Evaluation of the thiazide challenge test to differentiate primary from hypercalciuria-related hyperparathyroidism.

CONTEXT: treatment of primary hyperparathyroidism (PHPT) and secondary hyperparathyroidism due to idiopathic hypercalciuria (SHPT-IH) is markedly different. Robust diagnostic tools to differentiate between both entities are however lacking. OBJECTIVE: evaluate the thiazide challenge test (TCT) in clinical practice, its aid in clinical decision making, evaluate the accuracy (sensitivity, specificity) and potentially useful parameters of the TCT. DESIGN: monocentric observational retrospective cohort study from January 2017 to November 2023. SETTING: outpatient, Ghent University Hospital (Belgium). PATIENTS: 25 adult patients with hypercalciuria, elevated parathyroid hormone (PTH), and high-normal or elevated serum calcium that underwent a TCT. INTERVENTION: TCT. OUTCOME MEASURES: serum, urinary biochemical parameters before and after testing, clinical and imaging outcomes, treatment, and follow-up. RESULTS: patients with a TCT-based working diagnosis of PHPT show greater increases in albumin-adjusted calcium and total serum calcium concentration than patients with SHPT-IH (+0,11 ± 0,10 vs. + 0,0071 ± 0,10mmol/l; p = 0,025 and +0,14 ± 0,12 vs. + 0,012 ± 0,15mmol/l; p = 0,024 respectively). The TCT-based working diagnosis of PHPT has a sensitivity of 81,8%, a specificity of 77,8% and a likelihood ratio of 3,68 of estimating a correct final diagnosis.Urinary calcium excretion, PTH, calcium-phosphorous ratio, PTH-inhibition rate, and parathyroid function index do not differ significantly in patients with PHPT compared to those with SHPT-IH. CONCLUSION: the TCT aids in discriminating patients with PHPT from those with SHPT-IH based on a rise in serum calcium. Other parameters are not different between both groups. Larger prospective trials are necessary to further define the diagnostic potential of the TCT, its most appropriate biochemical outcome variables, and decision cut-offs.

Pharmacological interventions for preventing complications in patients with idiopathic hypercalciuria: A systematic review / Intervenciones farmacológicas para prevenir complicaciones en pacientes con hipercalciuria idiopática: una revisión sistemática

Objective: To assess the effects of pharmacological interventions in patients with idiopathic hypercalciuria. Methods: We performed a search of multiple databases, trial registries, grey literature and conference proceedings up to October 2019. We included randomized and quasi-randomized controlled trials that examined any pharmacological intervention for preventing complications of idiopathic hypercalciuria (given for at least four months and six of follow-up). The primary outcomes were stone-free patients, urinary symptoms and severe adverse events. Results: We included five RCTs (n=446 patients, all adults, 4 in individuals with kidney stones and 1 in postmenopausal women with osteoporosis). Diuretics were likely to increase the number of stone-free patients (RR 1.61, 95% CI 1.33–1.96, moderate quality of evidence (QoE)); 274 more stone-free patients/1000 patients treated (95% CI: 148–432) and produced a slight decrease in the stone formation rate (mean difference −0.18, 95% CI −0.30 to −0.06, low QoE); 180 fewer stones/year/1000 patients treated (95% CI: 300 r to 60). No data on urinary symptoms were reported. The association between diuretic use and severe adverse events was uncertain (RR 5.00, 95% CI 0.60–41.88, very low QoE); 4 more severe adverse events/1000 patients treated (95% CI: 0 fewer to 39 more). Conclusions: The addition of diuretics to a normal or modified diet probably reduces the number of stone recurrences and may decrease the stone formation rate. It is uncertain whether diuretics increase the occurrence of severe adverse events. There were no studies investigating other outcomes or in children. (AU)

