney transplant recipients. It remains unknown if Calcimimetic agents (as cinacalcet), oftenly used in this context, have an impact on mortality or morbidity. The objective of this work was to compare the renal and cardiovascular outcome of kidney transplanted patients with sHPT. Method Data from January 2008 to December 2019 were retrospectively extracted from the DIVAT database. 575 kidney transplant recipients with sHPT (PTH &amp;gt; 100 pg/ml) followed in Nantes University Hospital, were separated into two groups: Treated (cinacalcet) and sHPT Controls (no cinacalcet). A propensity score was used to match the patients (age, sex, first transplant, transplantation before/after 2015, time on dialysis, history of cardiovascular disease, initial condition, anti-HLA class I and II immunization, corticosteroids, serum parathormone level). Biological data (including estimated glomerular filtration rate by CKD-Epi formula), cardiovascular events (coronaropathy, obliterating arteriopathy of the lower limbs, stroke), return in dialysis or related death were extracted from one year of transplantation to the last follow-up. Time-varying exposure Cox PH model was used. Results 292 patients were included after matching (146 Treated, 146 sHPT Controls). After one year of transplantation, serum parathormone was significantly higher in Treated patients compared to sHPT Controls (152 pg/mL vs 111 pg/mL respectively, p &amp;lt; 0.001), suggesting a more severe sHPT in Treated patients. 7% of Treated and 10% of sHPT Controls suffered from a cardiovascular event or related death during the follow up (HR = 1.28 [0.52; 3.14], p = 0.6). Return to dialysis or related death were more frequent in the Treated patients (HR: 1.90 [0.97 - 3.75, p = 0.06]. At 48 months post-transplantation, estimated glomerular filtration rate was significantly decreased in Treated patients compared to sHPT controls (52.3 mL/min/1.73 m2 vs 44.1, p = 0.006). Conclusion Our study highlights that kidney transplant recipients with sHPT treated with cinacalcet have a worse kidney graft outcome than non-treated sHPT patients. It remains to be assessed if this reflects an underlying more severe sHPT condition or a direct effect of cinacalcet on the graft function. This study needs to be completed by the assessment of bone mineralization. Parathyroidectomy for sHPT should be discussed in kidney transplant recipients with impaired glomerular filtration rate and/or cardiovascular events.

Vitamin D and Chronic Kidney Disease Association with Mineral and Bone Disorder: An Appraisal of Tangled Guidelines.

Chronic kidney disease (CKD) is a highly prevalent condition worldwide in which the kidneys lose many abilities, such as the regulation of vitamin D (VD) metabolism. Moreover, people with CKD are at a higher risk of multifactorial VD deficiency, which has been extensively associated with poor outcomes, including bone disease, cardiovascular disease, and higher mortality. Evidence is abundant in terms of the association of negative outcomes with low levels of VD, but recent studies have lowered previous high expectations regarding the beneficial effects of VD supplementation in the general population. Although controversies still exist, the diagnosis and treatment of VD have not been excluded from nephrology guidelines, and much data still supports VD supplementation in CKD patients. In this narrative review, we briefly summarize evolving controversies and useful clinical approaches, underscoring that the adverse effects of VD derivatives must be balanced against the need for effective prevention of progressive and severe secondary hyperparathyroidism. Guidelines vary, but there seems to be general agreement that VD deficiency should be avoided in CKD patients, and it is likely that one should not wait until severe SHPT is present before cautiously starting VD derivatives. Furthermore, it is emphasized that the goal should not be the complete normalization of parathyroid hormone (PTH) levels. New developments may help us to better define optimal VD and PTH at different CKD stages, but large trials are still needed to confirm that VD and precise control of these and other CKD-MBD biomarkers are unequivocally related to improved hard outcomes in this population.

