The mechanism of hypocalciuria with NaCl cotransporter inhibition.

Thiazide diuretics are used to prevent the recurrence of calcium-containing kidney stones. The ability of these drugs to reduce urinary calcium excretion has a key role in this process. Although studies have shown a reduction in the recurrence rate of calcium-containing stones in patients treated with thiazides, whether hypocalciuria results from increased calcium reabsorption in the proximal or distal nephron is still unclear. When extracellular fluid volume is considerably reduced, the proximal tubule is likely to have a major role in thiazide-induced hypocalciuria. This process frequently occurs when high doses of thiazides and sodium restriction are prescribed for the treatment of kidney stone disease. The distal tubule is predominantly involved in NaCl cotransporter inhibition-induced hypocalciuria when the extracellular fluid volume is not reduced, a clinical scenario observed in patients with Gitelman syndrome. In this Perspectives article, we discuss the evidence supporting the hypocalciuric effects of NaCl cotransporter inhibition in the proximal and distal nephron.

Hipercalciuria idiopática: aspectos novedosos de su diagnostico y tratamiento / Ideophatic hipercalciuría: up date information

La hipercalciuria idiopática (hi) se define como aquella situación clínica en laque se comprueba un aumento mantenido en la eliminación urinaria de calcio, en ausencia de hipercalcemia y de otras causas conocidas de hipercalciuria. Es la anomalía metabólica más frecuente. Puede manifestarse en forma de hematuriamacroscópica o microscópica, síntomas miccionales, dolor abdominal o infección urinaria. Se han descrito numerosos mecanismos potencialmente causales de hipercalciuria. El 30-40 por ciento de los niños con hipercalciuria idiopática tienen osteopenia. El tratamiento inicial de la hipercalciuria es dietético. Sólo serecurre a los fármacos tiazídicos en los casos complicados. Es posible el diagnóstico y seguimiento desde la atención primaria (AU)

Superimposition of nutcracker syndrome in a hematuric child with idiopathic hypercalciuria and urolithiasis.

We report a 5-year-old girl with idiopathic hypercalciuria who developed gross hematuria and left flank pain despite normalization of calciuria, a renal stone, and microscopic hematuria. She was found to have nutcracker syndrome by renal Doppler ultrasound, which revealed the significant differences of the peak blood flow velocities in the two portions of the left renal vein.

Medical evaluation and treatment of urolithiasis.

Nephrolithiasis is responsible for 1 in 1000 to 1 in 7600 pediatric hospital admissions annually throughout the United States. Seventy-five percent of children with nephrolithiasis have an identifiable predisposition to stone formation. This article reviews the different causes and disease states associated with nephrolithiasis in the pediatric population. The initial evaluation and the metabolic evaluation of children with nephrolithiasis are reviewed. Treatment modalities for the different stone types are also described.

Familial hypomagnesemia with hypercalciuria and nephrocalcinosis: blocking endocytosis restores surface expression of a novel Claudin-16 mutant that lacks the entire C-terminal cytosolic tail.

Mutations in the gene for Claudin-16 (CLDN16) are linked to familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC), a renal Mg2+ and Ca2+ wasting disorder that leads to progressive kidney failure. More than 20 mutations have been identified in CLDN16, which, with a single exception, affect one of two extracellular loops or one of four transmembrane domains of the encoded protein. Here, we describe a novel missense mutation, Cldn16 L203X, which deletes the entire C-terminal cytosolic domain of the protein. Surface expression of Cldn16 L203X is strongly reduced and the protein is instead found in the endoplasmic reticulum (ER) and lysosomes. ER-retained Cldn16 L203X is subject to proteasomal degradation. Cldn16 L203X present in lysosomes reaches this compartment following transport to the plasma membrane and endocytosis. Blocking clathrin-mediated endocytosis increases surface expression of Cldn16 L203X. Thus, endocytosis inhibitors may provide a novel therapeutic approach for FHHNC patients carrying particular Cldn16 mutations.

Hypocitraturia: a risk factor for reduced bone mineral density in idiopathic hypercalciuria?

