Multicenter Retro-Prospective Observational Study on Chronic Hypoparathyroidism and rhPTH (1-84) Treatment

The use of recombinant human PTH (1-84) [rhPTH(1-84)] is approved as hormonal replacement therapy in patients with hypoparathyroidism not adequately controlled with conventional therapy. The objective of this study was to investigate the effects of 12 months of rhPTH (1-84) treatment in a cohort of patients selected according to the indications of recent hypoparathyroidism guidelines. It is a multicenter, observational, retro-prospective, open label study. Eleven Italian Endocrinological centers were involved. Fourteen adult subjects with chronic hypoparathyroidism treated with rhPTH (1-84) for 12 months were enrolled. Main outcome measures included serum and urinary parameters of mineral metabolism, renal function, oral calcium and vitamin D doses, and clinical manifestations. At 12 months, 61.5% of patients discontinued calcium supplement and 69.2% calcitriol. Mean serum calcium levels quickly normalized after initiation of rhPTH (1-84) treatment compared to baseline (p=0.009). Rare hypo-hypercalcemia episodes were reported. Renal function was maintained normal and no renal complications were reported. Serum and urinary phosphate and urinary calcium were maintained in the normal range. Mean phosphatemia levels linearly decreased from 3 months up to 12 months compared to baseline (p= 0.014). No severe adverse events were described. In conclusion, this study confirm the efficacy and safety of rhPTH (1-84) therapy.

Isolated idiopathic hypoparathyroidism that developed in adulthood: a case report

Hypoparathyroidism is a rare endocrine disease. In most cases in adult patients, the cause of hypoparathyroidism is damage or removal of parathyroid glands during surgical interventions on the neck; other causes are rarely observed.Case report. A 52-year-old man with episodes of seizures, intense muscle pain, progressing for 7 years and resistance to treatment with myorelaxant, anxiolytics and nonsteroidal anti-inflammatory drugs was examined and hypocalcemia associated with low parathyroid hormone and excessive urinary calcium excretion was found. Ultrasound examination didn't reveal any changes in parathyroid glands. The patient was diagnosed with idiopathic hypoparathyroidism. Treatment with calcium supplements and active metabolites of vitamin D led to an improvement in clinical symptoms and laboratory parameters.Discussion. Hypoparathyroidism as part of several genetic syndromes was excluded due to the late- onset of the disease and the absence of concomitant diseases. Ultrasound of the parathyroid glands made it possible to rule out metastasis and storage diseases. It is recommended to perform genetic testing of the chromosomes 22 and 10 to exclude rare variants of syndromic hypoparathyroidism with the late-onset in the form of isolated hypocalcemia.

Intermittent Bi-Daily Sub-cutaneous Teriparatide Administration in Children With Hypoparathyroidism: A Single-Center Experience

Introduction: The use of teriparatide has been reported in children with hypoparathyroidism as an investigational physiologic replacement therapy.Methods: We aimed to retrospectively report our pediatric experience of bi-daily sub-cutaneous teriparatide. Results are presented as median (25th−75th quartile). As part of the routine follow-up of these patients with hypoparathyroidism, total calcium at H0 (i.e., just before injection) and H4 (i.e., 4 h after teriparatide injection) and other biomarker parameters were regularly assessed.Results: At a median age of 10.7 (8.1–12.6) years, an estimated glomerular filtration rate (eGFR) of 110 (95–118) mL/min/1.73 m2, calcium levels of 1.87 (1.81–1.96) mmol/L and an age-standardized phosphate of 3.8 (2.5–4.9) SDS, teriparatide therapy was introduced in 10 patients at the dose of 1.1 (0.7–1.5) μg/kg/day (20 μg twice daily), with further adjustment depending on calcium levels. Six patients already displayed nephrocalcinosis. Severe side effects were reported in one child: two episodes of symptomatic hypocalcemia and one of iatrogenic hypercalcemia; one teenager displayed dysgueusia. Calcium levels at H0 did not significantly increase whilst calcium at H4 and phosphate levels significantly increased and decreased, respectively. After 12 months, eGFR, calcium and age-standardized phosphate levels were 108 (90–122) mL/min/1.73 m2, 2.36 (2.23–2.48) mmol/L, 0.5 (−0.1 to 1.5), and 68 (63–74) nmol/L, respectively, with a significant decrease in phosphate levels (p = 0.01). Urinary calcium and calcium/creatinine ratio remained stable; no nephrolithiasis was observed but two moderate nephrocalcinosis appeared.Conclusion: Intermittent teriparatide therapy significantly improves calcium and phosphate control, without increasing calciuria. It appears to be safe and well-tolerated in children.