Objetivo: Evaluar los efectos de intervenciones farmacológicas en pacientes con hipercalciuria idiopática. Métodos: Realizamos una búsqueda en múltiples bases de datos, registros de ensayos, literatura gris y actas de congresos hasta octubre de 2019. Incluimos ensayos clínicos aleatorizados y cuasialeatorizados que examinaban cualquier intervención farmacológica para prevenir las complicaciones de la hipercalciuria idiopática (mínimo 4 meses de intervención y 6 meses de seguimiento). Los outcomes primarios fueron pacientes libres de cálculos, síntomas urinarios y efectos adversos graves. Resultados: Incluimos 5 RCT (n=446 pacientes, todos adultos, 4 en individuos con cálculos renales y uno en mujeres posmenopáusicas con osteoporosis). Los diuréticos aumentaban probablemente el número de pacientes libres de cálculos (RR 1,61; IC 95%: 1,33 a 1,96, moderada calidad de evidencia [QoE]); 274 más pacientes libres de cálculos/1.000 pacientes tratados (IC 95%: 148 a 432) y producían una ligera disminución en la tasa de formación de cálculos (diferencia media −0,18; IC 95%: −0,30 a −0,06, baja QoE); 180 menos cálculos/año/1.000 pacientes tratados (IC 95%: 300 a 60). No se informaron datos sobre síntomas urinarios. La asociación entre el uso de diuréticos y los efectos adversos graves fue incierta (RR 5,00; IC 95%: 0,60 a 41,88, muy baja QoE); 4 efectos adversos severos más/1.000 pacientes tratados (IC 95%: 0 a 39). Conclusiones: Los diuréticos añadidos a una dieta normal o modificada probablemente reducen la aparición de cálculos y pueden disminuir su tasa de formación. Es incierto si los diuréticos incrementan la ocurrencia de efectos adversos graves. No se encontraron estudios que investigaran otros outcomes o realizados en niños. (AU)

Mutations in CLDN2 Are Not a Common Cause of Pediatric Idiopathic Hypercalciuria in Canada.

Background: Hypercalciuria is the most common risk factor for kidney stone formation, including in pediatric patients. However, the etiology is often unknown and children are frequently diagnosed with idiopathic hypercalciuria. Nearly 50% of children with hypercalciuria have a first-degree relative with kidney stones, suggesting a strong genetic basis for this disease. A failure of calcium reabsorption from the proximal nephron is implicated in the pathogenesis of hypercalciuria. Claudin-2 is a tight junction protein abundantly expressed in the proximal tubule. It confers paracellular permeability to calcium that is essential for transport across the proximal tubule where the majority of filtered calcium is reabsorbed. Objective: Our objective was to examine the frequency of coding variations in CLDN2 in a cohort of children with idiopathic hypercalciuria. Design: Mixed method including retrospective chart review and patient interview, followed by genetic sequencing. Setting: Three tertiary care centers in Canada. Patients: Children (age 1-18 years) with idiopathic hypercalciuria. Patients with other causes of hypercalciuria were excluded. Methods: Data were collected from 40 patients with idiopathic hypercalciuria. Informed consent to collect DNA was obtained from 13 patients, and the final and only coding exon of CLDN2 was sequenced. Results: The majority of patients were male, white, and had a positive family history of kidney stones. Parathyroid hormone levels were significantly lower than the reference range (P < .001). The levels of 1,25-dihydroxyvitamin D were also significantly higher in our patient cohort, relative to the reference range (P < .001). Sequence analysis of CLDN2 did not identify any coding variations. Limitations: Sequencing analysis was limited to the final coding exon and small sample size. Conclusions: CLDN2 coding variations are not a common cause of idiopathic hypercalciuria in Canadian children. Further study is needed to determine the causes of hypercalciuria in pediatric patients and develop targeted therapies.