UNLABELLED: The association between idiopathic hypercalciuria (IH) and reduced bone mineral density (BMD) has been described in adults and children. Frequently, hypocitraturia (HC) is an associated condition. To determine the effect that HC may have on bone metabolism of these patients, we studied 88 children with IH at diagnosis, divided into the following groups: group 1-44 (50%) patients with associated HC; group 2-44 (50%) patients without HC; group 3 (29 subjects), a healthy control group. Urinary and blood electrolytes, as long as urinary N-telopeptide, were measured. Lumbar spine (L2-L4) and femoral neck bone mineral density (BMD) and bone mineral content (BMC) were measured by dual energy X-ray absorptiometry. There was no difference in age between the three groups (P=0.80), but weight, height, body mass index, and bone age were lower (P<0.01) and serum intact parathyroid hormone (iPTH) was higher (P<0.05) in group 1 than in groups 2 and 3. N-telopeptide, measured in urine, did not differ between groups. The following bone densitometry parameters: lumbar spine BMC, BMC adjusted for height (BMCh), BMC adjusted for width of vertebrae (BMCw) and BMD, as well as femoral neck BMD, were significantly lower in group 1 than in groups 2 and 3 (P<0.01). When we corrected densitometry parameters for height, BMC was lower in group 1 and not in group 2 when compared with controls. CONCLUSIONS: Children with IH and associated HC may have a higher risk of bone mass loss and consequent osteopenia. Further studies are needed to assess the role that hypocitraturia may have in this form of bone disease.

Hypercalciuria and recurrent urinary tract infections: incidence and symptoms in children over 5 years of age.

Hypercalciuria is an important and common risk factor in the formation of renal stones. In this study we evaluated the incidence and the clinical presentation of hypercalciuria in 75 children over 5 years of age with the diagnosis of recurrent urinary tract infection (UTI). We measured random urinary calcium/creatinine value (three times), 24-h urinary calcium excretion, serum calcium, phosphorus, electrolytes, blood gas, blood urea nitrogen and creatinine levels. Hypercalciuria was found in 32 patients (43%). The mean urinary calcium/creatinine ratio for hypercalciuric patients was 0.50+/-0.21 mg/mg (min: 0.24, max: 2.60). The mean urinary calcium/creatinine ratio for the rest of the study population--those without hypercalciuria--was 0.10+/-0.04 mg/mg (min: 0.01, max: 0.18). Presenting symptoms of the hypercalciuric patients and normocalciuric patients were similar. History of familial urolithiasis was positive in 19 patients (59%). Predisposing urinary tract abnormalities in recurrent UTI was shown in 12 of the hypercalciuric patients (12/32, 37.5%) and 8 of the normocalciuric patients (8/43, 19%) without a statistically significant difference between. We conclude that hypercalciuria is not a rare finding among recurrent UTI cases in Turkish children. Hypercalciuria does not modify the clinical presentation of UTI, and we suggest the investigation of urinary calcium excretion in children with recurrent UTI.

Metabolic abnormalities and the medical management of calcium oxalate nephrolithiasis.

The lifetime prevalence of urolithiasis is approximately 12% for men and 7% for women in the United States and seems to be increasing; the cost of managing kidney stones continues to escalate. The most common kidney stones continue to be composed primarily of calcium and are an admixture of phosphate and oxalate. Of these, calcium oxalate stones are the most predominant. This review will focus only on the pathogenesis and medical management of calcium oxalate stones.

Bone mineral density and urinary N-acetyl-beta-D-glucosaminidase activity in paediatric patients with idiopathic hypercalciuria.

