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, and thus, 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.

Hereditary Hypophosphatemic Rickets with Hypercalciuria Presenting with Enthesopathy, Renal Cysts, and High Serum c-Terminal FGF23: Single-Center Experience and Systematic Review.

Hereditary hypophosphatemic rickets with hypercalciuria (HHRH) is a rare disorder of phosphate homeostasis. We describe a single-center experience of genetically proven HHRH families and perform systematic review phenotype-genotype correlation in reported biallelic probands and their monoallelic relatives. Detailed clinical, biochemical, radiological, and genetic data were retrieved from our center and a systematic review of Pub-Med and Embase databases for patients and relatives who were genetically proven. Total of nine subjects (probands:5) carrying biallelic SLC34A3 mutations (novel:2) from our center had a spectrum from rickets/osteomalacia to normal BMD, with hypophosphatemia and hypercalciuria in all. We describe the first case of genetically proven HHRH with enthesopathy. Elevated FGF23 in another patient with hypophosphatemia, iron deficiency anemia, and noncirrhotic periportal fibrosis led to initial misdiagnosis as tumoral osteomalacia. On systematic review of 58 probands (with biallelic SLC34A3 mutations; 35 males), early-onset HHRH and renal calcification were present in ~ 70% and late-onset HHRH in 10%. c.575C > T p.(Ser192Leu) variant occurred in 53% of probands without skeletal involvement. Among 110 relatives harboring monoallelic SLC34A3 mutation at median age 38 years, renal calcification, hypophosphatemia, high 1,25(OH)2D, and hypercalciuria were observed in ~30%, 22.3%, 40%, and 38.8%, respectively. Renal calcifications correlated with age but were similar across truncating and non-truncating variants. Although most relatives were asymptomatic for bone involvement, 6/12(50%) had low bone mineral density. We describe the first monocentric HHRH case series from India with varied phenotypes. In a systematic review, frequent renal calcifications and low BMD in relatives with monoallelic variants (HHRH trait) merit identification.

Identification of a Novel Homozygous Missense Mutation in the CLDN16 Gene to Decipher the Ambiguous Clinical Presentation Associated with Autosomal Dominant Hypocalcaemia and Familial Hypomagnesemia with Hypercalciuria and Nephrocalcinosis in an Indian Family.

Familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHNNC) is a rare autosomal recessive renal tubulopathy disorder characterized by excessive urinary loss of calcium and magnesium, polyuria, polydipsia, bilateral nephrocalcinosis, progressive chronic kidney disease, and renal failure. Also, sometimes amelogenesis imperfecta and severe ocular abnormalities are involved. The CLDN-16 and CLDN-19 genes encode the tight junction proteins claudin-16 and claudin-19, respectively, in the thick ascending loop of Henle in the kidney, epithelial cells of the retina, dental enamel, etc. Loss of function of the CLDN-16 and/or CLDN-19 genes leads to FHHNC. We present a case of FHHNC type 1, which was first confused with autosomal dominant hypocalcaemia (ADH) due to the presence of a very low serum parathyroid hormone (PTH) concentration and other similar clinical features before the genetic investigations. After the exome sequencing, FHHNC type 1 was confirmed by uncovering a novel homozygous missense mutation in the CLDN-16 gene (Exon 2, c.374 T > C) which causes, altered protein structure with F55S. Associated clinical, biochemical, and imaging findings also corroborate final diagnosis. Our findings expand the spectrum of the CLDN-16 mutation, which will further help in the genetic diagnosis and management of FHNNC.

A previously healthy 3-year-old female with hypertension, proteinuria, and hypercalciuria.