Primary Hyperparathyroidism in Homozygous Sickle Cell Patients: A Hemolysis-Mediated Hypocalciuric Hypercalcemia Phenotype?

Primary hyperparathyroidism (pHPT) has been reported to have a higher prevalence in sickle cell disease (SCD) patients, including a high rate of recurrence following surgery. However, most patients are asymptomatic at the time of diagnosis, with surprisingly infrequent hypercalciuria, raising the issue of renal calcium handling in SCD patients. We conducted a retrospective study including (1) 64 hypercalcemic pHPT non-SCD patients; (2) 177 SCD patients, divided into two groups of 12 hypercalcemic pHPT and 165 non-pHPT; (3) eight patients with a diagnosis of familial hypocalciuric hypercalcemia (FHH). Demographic and biological parameters at the time of diagnosis were collected and compared between the different groups. Determinants of fasting fractional excretion of calcium (FeCa2+) were also analyzed in non-pHPT SCD patients. Compared to non-SCD pHPT patients, our data show a similar ionized calcium and PTH concentration, with a lower plasmatic calcitriol concentration and a lower daily urinary calcium excretion in pHPT SCD patients (p < 0.0001 in both cases). Fasting FeCa2+ is also surprisingly low in pHPT SCD patients, and thus inadequate to be considered hypercalcemia, recalling the FHH phenotype. FeCa2+ is also low in the non-pHPT SCD control group, and negatively associated with PTH and hemolytic biomarkers such as LDH and low hemoglobin. Our data suggest that the pHPT biochemical phenotype in SCD patients resembles the FHH phenotype, and the fasting FeCa2+ association with chronic hemolysis biomarkers strengthens the view of a potential pharmacological link between hemolytic by-products and calcium reabsorption, potentially through a decreased calcium-sensing receptor (CaSR) activity.

Multiple urolithiases in pediatric acute lymphoblastic leukemia

Current study is a case report of a 5-year-old patient with T-cell acute lymphoblastic leukemia (ALL) and multiple urolithiasis. Complex factors, including glucocorticoid-induced hypercalciuria, fluid restriction for the syndrome of inappropriate secretion of antidiuretic hormone, and long-term bed rest, predispose children with ALL to develop urolithiasis. To prevent urinary urolithiasis formation, urinary calcium excretion should be monitored during chemotherapy and when administering glucocorticoids.

Mechanisms Underlying Calcium Nephrolithiasis

Nephrolithiasis is a worldwide problem with increasing prevalence, enormous costs, and significant morbidity. Calcium-containing kidney stones are by far the most common kidney stones encountered in clinical practice. Consequently, hypercalciuria is the greatest risk factor for kidney stone formation. Hypercalciuria can result from enhanced intestinal absorption, increased bone resorption, or altered renal tubular transport. Kidney stone formation is complex and driven by high concentrations of calcium-oxalate or calcium-phosphate in the urine. After discussing the mechanism mediating renal calcium salt precipitation, we review recent discoveries in renal tubular calcium transport from the proximal tubule, thick ascending limb, and distal convolution. Furthermore, we address how calcium is absorbed from the intestine and mobilized from bone. The effect of acidosis on bone calcium resorption and urinary calcium excretion is also considered. Although recent discoveries provide insight into these processes, much remains to be understood in order to provide improved therapies for hypercalciuria and prevent kidney stone formation. Expected final online publication date for the Annual Review of Physiology, Volume 84 is February 2022. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

The role of biased calcium-sensing receptor signalling in urinary calcium excretion and kidney stone disease

