calcitriol and Hypercalciuria

Hypercalcemia, hypercalciuria, and recurrent nephrolithiasis are all common clinical problems. This case report illustrates a newly described but possibly not uncommon cause of this presenting complex.. We report on a patient studied for over 30 years, with the diagnosis finally made with modern biochemical and genetic tools.. This study consists of a case report and review of literature conducted in a University Referral Center.. A single patient with hypercalcemia, hypercalciuria, and recurrent nephrolithiasis was treated with low-calcium diet, low vitamin D intake, prednisone, and ketoconazole.. We measured the patient's clinical and biochemical response to interventions above.. Calcium absorption measured by dual isotope absorptiometry was elevated at 37.4%. Serum levels of 24,25-dihydroxyvitamin D were very low, as measured in two laboratories (0.62 ng/mL [normal, 3.49 ± 1.57], and 0.18 mg/mL). Genetic analysis of CYP24A1 revealed homozygous mutation E143del previously described. The patient's serum calcium and renal function improved markedly on treatment with ketoconazole but not with prednisone.. Chronic hypercalcemia, hypercalciuria, and/or nephrolithiasis may be caused by mutations in CYP24A1 causing failure to metabolize 1,25-dihydroxyvitamin D.

Topics: Aged; Confusion; Delayed Diagnosis; Fatigue; Humans; Hypercalcemia; Hypercalciuria; Hypertension; Male; Nephrolithiasis; Recurrence; Steroid Hydroxylases; Vitamin D; Vitamin D3 24-Hydroxylase

Hypercalcemia is a highly prevalent complication of sarcoidosis. A medical history of a patient with sarcoidosis is shown as case report. Depending on the population studied about 2-63% of sarcoidosis patients show hypercalcemia. The major difference in the prevalence of hypercalcemia may be in part due to the undulating course of subacute sarcoidosis, so hypercalcemia may be missed when serum calcium is not frequently measured. Hypercalciuria appears to be twice as prevalent then hypercalcemia and should be looked for in every sarcoidosis patient. Hypercalcemia in sarcoidosis is due to the uncontrolled synthesis of 1,25-dihydroxyvitamin D3 by macrophages. 1,25-dihydroxyvitamin D3 leads to an increased absorption of calcium in the intestine and to an increased resorption of calcium in the bone. Immunoregulatory properties have been ascribed to 1,25-dihydroxyvitamin D3. It is an important inhibitor of interleukin-2 and of interferon-gamma-synthesis, two cytokines that are important in granuloma formation in sarcoidosis. It is thought that 1,25-dihydroxyvitamin D3 counterregulates uncontrolled granuloma formation. Treatment of hypercalcemia depends on the serum level of hypercalcemia and its persistence. Generally sarcoidotic patients should be advised to avoid sun exposition to reduce vitamin D3 synthesis in the skin, to omit fish oils that are rich of vitamin D and to produce more than two liters urine a day by adapting fluid intake. Although severe hypercalcemia seems to be rare, glucocorticosteroid treatment should be started if corrected total calcium level rises beyond 3 mmol/l. If hypercalcemia is symptomatic, treatment should be started even at lower levels. Glucocorticosteroids act by inhibition of the overly 1alpha-hydroxylase activity of macrophages. Alternatively, treatment with chloroquine or ketoconazole can be established. If isolated hypercalciuria without hypercalcemia is present with evidence for recurrent nephrolithiasis, patients can be treated with a thiazide diuretic.

Topics: Aged; Calcitriol; Calcium; Cross-Sectional Studies; Dose-Response Relationship, Drug; Female; Fluid Therapy; Humans; Hypercalcemia; Hypercalciuria; Kidney Failure, Chronic; Macrophages; Nephrocalcinosis; Parathyroid Hormone; Prednisone; Risk Factors; Sarcoidosis; Vitamin D