A 3-year-old female patient with no significant medical history presented to her pediatrician with foamy urine. Initial testing revealed moderate proteinuria on qualitative testing, although she was incidentally noted to have severe hypertension (240/200 mmHg). Physical examination of the carotid and femoral areas revealed significant systolic vascular murmurs. Labs showed elevated serum creatinine, hypokalemia, metabolic alkalosis, elevated renin and aldosterone and hypercalciuria. Echocardiography identified ventricular hypertrophy. Computed tomography (CT) of the abdomen and magnetic resonance angiography of the head showed multiple tortuous or interrupted arteries and multiple calcifications in the renal sinus area. B-mode ultrasonography suggested thickening of the carotid and femoral artery walls, with numerous spotted calcifications. Genetic testing revealed that ABCC6 had a complex heterozygous mutation (exon 24: c.3340C > T and intron 30: c.4404-1G > A). Our panel of experts reviewed the evaluation of this patient with hypertension, proteinuria, hypercalciuria, and vascular abnormalities as well as the diagnosis and appropriate management of a rare disease.

Impact of urinary calcium excretion on kidney, bone, and cardiovascular systems in patients with bone biopsy proven osteoporosis: a longitudinal long-term follow-up study.

The impact of urine calcium on kidney, bone, and cardiovascular systems in osteoporosis is not well-known. In this 7-year-follow-up study, high urine calcium did not affect kidney function but increased risk of kidney stones, while low urine calcium increased cardiovascular diseases. Maintaining normal urine calcium is beneficial for bone health. PURPOSE: Hypercalciuria is common in patients with osteoporosis. However, the long-term effect of urinary calcium excretion (UCaE) on patients' health is not well-examined. The current study aims to assess the impact of UCaE on kidney, bone, and cardiovascular outcomes in patients with bone biopsy proven osteoporosis. METHODS: Longitudinal study of all patients with osteoporosis who underwent bone biopsy and 24-h urine collection between 2008 and 2015 in the University of Kentucky. DXA scans, serum markers, kidney function, and cardiovascular events were recorded until last clinic visit in 2021. Exclusion criteria were secondary osteoporosis or conditions that might substantially impact UCaE. The significant results in univariate analysis were confirmed in multi-variable regression models involving clinically important covariates that might impact patients' outcomes. RESULTS: Study included 230 patients with mean follow-up of 7.2 ± 2.9 years. The mean age was 61 years, and the mean eGFR at baseline was 85 ± 19 ml/min/1.73 m2. Low bone turnover (LBT) was present in 57% and high bone turnover (HBT) in 43% of patients. Hypercalciuria was found in one-third of patients with no difference between LTB and HTB. UCaE correlated positively with eGFR but did not affect the rate of eGFR decline over time. Higher UCaE predicted kidney stones development. We observed U-shaped effect of UCaE on bone health. Hypercalciuria predicted loss of BMD at all sites, but also hypocalciuria was associated with higher loss in total hip BMD. Upper limb fractures were the most observed fractures, and their incidence was higher in patients with hyper- or hypo-calciuria. Lower UCaE independently predicted development of major adverse cardiac events (MACE) and cardiovascular disease (CVD). CONCLUSION: UCaE correlated with eGFR but it did not affect the change of eGFR over time. Patients with normal UCaE had lower incidence of upper limb fractures and less reduction in BMD. Low UCaE predicted MACE and CVD.

Idiopathic infantile hypercalcemia in children with chronic kidney disease due to kidney hypodysplasia.

