A case of a hemodialysis patient with secondary hyperparathyroidism who was resistant to etelcalcetide treatment but not to cinacalcet hydrochloride

Although both cinacalcet and etelcalcetide are calcimimetics that directly inhibit parathyroid hormone (PTH) secretion by activating the calcium (Ca)-sensing receptor (CaSR), their binding sites are different. We report a first case of a hemodialysis (HD) patient with secondary hyperparathyroidism (SHPT), in whom cinacalcet, but not etelcalcetide, could reduce serum intact PTH (i-PTH) levels. A HD patient received total parathyroidectomy (PTx) with auto-transplantation 16 years earlier. Due to SHPT relapse, cinacalcet was started at 7 years after PTx. His i-PTH levels had been controlled with both 75–100 mg of cinacalcet and 4.5 μg/week of calcitriol for a year before switching from cinacalcet to etelcalcetide. At 1 month following the switch, his serum i-PTH level increased to 716 pg/mL. The dose of etelcalcetide was gradually increased and finally reached the maximal dose of 45 mg/week. Because even the maximal dose of etelcalcetide for > 4 months did not reduce his serum i-PTH levels to < 700 pg/mL, etelcalcetide was switched to 50 mg/day of cinacalcet, which reduced the levels to 208 pg/mL at 2 months after the switch. Genomic sequencing test using whole blood revealed no mutation in the portion including Cys 482 of CaSR gene. The patient was resistant to etelcalcetide treatment but not to cinacalcet, suggesting the possibility that the enlarged parathyroid gland has some change in the portion including Cys 482 in the CaSR gene. Therefore, considering the possibility of etelcalcetide resistance during SHPT treatment should be kept in mind.

Effect of Pretransplant Use of Calcimimetic on Parathyroid Function after Renal Transplantation

Objective. Persistence of hyperparathyroidism (HPT) after renal transplantation leads to undesirable outcomes such as increase in cardiovascular events, graft dysfunction, and increased mortality. Options for therapy include medical management with calcimimetic or operative management. The present study was undertaken to evaluate the natural history of HPT after renal transplantation and to determine risk factors for persistent HPT in the era of calcimimetic. Design. The study is a retrospective review of data from 74 consecutive patients who underwent renal transplantation at our institution from April 2011 to November 2019. Methods. The natural history of HPT after renal transplantation and associations between intact parathyroid hormone (PTH) level after transplantation and clinical variables such as age, sex, duration of pretransplant dialysis, and use of calcimimetic before transplantation were evaluated. Results. Intact PTH decreased after renal transplantation in most of the patients without receiving parathyroidectomy. Known risk factors of persistent HPT did not associate with intact PTH level after renal transplantation in patients who had been receiving calcimimetic before transplantation. Conclusion. In conclusion, we have found that HPT after renal transplantation could be managed successfully by medical treatments. When predicting the prognosis of HPT after transplantation, pretransplant use of calcimimetic should be taken into consideration.

The impact of CASR A990G polymorphism in response to cinacalcet treatment in hemodialysis patients with secondary hyperparathyroidism

The objective of this study was to determine the impact of calcium sensing receptor (CASR) A990G genetic polymorphism on parathyroid hormone (PTH) lowering response to cinacalcet treatment when controlling for significant influencing clinical factors. This retrospective study was conducted on 135 Thai hemodialysis (HD) patients with secondary hyperparathyroidism (SHPT). CASR A990G genotypes were determined. The patients were identified as either G carriers (heterozygous or homozygous CASR 990G allele carriers) or noncarriers (homozygous CASR 990A carriers). Tested covariates were baseline PTH level (bPTH), baseline serum phosphate (bPhos), baseline serum calcium (bCa), baseline calcitriol equivalent dose (bCtriol), baseline ergocalciferol dose (bErgo), and age. The ANCOVA showed that intact PTH levels after 12 weeks of cinacalcet treatment (PTHw12) was significantly lower among G carriers compared with noncarriers after controlling for bPTH, bPhos, bCtriol, and bErgo (F(1, 127) = 15.472, p < 0.001), with the adjusted mean difference of 253.7 pg/mL. The logistic regression analysis revealed that the odds of a G carrier achieving 30% PTH reduction after 12-week cinacalcet treatment were 3.968 times greater than the odds for a noncarrier after adjusting for bPhos, bCtriol, and age. In conclusion, the CASR A990G polymorphism significantly influences cinacalcet response in HD patients with SHPT.

