Hypercalciuria: its value as a predictive risk factor for nephrolithiasis in asymptomatic primary hyperparathyroidism?

CONTEXT: The latest guidelines of the 4th International Workshop on Asymptomatic Primary Hyperparathyroidism (aPHPT) reintroduced hypercalciuria (i.e. urinary calcium > 400 mg/day) as criterion for surgery. However, the value of hypercalciuria as a predictor of nephrolithiasis and the correct cut-off values still need to be confirmed. OBJECTIVE: To evaluate the prevalence of silent kidney stones in a large series of patients with aPHPT and the sensibility, specificity and predictive value of different cut-off values of hypercalciuria in identifying patients with nephrolithiasis. DESIGN: One hundred seventy-six consecutive patients with aPHPT were evaluated at our Institution by serum and urinary parameters and kidney ultrasound. RESULTS: Silent nephrolithiasis was found in 38 (21.6%) patients. In the univariate and multivariate model, hypercalciuria was a predictor of nephrolithiasis using the criterion of 400 mg/24 h [(OR 2.30, (1.11-4.82) P = 0.025], 4 mg/kg/bw [OR 2.65, (1.14-6.25) P = 0.023], gender criterion [OR 2.79, (1.15-6.79) P = 0.023] and the cut-off value derived from the ROC analysis [(> 231 mg/24 h) OR 5.02 (1.68-14.97) P = 0.004]. Despite these several predictive criteria, however, hypercalciuria had a low positive predictive value (PPV), ranging from 27.4 to 32.7%. CONCLUSIONS: Hypercalciuria is a predictor of nephrolithiasis, but its PPV is low.

Effects of Tributyltin (TBT) on Rat Bone and Mineral Metabolism.

BACKGROUND/AIMS: Tributyltin (TBT) is an organotin (OTs) and biohazard organometallic pollutant. Recently our group has shown that TBT, even in very low doses, has deleterious effects on several tissues most likely due to its role as an endocrine-disrupting molecule. Other studies have confirmed that OT exposure could be responsible for neural, endocrine, and reproductive dysfunctions via in vitro and in vivo models. However, TBT effects on bone lack concise data despite the fact that bone turnover is regulated by endocrine molecules, such as parathormone (PTH), estrogen (E2), etc. Our group has already shown that TBT disrupts adrenal and female gonadal functions. METHODS: We studied the effects of TBT on bone metabolism and structure using DXA, microCT scan, and SEM. We also determined the calcium (Ca²âº) and phosphate (Pi) metabolism in TBT-treated rats as well as some biomarkers for bone formation and resorption. RESULTS: Surprisingly, we found that TBT leads to higher bone mineral density (BMD) although lesions in spinal bone were observed by either microCT scan or SEM. Biomarkers for bone resorption, such as the urinary deoxipyridinolines (DPD) excretion ratio was increased in TBT-treated animals versus mock-treated controls. Osteocalcin (OC) and alkaline phosphatase (AP) are markers of bone formation and are also elevated suggesting that the bone matrix suffers from a higher turnover. Serum Ca²âº (total and ionized) do not changed by TBT treatment although hypercalciuria is observed. CONCLUSION: It is known that Sn atoms have three valence states (Sn²âº, Sn³âº, and Sn4⁺); hence, we hypothesized that Sn (more likely Sn²âº) could be competing with Ca²âº and/or Mg²âº in hydroxyapatite mineral matrix to disturb bone turnover. Further work is needed to confirm this hypothesis.

Bone Status Among Patients With Nonsurgical Hypoparathyroidism, Autosomal Dominant Hypocalcaemia, and Pseudohypoparathyroidism: A Cohort Study.