BACKGROUND: Idiopathic infantile hypercalcemia (IIH) etiologies include pathogenic variants in CYP24A1, leading to increased 1,25(OH)2 D, hypercalciuria and suppressed parathyroid hormone (PTH), and in SLC34A1 and SLC34A3, leading to the same metabolic profile via increased phosphaturia. IIH has not been previously described in CKD due to kidney hypodysplasia (KHD). METHODS: Retrospective study of children with bilateral KHD and simultaneously tested PTH and 1,25(OH)2D, followed in a tertiary care center between 2015 and 2021. RESULTS: Of 295 screened patients, 139 had KHD, of them 16 (11.5%) had IIH (study group), 26 with normal PTH and any 1,25(OH)2D were controls. There were no differences between groups' gender, obstructive uropathy rate and baseline eGFR. Study patients were younger [median (IQR) age: 5.2 (3.2-11.3) vs. 61 (13.9-158.3) months, p < 0.001], had higher 1,25(OH)2D (259.1 ± 91.7 vs. 156.5 ± 46.4 pmol/l, p < 0.001), total calcium (11.1 ± 0.4 vs. 10.7 ± 0.3 mg/dl, p < 0.001), and lower phosphate standard deviation score (P-SDS) [median (IQR): - 1.4 (- 1.9, - 0.4) vs. - 0.3 (- 0.8, - 0.1), p = 0.03]. During 12 months of follow-up, PTH increased among the study group (8.8 ± 2.8 to 22.7 ± 12.4 pg/ml, p < 0.001), calcium decreased (11 ± 0.5 to 10.3 ± 0.6 mg/dl, p = 0.004), 1,25(OH)2D decreased (259.5 ± 91.7 to 188.2 ± 42.6 pmol/l, p = 0.1), P-SDS increased [median (IQR): - 1.4 (- 1.9, - 0.4) vs. - 0.3 (- 0.9, 0.4), p = 0.04], while eGFR increased. Five of 9 study group patients with available urine calcium had hypercalciuria. Five patients had nephrocalcinosis/lithiasis. Genetic analysis for pathogenic variants in CYP24A1, SLC34A1 and SLC34A3 had not been performed. CONCLUSIONS: Transient IIH was observed in infants with KHD, in association with hypophosphatemia, resembling SLC34A1 and SLC34A3 pathogenic variants' metabolic profile. A higher resolution version of the Graphical abstract is available as Supplementary information.

Normocalcaemic primary hyperparathyroidism: is nephrolithiasis more common than osteoporosis?

BACKGROUND: Normocalcaemic primary hyperparathyroidism (NPHPT) is often under-recognised in clinical practice. AIM: To determine the prevalence and clinical significance of NPHPT in an unselected sample in an acute hospital setting. METHODS: Patients aged >18 years who had measurement of an elevated serum parathyroid hormone (PTH ≥ 7 pmol/L) during 12 months from 1 January 2017 to 31 December 2017 were retrospectively studied. NPHPT was defined by the presence of elevated serum PTH with normal albumin-corrected serum calcium on two or more occasions after excluding secondary causes. Patients were followed up for 2 years. Relevant data were collected by review of electronic medical records. RESULTS: Of the 2593 patients who had PTH measured during the study period, 1278 had serum PTH ≥ 7 pmol/L. Hypercalcaemic primary hyperparathyroidism (PHPT) was diagnosed in 174 patients. Secondary causes for elevated serum PTH were identified in 993 patients: 815 (chronic kidney disease - estimated glomerular filtration rate < 60 mL/min/1.73 m2 or renal transplant), 98 (vitamin D deficiency - 25(OH)D < 50 nmol/L), 28 (gastric bypass surgery), 38 (medications), 13 (malabsorption or post-thyroidectomy) and 1 (hypercalciuria). Data were incomplete for 80 patients. The prevalence of NPHPT with and without the exclusion of hypercalciuria was 0.19% (5) and 0.39% (10) respectively. The prevalence of nephrolithiasis in NPHPT was higher than PHPT (100% vs 15% among five patients (P < 0.001) and 50% vs 15% among 10 patients (P = 0.014)). The prevalence of osteoporosis was not significantly different between NPHPT and PHPT (20% vs 45% among five patients (P = 0.389) and 30% vs 45% among 10 patients (P = 0.518)). CONCLUSION: These findings give further credence to the diagnosis of NPHPT as a clinical entity. Nephrolithiasis may be a greater problem than osteoporosis in NPHPT compared with PHPT. This needs prospective evaluation.

Familial Hypomagnesemia with Hypercalciuria and Nephrocalcinosis Due to CLDN16 Gene Mutations: Novel Findings in Two Cases with Diverse Clinical Features.