Interrelationships between sclerostin, secondary hyperparathyroidism, and bone metabolism in patients on hemodialysis

Context Sclerostin is an osteocyte-derived inhibitor of bone formation and is increased in kidney failure, but its role in the pathogenesis of renal bone disease remains unknown. Objective To explore the association of serum sclerostin with bone metabolism in patients undergoing hemodialysis, with a particular focus on parathyroid hormone (PTH)-dependent and PTH-independent pathways. Design Cross-sectional and prospective cohort study. Setting and participants 654 patients undergoing hemodialysis at 10 facilities in Japan. Main outcome measures We employed multivariable linear regression to explore whether sclerostin levels were associated with metacarpal bone mineral density (BMD), intact PTH, bone alkaline phosphatase (BAP), and tartrate-resistant acid phosphatase-5b (TRACP-5b). We employed mediation analyses to explore whether and to what extent the association of PTH with bone turnover markers is mediated by sclerostin. We also compared sclerostin levels between patients with and without previous or incident fractures. Results The median sclerostin level in hemodialysis patients was 3–4-fold higher than that in healthy individuals. Higher sclerostin levels were associated with higher metacarpal BMD and lower levels of intact PTH, BAP, and TRACP-5b. However, the relationships of sclerostin with bone turnover markers were substantially attenuated after adjustment for PTH. Mediation analysis suggested that the effects of PTH on bone turnover markers were mainly direct rather than mediated by sclerostin. Sclerostin levels were not associated with previous or incident fractures. Conclusions These findings suggest that in patients undergoing dialysis, sclerostin has only a limited role in bone metabolism and may not mediate the effect of PTH on bone turnover.

Ectopic Intact PTH Secretion Causing Humoral Hypercalcemia of Malignancy

Background: Tumor-generated ectopic intact PTH is difficult to diagnose and should be suspected in patients with apparent primary hyperparathyroidism but with normal parathyroid glands. Clinical Case: A 72-year-old man presented with symptoms of hypercalcemia including generalized weakness, polyuria, and polydipsia. Initial labs were consistent with primary hyperparathyroidism: calcium 12.1 mg/dL (n 8.6–10.3 mg/dL, albumin-corrected 12.5 mg/dL), intact PTH (iPTH) 115.6 pg/mL (n 10–65 pg/mL), low normal 25-OH vitamin D (25 ng/mL, n 25–100 ng/mL), and relatively high normal 1,25 dihydroxyvitamin D (52 pg/mL, n 18–78 pg/mL). 24-hour urine calcium was 381 mg/day (n 100–300 mg/day) and PTHrP was 1.6 pmol/L (n &lt;4.2 pmol/L). Neck ultrasound demonstrated a 0.5 x 1 cm hypoechoic mass near right thyroid inferior pole, though sestamibi SPECT/CT scan did not reveal scintographic evidence of a parathyroid adenoma. He underwent subtotal parathyroidectomy with largest excised gland weighing 0.262 grams. The left inferior parathyroid gland appeared normal intraoperatively, thus was clipped and left in place. PTH decreased from 194 pg/mL to 98 pg/mL postoperatively. Pathological examination revealed three normocellular parathyroid glands with enlargement of only the right superior gland. Venous sampling of the parathyroid vasculature failed to identify the source of autonomous iPTH post operatively. Due to refractory hypercalcemia, cinacalcet was initiated. However, hypercalcemia as high as 12.6 mg/dl and hyperparathyroidism to 672 pg/mL persisted despite dose escalation. He eventually received pamidronate with subsequent transition to denosumab due to declining renal function. A 68Ga DOTATATE scan was performed to locate occult ectopic parathyroid, which reported multiple foci of presumed somatostatin receptor expression involving the liver and intra-abdominal lymph nodes without significant uptake in the neck concerning for metastatic disease. Liver lesion biopsy was consistent with pancreato-biliary adenocarcinoma. Surprisingly, the biopsy was negative for iPTH and neuroendocrine tumor markers on staining/immunohistochemistry. Given his poor prognosis and multiple comorbidities, the patient opted not to pursue any further workup or therapy for his malignancy. Conclusion: Occult malignancy should be suspected for a patient with persistent hyperparathyroidism after parathyroidectomy. Treatment of the malignancy may lead to an improvement in hypercalcemia and iPTH levels. Employment of iPTH mRNA testing or intra-abdominal venous sampling to prove ectopic iPTH secretion would be ideal, as iPTH staining could be falsely negative. Further testing was not completed as the patient declined further evaluation.