Absorptive hypercalciuria (AH) is associated with elevated levels of 1,25-dihydroxyvitamin D (1,25(OH)(2)D). While no increase of 1,25(OH)(2)D after oral administration of 25-hydroxyvitamin D (25OHD) at high doses has been claimed in normal subjects, a substrate-product relationship has been reported in normal children, young people after UV irradiation, older persons, postmenopausal women, primary hyperparathyroidism, renal failure, osteomalacia, and sarcoidosis. No data of this relationship in AH is available. To investigate 25OHD-1,25(OH)(2)D substrate-product relationship in AH, 161 AH patients (mean age 60.9+/-11.7 years) and 110 age- and sex-matched controls (mean age 61.5+/-12.4 years) were studied. In 57 controls and 52 AH subjects 25OHD-1,25(OH)(2)D relationship in basal conditions and after 2-week oral 25OHD (25 microg/day) administration were evaluated. In basal conditions 25OHD and 1,25(OH)(2)D were correlated in both, controls and AH; 25OHD treatment was followed by an increase in serum 25OHD and 1,25(OH)(2)D in both groups. However, delta responses of 25OHD and 1,25(OH)(2)D to 25OHD were higher in AH suggesting an enhanced activity of 1 alpha-hydroxylase. In conclusion, the higher response of 1,25(OH)(2)D after oral 25OHD in AH patients suggests a differential capacity between both groups in handling the increases in 1,25(OH)(2)D.

Topics: Administration, Oral; Aged; Case-Control Studies; Female; Humans; Hypercalciuria; Male; Middle Aged; Seasons; Vitamin D

We investigated the frequency of hypercalcemia and/or hypercalciuria following parathyroid hormone (PTH) 1-34 and 1-84 administration in a crossover trial. Ten postmenopausal osteoporotic women previously treated with bisphosphonates were subdivided into two groups of five patients each. A 24-h urine collection to determine baseline calcium (Ca) and creatinine (Cr) the day before administration of PTH was followed by determination of serum ionized Ca (Ca(2+)), Cr, 25(OH)D, and 1,25(OH)(2)D at baseline. Thereafter, 100 mcg of PTH(1-84) or 20 mcg of PTH(1-34) was administered. A 24-h urinary collection and blood samples 2, 4, and 24-h after each PTH administration were again taken. One week after the first PTH administration patients were rechallenged with the second PTH. The PTH peptides did not differ with respect to changes in Ca(2+) at 2, 4, and 24 h postinjection; at the last time point the values were virtually identical to the initial values. There was no difference in urinary Ca on the day following PTH injection compared to baseline, in terms both of Ca/Cr and of Ca excretion. The two PTH peptides did not differ with respect to changes in 1,25(OH)(2)D at 2, 4, and 24 h considering both the absolute values and the percent changes with respect to baseline (24-h 1-84 = 125.6 + or - 58.6 pg/ml, 153% increase; 1-34 = 124.1 + or - 64.7, 130%). Our results indicate no difference in postinjection serum Ca(2+), 1,25(OH)(2)D, or urinary Ca excretion after a single dose of either PTH(1-84) or PTH(1-34) in patients previously treated with bisphosphonates.

Topics: Aged; Aged, 80 and over; Calcium; Creatinine; Cross-Over Studies; Diphosphonates; Female; Humans; Hypercalcemia; Hypercalciuria; Injections, Subcutaneous; Middle Aged; Osteoporosis, Postmenopausal; Parathyroid Hormone; Pilot Projects; Prevalence; Time Factors; Vitamin D