Biallelic loss of function mutations in the CLDN16 gene cause familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC), and chronic kidney disease. Here we report two cases of FHHNC with diverse clinical presentations and hypercalcemia in one as a novel finding. Pt#1 initially presented with urinary tract infection and failure to thrive at 5.5 months of age to another center. Bilateral nephrocalcinosis, hypercalcemia (Ca: 12.2 mg/dl), elevated parathyroid hormone (PTH) level, and hypercalciuria were detected. Persistently elevated PTH with high/normal Ca levels led to subtotal-parathyroidectomy at the age of 2.5. However, PTH levels remained elevated with progressive deterioration in renal function. At 9-year-old, she was referred to us for evaluation of hyperparathyroidism and, hypomagnesemia together with hypercalciuria, elevated PTH with normal Ca levels, and medullary nephrocalcinosis were detected. Compound heterozygosity of CLDN16 variants (c.715G>A, p.G239R; and novel c.360C>A, p.C120*) confirmed the diagnosis. Pt#2 was a 10-month-old boy, admitted with irritability and urinary crystals. Hypocalcemia, hypophosphatemia, elevated PTH and ALP, low 25(OH)D levels, and radiographic findings of rickets were detected. However, additional findings of hypercalciuria and bilateral nephrocalcinosis were inconsistent with the nutritional rickets. Low/normal serum Mg levels suggested the diagnosis of FHHNC which was confirmed genetically as a homozygous missense (c.602G > A; p.G201E) variant in CLDN16. Yet, hypocalcemia and hypomagnesemia persisted in spite of treatment. In conclusion, FHHNC may present with diverse clinical features with mild hypomagnesemia leading to secondary hyperparathyroidism with changing Ca levels from low to high. Early and accurate clinical and molecular genetic diagnosis is important for proper management.

Dent-2 disease with a Bartter-like phenotype caused by the Asp631Glu mutation in the OCRL gene.

BACKGROUND: Dent disease is an X-linked disorder characterized by low molecular weight proteinuria (LMWP), hypercalciuria, nephrolithiasis and chronic kidney disease (CKD). It is caused by mutations in the chloride voltage-gated channel 5 (CLCN5) gene (Dent disease-1), or in the OCRL gene (Dent disease-2). It is associated with chronic metabolic acidosis; however metabolic alkalosis has rarely been reported. CASE PRESENTATION: We present a family with Dent-2 disease and a Bartter-like phenotype. The main clinical problems observed in the proband included a) primary phosphaturia leading to osteomalacia and stunted growth; b) elevated serum calcitriol levels, leading to hypercalcemia, hypercalciuria, nephrolithiasis and nephrocalcinosis; c) severe salt wasting causing hypotension, hyperaldosteronism, hypokalemia and metabolic alkalosis; d) partial nephrogenic diabetes insipidus attributed to hypercalcemia, hypokalemia and nephrocalcinosis; e) albuminuria, LMWP. Phosphorous repletion resulted in abrupt cessation of hypercalciuria and significant improvement of hypophosphatemia, physical stamina and bone histology. Years later, he presented progressive CKD with nephrotic range proteinuria attributed to focal segmental glomerulosclerosis (FSGS). Targeted genetic analysis for several phosphaturic diseases was unsuccessful. Whole Exome Sequencing (WES) revealed a c.1893C > A variant (Asp631Glu) in the OCRL gene which was co-segregated with the disease in male family members. CONCLUSIONS: We present the clinical characteristics of the Asp631Glu mutation in the OCRL gene, presenting as Dent-2 disease with Bartter-like features. Phosphorous repletion resulted in significant improvement of all clinical features except for progressive CKD. Angiotensin blockade improved proteinuria and stabilized kidney function for several years.

AN INFANT WITH IDIOPATHIC HYPERCALCIURIA AND NEPHROLITHIASIS ASSOCIATED WITH CYP24A1 ENZYME POLYMORPHISM: A CASE REPORT.