Night Sweats as the Presenting Symptom of Primary Hyperparathyroidism

Background: Approximately 25–40% of patients report night sweats in the previous month during appointments with their primary care clinicians. The differential diagnosis for night sweats is broad, with hyperthyroidism, carcinoid syndrome, pheochromocytoma, medullary thyroid carcinoma, insulinoma, and acromegaly as established endocrine causes. We present a case of primary hyperparathyroidism (PHPT) in which the patient’s chief complaint was night sweats and resolution occurred after parathyroidectomy. Case. A 39-year-old female reported one-year of daily night sweats that required changes of clothes and bedding. She denied excessive daytime sweating, frequent palpitations, tremors, nightmares, rashes, fevers, chills, cough, headaches, dizziness, abdominal pain, diarrhea, disrupted menses, or unintentional weight loss. Vital signs and examination were unremarkable. Hypercalcemia (11.0 mg/dL, 8.6–10.3) was noted and confirmed by additional serum calcium measurements. Intact PTH ranged from 27–33 pg/mL (12–88), and 24 h urine calcium (258 mg) excluded familial hypocalciuric hypercalcemia (FHH). Parathyroid scintigraphy and neck ultrasound identified a left neck mass, and the patient underwent successful resection of a left inferior parathyroid adenoma. Hypercalcemia and night sweats initially resolved after surgery, but the patient returned six weeks later with recurrence of night sweats. Reevaluation was notable for serum calcium 10.4 mg/dL, phosphorus 2.4 mg/dL (2.5–5.0), and intact PTH 104 pg/mL. A right superior parathyroid adenoma was identified on repeat parathyroidectomy, and the patient experienced durable resolution of night sweats and hypercalcemia following her second parathyroid surgery. She was screened for multiple endocrine neoplasia type 1 (MEN1) due to multiple parathyroid tumors, though no known pathogenic menin gene variants were identified. Conclusions: A title/abstract search in PubMed linking “hyperparathyroidism” and “hypercalcemia” to “night sweats,” “sleep hyperhidrosis,” “sweating,” “hot flashes,” “hot flushes,” “diaphoresis” and “vasomotor symptoms” yielded only one relevant case of a postmenopausal woman with hot flushes unresponsive to hormone replacement that resolved after parathyroidectomy for PHPT. Hypercalcemia is known to affect central nervous system function. It is possible that in rare cases hypercalcemia alters function of the medial preoptic area, lowering the temperature threshold above which peripheral vasodilatation and perspiration occur to dissipate heat. The patient’s predisposition to only night sweats is unclear, though unlike the first patient reported with PHPT and sweating, our patient is premenopausal. This case indicates that vasomotor symptoms may occur with PHPT and resolve after successful parathyroid surgery.

