ResearchPad - new-insights-into-pth-and-calcium-receptor-signaling Default RSS Feed en-us © 2020 Newgen KnowledgeWorks <![CDATA[OR07-03 Continuous Subcutaneous Delivery of RhPTH(1-84) by Pump in Adults with Hypoparathyroidism]]> More than 80,000 people in the United States have hypoparathyroidism, a disease of low or absent parathyroid hormone (PTH) leading to hypocalcemia and hyperphosphatemia. Conventional treatment with oral calcium and active vitamin D increases serum calcium concentrations but does not replace the physiologic functions of PTH. Once-daily subcutaneous injections of recombinant human (rh) PTH(1-84) were recently approved for the treatment of hypoparathyroidism, but are not consistent in correcting biochemical abnormalities and alleviating symptoms for all patients. In cases in which single or multiple daily injections of rhPTH(1-84) are insufficient for controlling symptoms, continuous subcutaneous infusion via insulin pump is used as a therapeutic alternative. Pump therapy with PTH(1-34) has some support in the literature as an effective form of treatment for hypoparathyroidism.1However, the effects of pump therapy with rhPTH(1-84) in patients with hypoparathyroidism have not been reported. Five women with chronic postsurgical hypoparathyroidism who received treatment at three different endocrine outpatient clinics in the United States were transitioned from multiple daily injections of rhPTH(1-84) to continuous delivery of rhPTH(1-84) using the Omnipod insulin pump. The patients’ ages ranged from 27 to 60 years old and all had had hypoparathyroidism for at least 5 years. All of the patients were transitioned from conventional therapy with oral calcium and calcitriol to subcutaneous injections of rhPTH(1-84), and then switched to continuous subcutaneous administration using an insulin pump. In all five patients, increased serum calcium concentrations and decreased serum phosphate concentrations were observed with increased frequency of PTH administration. Serum calcium concentrations were within the normal to high-normal range and serum phosphate concentrations were in the normal range on pump therapy. Urinary calcium was well-controlled (<250 mg/day) in four of the five patients. All of the women reported a decrease in symptoms while receiving pump-administered rhPTH(1-84), including a lower incidence of fatigue, brain fog, tingling, and muscle cramps compared to standard therapy and daily injections. This is the first report of patients with hypoparathyroidism on long-term therapy with continuously infused subcutaneous rhPTH(1-84) using a pump. Pump therapy improved key parameters of mineral metabolism; normalizing serum calcium in all patients and urinary calcium in four out of five patients. Clinical trials with larger cohorts are needed to confirm the efficacy of this promising mode of administration of rhPTH(1-84). Reference: 1. Winer KK. Advances in the treatment of hypoparathyroidism with PTH 1-34. Bone. 2019;120:535-541.

<![CDATA[OR07-06 The Roles of GNAQ and GNA11 in Calcium-Sensing Receptor (CaSR) Signalling]]> The G-protein subunits Gα 11 and Gα q, which share >90% peptide sequence identity and are encoded by the GNA11 and GNAQ genes, respectively, mediate signalling by the calcium-sensing receptor (CaSR), a class C G-protein coupled receptor (GPCR) that regulates extracellular calcium (Ca2+e) homeostasis. Germline Gα 11 inactivating and activating mutations cause familial hypocalciuric hypercalcaemia type-2 (FHH2) and autosomal dominant hypocalcaemia type-2 (ADH2), respectively, but such Gα q mutations have not been reported. We therefore investigated the DiscovEHR cohort database, which has exomes from 51,289 patients with matched phenotyping data, for such GNAQ mutations. The DiscovEHR cohort was examined for rare GNAQ variants, which were transiently expressed in CaSR-expressing HEK293A Gα q/11 knockout cells, and their effects on CaSR-mediated intracellular calcium (Ca2+i) release and MAPK activity, in response to increasing concentrations of extracellular calcium were assessed using a nuclear factor of activated T-cells response element (NFAT-RE) luciferase reporter construct and a serum response element (SRE) luciferase reporter construct, respectively. Responses were compared to those of wild-type (WT), inactivating FHH2-associated GNA11 mutations (Leu135Gln and Phe220Ser), and engineered GNAQ mutations that were equivalent to the FHH2-causing GNA11 mutations. Gα q/11 protein expression was confirmed by Western blot analysis. Six rare missense GNAQ variants (Arg19Trp, Ala110Val, Gln299His, Ala302Ser, Ala331Thr, Val344Ile) were identified in DiscovEHR individuals, all of whom had mean plasma calcium values in the normal range (8.30–10.00 mg/dL). Functional characterisation of all six Gα q variants showed no significant difference to WT Gα q responses, thereby indicating that these variants are unlikely to be disease-causing mutations. In addition, the FHH2-causing GNA11 mutations (Leu135Gln and Phe220Ser) had significantly reduced responses, compared to WT Gα 11; however, this could be compensated by WT Gα q. GNAQ Leu135Gln and Phe220Ser, in contrast to their Gα 11 counterparts, showed no differences in protein expression or signalling responses when compared to WT Gα q. Our study, which provides mechanistic insights into the differences between Gα q and Gα 11, indicates that Gα q, unlike Gα 11, does not play a major role in the pathogenesis of FHH2 or ADH2.