CYP24A1 is an enzyme that inactivates vitamin D and encodes vitamin D 24-hydroxylase. Mutations in this enzyme have been linked with idiopathic infantile hypercalcemia, nephrolithiasis, and nephrocalcinosis. Genetic testing for this mutation should be considered in the presence of calciuria, elevated serum calcium, elevated 1,25- dihydroxyvitamin D, and suppressed parathyroid hormone. We present a previously healthy eight-month-old male infant with macrohematuria, hypercalciuria (6 mg/kg/24 h), albuminuria (54 mg/24 h) and left-sided nephrolithiasis found on urinary tract ultrasound. The values of alpha 1 microglobulin, parathyroid hormone, vitamin D, serum electrolytes, amino acids, glycols, oxalates and citrates in urine, as well as coagulation tests were normal. Genetic testing excluded suspected Dent's disease but confirmed heterozygous missense variant CYP24A1 c.469C>T, p.(Arg157Trp) classified as polymorphism. He was treated with hydrochlorothiazide and potassium citrate. Children presenting with hypercalcemia, hypercalciuria and nephrolithiasis should be tested because of the importance of recognition, genetic diagnosis and proper treatment of CYP24A1 mutations that can present with a wide range of phenotypic presentations, from asymptomatic to chronic renal disease.

Determinants of hypercalciuria and renal calcifications in chronic hypoparathyroidism: A cross-sectional study.

OBJECTIVE: Hypercalciuria, impaired kidney function and renal calcifications are common in chronic hypoparathyroidism (HypoPT). We aimed to study associations between indices of known importance to the kidney in HypoPT by hypothesizing adverse effects of hypercalciuria on renal outcomes. DESIGN: We used cross-sectional design. PATIENTS: We identified all patients followed for chronic HypoPT at our department and who had been examined by a 24-h urine collection for measurement of renal calcium excretion (24 h U-Ca). MEASUREMENTS: By chart review, we identified additional biochemistry measured in close connection with the collection of urine, as well as demographic, treatments and anthropometrics. RESULTS: The 166 included patients (79.5% females) had a high prevalence of hypercalciuria (65.7%). In multiple adjusted analyses, hypercalciuria was in an independent manner inversely associated with (residual) levels of plasma PTH and positively associated with levels of 1,25-dihydroxyvitamin D and ionized calcium as well as 24 h U-phosphate, gender, and etiology (surgical vs. non-surgical). Overall, this model explained 54% (p < .001) of the variation in the presence of hypercalciuria. Chronic kidney disease stage three or above was present in 18.3% of the patients, and 42.6% of the 54 patients examined by renal imaging had renal calcifications. However, neither renal function nor renal calcifications were associated with 24 h U-Ca. CONCLUSIONS: Hypercalciuria, impaired renal function and renal calcifications are common in hypoparathyroidism. Hypercalciuria is to a large extent explained by indices of known physiological importance to 24 h U-Ca. However, in the present study, a high renal calcium excretion did not explain renal impairment or kidney calcifications.

Familial hypomagnesemia with hypercalciuria and nephrocalcinosis.

Familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC; OMIM 248250) is a rare autosomal recessive kidney disease caused by mutations in the CLDN16 or CLDN19 genes encoding the proteins claudin-16 and claudin-19, respectively. These are involved in paracellular magnesium and calcium transport in the thick ascending limb of Henle's loop and account for most of the magnesium reabsorption in the tubules. FHHNC is characterized by hypomagnesaemia, hypercalciuria, and nephrocalcinosis, and progresses to kidney failure, requiring dialysis and kidney transplantation mainly during the second to third decades of life. Patients carrying CLDN19 mutations frequently exhibit associated congenital ocular defects leading to variable visual impairment. Despite this severe clinical course, phenotype variability even among siblings has been described in this disease, suggesting unidentified epigenetic mechanisms or other genetic or environmental modifiers. Currently, there is no specific therapy for FHHNC. Supportive treatment with high fluid intake and dietary restrictions, as well as magnesium salts, thiazides, and citrate, are commonly used in an attempt to retard the progression of kidney failure. A kidney transplant remains the only curative option for kidney failure in these patients. In this review, we summarize the current knowledge about FHHNC and discuss the remaining open questions about this disorder.

A nationwide retrospective study in Turkish children with nephrocalcinosis.