Contexte: L'hypercalciurie est le facteur de risque le plus courant pour la formation de calculs rénaux, y compris chez les patients pédiatriques. Son étiologie est cependant souvent inconnue et les enfants sont fréquemment diagnostiqués avec une hypercalciurie idiopathique. Près de 50 % des enfants atteints d'hypercalciurie ont un parent de premier degré souffrant de calculs rénaux, ce qui suggère une importante contribution génétique à cette maladie. Une atteinte de la réabsorption du calcium au niveau du néphron proximal est impliquée dans la pathogenèse de l'hypercalciurie. La claudine-2, une protéine de jonction abondamment exprimée dans le tubule proximal, confère une perméabilité paracellulaire au calcium, laquelle est essentielle pour le transport à travers le tubule proximal, où la majorité du calcium filtré est réabsorbée. Objectif: Étudier la fréquence des variations dans le codage de CLDN2 dans une cohorte d'enfants atteints d'hypercalciurie idiopathique. Conception de l'étude: Une méthode mixte, comprenant un examen rétrospectif des dossiers médicaux et un entretien avec les patients, suivie d'un séquençage génétique. Cadre: Trois centres de soins tertiaires au Canada. Sujets: Des enfants (1 à 18 ans) atteints d'hypercalciurie idiopathique. Les patients dont l'hypercalciurie avait une autre cause ont été exclus. Méthodologie: Les données proviennent de 40 patients atteints d'hypercalciurie idiopathique. Le consentement éclairé à la collecte d'ADN a été obtenu pour treize patients. L'exon final et le seul exon codant pour CLDN2, a été séquencé. Résultats: La majorité des sujets étaient des garçons d'origine caucasienne et avaient des antécédents familiaux de calculs rénaux. Les taux d'hormone parathyroïdienne étaient significativement plus faibles que les valeurs de référence (p < 0,001). Les taux de 1,25 dihydroxyvitamine D étaient significativement plus élevés dans notre cohorte de patients, par rapport à l'intervalle de référence (p < 0,001). Le séquençage de CLDN2 n'a pas révélé de variations dans le codage. Limites: L'étude porte sur un faible échantillon de patients et le séquençage s'est limité à l'exon final du gène. Conclusion: Les mutations du gène CLDN2 ne sont pas une cause fréquente d'hypercalciurie idiopathique chez les enfants canadiens. D'autres études sont nécessaires pour préciser la ou les causes de l'hypercalciurie chez les patients pédiatriques et développer des traitements ciblés.

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.

Role of claudins in idiopathic hypercalciuria and renal lithiasis.

Paracellular transport in the kidney is mediated by a family of proteins located in the tight junctions called claudins which confers its ionic selectivity. Claudin-2 is highly expressed in the proximal tubule and descending limb of Henle and mediate paracellular reabsorption of sodium and calcium cations. In the thick ascending limb of Henle (TALH) calcium is reabsorbed by a paracellular channel formed by Claudin-16 and-19. Claudin-16 mediates cationic permeability while Claudin-19 increases the cationic selectivity of Claudin-16 by blocking anionic permeability. On the other hand, Claudin 14, that is also located in TALH, inhibits the paracellular permeability of Claudin-16 to calcium. Recent wide genomic association analysis studies have detected four common synonymous variants (genetic polymorphisms of a single nucleotide, SNPs) at the locus of Claudin-14 gene that were significantly associated with the presence of renal lithiasis. Another study of wide genomic association and nephrolithiasis was carried out in the general population but including chromosome X, where claudin-2 gene is located. They detected nine SNPs that had a significant association with renal lithiasis risk. A greater knowledge of the paracellular pathway controlled by claudins and its regulation will allow us to develop future new treatments for idiopathic hypercalciuria and renal lithiasis.

Pharmacological interventions for preventing complications in patients with idiopathic hypercalciuria: A systematic review.

OBJECTIVE: To assess the effects of pharmacological interventions in patients with idiopathic hypercalciuria. METHODS: We performed a search of multiple databases, trial registries, grey literature and conference proceedings up to October 2019. We included randomized and quasi-randomized controlled trials that examined any pharmacological intervention for preventing complications of idiopathic hypercalciuria (given for at least four months and six of follow-up). The primary outcomes were stone-free patients, urinary symptoms and severe adverse events. RESULTS: We included five RCTs (n=446 patients, all adults, 4 in individuals with kidney stones and 1 in postmenopausal women with osteoporosis). Diuretics were likely to increase the number of stone-free patients (RR 1.61, 95% CI 1.33-1.96, moderate quality of evidence (QoE)); 274 more stone-free patients/1000 patients treated (95% CI: 148-432) and produced a slight decrease in the stone formation rate (mean difference -0.18, 95% CI -0.30 to -0.06, low QoE); 180 fewer stones/year/1000 patients treated (95% CI: 300 r to 60). No data on urinary symptoms were reported. The association between diuretic use and severe adverse events was uncertain (RR 5.00, 95% CI 0.60-41.88, very low QoE); 4 more severe adverse events/1000 patients treated (95% CI: 0 fewer to 39 more). CONCLUSIONS: The addition of diuretics to a normal or modified diet probably reduces the number of stone recurrences and may decrease the stone formation rate. It is uncertain whether diuretics increase the occurrence of severe adverse events. There were no studies investigating other outcomes or in children.