MO571PRACTICE PATTERNS ON THE MANAGEMENT OF SECONDARY HYPERPARATHYROIDISM IN THE UNITED STATES: RESULTS FROM A MODIFIED DELPHI PANEL

Background and Aims The 2017 Kidney Disease Improving Global Outcomes (KDIGO) Chronic Kidney Disease-Mineral Bone Disorder (CKD-MBD) guidelines inform clinical practice for the management of secondary hyperparathyroidism (SHPT) internationally; however, many recommendations lacked high or moderate clinical evidence as defined by KDIGO. An expert panel was convened to establish clinical consensus for the current management of SHPT in the United States (US). Method The panel comprised 10 US healthcare providers (HCPs; [6 nephrologists, 1 surgeon, 1 nurse practitioner, 1 pharmacist, 1 dietician]) and 1 patient. HCP panelists participated in a modified Delphi process over 3 phases, addressing 126 questions based on a review of the literature and published guidelines. The threshold for consensus was 66%. In phases 1 and 2, panelists anonymously completed electronic surveys considering a ‘typical’ patient with SHPT unless otherwise specified. In phase 1, panelists answered 126 questions based on their own knowledge and experiences. In phase 2, panelists were reminded of their answers to closed-ended questions that did not achieve consensus in phase 1 and were asked if they would change their responses in light of the most common response. For open-ended questions, they were asked if they agreed with summary statements that captured the most common answers. Phase 3 was an unblinded virtual meeting where panelists reviewed the consensus reached in phases 1 and 2, and through active discussion, resolved those questions that had not reached consensus. The patient completed a separate electronic survey, which complemented key points in the HCP survey, and provided perspective during the virtual meeting. Results All 11 panelists completed the entire modified Delphi process. Sixty-three out of 126 (50%) and 116/126 (92.1%) questions reached consensus or addressed practice-specific information not requiring consensus by the end of phase 1 and 2, respectively; all questions reached consensus by the end of phase 3, including modification of 2 questions and the addition of 1 question. The panel unanimously agreed that SHPT treatment is often started too late and suggested additional markers for early identification of patients requiring treatment are needed. Serum levels of calcium, phosphate, and parathyroid hormone (PTH) should be monitored starting at CKD stage G3a at intervals of every 6 months, 3–6 months for CKD G3b, and at least every 3 months at CKD G4 and above. Thresholds for interventions could not be defined in absolute terms for all patients due to patient-and practice-specific factors. However, in patients on dialysis, serum levels of phosphate &gt; 5.5 mg/dL (1.8 mmol/L) and calcium &gt; 9.5 mg/dL (2.4 mmol/L), warrant increased monitoring and consideration of therapeutic interventions. Serum intact PTH &gt; 300 pg/mL (32 pmol/L) typically indicates a need for SHPT treatment, with a consensus preferred target of 150–300 pg/mL (16–32 pmol/L); patients on dialysis were considered out of PTH target at ≥ 8 times the upper limit of normal (&gt; 520 pg/mL [55 pmol/L] intact PTH). HCPs were concerned about vascular calcification in all patients with CKD 3a–G5D. The panel reached consensus on the use of several SHPT interventions, including a consensus preference for the intravenous calcimimetic etelcalcetide over the oral calcimimetic cinacalcet in appropriate in-center dialysis patients requiring PTH-lowering therapy; cinacalcet was agreed to be first-line therapy in appropriate patients on home dialysis (Table 1). Factors such as formularies and dialysis center protocols were recognized to influence therapeutic choices. Conclusion Ten US HCPs reached consensus on many aspects of SHPT management, further defining therapeutic strategies and highlighting the need to be proactive. While the panel expressed evidenced-based preferences for certain therapies, factors such as cost and dialysis center protocols may affect decision making.