BACKGROUND: Nephrocalcinosis (NC) is defined as calcium deposition in the kidney parenchyma and tubules. This study aims to determine the etiology, risk factors, and follow-up results of patients with NC in Turkey. METHODS: Patients diagnosed with NC in the pediatric nephrology Department Units of 19 centers from all geographical regions of Turkey over a 10-year period (2010-2019) were included in the study. The medical records from the centers were reviewed and demographic data, admission complaints, medical history, systemic and genetic disorders, risk factors for NC, treatment details, and presence of NC after one-year follow-up, were recorded retrospectively. RESULTS: The study sample included 195 patients (88 females, 107 males). The mean age at diagnosis was 39.44 ± 47.25 (0.5-208) months; 82/190 patients (43.2%) were diagnosed incidentally; 46/195 patients (23.6%) had an underlying disease; idiopathic hypercalciuria was detected in 75/195 (38.4%) patients. The most common systemic diseases were distal renal tubular acidosis in 11/46 patients (23.9%), primary hyperoxaluria in 9/46 patients (19.6%) and Bartter syndrome in 7/46 patients (15.3%). After one year of follow-up, NC resolved in 56/159 patients (35.2%) and they all did not have an underlying systemic disease. DISCUSSION: The most common presentation of NC was incidental. Distal renal tubular acidosis and primary hyperoxaluria were the main systemic diseases leading to NC, while hypercalciuria was the most common metabolic risk factor. Nephrocalcinosis was found to remain in most of the patients at a one-year follow-up. It may resolve particularly in patients with no underlying systemic disease.

Chlorthalidone Is Superior to Potassium Citrate in Reducing Calcium Phosphate Stones and Increasing Bone Quality in Hypercalciuric Stone-Forming Rats.

BACKGROUND: The pathophysiology of genetic hypercalciuric stone-forming rats parallels that of human idiopathic hypercalciuria. In this model, all animals form calcium phosphate stones. We previously found that chlorthalidone, but not potassium citrate, decreased stone formation in these rats. METHODS: To test whether chlorthalidone and potassium citrate combined would reduce calcium phosphate stone formation more than either medication alone, four groups of rats were fed a fixed amount of a normal calcium and phosphorus diet, supplemented with potassium chloride (as control), potassium citrate, chlorthalidone (with potassium chloride to equalize potassium intake), or potassium citrate plus chlorthalidone. We measured urine every 6 weeks and assessed stone formation and bone quality at 18 weeks. RESULTS: Potassium citrate reduced urine calcium compared with controls, chlorthalidone reduced it further, and potassium citrate plus chlorthalidone reduced it even more. Chlorthalidone increased urine citrate and potassium citrate increased it even more; the combination did not increase it further. Potassium citrate, alone or with chlorthalidone, increased urine calcium phosphate supersaturation, but chlorthalidone did not. All control rats formed stones. Potassium citrate did not alter stone formation. No stones formed with chlorthalidone, and rats given potassium citrate plus chlorthalidone had some stones but fewer than controls. Rats given chlorthalidone with or without potassium citrate had higher bone mineral density and better mechanical properties than controls, whereas those given potassium citrate did not. CONCLUSIONS: In genetic hypercalciuric stone-forming rats, chlorthalidone is superior to potassium citrate alone or combined with chlorthalidone in reducing calcium phosphate stone formation and improving bone quality.

Gitelman syndrome associated with chondrocalcinosis and severe neuropathy: a novel heterozygous mutation in SLC12A3 gene.

Gitelman syndrome (GS) is an inherited salt-wasting tubulopathy characterized by hypocalciuria, hypokalemia, hypomagnesemia and metabolic alkalosis, due to inactivating mutations in the SLC12A3 gene. Symptoms may be systemic, neurological, cardiovascular, ophthalmological or musculoskeletal. We describe a 70 year-old patient affected by recurrent arthralgias, hypoesthesia and hyposthenia in all 4 limbs and severe hypokalemia, complicated by atrial flutter. Moreover, our patient reported eating large amounts of licorice, and was treated with medium-high dosages of furosemide, thus making diagnosis very challenging. Genetic analysis demonstrated a novel heterozygous mutation in the SLC12A3 gene; therefore, we diagnosed GS and started potassium and magnesium replacement. GS combined with chondrocalcinosis and neurological involvement is quite common, but this is the first case of an EMG-proven severe neuropathy associated with GS. Herein, we underline the close correlation between hypomagnesemia, chondrocalcinosis and neurological involvement. Moreover, we report a new heterozygous mutation in exon 23 (2738G>A), supporting evidence of a large genetic heterogeneity in this late-onset congenital tubulopathy.