Hipercalciuria idiopática: diagnóstico, clasificación y tratamiento / Idiopathic hypercalciuria: diagnosis, classification, and treatment

Resumen Introducción: La hipercalciuria idiopática se define como la excreción de calcio superior a 220 y 300 mg/día en mujeres y hombres respectivamente o bien mayor a 4 mg/kg peso bajo dieta habitual. Objetivo: Revisar el diagnóstico, clasificación y tratamiento del paciente hipercalciúrico con litiasis renal. Material y métodos: Se incluyeron 250 pacientes con litiasis renal e hipercalciuria idiopática y 80 individuos sanos como controles. Todos realizaron un estudio bioquímico para litiasis renal. Resultados: Si bien el estándar de oro es la medición de la calciuria en 24 h, en el presente estudio sugerimos considerar también la relación Ca/Kg >4 mg/Kg o bien el índice de calciuria >140 mg/gr de creatinina urinaria. Con respecto a los tipos de hipercalciuria, luego de someterlos a una dieta restringida, los dividimos en hipercalciuria dieta dependiente y dieta independiente del calcio. Con respecto al tratamiento sugerimos una diuresis entre 2 y 2 ½ litros/d. En casos de hipercalciuria dieta dependiente aconsejamos una dieta de 600-800 mg de calcio y moderada restricción de proteínas animales y sal. En caso de no respuesta y en aquellos con hipercalciuria dieta independiente, el agregado de tiazidas, clortalidona, indapamida y ocasionalmente bisfosfonatos pueden controlar la hipercalciuria con menor riesgo de recurrencia de litiasis renal y un mejor estado óseo. Conclusiones: Consideramos importante no solo tener en cuenta las distintas formas de diagnóstico de hipercalciuria sino también la clasificación de esta, que permita un tratamiento más específico.

Abstract Introduction: Idiopathic hypercalciuria is defined as urine calcium excretion greater than 220 mg/day in women and 300 mg/day in men, or greater than 4 mg/kg under regular dietary conditions. Objective: The aim of this study is to review the diagnosis, classification, and treatment of hypercalciuric patients with renal lithiasis. Methods: We enrolled 250 patients suffering from renal lithiasis and idiopathic hypercalciuria and 80 healthy subjects as control group. Lab tests were performed to diagnose renal lithiasis. Results: Although the 24-hour urine test is the gold standard to determine calciuria, in this study we propose considering the Ca/Kg >4 mg/Kg ratio or an index of >140 mg of Ca per gram urine creatinine. Regarding the different types of hypercalciuria, after following a strict diet, subjects were divided into two groups: diet-dependent and diet-independent hypercalciuria. Concerning the treatment, we suggest diuretic therapy to achieve a urine output of 2-2.5 liters per day. In the case of subjects with diet-dependent hypercalciuria, we advise an intake of 600-800 mg of calcium and a moderate reduction in animal protein and salt intake. In cases of non-response to treatment in subjects with diet-dependent hypercalciuria, thiazides, chlorthalidone, indapamide and, in some cases, bisphosphonates may help control hypercalciuria with a lower risk of lithiasis recurrence and healthier bones. Conclusions: We believe it is important to consider not only the methods to diagnose hypercalciuria but also its classification to provide a better treatment.

Pharmacological interventions for preventing complications in patients with idiopathic hypercalciuria: A systematic review.

OBJECTIVE: To assess the effects of pharmacological interventions in patients with idiopathic hypercalciuria. METHODS: We performed a search of multiple databases, trial registries, grey literature and conference proceedings up to October 2019. We included randomized and quasi-randomized controlled trials that examined any pharmacological intervention for preventing complications of idiopathic hypercalciuria (given for at least four months and six of follow-up). The primary outcomes were stone-free patients, urinary symptoms and severe adverse events. RESULTS: We included five RCTs (n=446 patients, all adults, 4 in individuals with kidney stones and 1 in postmenopausal women with osteoporosis). Diuretics were likely to increase the number of stone-free patients (RR 1.61, 95% CI 1.33-1.96, moderate quality of evidence (QoE)); 274 more stone-free patients/1000 patients treated (95% CI: 148-432) and produced a slight decrease in the stone formation rate (mean difference -0.18, 95% CI -0.30 to -0.06, low QoE); 180 fewer stones/year/1000 patients treated (95% CI: 300 r to 60). No data on urinary symptoms were reported. The association between diuretic use and severe adverse events was uncertain (RR 5.00, 95% CI 0.60-41.88, very low QoE); 4 more severe adverse events/1000 patients treated (95% CI: 0 fewer to 39 more). CONCLUSIONS: The addition of diuretics to a normal or modified diet probably reduces the number of stone recurrences and may decrease the stone formation rate. It is uncertain whether diuretics increase the occurrence of severe adverse events. There were no studies investigating other outcomes or in children.