Hypercalciuria is an adverse event of postsurgical hypoparathyroidism treatment that can lead to renal complications. The collection of 24-hour urine to detect hypercalciuria is often considered unreliable.. The purpose of this study was to find useful predictive biomarkers of hypercalciuria in patients with permanent postsurgical hypoparathyroidism receiving treatment with oral calcium and calcitriol supplements.. The investigation was designed as a prospective cross-sectional study. An outpatient hospital clinic served as the study setting.. Fifty-four consecutive observations were made of 34 stable outpatients with postsurgical hypoparathyroidism taking oral calcium and calcitriol supplements, and 17 adult controls without hypoparathyroidism.. There were no interventions.. Hypercalciuria was defined as 24-hour urine calcium >300 mg.. Patients without hypercalciuria (n = 21) vs those with hypercalciuria (n = 33) had lower levels of serum 1,25-dihydroxyvitamin D (33.5 ± 11.9 pg/mL vs 45.8 ± 9.5 pg/mL; P < 0.001), similar albumin-corrected serum calcium (8.3 ± 0.5 vs 8.6 ± 0.5 mg/dL; P = nonsignificant), and serum parathyroid hormone (12.5 ± 5.7 vs 10.7 ± 6.8 pg/mL; P = nonsignificant). Multiple linear regression analysis showed an independent relationship between 1,25-dihydroxyvitamin D and urinary calcium excretion (B = 6.2 ± 1.423; P < 0.001). A cutoff value of 33.5 pg/mL for serum 1,25-dihydroxyvitamin D to predict the absence of hypercalciuria had 100% sensitivity and 63.6% specificity, and the area under the receiver operating characteristic curve was 0.797. No patients with serum 1,25-dihydroxyvitamin D levels of <33.5 pg/mL presented with hypercalciuria, regardless of the level of albumin-corrected serum calcium.. Routine measurement of serum 1,25-dihydroxyvitamin D may be useful as a biomarker to predict the absence of hypercalciuria in patients with permanent postsurgical hypoparathyroidism who are receiving treatment with oral calcium and calcitriol supplements.

Topics: Adult; Biomarkers; Calcium; Case-Control Studies; Cross-Sectional Studies; Female; Follow-Up Studies; Humans; Hypercalciuria; Hypoparathyroidism; Male; Middle Aged; Parathyroidectomy; Postoperative Complications; Prognosis; Prospective Studies; ROC Curve; Vitamin D

Loss-of-function mutations of CYP24A1, the enzyme that converts the major circulating and active forms of vitamin D to inactive metabolites, recently have been implicated in idiopathic infantile hypercalcemia. Patients with biallelic mutations in CYP24A1 present with severe hypercalcemia and nephrocalcinosis in infancy or hypercalciuria, kidney stones, and nephrocalcinosis in adulthood. We describe a cohort of 7 patients (2 adults, 5 children) presenting with severe hypercalcemia who had homozygous or compound heterozygous mutations in CYP24A1. Acute episodes of hypercalcemia in infancy were the first symptom in 6 of 7 patients; in all patients, symptoms included nephrocalcinosis, hypercalciuria, low parathyroid hormone (PTH) levels, and higher than expected 1,25-dihydroxyvitamin D levels. Longitudinal data suggested that in most patients, periods of increased sunlight exposure tended to correlate with decreases in PTH levels and increases in calcemia and calciuria. Follow-up of the 2 adult patients showed reduced glomerular filtration rate and extrarenal manifestations, including calcic corneal deposits and osteoporosis. Cases of severe PTH-independent hypercalcemia associated with hypercalciuria in infants should prompt genetic analysis of CYP24A1. These patients should be monitored carefully throughout life because they may be at increased risk for developing chronic kidney disease.

Topics: Bone Density Conservation Agents; Calcium; Child; Child, Preschool; Diphosphonates; Female; Fluid Therapy; Humans; Hypercalcemia; Hypercalciuria; Infant; Kidney Function Tests; Male; Middle Aged; Monitoring, Physiologic; Mutation; Nephrocalcinosis; Nephrolithiasis; Parathyroid Hormone; Renal Insufficiency, Chronic; Seasons; Sunlight; Treatment Outcome; Vitamin D; Vitamin D3 24-Hydroxylase