BACKGROUND: Idiopathic hypercalciuria (IH) is defined as hypercalciuria that persists after correction of dietary inbalances and has no detectable causes. Patients with IH have a higher prevalence of osteoporosis. Defective reabsorption of calcium by the renal tubule is considered a likely mechanism of IH. N-acetyl-beta-D-glucosaminidase (NAG) is a lysosomal enzyme that is a very sensitive marker of renal tubular impairment. METHODS: Fifteen patients (nine boys and six girls, mean age 12.4 +/- 4.0 years) with IH (urinary calcium excretion >0.1 mmol/kg per 24 h) had their bodyweight, height, body mass index (BMI), urinary NAG/creatinine ratio (U-NAG/Cr) and 24-h urinary calcium excretion (U-Ca/24 h) assessed. L1-L4 bone mineral density (BMD) was measured by dual energy X-ray absorptiometry and volumetric BMD (BMDvol) was calculated. The obtained results were expressed as Z-scores. RESULTS: The values of basic anthropometric parameters did not differ significantly from the values of the reference population and there was a tendency to short stature, which did not reach statistical significance (P = 0.08). The values of calciuria and U-NAG/Cr were significantly higher while BMD was significantly lower when compared to the reference values (P < 0.0006, P < 0.006 and P < 0.001, respectively). Inverse and significant correlations were found between U-Ca/24 h and BMD, U-Ca/24 h and body height, and U-Ca/24 h and BMDvol (r = -0.64 and -0.70, respectively, P < 0.01; r = -0.55, P < 0.05), while there was no correlation between U-NAG/Cr and U-Ca/24 h, nor between BMD and weight or BMD and BMI. CONCLUSION: Tubular impairment is highly probable in children with IH, but there is a poor relationship with the degree of calcium leakage. Idiopathic hypercalciuria should be considered as a risk factor for stunted growth and low bone mass.

Effect of indapamide on urinary calcium excretion in patients with and without urinary stone disease.

BACKGROUND: Indapamide is an antihypertensive agent similar to thiazides, but with some different effects. Thiazide and thiazide-like diuretics are useful in preventing recurrent urinary stone formation due to their hypocalciuric effects. OBJECTIVE: To determine the hypocalciuric and other effects on certain laboratory parameters of indapamide 1.5 mg in different patient groups. METHODS: Four groups of patients recruited from urology and nephrology outpatient departments were experiencing non-hypercalciuric urinary stone disease (group 1), idiopathic hypercalciuria (group 2), urinary stone disease with hypercalciuria (group 3), and essential hypertension (group 4). In all patients, fasting serum uric acid, calcium, sodium, potassium, cholesterol, triglyceride, parathyroid hormone (PTH) values, and morning second-spot urine calcium and creatinine levels were assessed before and 8 weeks after treatment with indapamide. RESULTS: Urinary calcium excretion was reduced significantly in all groups: group 1 from 0.10 +/- 0.02 to 0.07 +/- 0.03 (mean +/-SD; 30% reduction; p < 0.001), group 2 from 0.30 +/- 0.15 to 0.15 +/- 0.10 (50% reduction; p < 0.001), group 3 from 0.35 +/- 0.15 to 0.20 +/- 0.10 (43% reduction; p < 0.001), and group 4 from 0.10 +/- 0.03 to 0.08 +/- 0.02 (20% reduction; p < 0.0010). These results should be interpreted with caution since no control group was included in this study. Mean serum uric acid and triglyceride levels were significantly increased, and mean PTH and potassium levels and diastolic and systolic blood pressure were significantly decreased in all groups. Few temporary adverse effects, such as dizziness and fatigue, were noticed and none of them caused discontinuation of treatment. CONCLUSIONS: Indapamide 1.5 mg/day is effective in decreasing calciuria in patients with non-hypercalciuric urinary stone disease, idiopathic hypercalciuria, urinary stone disease with hypercalciuria, and essential hypertension. This could be achieved with few adverse effects similar to those of thiazides and indapamide 2.5 mg. Indapamide decreased the PTH levels in all groups. Long-term clinical benefits of these effects should be evaluated prospectively with further randomized studies.

Increased gastrin and calcitonin secretion after oral calcium or peptones administration in patients with hypercalciuria: a clue to an alteration in calcium-sensing receptor activity.

The calcium-sensing receptor (CaSR) has been detected in human antral gastrin-secreting cells, where, upon calcium and/or amino acid allosteric activation, it stimulates gastrin secretion. Patients with absorptive hypercalciuria (AH) display an enhanced gastric acid output; therefore, we evaluated the secretion of gastrin in subjects with AH (30 subjects vs. 30 healthy female controls, all postmenopausal) after oral calcium administration (1 g calcium gluconate) and, on a separate occasion, after peptone loading test (protein hydrolyzed, 10 g). Gastrin and monomeric calcitonin responses were higher in AH after both oral calcium administration (P < 0.01) and peptone loading (P < 0.01). Because the activation of CaSR by oral calcium and peptones directly induces gastrin release, the higher gastrin responses to these stimuli suggest an increased sensitivity of gastrin-secreting cells CaSR in patients with AH. A similar alteration in thyroid C cells might explain the enhanced calcitonin responses to both calcium and peptones. If the same alterations should in addition be present in the distal tubule (where CaSR is expressed as well), then a possible explanation for amino acid-induced hypercalciuria in AH would have been identified.