COMMD5 is involved in the mechanisms of hypotension after parathyroidectomy in patients receiving hemodialysis

BackgroundSecondary hyperparathyroidism (SHPT) is a common complication of end-stage renal disease. Parathyroidectomy (PTx) is often employed for treatment of severe SHPT. However, PTx may cause hypotension via unknown mechanisms. COMM domain-containing protein 5 (COMMD5) in the parathyroid glands has been linked to blood pressure regulation of spontaneously hypertensive rats. ObjectiveTo explore the relationship between COMMD5 levels and reduced BP after PTx in patients receiving hemodialysis (HD). Methods and results(1) The study cohort included 31 patients receiving HD who underwent PTx. Serum COMMD5 levels were higher post-PTx vs. pre-PTx. (2) Sprague-Dawley rats (n = 22) were assigned to a 5/6 nephrectomy group or sham surgery group, vascular rings of the thoracic aorta from rats with CKD were incubated with COMMD5, and changes in vascular tension were compared. COMMD5 inhibited vasoconstriction of vascular rings with intact endothelium, but had no effect on vascular rings without the endothelium. (3) Human umbilical vein endothelial cells were stimulated with COMMD5 or small interfering RNA (siRNA). The expression levels of atrial natriuretic peptide (ANP) and endothelial nitric oxide synthase (eNOS) were up-regulated and down-regulated, respectively. ConclusionsSerum COMMD5 levels were increased after PTx in SHPT patients. COMMD5 promoted high expression of ANP and eNOS in endothelial cells, leading to vasodilation and resulting in hypotension.

Clinical Features and Prognosis of Severe Secondary Hyperparathyroidism: A Retrospective Study from a Single Center

PurposeSecondary hyperparathyroidism (SHPT) is one of the most common complications of chronic kidney disease and has a high rate of morbidity and mortality. Current studies on prognostic factors in SHPT are inadequate. We aimed to identify a single-center cohort of severe SHPT to elucidate relevant clinical and laboratory features and explore laboratory indicators that related to its prognosis.MethodsThe clinical data of 46 patients with SHPT, admitted to the intensive care unit (ICU) of the First Affiliated Hospital of Zhengzhou University in the time period ranging from January 2019 to March 2022 were analyzed retrospectively. Clinical data collected were screened univariately for influences that were associated with poor prognosis. A binary logistic regression model was constructed to analyze the independent risk factors for poor clinical prognosis, using correlated influences. The value of each indicator in predicting patient prognosis was analyzed using receiver operating characteristic curves (ROC) curves.ResultsThe causes of death among the 46 patients with severe SHPT were cardiogenic death (malignant arrhythmia, cardiac arrest) in 11 cases (47.8%), sepsis in 9 cases (39.2%), and neurogenic death (intracranial hemorrhage) in 3 cases (13.0%). Patients were divided into a good prognosis group and a poor prognosis group according to their status at the time of leaving the ICU. There was no statistically significant difference in sex, BUN, NT-pro BNP, ALP, Scr, Mg, Ca, Pi, K, CRP, Hb, and PLT between the poor prognosis group and the good prognosis groups. The age, PTH, PCT, WBC, APACHE II, and neutrophil ratio of the poor prognosis group were higher than those of the good prognosis group, and the ALB level was lower than that of the good prognosis group, with a statistically significant difference of P < 0.05. The 19 clinical indicators mentioned above were screened univariately. Among them, age, PTH, WBC, ALB, APACHE II and neutrophil ratio were significantly associated with prognosis, P < 0.05. Binary logistic regression analysis showed that age (OR = 1.076, 95% CI (1.011, 1.145)), PTH (OR = 1.004, 95% CI (1.000, 1.007)), WBC (OR = 1.295, 95% CI (1.026, 1.634)) were indicators for poor prognosis in patients with severe SHPT, and ALB (OR = 0.803, 95% CI (0.645, 0.998)) was a protective factor for poor prognosis. The ROC curve showed that the optimal cut-off point for patient age was 51 years, with a sensitivity of 86.9% and specificity of 52.2%; the optimal cut-off point for PTH was 346 pg/ml, with a sensitivity of 59.1% and specificity of 82.6%; the optimal cut-off point for WBC was 11.95 × 10^9/L, with a sensitivity of 56.52% and specificity of 91.3%; the optimal cut-off point for neutrophil ratio was 82.4%, sensitivity 82.6%, specificity 73.9%.ConclusionAge, PTH, and WBC are independent risk factors for poor prognosis of severe SHPT, and ALB is an independent protective factor for poor prognosis. Patients with severe SHPT should be assessed for risk of the poor prognosis based on age, admission PTH, WBC, ALB, and neutrophil ratio as early as possible to adjust the treatment strategy.