Evolution of bone mineral density in patients with idiopathic hypercalciuria: a 20-year longitudinal study.

BACKGROUND: Several recent studies reported bone mineral density (BMD) reduction in pediatric patients with idiopathic hypercalciuria (IH). This longitudinal study aimed to evaluate BMD evolution in IH patients through three bone densitometry studies conducted over 20 years on average. A second objective was to evaluate urine calcium and citrate excretion during this period. METHODS: Case notes of 34 patients diagnosed with IH at age 7.9 ± 3, alongside results of two bone densitometry studies, performed at 10.5 ± 2.7 (BMD1) and 14.5 ± 2.7 (BMD2) years of age, were reviewed. Patients underwent a third densitometry study in adulthood (BMD3) aged 28.3 ± 2.9. Mean follow-up duration (time-lapse between BMD1 and BMD3) was 17.7 ± 1.4 years. RESULTS: Statistically significant differences were found between z-BMD3 (- 0.85 ± 1.10) and z-BMD1 (- 1.47 ± 0.99) (P = 0.001) as well as between z-BMD3 and z-BMD2 (- 1.33 ± 1.20) (P = 0.016). At the end of follow-up, z-BMD3 was superior to z-BMD2 in 23 adult patients (67.6%) and lower in 11 patients (5M, 6F; 32.3%). Both men and women showed increased bone mass over time, although such increases were significant only for women. The gradual decrease observed in calcium/creatinine and citrate/creatinine ratios could be related to improvement in osteoblastic activity and especially reduction in osteoclastic activity. CONCLUSIONS: In patients with IH, BMD improves, which may be related especially to female sex, increment of body mass, and reduction in bone resorption. Upon reaching adulthood, urine calcium and citrate excretion tend to decrease so lithogenic risk still remains. The cause of the latter is unknown, although it likely relates to changes in bone activity.

Aspectos clínicos, epidemiológicos y terapéuticos en niños y adolescentes con hipercalciuria idiopática / Clinical, epidemiological and therapeutic aspects in children and adolescents with idiopathic hypercalciuria

Introducción: La hipercalciuria idiopática es un trastorno metabólico frecuente y poco reconocido, cuyo curso clínico depende en gran medida de cambios en los hábitos dietéticos desde la infancia. Objetivo: Caracterizar a niños y adolescentes con hipercalciuria idiopática según variables clínicas, epidemiológicas y terapéuticas. Métodos: Se realizó una investigación observacional, longitudinal y prospectiva de 44 pacientes con hipercalciuria idiopática, atendidos en el Servicio de Miscelánea del Hospital Pediátrico Docente Sur Antonio María Béguez César de Santiago de Cuba, desde enero de 2014 hasta diciembre de 2015. Resultados: Las formas sintomáticas de la enfermedad resultaron ser las más frecuentes (68,2 %); asimismo, predominó el sexo masculino (72,7 %) y el promedio de edad fue de 7,2 ± 4 años. Existió asociación estadística entre las edades preescolar y escolar en cuanto al diagnóstico de hipercalciuria idiopática. La hematuria macroscópica recurrente fue el síntoma más usual en la mayoría de los casos (59,1 %); en tanto, 25,0 % de los pacientes presentó litiasis renal y el tratamiento no farmacológico a base de líquidos y dieta se relacionó con una evolución satisfactoria en 68,2 % de los afectados, a pesar de que el restante 31,8 % necesitó tratamiento medicamentoso. Conclusiones: Las características clínicas y epidemiológicas de los pacientes con hipercalciuria idiopática de esta casuística no difirieron de las registradas a nivel mundial, considerando que este trastorno metabólico es relativamente frecuente en los servicios de pediatría.