Nonsurgical hypoparathyroidism (Ns-HypoPT) and pseudohypoparathyroidism (PHP) are both rare diseases, characterized by hypocalcemia. In Ns-HypoPT, PTH levels are low, whereas patients with PHP often have very high levels due to receptor-insensitivity to PTH (PTH-resistance). Accordingly, we hypothesized that indices of bone turnover and bone mineralization/architecture are similar in Ns-HypoPT and PHP despite marked differences in PTH levels. We studied 62 patients with Ns-HypoPT and 31 with PHP as well as a group of age- and sex-matched healthy controls. We found a significantly higher areal BMD (aBMD) by DXA among patients with Ns-HypoPT, both compared with PHP and the background population. Compared with Ns-HypoPT, PHP patients had significantly lower total and trabecular volumetric BMD (vBMD) assessed by quantitative computed tomography (QCT) scans at the spine and hip. High-resolution peripheral quantitative computed tomography (HRpQCT) scans showed a lower trabecular area and vBMD as well as a lower trabecular number at the tibia in PHP compared to Ns-HypoPT and matched controls. In PHP, PTH levels correlated with levels of markers of bone formation (osteocalcin, bone-specific alkaline phosphatase, P1NP), and bone resorption (CTx). In adult males, levels of bone markers were significantly higher in PHP compared with Ns-HypoPT. Levels of procalcitonin and calcitonin were significantly higher in PHP compared with Ns-HypoPT. In conclusion, indices of bone turnover, density, and microarchitecture differ between patients with Ns-HypoPT and PHP. Our data suggest that patients with PHP do not have a complete skeletal resistance to PTH and that the effects of chronically high PTH levels in PHP are mostly confined to the trabecular tissue. © 2017 American Society for Bone and Mineral Research.

Impaired growth and intracranial calcifications in autosomal dominant hypocalcemia caused by a GNA11 mutation.

OBJECTIVE: Autosomal dominant hypocalcemia (ADH) is characterized by hypocalcemia and inappropriately low PTH concentrations. ADH type 1 is caused by activating mutations in the calcium-sensing receptor (CASR), a G-protein-coupled receptor signaling through α11 (Gα11) and αq (Gαq) subunits. Heterozygous activating mutations in GNA11, the gene encoding Gα11, underlie ADH type 2. This study describes disease characteristics in a family with ADH caused by a gain-of-function mutation in GNA11. DESIGN: A three-generation family with seven members (3 adults, 4 children) presenting with ADH. METHODS: Biochemical parameters of calcium metabolism, clinical, genetic and brain imaging findings were analyzed. RESULTS: Sanger sequencing revealed a heterozygous GNA11 missense mutation (c.1018G>A, p.V340M) in all seven hypocalcemic subjects, but not in the healthy family members (n=4). The adult patients showed clinical symptoms of hypocalcemia, while the children were asymptomatic. Plasma ionized calcium ranged from 0.95 to 1.14mmol/L, yet plasma PTH was inappropriately low for the degree of hypocalcemia. Serum 25OHD was normal. Despite hypocalcemia 1,25(OH)2D and urinary calcium excretion were inappropriately in the reference range. None of the patients had nephrocalcinosis. Two adults and one child (of the two MRI scanned children) had distinct intracranial calcifications. All affected subjects had short stature (height s.d. scores ranging from -3.4 to -2.3 vs -0.5 in the unaffected children). CONCLUSIONS: The identified GNA11 mutation results in biochemical abnormalities typical for ADH. Additional features, including short stature and early intracranial calcifications, cosegregated with the mutation. These findings may indicate a wider role for Gα11 signaling besides calcium regulation.

Chondrocalcinosis related to familial hypomagnesemia with hypercalciuria and nephrocalcinosis.

Calcium pyrophosphate dehydrate (CPPD) crystal deposition disease (also known as chondrocalcinosis, CC) is a rare metabolic arthropathy mostly seen in elderly patients. Chondrocalcinosis may be associated with metabolic diseases such as hypomagnesemia when it occurs in young people. We report here a case with hypomagnesemia due to familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC) who developed CC during clinical follow-up. To our best knowledge this is the first case of a young patient with CPPD associated with FHHNC.