Adult Presentation of X-Linked Hypophosphatemia

Adult X-linked hypophosphatemia (XLH) patients present with specific symptoms, including enthesopathies (e.g., ossification of longitudinal ligaments (OPLL), osteophytes around large joints, and enthesopathy in the Achilles tendons), early osteoarthritis, the development of severe secondary and tertiary hyperparathyroidism (SHPT/THPT), and the subsequent progression of chronic kidney disease (CKD). In addition, these patients exhibit the typical phenotypes of osteomalacia, such as pseudofracture and fracture in weight-bearing bones, odontitis, and tooth abscesses. The mechanism underlying enthesopathy development is unknown; however, a common underlying mechanism among XLH and autosomal recessive hypophosphatemic rickets (ARHR1/2) due to mutations in PHEX, DMP1, and ENPP1 is assumed. Clarification of the pathogenesis and drug discovery for this complication is an urgent issue, as many adult XLH patients suffer subsequent debilitating nervous symptoms or impingement syndrome, and existing treatments are ineffective. Severe SHPT and THPT are associated with conventional therapy, including active vitamin D and phosphate supplementation, and complicated and careful adjustment of dosages by experienced clinicians is required to avoid SHPT/THPT. Burosumab is a very effective therapy without risk for the development of SHPT/THPT. However, indications for this drug should be carefully considered, along with cost-effectiveness, guidelines or recommendations, and the health care system of each country.

A retrospective observational study of patients on maintenance hemodialysis receiving parathyroidectomy by ultrasonic scalpel

BackgroundSecondary hyperparathyroidism (SHPT) remains a common complication in many patients on maintenance hemodialysis. Kidney Disease Improve Global Outcomes (KDIGO) 2017 guidelines suggest that parathyroidectomy (PTX) should be performed in severe SHPT patients with chronic kidney disease stage 3a-stage 5D. In the present study, we observed the efficacy of ultrasonic scalpel for PTX in SHPT patients on maintenance hemodialysis.MethodsA total of 74 patients on maintenance hemodialysis who underwent PTX (34 with traditional electrocautery and 40 with an ultrasonic scalpel) were observed between August 2020 and August 2021 at Xiangyang Central Hospital (Hubei University of Arts and Science). Baseline demographic and clinic characteristics were collected pre- and post-PTX. Moreover, the postoperative complications and operation time were assessed between the two groups.ResultsThe univariate analysis showed that there was no statistical significance in weight, dialysis duration, serum potassium, serum calcium, serum magnesium, alkaline phosphate, triglyceride, and intact parathyroid hormone (iPTH) before and after PTX between the two groups (P > 0.05). The operation time in the ultrasonic scalpel group was significantly decreased compared with the traditional electrocautery group (P < 0.05). Compared with the traditional electrocautery group, the drainage amount was significantly reduced in the ultrasonic scalpel group, and the number of days with drain and postoperative hospital stay were also remarkably decreased (P < 0.05).ConclusionsThe use of ultrasonic scalpel significantly reduced the operation time and postoperative hospital stay in patients on maintenance hemodialysis undergoing PTX.

Changes in bone microarchitecture following parathyroidectomy in patients with secondary hyperparathyroidism

BackgroundSecondary hyperparathyroidism (SHPT) in patients with chronic kidney disease (CKD) has a significant effect on bone, affecting both trabecular and cortical compartments. Although parathyroidectomy results in biochemical improvement in mineral metabolism, changes in bone microarchitecture as evaluated by high-resolution imaging modalities are not known. Magnetic resonance imaging (MRI) provides in-depth three-dimensional assessment of bone microarchitecture, as well as determination of mechanical bone strength determined by finite element analysis (FEA). MethodsWe conducted a single-centre longitudinal study to evaluate changes in bone microarchitecture with MRI in patients with SHPT undergoing parathyroidectomy. MRI was performed at the distal tibia at baseline (time of parathyroidectomy) and at least 12 months following surgery. Trabecular and cortical topological parameters as well as bone mechanical competence using FEA were assessed. ResultsFifteen patients with CKD (12 male, 3 female) underwent both MRI scans at the time of surgery and at least 12 months post-surgery. At baseline, 13 patients were on dialysis, one had a functioning kidney transplant, and one was pre-dialysis with stage 5 CKD. Seven patients received a kidney transplant following parathyroidectomy prior to follow-up MRI. MRI parameters in patients at follow up were consistent with loss in trabecular and cortical bone thickness (p = 0.006 and 0.03 respectively). Patients who underwent a kidney transplant in the follow-up period had reduction in trabecular thickness (p = 0.05), whereas those who continued on dialysis had reduction in cortical thickness (p = 0.04) and mechanical bone strength on FEA (p = 0.03). ConclusionPatients with severe SHPT requiring parathyroidectomy have persistent changes in bone microarchitecture at least 12 months following surgery with evidence of ongoing decline in trabecular and cortical thickness.