Paracellular calcium transport in the proximal tubule and the formation of kidney stones.

The proximal tubule (PT) is responsible for the majority of calcium reabsorption by the kidney. Most PT calcium transport appears to be passive, although the molecular facilitators have not been well established. Emerging evidence supports a major role for PT calcium transport in idiopathic hypercalciuria and the development of kidney stones. This review will cover recent developments in our understanding of PT calcium transport and the role of the PT in kidney stone formation.

Vitamin D and Calcium Homeostasis in Infants with Urolithiasis.

The incidence of urolithiasis in infants is unknown. The aim of this study was to investigate clinical characteristics, nutrition, calcium, phosphate, 25-hydroxyvitamin D (25(OH)D), alkaline phosphate, and parathyroid hormone in infants with urolithiasis. There were 32 infants (23 boys and 9 girls) of the mean age of 6.4 ± 3.7 months (range 2-12 months), with diagnosis of urolithiasis enrolled into the study. Boys were younger than girls (5.3 vs. 9.1 months, respectively; p < 0.05). The infants were receiving prophylactic vitamin D3. Twenty-one of them were fed with milk formula, 9 were breastfed, and 2 were on a mixed diet. The major clinical symptoms consisted of irritability in 19 (59%) and urinary tract infection in 6 (19%) infants. Hypercalcemia and hyperphosphatemia were detected in the serum in 30 (94%) and 19 (60%) infants, respectively. The serum calcium level was higher in boys than girls (10.8 vs. 9.8 mg/dL, respectively; p < 0.05). Four (12.5%) infants had increased activity of alkaline phosphatase. The serum level of 25(OH)D was high in 3 (9%), low in 2 (6%), and normal in 27 (85%) infants. Parathyroid hormone was low in eight (25%) infants. Hypercalciuria and hyperphosphaturia were found in 11 (34%) boys and 8 (25%) girls. Family history of urolithiasis was positive in eight (25%) infants. We conclude that urolithiasis occurs in infancy more often in boys fed with milk formula and in those who received vitamin D supplementation. Hypercalcemia, hyperphosphatemia, and hypercalciuria are the most common changes present in clinical metabolic tests.

Effect of vitamin D supplementation on 24-hour urine calcium in patients with calcium Urolithiasis and vitamin D deficiency.

PURPOSE: Hypercalciuria is one of the risk factors for calcium kidney stone formation (the most common type of urinary stones). Although vitamin D deficiency is prevalent among urolithiasis patients, the effect of vitamin D supplementation on urine calcium in these patients is still unclear. MATERIALS AND METHODS: In this retrospective study, medical and laboratory tests records of 26 patients with recurrent calcium kidney stones and vitamin D deficiency treated with 50000IU vitamin D per week for 8-12 weeks were analyzed. The changes in 24-hour urine calcium (24-h Ca), serum 25-hydroxyvitamin D (25 (OH) D), serum parathormone (PTH), other 24-hour urine metabolites and calculated relative supersaturations of calcium oxalate (CaOxSS), calcium phosphate (CaPSS) and uric acid (UASS) were assessed. Moreover, correlations between changes in 24-h Ca and other aforementioned variables were assessed. RESULTS: Serum 25 (OH) D and 24-h Ca increased after vitamin D supplementation, while serum PTH decreased (p < 0.001, for all analyses). The levels of 24-hour urine sodium and urea increased significantly (p = 0.005 and p = 0.031, respectively). The levels of CaOxSS and CaPSS increased, but the changes were not significant (p = 0.177, and p = 0.218, respectively). There were no correlations between the changes in 24-h Ca and serum 25 (OH) D or PTH. CONCLUSIONS: The result of current study suggests that although urine Ca increased in vitamin D supplemented patients, this increase was not associated with the increase in serum vitamin D and may be due to other factors such as dietary factors. Further randomized clinical trials considering other factors associated with urine Ca are warranted.