BONE MINERAL DENSITY IN CHILDREN WITH IDIOPATHIC HYPERCALCIURIA.

UNLABELLED: The aim of the study was to evaluate bone mineral density (BMD) in the lumbar spine in children with idiopathic hypercalciuria. PATIENTS AND METHODS: The study group included 31 children (14 boys, 17 girls) aged 5 to 17 years (mean age 9.8 ± 4.0 years) with idiopathic hypercalciuria. All children remained on normal calcium diet, without vitamin D and citrate supplementation. We evaluated lumbar spine (L1-L4) BMD (L1-L4 BMD) (expressed as Z-score) and blood serum levels of 25-hydroxyvitamin D3 (250HD3), calcium (Ca), phosphorus (P), alkaline phosphatase (ALP), and intact parathormone (iPTH). We also evaluated 24-hour urinary Ca, P, and sodium (Na) excretion. RESULTS: Reduced L1-L4 BMD Z-score <-1 was found in 25.8% of children, Z-score values from -1 to 1 in 64.5% of children, and Z-score > 1 in 9.7% of children. Reduced 250HD3 level (< 20 ng/mL) was found in 71% of children, levels in the range of 20-30 ng/mL in 22.6% of children, and levels > 30 ng/mL in 6.4% of children. Seven out of 8 children with L1-L4 BMD Z-score <-1 were found to have 250HD3 deficiency (level < 20 ng/mL). Among children with reduced lumbar spine BMD, most were girls at the mean age of 13.8 years. Ca and P levels were normal in all children. We did not find significant differences in 25OHD3, Ca, and P levels in relation to gender and age. We found a positive correlation between L1-L4 BMD Z-score and serum 250HD3 level. Concomitant nephrolithiasis was found in 50% of patients with reduced lumbar spine BMD. CONCLUSIONS: Reduced lumbar spine BMD in patients with idiopathic hypercalciuria seems to be related to vitamin D3 deficiency.

Reduced bone mass in 7-year-old children with asymptomatic idiopathic hypercalciuria.

BACKGROUND: Idiopathic hypercalciuria (IHC), i.e. an elevated urinary calcium excretion without concomitant hypercalcemia, is a common disorder in children and can have a range of urinary clinical presentations and decreased bone mineral density (BMD). AIM: To assess the effect of IHC on bone mineral content in children without urological symptoms. METHODS: Calcium excretion, BMD (by dual-energy X-ray absorptiometry), and anthropometry were assessed in 175 seven-year-old children who were classified as IHC or controls. Calcium intake and physical activity were measured as confounding factors. RESULTS: The prevalence of IHC was 17.7%. Both groups (controls and IHC) showed similar baseline characteristics in terms of their anthropometry, gender distribution, and protein and calcium dietary intakes as well as physical activity scores. Urinary calciuria was independent of the calcium dietary intake and anthropometry. BMD correlated with anthropometry and physical activity but not with calcium dietary intake. IHC children had lower whole-body BMD z-scores compared to controls. The role of IHC in reducing the whole-body BMD z-score was still significant even when anthropometry, physical activity, and calcium intake were included as confounders in multivariate analyses. CONCLUSIONS: The prevalence of IHC in this population of 7-year-old children was about 17%. IHC diagnosis was associated with lower BMD z-scores and osteopenia in 22% of them.

Association between compound heterozygous mutations of SLC34A3 and hypercalciuria.