MO800EFFICACY AND SAFETY OF CINACALCET IN CHINESE MAINTAINANCE HEMODIALYSIS PATIENTS WITH DIFFERENT STAGES OF SECONDARY HYPERPARATHYROIDISM: RESULTS OF ACTIVE STUDY

Abstract Background and Aims Secondary hyperparathyroidism (SHPT), as a common complication in advanced chronic kidney disease (CKD) has become a global public health problem. Published literatures showed higher risk of bone fracture, cardiovascular events and all-cause mortality was associated with uncontrolled SHPT in patients with CKD. Cinacalcet, a calcimimetic agent was reported to reduce intact parathyroid hormone (iPTH) levels in patients with SHPT. However, there is no large-cohort study and stratified analysis of cinacalcet based on the level of iPTH in China. The ACTIVE study was designed to test the efficacy and safety of cinacalcet in treating Chinese maintenance hemodialysis patients with mild-to-severe SHPT, as well as to investigate the benefit of long-term, continuous medication with cinacalcet in the real-world setting. Method ACTIVE study was a phase IV, open-label, multicenter clinical trial including two phases: Phase 1 was a cohort study with 32 weeks’ follow-up. Phase 2 was a real-world study of 20 additional weeks in which patients who completed the cohort study decided independently whether to continue taking cinacalcet at their own cost. Eligible maintenance hemodialysis (MHD) patients with baseline iPTH ≥300 pg/mL from April 2017 to September 2019 in 23 centers in China were treated with cinacalcet orally. Patients were grouped based on their iPTH level as mild (300-600 pg/mL), moderate (600-900 pg/mL) or severe (≥900 pg/mL) SHPT. Results 911 patients were screened and of 750 eligible patients, 275 were identified as mild, 224 were considered as moderate and left 251 were grouped as severe SHPT. The number of people who completed all 52-week follow-up in the mild, moderate and severe SHPT groups were 184 (66.91%), 164 (73.21%), and 166 (66.14%), respectively(Fig 1). The baseline and interim analysis results was published on 2020 EDTA. The number of patients achieving iPTH target (150-300 pg/mL) was 85 (31.02%) in mild group, 56 (25.00%) in moderate group and 27 (10.76%) patients in severe group at 20-week visit, and the proportion of patients achieving iPTH target was 33.94% (n=93), 24.11% (n=54) and 13.55% (n=34) at 32-week visit. The trends of the proportion of patients achieving iPTH target increased in all 3 different groups (Fig 2). The number of patients who reached both targets of serum calcium (Ca2+) and serum phosphorus (P) in the mild, moderate and severe SHPT group was 61 (22.26%), 42 (18.75%), 37 (14.74%) at 20-week visit, and 44 (16.06%), 34 (15.18%), 41 (16.33%) at 32-week visit, respectively. At the end of the 20th and the 32nd week of treatment, serum Ca2+×P and fibroblast growth factor-23 (FGF-23) decreased significantly compared with their baseline values (Table 1). In the extension 32-52 weeks study, the corresponding proportion of patients who achieved iPTH target in the three SHPT groups was 11.41%, 6.06%, and 4.81%, respectively. The safety analysis showed the most common treatment-related AE were hypocalcemia, hyperlipidemia and loss of appetite. This study is sponsored by Kyowa Kirin China Pharmaceutical Co., Ltd. Conclusion Oral cinacalcet HCl was effective and safe in reducing iPTH in patients receiving HD with mild-to-severe SHPT.

Bone microarchitecture in patients undergoing parathyroidectomy for management of secondary hyperparathyroidism