Increased bone resorption, low bone formation, and abnormal mineralization have been described in stone formers with idiopathic hypercalciuria. It has been previously shown that the receptor activator of NF-κB ligand mediates bone resorption in idiopathic hypercalciuria (IH). The present study aimed to determine the expression of fibroblast growth factor 23 (FGF-23), vitamin D receptor (VDR), and sclerostin in bone tissue from IH stone formers.. Immunohistochemical analysis was performed in undecalcified bone samples previously obtained for histomorphometry from 30 transiliac bone biopsies of idiopathic hypercalciuria stone-forming patients between 1992 and 2002 and 33 healthy individuals (controls). Serum parameters were obtained from their medical records.. Histomorphometry disclosed 21 IH patients with high and 9 IH patients with normal bone resorption. Importantly, eroded surfaces (ES/BS) from IH patients but not controls were significantly correlated with VDR immunostaining in osteoblasts (r=0.51; P=0.004), sclerostin immunostaining in osteocytes (r=0.41; P=0.02), and serum 1,25-dihydroxyvitamin D (r=0.55; P<0.01). Of note, both VDR and sclerostin immunostaining were significantly correlated with serum 1,25-dihydroxyvitamin D in IH patients (r=0.52; P=0.01 and r=0.53; P=0.02, respectively), although VDR and sclerostin expression did not differ between IH and controls. IH patients with high bone resorption exhibited a significantly stronger sclerostin immunostaining than IH patients with normal bone resorption. FGF-23 expression in osteocytes from IH patients did not differ from controls and was not correlated with any histomorphometric parameter.. These findings suggest the contribution of VDR and sclerostin, as well as 1,25-dihydroxyvitamin D, to increase bone resorption in idiopathic hypercalciuria but do not implicate FGF-23 in the bone alterations seen in these patients.

Topics: Adaptor Proteins, Signal Transducing; Adult; Bone Morphogenetic Proteins; Bone Resorption; Female; Fibroblast Growth Factor-23; Fibroblast Growth Factors; Genetic Markers; Humans; Hypercalciuria; Ilium; Immunohistochemistry; Male; Middle Aged; Osteoblasts; Osteocytes; Receptors, Calcitriol; Retrospective Studies; Urolithiasis; Vitamin D

Genetic hypercalciuric stone-forming (GHS) rats have increased intestinal Ca absorption, decreased renal tubule Ca reabsorption and low bone mass, all of which are mediated at least in part by elevated tissue levels of the vitamin D receptor (VDR). Both 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) and bone morphogenetic protein 2 (BMP2) are critical for normal maintenance of bone metabolism and bone formation, respectively. The complex nature of bone cell regulation suggests a potential interaction of these two important regulators in GHS rats. In the present study, BMP2 expression is suppressed by the VDR-1,25(OH)2D3 complex in Bone Marrow Stromal Cells (BMSCs) from GHS and SD rat and in UMR-106 cell line. We used chromatin immunoprecipitation (ChIP) assays to identify VDR binding to only one of several potential binding sites within the BMP2 promoter regions. This negative region also mediates suppressor reporter gene activity. The molecular mechanisms underlying the down-regulation of BMP2 by 1,25(OH)2D3 were studied in vitro in BMSCs and UMR-106 cells using the DNA methyltransferase inhibitor 5-aza-2'-deoxycytidine (DAC) and the histone deacetylase inhibitor trichostatin A (TSA). Both DAC and TSA activate BMP2 expression in combination with 1,25(OH)2D3. Bisulfite DNA pyrosequencing reveals 1,25(OH)2D3 to completely hypermethylate a single CpG site in the same BMP2 promoter region identified by the ChIP and reporter gene assays. ChIP assays also show that 1,25(OH)2D3 can increase the repressive histone mark H3K9me2 and reduce the acetylation of histone H3 at the same BMP2 promoter region. Taken together, our results indicate that 1,25(OH)2D3 binding to VDR down-regulates BMP2 gene expression in BMSCs and osteoblast-like UMR-106 cells by binding to the BMP2 promoter region. The mechanism of this 1,25(OH)2D3-induced transcriptional repression of BMP2 involves DNA methylation and histone modification. The study provides novel evidence that 1,25(OH)2D3 represses bone formation through down-regulating BMP2 expression both in vivo and in vitro.

Topics: Animals; Azacitidine; Bone Morphogenetic Protein 2; Decitabine; DNA Methylation; Epigenesis, Genetic; Female; Histones; Hypercalciuria; Male; Promoter Regions, Genetic; Protein Binding; Protein Processing, Post-Translational; Rats; Rats, Sprague-Dawley; Receptors, Calcitriol; Response Elements; Transcription, Genetic; Vitamin D