Vitamin D receptor gene polymorphism in hypercalciuric children.

Idiopathic hypercalciuria is a complex disease resulting from an interaction between environmental and genetic factors. Recently, the relationship between vitamin D receptor ( VDR) alleles and calcium homeostasis has been investigated. This study was conducted to explore the association of VDR gene polymorphism with the risk of absorptive hypercalciuria (AH). We investigated the VDR gene polymorphisms, ApaI, BsmI, and TaqI, in relation to intact parathormone (PTH), osteocalcin, and 25-hydroxyvitamin D in 80 children (42 males, 38 girls) with AH and in 86 healthy children without hypercalciuria. A significant difference in the ApaI genotype was observed between the AH group and the control group ( chi(2)=7.21, P=0.027). The AA genotype was associated with a 3.5-fold increased risk for idiopathic hypercalciuria compared with the Aa/aa genotype (odds ratio 3.5, 95% confidence interval 1.1-11). The BsmI and TaqI polymorphisms did not show any significant association with AH. Serum osteocalcin levels were significantly higher in the group with the AA genotype compared with those with the Aa or aa genotype ( P=0.02, P=0.05, respectively). The results indicate that the ApaI AA genotype of the VDR gene is not only associated with AH but is also related to differences in serum osteocalcin.

Gestational urinary hyperthiosulfaturia protects hypercalciuric normal pregnant women from nephrolithiasis.

Urinary calcium excretion increases by 1-2-fold during gestation in normal, uncomplicated pregnant women. Hypercalciuria occurs in all trimesters and elevates urine supersaturation with regards to calcium oxalate. However, crystalluria has not been a frequent clinical finding and stone formation is not a common complication of pregnancy. To elucidate this discrepancy we measured various chemical entities (i.e. calcium, oxalate, uric acid, phosphorous, magnesium, citrate, sulfate and thiosulfate) in urine at the end of each trimester of 25 pregnant women. Twenty-five healthy women served as controls. Our observations show that endogenous thiosulfate, a natural component of urine, increased considerably during pregnancy to approximately 36, 38 and 40 microM/24 hour at the end of each three trimesters. One month after delivery, endogenous thiosulfaturia and hypercalciuria, in parallel, returned to initial normal values. Consequently, it seems that gestational hyperthiosulfaturia protects hypercalciuric normal pregnant women from the risk of nephrolithiasis.

Hypercalciuria is a common and important finding in postmenopausal women with osteoporosis.

OBJECTIVE AND DESIGN: The prevalence and the effects of hypercalciuria on bone in patients with primary osteoporosis are poorly defined. We therefore retrospectively analyzed the data of 241 otherwise healthy women. They were 45-88 years of age and had been referred for their first visit to our Unit for Metabolic Bone Diseases over a 2-year period because of primary osteoporosis (bone density T-score < -2.5). METHODS: The main parameters of calcium and skeletal metabolism had been analyzed in all subjects. This population was then divided into two groups, according to the presence (HC+) or absence (HC-) of hypercalciuria. RESULTS: Elevated urinary calcium was present in 19% of the subjects. Due to the selection criteria, spinal and femoral bone loss was similar in the two groups. Urinary calcium, phosphate and fractional calcium excretion were higher in hypercalciuric patients. In a logistic regression model, the higher the Tm of phosphate, the lower the risk of hypercalciuria (odds ratio 0.33, confidence interval 0.18-0.62). On the contrary, hypercalciuria was the most important predictor of low bone mass in HC+ (accounting for more than 50% of the variance in spinal bone density). CONCLUSIONS: Hypercalciuria is a common feature in postmenopausal bone loss. Since increased urinary calcium excretion and low bone mass appear to be linked, hypercalciuria seems to be an important determinant of reduced bone density in this setting as well.