BackgroundSecondary hyperparathyroidism (SHPT) in patients with chronic kidney disease (CKD) leads to complex bone disease, affecting both trabecular and cortical bone, and increased fracture risk. Optimal assessment of bone in patients with CKD is yet to be determined. High-resolution magnetic resonance imaging (MRI) can provide three-dimensional assessment of bone microarchitecture, as well as determination of mechanical strength with finite element analysis (FEA). MethodsWe conducted a single-centre, cross-sectional study to determine bone microarchitecture with MRI in CKD patients with SHPT undergoing parathyroidectomy. Within two weeks of surgery, MRI was performed at the distal tibia and biochemical markers of SHPT (parathyroid hormone [PTH] and alkaline phosphatase [ALP]) were collected. Trabecular and cortical topological parameters as well as bone mechanical competence using FEA were assessed. Correlation of MRI findings of bone was made with biochemical markers. ResultsTwenty patients with CKD (15 male, 5 female) underwent MRI at the time of parathyroidectomy (16 on dialysis, 3 with functioning kidney transplant, one pre-dialysis with CKD stage 5). Median PTH at the time of surgery was 138.5 pmol/L [39.6–186.7 pmol/L]. MRI parameters in patients were consistent with trabecular deterioration, with erosion index (EI) 1.01 ± 0.3, and trabecular bone volume (BV/TV) 10.8 ± 2.9%, as well as poor trabecular network integrity with surface-to-curve ratio (S/C) 5.4 ± 2.3. There was also evidence of reduced cortical thickness, with CTh 2.698 ± 0.630 mm, and FEA demonstrated overall poor bone mechanical strength with mean elastic modulus of 2.07 ± 0.44. ConclusionPatients with severe SHPT requiring parathyroidectomy have evidence of significant changes in bone microarchitecture with trabecular deterioration, low trabecular and cortical bone volume, and reduced mechanical competence of bone.

Skeletal and mineral metabolic effects of risedronate in a rat model of high-turnover renal osteodystrophy.

High-turnover bone disease is a major consequence of SHPT and may explain the high risk for fracture in patients with advanced chronic kidney disease (CKD). Bisphosphonates suppress bone turnover and improve bone strength, but their effects have not been fully characterized in advanced CKD with severe SHPT. Bisphosphonates also increase 1,25-dihydroxyvitamin D levels in normal and uremic rats, but the underlying mechanism remains to be determined. We investigated the skeletal and mineral metabolic effects of RIS, a pyridinyl bisphosphonate, in rats with severe SHPT induced by 5/6 nephrectomy plus a high phosphate diet. Nephrectomized rats developed severe SHPT, along with hyperphosphatemia, low 1,25-dihydroxyvitamin D, and markedly increased FGF23. Moreover, these rats exhibited characteristic features of high-turnover renal osteodystrophy, including increased indices of trabecular bone turnover, decreased cortical bone thickness, inferior cortical biomechanical properties, and a prominent increase in peritrabecular fibrosis. RIS treatment increased bone volume and partially attenuated trabecular bone remodeling, cortical bone loss, and mechanical properties, whereas it produced a marked improvement in peritrabecular fibrosis along with a corresponding decrease in osteogenic gene markers. RIS treatment also suppressed the elevation of FGF23, which was associated with increased 1,25-dihydroxyvitamin D. In a rat model of severe SHPT, treatment with RIS partially attenuated histological manifestations of high-turnover bone disease. RIS treatment also suppressed the elevation of FGF23, which may explain the increased 1,25-dihydroxyvitamin D production during the treatment.

A hemodialysis patient with bone disease after pregnancy: a case report

BackgroundPregnancy is rare in women on hemodialysis. Recommendations for the treatment of secondary hyperparathyroidism (sHPT) and preservation of bone health in pregnant dialysis patients are lacking.Case presentationWe present the case of a young woman with end-stage kidney disease (ESKD) due to lupus nephritis, who developed multiple brown tumors while on hemodialysis during her second pregnancy. During her first pregnancy sHPT was well controlled and no skeletal complications occurred. Before the second pregnancy she developed severe sHPT. During pregnancy, dialysis time was increased to 24 h per week, the patient was given oral calcitriol, and the dialysate calcium concentration was set at 1.5 mmol/l. In week 20 the patient complained about bone pain in her left hip. Magnetic resonance imaging revealed a cystic lesion compatible with a brown tumor. The baby was delivered in the 36th week by cesarean section. Further assessment identified multiple brown tumors of her skeleton, including the acetabulum, tibia, ribs, skull, thoracic spine and thumb. She required multiple orthopedic surgeries. Three months after pregnancy, etelcalcetide was started, which brought about a gradual improvement in her sHPT.ConclusionsThis case demonstrates that the combination of pregnancy and severe sHPT in dialysis patients can have deleterious consequences for bone health.

An integrated analysis of safety and tolerability of etelcalcetide in patients receiving hemodialysis with secondary hyperparathyroidism.