Hypercalcemia in a Patient Treated With Abaloparatide

Introduction: The antifracture efficacy of newer agents like PTHrP analogues is promising but knowledge about the mechanism of action and safety profile is needed in order to use these agents effectively. The reported incidence of hypercalcemia defined as albumin-adjusted serum calcium ≥10.7mg/dL was 3.4% in Abaloparitide. Case Presentation: A 59 year-old female with past medical history significant for diabetes mellitus type 2, hypothyroidism, necrotizing autoimmune myositis, osteoporosis and renal stones presented with complaints of generalized body aches and pains with swelling and redness of the left leg. The patient was diagnosed with osteoporosis based on atraumatic L4 compressive injury involving superior end plate. Her only DXA scan was 8 years ago which showed osteopenia, with the lowest T score of -1.2 at lumbar spine. Subsequent evaluation with DXA scan was unable to be performed due to physical disabilities. She was intolerant to oral bisphosphonates and was started on abaloparatide subcutaneous injections 2 weeks prior to her current admission. Her physical examination was positive for obesity, proximal muscle weakness and bilateral leg edema with bruises and left leg erythema. Laboratory findings showed hypercalcemia with corrected calcium levels of 12.48 mg/dl, suppressed intact PTH 4 pg/ml. Evaluations for secondary causes of hypercalcemia were negative. Her last dose of abaloparatide injection was the morning prior to her presentation to the emergency room. The patient was treated with IV fluids and her calcium level improved within 24 hours with normalization of intact PTH level in 72hrs. Abaloparatide injection was suspended on admission. Hypercalcemia with suppressed PTH was most likely secondary to abaloparatide given the timing of the hypercalcemia after the injection and resolution of hypercalcemia and normalization of PTH. Conclusions: Abaloparatide is a peptide that selectively binds to the RG conformation of the parathyroid hormone type 1 receptor. Abaloparatide is increasingly used following the results from the ACTIVE and ACTIVExtend trials which demonstrate significant increase in bone mineral density and risk reduction of vertebral, nonvertebral, clinical, and major osteoporotic fractures. Hypercalcemia was reported as a side effect, but there is no guidance on further evaluation or management of these patients. The incidence of hypercalcemia defined as albumin-adjusted serum calcium ≥10.7mg/dL is 3.4 % and risk is increased in patients with renal impairment. As in our case, transient hypercalcemia and PTH suppression may be associated with abaloparatide. Efficacy of abaloparatide and impact on bone density with delay or interrupted treatment are not available. Further studies are needed to guide monitoring and treatment of clinically symptomatic transient hypercalcemia in patients taking abaloparatide.

A Case of an Ectopic Parathyroid Adenoma With a Concomitant 99mTc-sestamibi-avid Papillary Thyroid Carcinoma

Background: The evaluation and management of parathyroid adenomas have improved over the years. Localization of parathyroid adenomas in patients with primary hyperparathyroidism was simplified with the use of 99mTc-sestamibi scintigraphy. In the advent of minimally invasive parathyroid surgery, use of radionuclide probes reduced the need for neck exploration and intraoperative frozen section leading to fewer complications, shorter operative time and hospitalization and rapid postoperative recovery. However, limitations of these techniques should be taken into consideration in certain cases. Clinical Case: A 60 year-old female diagnosed with primary hyperparathyroidism presented with recurrent nephrolithiasis and osteoporosis. Initial laboratory evaluation showed elevated serum calcium and intact PTH (1.54 mmol/L and 146 pg/mL, respectively). 99mTc-sestamibi scintigraphy showed a sestamibi-avid focus in the inferior aspect of the right lobe suggestive of a parathyroid adenoma or hyperplasia. Pre-operative neck ultrasound showed non-specific thyroid parenchymal changes and nodules on both lobes with benign sonographic features. She underwent radionuclide-guided focused right parathyroidectomy. The identified enlarged right inferior parathyroid gland registered a highest reading of 70 cps on radionuclide probe. Post-operatively, repeat intact PTH level was still elevated (171.2 pg/mL). There was an interval non-demonstration of the sestamibi-avid focus in the inferior aspect of the right thyroid lobe with an increased sestamibi uptake in the left thyroid lobe compared to the previous parathyroid scan. Histopathologic examination showed a normocellular parathyroid gland and a multifocal papillary thyroid carcinoma. She underwent total thyroidectomy with central neck dissection and 4 parathyroid gland exploration with intraoperative parathyroid hormone assay. However, serial PTH monitoring after left inferior parathyroidectomy and after bilateral partial superior parathyroidectomy still showed elevated levels. Histopathologic examination showed mildly enlarged, normocellular parathyroid gland. The bilateral carotid sheath, retropharyngeal region and superior mediastinum were explored but no ectopic parathyroid tissues were seen. Post-operatively, calcium and PTH were still elevated (1.48 mmol/L and 200.5 pg/mL, respectively). Conclusion: This case highlights the predicaments in the management of parathyroid adenomas, recognizing the possibility of false-positive sestamibi scans due to malignant thyroid nodules and the possibility of the two diseases occurring concurrently, albeit rare.