[Study of the renal acidification capacity in children diagnosed of idiopathic hypercalciuria]. / Estudio de la capacidad de acidificación renal en niños diagnosticados de hipercalciuria idiopática.

OBJECTIVE: To study the capacity of renal acidification in a group of children diagnosed of idiopathic hypercalciuria. PATIENT AND METHODS: 36 children were studied, to those that were determined the pCO2 (UpCO2) maximum urinary with two different stimuli, acetazolamide and sodium bicarbonate (NaHCO3). At 33 of them, was performed an acidification test with frusemide stimulus. We studied a control group of 13 healthy children so much for the first one as the second tests and other 14 healthy children for the acidification test with frusemide. RESULTS: In the tests performed with NaHCO3 and acetazolamide stimulus, they were not proven differences in the values of UpCO2 neither in the urinary concentration of HCO3- (UHCO3-) than control children. Nevertheless, the UpCO2 and the concentration of UHCO3- in the patients were significantly lower with acetazolamide with regard to the NaHCO3 stimulus. In the acidification test with frusemide, significantly lower values of titratable acid and ammonium were obtained than control children. CONCLUSIONS: In children with idiopathic hypercalciuria, the capacity of secretion of H+ is normal, what is evidenced, especially, when studying the maximum UpCO2 after stimulus with NaHCO3. When diuretics are used as stimuli, exists more negative results that can be due to a certain partial resistance to the action of the same ones or to that are less potent to induce the secretion of H+.

Estudio de la capacidad de acidificación renal en niños diagnosticados de hipercalciuria idiopática / Study of renal acidification capacity in children diagnosed of idiopathic hypercalciuria

Objetivo: Estudiar la capacidad de acidificación renal en un grupo de niños diagnosticados de hipercalciuria idiopática. Pacientes y Métodos: Se estudiaron 36 niños, a los que se les determinó la pCO2 (UpCO2) urinaria máxima con dos estímulos diferentes, acetazolamida y bicarbonato sódico (CO3HNa). A 33 de ellos, se les realizó una prueba de acidificación con estímulo de furosemida. Se estudiaron 13 controles tanto para la primera como la segunda pruebas y otros 14 para la prueba de acidificación con furosemida. Resultados: En la pruebas realizadas tanto con CO3HNa como con acetazolamida, no se comprobaron diferencias en los valores de UpCO2 ni en la concentración urinaria de CO3H- (UCO3H-) con respecto al grupo control. No obstante, la UpCO2 y la concentración de UCO3H- en los pacientes fueron significativamente inferiores con acetazolamida con respecto al estímulo de CO3HNa. En la prueba de acidificación con furosemida, se alcanzaron valores significativamente inferiores de acidez titulable y de amonio en relación al grupo control. Conclusiones: En niños diagnosticados de hipercalciuria idiopática, la capacidad de secreción de H+ es normal lo que se evidencia, especialmente, al estudiar la UpCO2 máxima con estímulo de CO3HNa. Cuando se utilizan diuréticos como estímulos, existen más resultados negativos, que pueden deberse a una cierta resistencia parcial a la acción de los mismos o a que son menos potentes para inducir la secreción de H+

Objective: To study the capacity of renal acidification in a group of children diagnosed of idiopathic hypercalciuria. Patient and Methods: 36 children were studied, to those that were determined the pCO2 (UpCO2) maximum urinary with two different stimuli, acetazolamide and sodium bicarbonate (NaHCO3). At 33 of them, was performed an acidification test with frusemide stimulus. We studied a control group of 13 healthy children so much for the first one as the second tests and other 14 healthy children for the acidification test with frusemide. Results: In the tests performed with NaHCO3 and acetazolamide stimulus, they were not proven differences in the values of UpCO2 neither in the urinary concentration of HCO3 - (UHCO3 -) than control children. Nevertheless, the UpCO2 and the concentration of UHCO3 - in the patients were significantly lower with acetazolamide with regard to the NaHCO3 stimulus. In the acidification test with frusemide, significantly lower values of titratable acid and ammonium were obtained than control children. Conclusions: In children with idiopathic hypercalciuria, the capacity of secretion of H+ is normal, what is evidenced, especially, when studying the maximum UpCO2 after stimulus with NaHCO3. When diuretics are used as stimuli, exists more negative results that can be due to a certain partial resistance to the action of the same ones or to that are less potent to induce the secretion of H+

Urinary calcium excretion in children with vesicoureteral reflux.