BackgroundCalcimimetics have been shown to be effective and safe therapies for the treatment of secondary hyperparathyroidism (sHPT), a serious complication of disordered mineral metabolism associated with dialysis-dependent chronic kidney disease. Etelcalcetide, a recently approved intravenous calcimimetic, reduces serum parathyroid hormone (PTH), calcium, phosphorus, and fibroblast growth factor-23 concentrations. Here we report the first integrated safety profile of etelcalcetide using pooled data from five pivotal clinical trials.MethodsThis analysis included data from patients receiving hemodialysis with moderate to severe sHPT enrolled in two randomized, placebo-controlled trials; a randomized active-controlled (with cinacalcet) trial; and two single-arm, open-label extension trials. Patients initially received etelcalcetide intravenously 5 mg three times weekly (TIW) after hemodialysis; with potential dose increases of 2.5 or 5 mg at 4-week intervals to a maximum dose of 15 mg TIW, depending on serum PTH and calcium levels. The nature, frequency, and severity of treatment-emergent adverse events (AEs) and changes in laboratory parameters were assessed.ResultsOverall, we evaluated 1023 patients from the placebo-controlled trials, 683 from the active-controlled trial, and 1299 from open-label extensions. The frequency and nature of common treatment-emergent AEs reported for the etelcalcetide arm were consistent among the placebo-controlled and active-controlled trials. The most common AEs were those related to mineral metabolism (decreased blood calcium, hypophosphatemia, muscle spasms) or gastrointestinal abnormalities (diarrhea, nausea, vomiting). Hypocalcemia leading to discontinuation of either calcimimetic was experienced in ≤ 1% of patients.ConclusionsThis integrated safety assessment of etelcalcetide across placebo- and active-controlled trials showed an overall favorable risk/benefit profile, with safety similar to that of cinacalcet. Consistent with its mechanism of action, the most important risks associated with etelcalcetide were serum calcium reductions and hypocalcemia-related AEs; no new safety findings were identified in the pooled long-term extension trials.

Effects of the Intravenous Calcimimetic Etelcalcetide on Bone Turnover and Serum Fibroblast Growth Factor 23: Post Hoc Analysis of an Open-label Study

PurposeSecondary hyperparathyroidism (SHPT) is a serious complication that increases the risk of bone disorders in patients with chronic kidney disease (CKD) undergoing hemodialysis. Etelcalcetide is the first injectable calcimimetic approved for treatment of SHPT, which reduces bone turnover markers and suppresses intact fibroblast growth factor 23 (iFGF-23). This study aimed to explore the associations between etelcalcetide-induced changes in circulating factors and serum iFGF-23 levels. MethodsThis study was a post hoc analysis of data from a previous multicenter, open-label study of etelcalcetide administered to 191 Japanese patients with SHPT undergoing hemodialysis for 52 weeks. Correlations were analyzed between changes from baseline in serum iFGF-23 and serum intact parathyroid hormone (iPTH), corrected calcium, phosphate, bone alkaline phosphatase (BAP), tartrate-resistant acid phosphatase-5b (TRACP-5b), and 1α,25-dihydroxyvitamin D (1,25[OH]2D) levels at 1, 2, 3, 6, and 12 months. Akaike's Information Criterion (AIC) was calculated using serum iPTH, corrected calcium, phosphate, BAP, TRACP-5b, and 1,25(OH)2D levels as potential predictor variables at each time point. Four models with the smallest AIC at the 3-month time point were chosen as the fitted models to predict changes in iFGF-23 levels, and stepwise multivariate analysis was performed to determine the predictor variables with the greatest contribution to the change in iFGF-23 levels by calculating the partial coefficients of determination. FindingsThe etelcalcetide-induced reduction in iFGF-23 was positively correlated with serum levels of corrected calcium and phosphate and negatively with BAP. By calculating the AIC, corrected calcium, phosphate, iPTH, BAP, and TRACP-5b were suggested to be predictors of iFGF-23 levels. Stepwise multivariate analysis found that phosphate, corrected calcium, BAP, and TRACP-5b correlated with iFGF-23, in order from strongest to weakest. ImplicationsThese results suggest that etelcalcetide effectively lowered iFGF-23 and that this reduction may occur via improvements in phosphate, corrected calcium, BAP, and TRACP-5b. Etelcalcetide is thus a promising calcimimetic for decreasing iFGF-23 and improving bone turnover in patients with CKD undergoing hemodialysis with severe SHPT, in addition to decreasing PTH itself. JapicCTI identifier: 142,665.