An Unusual Presentation of Primary Hyperparathyroidism: Ectopic Parathyroid Gland and Multiglandular Disease

Primary hyperparathyroidism (PHPT) can be associated as a single parathyroid adenoma in approximately 85% of patients, the remaining 15% of them correspond to individuals with hyperplasia. The multiglandular parathyroid disease varies in range 7–33% and contribute a persistent PHPT. We report a case of primary hyperparathyroidism with an unusual presentation of ectopic mediastinal parathyroid. The case was of a 54-year-old female, who started her illness 3 years ago, with frequent headache, regular fatigue and muscle pain, denied losing weight. She was admitted to emergency room for a urinary infection. During the hospitalization showed bilateral nephrocalcinosis, hypercalcemic crisis. She has a background of total thyroidectomy and subtotal parathyroidectomy because a thyroid adenomatous hyperplasia and parathyroid hyperplasia with removal of a total of three parathyroid glands. She had very high PTH level. Laboratory: serum calcium: 16.8mg/dl; ionic calcium: 2.37 mmol/L; P: 1.9 (2.7–4.5g/dL); Hb: 9 g/dL; Platelets: 558 000 per microliter; Leukocytes 9 600 cells/mcL; Albumin: 4g/dl; TSH: 0.06 mU/L; fT4: 1.29 (L-T4 doses were 100 ug). Four months after parathyroid surgery, the intact PTH level dropped from 1602 ng/l to 550 (15–65 ng/L). Computed tomography and Tc-sestamibi scintigraphy - SPECT revealed a residual cervicothoracic mass in retroesophageal region (D1-D2) (Fig1 -2). The patient underwent a new surgery and the intact PTH dropped 39ng/L. Histopathology revealed characteristic features of a parathyroid adenomatous (10 gram weight) (Fig.3); additionally a retroesternal ectopic thyroid tissue. There was not reappearance of high blood calcium and parathormone levels more than 6 months after second surgery for PHPT. An unusual case of PHPT caused by a multiglandular disease parathyroid varies (four glands and a ectopic gland), reliable histopathologic adenomatous and hyperplastic parathyroid disease, and persistent primary hyperparathyroidism with very high serum intact PTH level. Reference: (1) Masi L. Primary Hyperparathyroidism. Brandi ML (ed): Parathyroid Disorders. Focusing on Unmet Needs. Front Horm Res. Basel, Karger, 2019, vol 51, pp 1–12. (2) Pecheva M, Mahendran K, Kadlec J, Lofthouse M1, Van Tornout F. Mediastinal giant parathyroid adenoma-a minimally invasive mediastinal surgical approach for an emergency presentation. Ann Cardiothorac Surg. 2016 Jan;5(1):70–3. (3) Cakmak H 1, Tokat AO, Karasu S, Özkan M. Adenoma paratiroideo mediastínico gigante. Tuberk Toraks. 2011; 59 (3): 263–5. (4)Thier M, Daudi S, Bergenfelz A, Almquist M. Predictors of multiglandular disease in primary hyperparathyroidism. Langenbecks Arch Surg. 2018;403(1):103–109.