Michelle Goldsworthy1,2, Asha Bayliss2, Anna Gluck2, Akira Wiberg3, Benjamin Turney1, DominicFurniss3, Rajesh Thakker2, Sarah Howles1,2 1Nuffield Department of Surgical Sciences, University of Oxford, United Kingdom.2Academic Endocrine Unit, Radcliffe Department of Medicine, University of Oxford, UnitedKingdom.3Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, Universityof Oxford, United Kingdom. Nephrolithiasis is a major health burden with a poorly understood pathogenesis. We conducted a genome-wide association study in British and Japanese populations identifying twenty nephrolithiasis-associated loci. Mutations in the calcium-sensing receptor (CaSR) cause disorders of calcium homeostasis and five identified loci (DGKD, DGKH, WDR72, GPIC1 and BCR) were predicted to influence CaSR-signalling. In a validation population, we demonstrated that genotype at the DGKD-associated locus correlated with urinary calcium excretion but not serum calcium concentration. In vitro studies demonstrated that knockdown and overexpression of DGKD resulted in biased CaSR-signalling. Thus, treatment of CaSR-expressing HEK cells with DGKD-targeted siRNA (DGKD-KD), resulted in decreased MAPK responses to alterations in extracellular calcium concentration [Ca2+]e, as assessed by SRE-reporter and ERK-phosphorylation (pERK) assays, when compared to cells treated with scrambled siRNA (WT) but without alteration in intracellular calcium responses [Ca2+]i as assessed by NFAT-reporter and Fluo-4 calcium assays (SRE maximal response DGKD-KD =5.28 fold change vs. WT=7.20 p=0.0065, pERK maximal response DGKD-KD=24.77, vs. WT= 39.46 fold change, p=0.0056). Conversely, DGKD overexpression (DGKD-OE) increased MAPK responses but suppressed [Ca2+]i responses to alterations in [Ca2+]e (SRE maximal response DGKD-OE =14.13 fold change vs. WT=9.06 fold change, p=0.01; NFAT maximal response DGKD-OE=13.67 fold change vs WT=59.16 fold change, p=0.0001). Our results demonstrate that alterations in DGKD expression cause biased CaSR-signalling. This biased signalling may provide an explanation for the correlation of genotype at the DGKD-associated locus with urinary calcium excretion but not serum calcium concentration. Our findings suggest that biased CaSR-signalling may be a common cause of nephrolithiasis.

The role of biased calcium-sensing receptor signalling in urinary calcium excretion and kidney stone disease

Michelle Goldsworthy1,2, Asha Bayliss2, Anna Gluck2, Akira Wiberg3, Benjamin Turney1, DominicFurniss3, Rajesh Thakker2, Sarah Howles1,2 1Nuffield Department of Surgical Sciences, University of Oxford, United Kingdom.2Academic Endocrine Unit, Radcliffe Department of Medicine, University of Oxford, UnitedKingdom.3Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, Universityof Oxford, United Kingdom. Nephrolithiasis is a major health burden with a poorly understood pathogenesis. We conducteda genome-wide association study in British and Japanese populations identifying twentynephrolithiasis-associated loci. Mutations in the calcium-sensing receptor (CaSR) causedisorders of calcium homeostasis and five identified loci (DGKD, DGKH, WDR72, GPIC1 and BCR)were predicted to influence CaSR-signalling. In a validation population, we demonstrated that genotype at the DGKD-associated locuscorrelated with urinary calcium excretion but not serum calcium concentration. In vitro studiesdemonstrated that knockdown and overexpression of DGKD resulted in biased CaSR-signalling.Thus, treatment of CaSR-expressing HEK cells with DGKD-targeted siRNA (DGKD-KD), resulted indecreased MAPK responses to alterations in extracellular calcium concentration [Ca2+]e, asassessed by SRE-reporter and ERK-phosphorylation (pERK) assays, when compared to cellstreated with scrambled siRNA (WT) but without alteration in intracellular calcium responses[Ca2+]i as assessed by NFAT-reporter and Fluo-4 calcium assays (SRE maximal response DGKD-KD=5.28 fold change vs. WT=7.20 p=0.0065, pERK maximal response DGKD-KD=24.77, vs. WT=39.46 fold change, p=0.0056). Conversely, DGKD overexpression (DGKD-OE) increased MAPKresponses but suppressed [Ca2+]i responses to alterations in [Ca2+]e (SRE maximal responseDGKD-OE =14.13 fold change vs. WT=9.06 fold change, p=0.01; NFAT maximal response DGKDOE=13.67 fold change vs WT=59.16 fold change, p=0.0001). Our results demonstrate that alterations in DGKD expression cause biased CaSR-signalling. Thisbiased signalling may provide an explanation for the correlation of genotype at the DGKDassociatedlocus with urinary calcium excretion but not serum calcium concentration. Ourfindings suggest that biased CaSR-signalling may be a common cause of nephrolithiasis.