Cinacalcet as rescue therapy for refractory hyperparathyroidism in young children with advanced chronic kidney disease.

Studies in the use of the calcimimetic, cinacalcet, in pediatric chronic kidney disease (CKD) are few and limited to older children with secondary hyperparathyroidism (sHPT), a major morbid complication contributing to poor growth, bone deformities, and cardiovascular disease. Our objectives were to determine a safe and effective dosing regimen of cinacalcet in the treatment of infants and young children with sHPT that was refractory to standard care and to examine their growth during treatment. Ten young pediatric patients with advanced CKD were studied retrospectively during 11 courses of treatment with cinacalcet. All had severe sHPT with intact parathyroid hormone (iPTH) levels ≥ 500pg/ml and were refractory to standard therapy with phosphate binders and active vitamin D analogs at high doses for > 30days. The cinacalcet dose was advanced by 50% every 2-4weeks to achieve a decline in the iPTH to a goal of 150-300pg/ml. Linear growth was assessed at 6-month intervals by change in z-scores (△SDS) for length before and during cinacalcet therapy. Median age at initiation of cinacalcet was 18months (IQR 6, 36) with an average starting dose of 0.7 ± 0.2mg/kg/day. Median effective dose required to reach iPTH goal of 150-300pg/ml was 2.8mg/kg/day (IQR 2.0, 3.1), and time to goal was 112days (IQR 56, 259) with a median overall decline in iPTH of 82% from baseline by 6months (p < 0.0001). No subject experienced a clinical adverse event, although 4 had biochemical asymptomatic hypocalcemia. Linear growth improved significantly during cinacalcet therapy (△SDS - 0.62 ± 1.2 versus + 0.91 ± 1.4; p < 0.005). By multiple regression analysis, the primary determinants of growth were concurrent treatment with growth hormone and age < 2years (R2 = 89.6%; p < 0.001). A shorter treatment time required to achieve iPTH goals also was associated with improved growth (r = - 0.75; p < 0.01). Cinacalcet may be used effectively and safely in infants and small children with refractory sHPT in advanced CKD using a cautious dosing regimen. Cinacalcet successfully brings iPTH to target level and supports growth when other treatments have been ineffective.

Severe secondary hyperparathyroidism in patients on haemodialysis is associated with a high initial serum parathyroid hormone and beta-CrossLaps level: Results from an incident cohort.

BackgroundSecondary hyperparathyroidism (SHPT) is a frequent complication of renal disease and most commonly occurs in patients on haemodialysis (HD) with metabolic, vascular, endocrine, and bone complications. The aim of this study was to analyze the evolution of mineral metabolism parameters during the first 36 months of HD treatment and identify the initial factors associated with severe SHPT.MethodsSerum parathyroid hormone (PTH), calcium and phosphate levels were measured monthly; bone-specific alkaline phosphatase (b-ALP) and beta-CrossLaps (CTX) were measured biannually. Severe SHPT was defined as the need for cinacalcet treatment. Patients with less than 24 months of follow-up were excluded.ResultsOne hundred thirty-three incident HD patients were included. Baseline mean PTH was 275 ± 210 pg/mL. After an initial drop at the third month (172 ± 133 pg/mL), the serum PTH level progressively increased to the maximum at 36 months (367 ± 254 pg/mL). This initial drop was associated with the initial correction of both hypocalcaemia and hyperphosphataemia. Serum CTX and b-ALP revealed no significant changes over time. Severe SHPT was observed in 18% of patients and was associated with higher mean calcaemia and phosphataemia. In logistic regression, the initial factors associated with the risk of severe SHPT were: female sex, higher baseline PTH and CTX values. A receiver operation characteristic curve analysis identified a cut-off value of >374 pg/mL for baseline PTH and >1.2 μg/L for CTX for increased risk of developing severe SHPT. The relative risk of developing severe SHPT was 3.7 (1.8–7.5, p = 0.002) for high baseline CTX, 4.9 (2.4–9.7, p = 0.001) for high baseline PTH, and 7.7 (3.6–16, p< 0.0001) when both criteria were present.ConclusionAfter an initial drop, a progressive increase in the serum PTH level during the first 3 years of HD treatment was observed despite aggressive therapy. High baseline levels of PTH and CTX increased the risk of developing severe SHPT.