Does idiopathic hypercalciuria affect bone metabolism during childhood? A prospective case-control study.

BACKGROUND: A limited number of studies have evaluated biochemical bone metabolism markers in children with idiopathic hypercalciuria, which in adults has been linked with osteopenia. Our aim was to investigate in children with idiopathic hypercalciuria biochemical markers of bone formation and resorption and the osteoprotegerin (OPG) and soluble receptor activator of nuclear factor kB ligand (sRANKL) system which is involved in the osteoclastogenesis process. METHODS: A prospective study was conducted on 50 children with idiopathic hypercalciuria and 50 healthy age-, sex-, and Tanner stage-matched control subjects. Following the diagnosis, patients were requested to follow a 3-month dietary recommendation for idiopathic hypercalciuria. In patients, at diagnosis and at 3 months of follow-up, and in controls, bone-related hormones and serum/urine biochemical parameters were studied. The bone formation markers (total ALP and osteocalcin) and the bone resorption markers (ß-Crosslaps) and the OPG and sRANKL levels were determined. RESULTS: No differences were found in the bone formation markers or OPG and sRANKL between the children with idiopathic hypercalciuria and controls. The ß-Crosslaps and the ß-Crosslaps/osteocalcin ratio were higher in the patients at diagnosis than in controls (p = 0.019 and p = 0.029, respectively), with a trend to decrease after the 3-month dietary intervention. The initially increased 24-h urinary Ca in the patients decreased after the 3-month dietary intervention (p = 0.002). CONCLUSIONS: Children with idiopathic hypercalciuria had biochemical markers compatible with normal bone formation but increased bone resorption. After a 3-month dietary intervention, the trend observed towards decrease in the serum ß-Crosslaps may reflect a beneficial response.

Familial hypomagnesaemia, Hypercalciuria and Nephrocalcinosis associated with a novel mutation of the highly conserved leucine residue 116 of Claudin 16 in a Chinese patient with a delayed diagnosis: a case report.

BACKGROUND: Sixty mutations of claudin 16 coding gene have been reported in familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC) patients. Recent investigations revealed that a highly conserved glycine-leucine-tryptophan (115G-L-W117) motif in the first extracellular segment (ESC1) of claudin 16 might be essential for stabilization of the appropriately folded ECS1 structure and conservation of normal claudin 16 function. However, neither missense nor nonsense mutation has ever been described in this motif. Our study aimed at identifying mutations in a Chinese patient with FHHNC and exploring the association between genotype and phenotype. CASE PRESENTATION: A 33-year-old female presented with 4 years history of recurrent acute pyelonephritis without other notable past medical history. Her healthy parents, who aged 56 and 53 respectively, were second cousins, and her only sibling died from renal failure without definite cause at age 25. Renal ultrasound imaging demonstrated atrophic kidneys and bilateral nephrocalcinosis. The laboratory workup revealed impaired renal function (Stage CKD IV), hypocalcemia and mild hypomagnesemia, accompanied with marked renal loss of magnesium and hypercalciuria. During the follow-up, treatment with calcitriol and calcium but not with magnesium was difficult to achieve normal serum calcium levels, whereas her serum magnesium concentration fluctuated within normal ranges. In the end, the patient unavoidably reached ESRD at 36 years old. The clinical features and family history suggested the diagnosis of FHHNC. To make a definite diagnosis, we use whole-exome sequencing to identify the disease-causing mutations and Sanger sequencing to confirm the mutation co-segregation in the family. As a result, a novel homozygous mutation (c.346C > G, p.Leu116Val) in 115G-L-W117 motif of claudin 16 was identified. Her parents, grandmother and one of her cousins carried heterozygous p.Leu116Val, whereas 200 unrelated controls did not carry this mutation. CONCLUSIONS: We described a delayed diagnosis patient with FHHNC in the Chinese population and identified a novel missense mutation in the highly conserved 115G-L-W117 motif of claudin 16 for the first time. According to the reported data and the information deduced from 3D modeling, we speculate that this mutation probably reserve partial residual function which might be related to the slight phenotype of the patient.