Estimation of Urinary Calcium as a Predictor of Pregnancy Induced Hypertension

Hypertensive diseases are still a leading cause of death among mothers all over the world. It’s complicated aetiology, which begins with aberrant placentation and ends with endothelial dysfunction, is yet unknown. The goal of this study is to learn about changes in serum and urine calcium levels in women who have Gestational Hypertension. 200 normotensive pregnant women between 24-28 weeks were included in the study based on inclusion and exclusion criteria. Urine calcium and creatinine and serum uric acid, total protein, albumin and serum sodium were estimated in corresponding samples collected from patients. The study showed a sensitivity of 80%, specificity of 71%, positive predictive value was 77%, negative predictive value 74%, and diagnostic accuracy as 74%. A single estimation of calcium to creatinine ratio in asymptomatic pregnant women between 24-28 week of gestation is a simple and cost-effective test.

The role of calcium metabolism disorders in the formation of different density calculi with calcium oxalate nephrolithiasis

Objective To investigate the relationship between calcium metabolism disorders, stone formation inhibitor levels and stone density in primary and recurrent calcium-oxalate nephrolithiasis.Material and Methods Sixty nine patients with urolithiasis were examined, their average age was 41,4 ± 9,5 years. Two main groups were distinguished: Group 1 – primary calcium-oxalate nephrolithiasis (PN), Group 2 – recurrent calcium-oxalate nephrolithiasis (RN). Then each group was divided into two subgroups – A and B according to stone density: 500–1000 HU and from 1000–1500 HU, respectively. Stone density was determined by computed tomography (CT). PTH (parathormone), PTHrP (parathyroid hormone related protein), vitamin D, total blood calcium (Ca), ionized blood Ca, total blood protein, Ca and urine pH were also examined. After the examination, patients underwent surgical removal of the stones.Results It was found that 41.9% of group 1 and 46.9% of group 2 patients had grade I obesity. Average creatinine level in group 2 was 9.7% higher than in group 1 (p < 0.05). Urea level in both groups was not statistically significantly different. Glomerular filtration rate (GFR) was comparable. Groups 2A and 2B had higher PTHrP values (77.61 and 76.98 pg/mL, respectively) combined with relatively high PTH levels (2A – 4.4 pg/mL and 2B – 5.1 pg/mL), relatively low osteopontin concentration (2A – 0.044 pg/ mL, 2B – 1.106 pg/mL), compared to those in group 1 (p < 0.05). Pairwise unidirectional differences between groups 1A and 2A, 1B and 2B were found to correlate positively with density values: for osteopontin: r = 0.992 (p < 0.05); for vitamin D: r = 0.831 (p < 0.05); for blood Ca2+ ions: r = 0.836 (p < 0.05); for urine pH: r = 0.863 (p < 0.05). There was a negative correlation with the daily concentration of urinary calcium ions with the density of concrements: r = -0.663; p < 0.05. The concentration of osteopontin was significantly higher in Group 1B and 2B patients, and it was significantly lower in patients with stones of < 1000 HU density. Higher values of osteopontin concentration were noted in groups 1B and 2B in relation to groups 1A (p < 0.05) and 2A (p < 0.05). The increase of blood Ca2+ ions in patients in groups 1B and 2B in relation to groups 1A (p < 0.05) and 2A (p < 0.05) was also accompanied by higher values of vitamin D.Conclusion Patients with denser stones showed high values of osteopontin and PTHrP in serum and low values of urinary calcium ions, which may lead to the formation of concrements on the matrix with an organic base. Determination of calcium metabolism makes it possible to predict recurrence of KSD in primary calcium oxalate nephrolithiasis and assess the severity of mineral metabolism disorders in recurrent calcium oxalate nephrolithiasis.