BACKGROUND: Mutations in SLC34A3 have been shown to cause hereditary hypophosphatemic rickets with hypercalciuria (HHRH). Patients with compound heterozygous or homozygous mutations develop skeletal lesions in addition to hypercalciuria, hypophosphatemia and/or elevated 1,25-dihydroxy vitamin D [1,25-(OH)2D] levels. Here, we report a case of hypercalciuria without skeletal lesions in a patient with compound heterozygous mutations of SLC34A3. CASE PRESENTATION: A 3-year-old girl presented with microscopic hematuria. Laboratory data revealed elevated 1,25-(OH)2D levels and serum calcium, reduced serum inorganic phosphorus and hypercalciuria. In addition, the ratio of maximal rate of renal tubular reabsorption of phosphate to glomerular filtration rate was reduced. Abdominal ultrasound revealed bilateral nephrocalcinosis. These data were consistent with HHRH, but the patient had no clinical features of rickets or any family history of skeletal disease. Genetic analysis revealed compound heterozygous mutations of c.175+1 G>A and c.1234 C>T in SLC34A3. CONCLUSIONS: This is the report of a patient with compound heterozygous mutations of SLC34A3 and normal skeletal features. Biallelic mutations in SLC34A3 can thus be associated with hypercalciuria not accompanied by rickets. Orally administered inorganic phosphate is predicted to improve symptoms in these patients, hence screening for SLC34A3 mutations should be considered in patients with hypercalciuria of unknown etiology.

A compound heterozygous mutation in SLC34A3 causes hereditary hypophosphatemic rickets with hypercalciuria in a Chinese patient.

Hereditary hypophosphatemic rickets with hypercalciuria (HHRH) is a rare metabolic disorder inherited in an autosomal recessive fashion and characterized by hypophosphatemia, short stature, rickets and/or osteomalacia, and secondary absorptive hypercalciuria. HHRH was recently mapped to chromosome 9q34, which contains the gene SLC34A3 which encodes the renal proximal tubular sodium-phosphate cotransporter NaPi-IIc. Here we describe a 29-year-old man with a history of childhood rickets who presented with increased renal phosphate clearance leading to hypophosphatemia, hypercalciuria, low serum parathyroid hormone (PTH), elevated serum 1,25-dihydroxyvitamin D (1,25(OH)2D) and recurrent nephrolithiasis. We performed a mutation analysis of SLC34A3 (exons and adjacent introns) of the proband and his parents to determine if there was a genetic contribution. The proband proved to be compound heterozygous for two missense mutations in SLC34A3: one novel mutation in exon 7 c.571G>C (p.G191R) and one previously identified mutation in exon 13 c.1402C>T (p.R468W). His parents were both asymptomatic heterozygous carriers of one of these two mutations. We also performed an oral phosphate loading test and compared serum phosphate, intact PTH, and intact fibroblast growth factor 23 (iFGF23) in this patient versus patients with other forms of hypophosphatemic rickets, the results of which further revealed that the mechanism of hypophosphatemia in HHRH is independent of FGF23. This is the first report of HHRH in the Chinese population. Our findings of the novel mutation in exon 7 add to the list of more than 20 reported mutations of SLC34A3.

Plasma and urinary levels of cytokines in patients with idiopathic hypercalciuria.

BACKGROUND: Recent studies suggest that cytokines modulate bone turnover. Idiopathic hypercalciuria (IH) seems to be associated with bone mineral loss. Therefore, the aim of this study was to assess cytokines involved in bone turnover in patients with IH. METHODS: Plasma and spot-urine levels of interleukin (IL)-1ß, IL-6, IL-8, tumor necrosis factor alpha (TNF-α), transforming growth factor ß1 (TGF-ß1), and monocyte chemoattractant protein (MCP-1) were measured in 70 children and adolescents with IH and in 37 healthy controls. Patients with IH were subdivided according to their calciuria at the time of sample collection: ≥4 mg/kg/day (persistent IH, n=27) and below 4 mg/kg/day (controlled IH, n=43). Cytokines were determined by enzyme-linked immunoassay. RESULTS: Plasma and urinary concentrations of IL-1ß, IL-6, IL-8, and TNF-α were undetectable in all groups. No differences were found between controlled and persistent hypercalciuria for plasma and urinary levels of MCP-1 and TGF-ß1. On the other hand, MCP-1 levels were significantly higher in both subgroups of IH in comparison to healthy controls. Furthermore, urinary MCP-1 levels of IH patients correlated positively with bone mineral content (p=0.013). CONCLUSION: Although cytokine measurements did not allow the differentiation between persistent and controlled IH, our findings suggest that MCP-1 might play a role in patients with IH.