Introduction: The idiopathic hypercalciuria is a frequent and not very recognized metabolic disorder which clinical course depends in great extent on changes in the dietary habits from the childhood. Objective: To characterize children and adolescents with idiopathic hypercalciuria according to the clinical, epidemiological and therapeutic variables. Methods: An observational, longitudinal and prospective investigation was carried out in 44 patients with idiopathic hypercalciuria, assisted in the Miscellaneous Service of Antonio María Béguez Cesar Southern Teaching Children Hospital in Santiago de Cuba, from January, 2014 to December, 2015. Results: The symptomatic forms of the disease were the most frequent (68.2 %); also, the male sex prevailed (72.7 %) and the average age was 7.2 ± 4 years. Statistical association existed among the preschool and school ages as for the diagnosis of idiopathic hypercalciuria. The recurrent macroscopic hematuria was the most usual symptom in the majority of cases (59.1 %); as long as, the 25.0 % of patients presented renal lithiasis and the diet and liquids-based non pharmacological treatment was associated with a satisfactory evolution in 68.2 % of the affected patients, although the remaining 31.8 % needed drugs treatment. Conclusions: The clinical and epidemiological characteristics of patients with idiopathic hypercalciuria of this case material didn't differ from the ones registered worldwide, taking into account that this metabolic disorder is relatively frequent in pediatric services.

Effect of Vitamin D Treatment on Dynamics of Stones Formation in the Urinary Tract and Bone Density in Children with Idiopathic Hypercalciuria.

Vitamin D supplementation in patients with urolithiasis and hypercalciuria is considered to be unsafe. We analyzed the impact of vitamin D supplementation on selected health status parameters in children with idiopathic hypercalciuria. The study included 36 children with urolithiasis resulting from excessive calcium excretion. The level of calcium and 25(OH)D (hydroxylated vitamin D - calcidiol) in serum, urinary calcium excretion and the presence of stones in urinary tract were assessed prospectively. Blood and urine samples were collected at the time when the patient was qualified for the study and every three months up to 24 month of vitamin D intake at a dose of 400 or 800 IU/day. At time zero and at 12, and 24 months of vitamin D supplementation, densitometry was performed. Supplementation with vitamin D caused a statistically significant increase in the concentration of 25(OH)D in serum. There were no significant changes in calcium concentration in serum, excretion of calcium in urine but also in bone density. There was no significant increase in the risk of formation or development of stones in the urinary tract. Supplementation with vitamin D (400-800 IU/day) in children with idiopathic hypercalciuria significantly increases 25(OH)D concentration, does not affect calciuria, but also does not improve bone density.

Longitudinal study of kidney water management in patients diagnosed with idiopathic hypercalciuria in childhood. / Estudio longitudinal del manejo renal del agua en pacientes diagnosticados de hipercalciuria idiopática en la infancia.

INTRODUCTION: There is much debate about whether idiopathic hypercalciuria (IH) affects kidney water management. For the first time in the literature, we carried out a longitudinal study of kidney water management (KWM) in patients diagnosed with IH in childhood and followed-up until adulthood (mean follow-up 17.7±1.4 years). METHODS: Twenty-nine patients (7 M, 22 F) over the age of 24 years (mean 28.2±2.9 years, range: 24.1-35.9) who were diagnosed with IH in childhood (mean 7.6±3.2 years, range: 1-14) were included. Maximum urine osmolality (UO) and/or urine volume adjusted for 100ml of glomerular filtration rate (V/GFR) in both age groups (paediatric and adult) were determined. Moreover, whenever possible, in both age groups plasma creatinine levels, plasma sodium levels, uric acid levels, the citrate/creatinine ratio and the calcium/citrate ratio were recorded and a renal and bladder ultrasound was performed. RESULTS: In the paediatric age group, KWM was altered in 9/29 cases (31%) (4 with reduced maximum UO and 5 with elevated V/GFR). In adulthood, KWM was found to be affected in 7/29 cases (24.1%) (6 with reduced UO and one with elevated V/GFR). Compared to the paediatric age group, adult patients had lower V/GFR, calcium/creatinine and citrate/creatinine values, as well as higher plasma creatinine, uric acid and calcium/citrate. There were no differences in the maximum UO in both age groups. However, UO in adulthood was significantly lower in subjects who had renal colic compared to those who did not (P=.04). CONCLUSIONS: KWM was affected in approximately one third of patients with IH, which persisted 20 years after diagnosis. We think that these results may be due to adherence to the recommended protective diet and to the pharmacological treatment administered at the diagnosis of IH during childhood.