Sixty-Two-Year-Old Male Suffering From Uremic Leontiasis Ossea Caused by Severe Secondary Hyperparathyroidism.

ABSTRACTSecondary hyperparathyroidism (SHPT) is a long‐term complication of chronic kidney disease–mineral and bone disorder (CKD‐MBD). SHPT is characterized by hyperplasia of the parathyroid glands and abnormal secretion of parathyroid hormones (PTH), calcium and phosphorous metabolic disorders, renal osteodystrophy, vascular and soft tissue calcification, malnutrition, and other multiple system complications, which can seriously affect the quality of life of the patient and increase the risk of cardiovascular disease and mortality rate. Uremic leontiasis ossea (ULO) is a medical condition only rarely encountered clinically. SHPT causes craniofacial bone deformity accompanied by lesions of the nerve, cardiovascular, respiratory, bone, or other systems within the body. The case discussed here is related to severe SHPT. A 62‐year‐old male patient was suffering from leontiasis ossea, pectus excavatum, vascular calcification, spontaneous bone fractures, and lower limb deformities. He was undergoing hemodialysis and given total parathyroidectomy (TPTX) with autotransplantation (AT). We further analyzed the multivariate therapeutic effects of TPTX on this patient in order to provide clinical data for standardized treatment of individuals with CKD‐MBD. © 2018 The Authors JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.

Effects of preoperative cinacalcet hydrochloride treatment on the operative course of parathyroidectomy and pathological changes in resected parathyroid glands

BackgroundSecondary hyperparathyroidism (SHPT) is associated with higher cardiovascular risk and mortality in patients undergoing dialysis. Cinacalcet hydrochloride (CH), which has been clinically available in Japan since 2008, could effectively reduce parathyroid hormone (PTH) levels even in patients with severe SHPT. However, parathyroidectomy (PTx) is performed in patients with severe SHPT refractory to CH. This study investigated the effects of preoperative CH treatment on the operative course and pathological findings of resected parathyroid glands (PTGs) in patients undergoing PTx.MethodsWe retrospectively analyzed 194 PTx cases for SHPT in long-term hemodialysis patients at Showa University Northern Yokohama Hospital from April 2002 to March 2014.ResultsA total of 45 patients were administered CH before PTx (CH group), and 149 patients never received CH (non-CH group). No significant difference was seen in intact PTH levels, the number of resected PTGs, or operative time between the two groups. However, the total volume of all PTGs and the volume of the largest PTG were significantly lower in the CH than in the non-CH group. Patients with PTG adhesion to surrounding tissues were significantly more prevalent in the CH than in the non-CH group. In addition, cystic changes or hemorrhagic necrosis in the resected PTGs was observed more frequently in the CH group than in the non-CH group.ConclusionsThe results of the present study suggest that preoperative CH treatment might introduce pathological changes in resected PTGs in PTx for severe SHPT, but it does not affect the operative time.

Associations of the calcium-sensing receptor gene CASR rs7652589 SNP with nephrolithiasis and secondary hyperparathyroidism in haemodialysis patients

Nephrolithiasis, secondary hyperparathyroidism (sHPT), and cardiovascular complications are associated with disturbances in Ca handling and contribute to morbidity/mortality during haemodialysis (HD). Calcimimetics, activators of the calcium-sensing receptor (CaSR), provide an effective means of reducing parathyroid hormone (PTH) secretion in sHPT. Polymorphism in CaSR gene (CASR) influences Ca-related parameters, however it was not shown in HD patients for CASR rs7652589. The minor allele at this polymorphism modifies the binding sites of transcription factors and CaSR expression. We hypothesized that CASR rs7652589 variants may also influence CaSR in end stage renal disease (ESRD). We aimed to determine the associations of rs7652589 with nephrolithiasis-related ESRD, Ca, P, ALP, PTH, response to treatment with cinacalcet, prevalence of coronary artery disease, and all-cause/cardiovascular mortality in HD patients (n = 1162). Healthy individuals (n = 918) were controls. This study shows that the A allele of rs7652589 is a risk allele for nephrolithiasis-related ESRD. The AA genotype is associated with more severe sHPT (higher Ca and PTH concentrations). The A allele is associated with reduced CaSR transcript level in peripheral blood mononuclear cells. According to computational analysis, potential binding sites for GLI3, AHR and TP53 are removed by the A allele, whereas binding sites for SOX18 and TP63 are created.