BACKGROUND: Renal malformations including vesico-ureteral reflux (VUR) are associated with urolithiasis. However, studies on urinary calcium excretion in children with VUR have not been reported. This study was conducted to find out whether children with VUR have a higher prevalence of hypercalciuria and whether their family members are affected by hypercalciuria and/or urolithiasis. METHODS: We studied the prevalence of hypercalciuria and urolithiasis in 46 children (12 males and 34 females) with VUR and in their parents. RESULTS: Three out of 46 children had renal colic and nine out of 46 exhibited calyceal microlithiasis in the renal sonography. According to Stapleton's criteria, we found that 27 out of 46 children (58.6%) had hypercalciuria. These children were significantly shorter than children with normal calciuria and showed lower values of maximal urinary osmolality. We found no differences in urinary calcium excretion values related to the VUR grading, or to the presence or absence of renal scars, or to whether VUR was still unresolved or already resolved at the time of study. Seventeen out of 27 children with hypercalciuria (63%) had one or both parents affected by hypercalciuria, and there was a history of urolithiasis in six first-degree relatives and in four second-degree relatives (37%). Besides, 10 out of 19 children without hypercalciuria (52.6%) had one or both parents affected by hypercalciuria and there was a history of urolithiasis in three first-degree relatives and in three second-degree relatives (31.6%). Among the 27 children whose parents had hypercalciuria, four had both parents affected, 19 had only the mother affected and in four patients only the father was affected. CONCLUSION: Our results showed that the prevalence of hypercalciuria was greater in paediatric patients with VUR than in the general population. Urolithiasis in patients with VUR had a metabolic origin. Hypercalciuria was inherited as an autosomal dominant trait although with a higher probability to be inherited from the mother.

Bone alterations in children with idiopathic hypercalciuria at the time of diagnosis.

Some children with idiopathic hypercalciuria (IH) develop bone alterations at some stage of the disease. The aims of this study were to evaluate bone mass in 88 children with IH (G1) at the time of diagnosis and to compare the findings with data for a control group of 29 normal children (G2). Kidney and bone metabolism markers were measured in both groups, and bone densitometry was performed. Serum alkaline phosphatase, intact parathyroid hormone, urinary calcium and uric acid were significantly higher in G1, whereas urinary volume and urinary citrate excretion were lower. The following densitometric parameters were significantly lower in G1: (1) lumbar spine (L(2)-L(4)) bone mineral density (BMD), bone mineral content (BMC), BMC corrected for height and for width of the vertebra, volumetric BMD (BMDvol), and Z score; (2) whole-body BMD; (3) femoral neck BMD. Lumbar spine BMDvol was reduced (osteopenia) in 35% of the patients compared with G2. N telopeptide, a urinary marker of bone resorption, was significantly higher in G1 than in G2, and was negatively correlated with lumbar spine BMD and BMDvol. Children with urinary lithiasis or idiopathic hyperuricosuria associated with IH showed no significant differences in bone metabolism compared with children without these associations. We conclude that (1) there is an altered bone metabolism in IH, with osteopenia already present at diagnosis in 35% of the patients; (2) N telopeptide is one of the most useful markers of bone alterations in IH, especially at an early stage of the disease; (3) investigation of bone metabolism is necessary in IH to prevent future serious consequences such as osteoporosis and bone fractures.

Hypercalciuria in Beckwith-Wiedemann syndrome.

We determined the incidence of hypercalciuria (HC) and its association with nephrocalcinosis and nephrolithiasis in 18 consecutive patients with Beckwith-Weidemann syndrome (BWS). Random, nonfasting urine samples were obtained from each patient. All patients had abdominal ultrasonography, most on several occasions. Four patients (22%) had HC. Of these, 2 had nephrocalcinosis, one had hyperechoic kidneys, and one had normal renal imaging. Serum calcium was normal in all patients with HC. Because we found that an increased prevalence in the occurrence of HC and its complications in a group of children with BWS, any child with BWS should be evaluated for HC.