<![CDATA[OR07-05 Is Urinary Calcium the Only Predictor of Nephrolithiasis in Patients with Asymptomatic Primary Hyperparathyroidism?]]> The 4th International Workshop for the management of asymptomatic PHPT included, among the criteria for parathyroidectomy, the presence of hypercalciuria (dUCa> 400 mg/day) and increased biochemical stone risk profile.

The aim of the present study was to evaluate the biochemical stone risk profile in 176 consecutive patients (143 females and 33 males) with asymptomatic PHPT. We recorded clinical and biochemical data, including 24 hours urinary measurements of the following parameters: volume and pH, creatinine, calcium, magnesium, sodium, potassium, ammonium, uric acid, oxalate, citrate, phosphate, inorganic sulphate and chloride and kidney ultrasound.

In our cohort dUCa> 400mg/day showed a low sensitivity and positive predictive value (PPV) for nephrolithiasis with high specificity (46.2, 32.7, 73.0% respectively), while hypercalciuria by 4 mg/kg/bw (d-UCa>4mg/kg) had a high sensibility, with low PPV and specificity (79.5, 27.7, 40.1%)

Daily hypomagnesuria (d-HypoMg), but not any other urinary parameter, was an independent predictor of nephrolithiasis in the univariate (OR 2.97 CI 1.27-7.09 P=0.014) and multivariate analyses adjusting for age, sex, BMI, and eGFR (OR 3.13 CI 1.17-8.42 P=0.02). d-HypoMg was relatively lower in the regression analysis with urinary calcium in patients with nephrolithiasis compared with those without. The mean ratio between (dUCa) and (dUMg) was higher in patients with nephrolithiasis compared with those without (4.6±2.0 vs 3.3±4.1; P<0.001). In the univariate and multivariate analyses the dUCa/dUMg ratio was a significant predictor of nephrolithiasis [OR 4.9 (2.3-10.5); P<0.001; OR 5.3 (2.4-11.6), P<0.001, respectively]. The AUC using the dUCa/dUMg ratio as variables was 0.69 (CI 0.60-0.79; P<0.0001). The best cut-off value, set at the highest Youden index, was equal to 4.0, with a sensitivity of 59.0% and a specificity of 77.4%.

In patients with hypercalciuria (>400 mg/24-hour) dUMg was positively correlated with dUCa in those without nephrolithiasis (r=0.50, β=0.2, P=0.002) but not in those with nephrolithiasis (r=0.05, β= 0.014; P=0.8). In patients without hypercalciuria we found that hypomagnesuria remained a predictor of nephrolithiasis using either 400 mg/die (P=0.002, OR 5.12 (1.84-14.24) or 4 mg/kg bw (P=0.014, OR 6.24 (1.45-26.8). Moreover, the OR for nephrolithiasis improved using the combination of d-HypoMg with d-UCa>4mg/kg (OR 8.12, CI 1.92-34.18, P=0.004), but not with dUCa> 400mg/day.

The current urinary calcium threshold of >400 mg/24-hour has a low sensitivity in detecting nephrolithiasis; our data suggest that sensitivity, specificity and positive predictive value could be improved including dUMg, dUCa/dUMg ratio and the combination of d-HypoMg with d-UCa>4mg/kg in the stone risk evaluation.

<![CDATA[OR07-01 Identification of the First Case of Acquired Autoimmune Parathyroid Hormone (PTH) Resistance Due to PTH1 Receptor (PTH1R) Autoantibodies]]> <![CDATA[OR07-04 A Novel Ex Vivo Live-Cell Interrogative Assay of Human Parathyroid Tissue Reveals Distinct Mechanisms of Calcium Sensing Failure in Primary, Secondary, and Tertiary Hyperparathyroidism]]>