Longitudinal study of bone mineral density in children with idiopathic hypercalciuria.

Children with idiopathic hypercalciuria (IH) may have a reduced bone mineral density (BMD), which could impact on bone health in adulthood. There is currently no strong evidence for a preferred treatment of such children. The aim of our study was to evaluate the BMD z-score before and after treating children and adolescents with IH with potassium citrate and thiazides. The study consisted of a historical cohort of 80 pediatric patients who were evaluated between October 1989 and November 2010. Bone scanning and densitometry measurements were made with dual-emission X-ray absorptiometry. Lumbar-spine BMD (g/cm(2)) and BMD z-score were evaluated before and after treatment. The t test and Mann-Whitney U test were used for statistical analysis. Forty-three boys and 37 girls were followed for a median time of 6.0 years. Median calcium excretion before and after treatment was 5.0 and 2.6 mg/kg/24 h, respectively. The BMD z-score changed significantly from -0.763 ± 0.954 (mean ± SD) to -0.537 ± 0.898 (p < 0.0001) before and after treatment, respectively. The BMD z-score of the patients improved with treatment, suggesting a beneficial effect and potential need for treatment. However, the lack of a control group points to the need for future studies to corroborate this outcome.

Hypophosphatemic rickets with hypercalciuria due to mutation in SLC34A3/NaPi-IIc can be masked by vitamin D deficiency and can be associated with renal calcifications.

Hereditary hypophosphatemic rickets with hypercalciuria (HHRH) is caused by mutations in SLC34A3, the gene encoding the renal sodium-phosphate co-transporter NaPi-IIc. Despite increased urinary calcium excretion, HHRH is typically not associated with kidney stones prior to treatment. However, here we describe two sisters, who displayed nephrolithiasis or nephrocalcinosis upon presentation. The index patient, II-4, presented with short stature, bone pain, and knee X-rays suggestive of mild rickets at age 8.5 years. Laboratory evaluation showed hypophosphatemia, elevated 1,25(OH) (2) vitamin D levels, and hypercalciuria, later also developing vitamin D deficiency. Her sister, II-6, had a low normal serum phosphorous level, biochemically vitamin D deficiency and no evidence for osteomalacia, but had undergone left nephro-ureterectomy at age 17 because of ureteral stricture secondary to renal calculi. Nucleotide sequence analysis of DNA from II-4 and II-6 revealed a homozygous missense mutation c.586G>A (p.G196R) in SLC34A3/NaPi-IIc. Ultrasonographic examinations prior to treatment showed grade I nephrocalcinosis for II-4, while II-6 had grade I-II nephrocalcinosis in her remaining kidney. Four siblings and the mother were heterozygous carriers of the mutation, but showed no biochemical abnormalities. With oral phosphate supplements, hypophosphatemia and hypercalciuria improved in both homozygous individuals. Renal calcifications that are presumably due to increased urinary calcium excretion can be the presenting finding in homozygous carriers of G196R in SLC34A3/NaPi-IIc, and some or all laboratory features of HHRH may be masked by vitamin D deficiency.

Hypercalciuria associated with pediatric prostatic calculi.

Prostatic calculi, though common in adult men, are rare in children. We report three cases of pediatric prostatic calculi seen at our clinic that were associated with hypercalciuria and elevated urinary calcium/creatinine ratios. The patients had no symptoms from their prostatic calcification, but one patient had recurrent symptomatic renal calculi. In patients with prostatic calculi, determination of spot urine calcium/creatinine ratios is recommended. If significant hypercalciuria is found, treatment to prevent upper urinary tract calculi may be considered.