[Idiopathic hypercalciuria: can the diuretics be avoided?] / Hipercalciuria idiopática ¿Se pueden evitar los diuréticos?

Idiopathic hypercalciuria is defined as calcium excretion greater than 220 and 300 mg/day in women and men respectively, or greater than 4 mg/kg body weight. In women with osteoporosis it is observed in 19% of cases, while in kidney stones cases varies between 50 and 70%. We selected 206 hypercalciuric patients from our database, with and without renal lithiasis, to whom a restricted diet had been indicated. We divided them, according to the response, into a dependent diet and an independent diet. We considered 122 patients with diagnosis of hypercalciuria diet dependent (105 women and 17 men), which were followed with dietary control (800 mg of calcium, around 1 g of animal proteins and < 100 mEq sodium a day). The appearance of stones, or the recurrence of stones, was not considered, nor was bone involvement. After an average of 17 months, everyone had their calciuria controlled and there were even 16 (13%) who, after 42 months of follow-up, continued to be normocalciuric only on a diet. We conclude that the division of the hypercalciurias is fundamental, according to their response to a restricted diet, in order to avoid or postpone the use of diuretics and its adverse effects, with an adequate management of the diet.

La hipercalciuria idiopática se define como la excreción de calcio superior a 220 y 300 mg/día en mujeres y hombres respectivamente o bien mayor a 4 mg/kg peso. En mujeres con osteoporosis se observa en el 19% de los casos, mientras que en litiasis renal varía entre el 50 y 70%. Seleccionamos 206 pacientes hipercalciúricos, de nuestra base de datos, con y sin litiasis renal, a los que se les había indicado una dieta restringida. Luego los dividimos, de acuerdo a la respuesta, en dieta dependiente y dieta independiente. De estos solo consideramos 122 pacientes con diagnósticos de hipercalciuria dieta-dependiente (105 mujeres y 17 hombres), que fueron seguidos con control dietario (800 mg de calcio, alrededor de 1 g de proteínas animales y < 100 mEq de sodio diarios). No se consideró la aparición de cálculos, o la recurrencia de los mismos, como tampoco el compromiso óseo. Luego de una media de 17 meses todos tenían controlada la calciuria e incluso hubo 16 (13%) que luego de 42 meses de seguimiento persistían normocalciúricos solo con dieta. Concluimos que es fundamental la división de las hipercalciurias, según su respuesta a una dieta restringida, con el fin de evitar o postergar el uso de diuréticos y sus efectos adversos, con una administración adecuada de la dieta.

Hipercalciuria idiopática ¿se pueden evitar los diuróticos? / Idiopathic hypercalciuria: can the diuretics be avoided?

La hipercalciuria idiopática se define como la excreció;n de calcio superior a 220 y 300 mg/día en mujeres y hombres respectivamente o bien mayor a 4 mg/kg peso. En mujeres con osteoporosis se observa en el 19% de los casos, mientras que en litiasis renal varía entre el 50 y 70%. Seleccionamos 206 pacientes hipercalció;ºricos, de nuestra base de datos, con y sin litiasis renal, a los que se les había indicado una dieta restringida. Luego los dividimos, de acuerdo a la respuesta, en dieta dependiente y dieta independiente. De estos solo consideramos 122 pacientes con diagnó;sticos de hipercalciuria dieta-dependiente (105 mujeres y 17 hombres), que fueron seguidos con control dietario (800 mg de calcio, alrededor de 1 g de proteínas animales y < 100 mEq de sodio diarios). No se consideró; la aparició;n de cálculos, o la recurrencia de los mismos, como tampoco el compromiso ó;seo. Luego de una media de 17 meses todos tenían controlada la calciuria e incluso hubo 16 (13%) que luego de 42 meses de seguimiento persistían normocalció;ºricos solo con dieta. Concluimos que es fundamental la divisió;n de las hipercalciurias, segó;ºn su respuesta a una dieta restringida, con el fin de evitar o postergar el uso de diuró;©ticos y sus efectos adversos, con una administració;n adecuada de la dieta.

Idiopathic hypercalciuria is defined as calcium excretion greater than 220 and 300 mg / day in women and men respectively, or greater than 4 mg / kg body weight. In women with osteoporosis it is observed in 19% of cases, while in kidney stones cases varies between 50 and 70%. We selected 206 hypercalciuric patients from our database, with and without renal lithiasis, to whom a restricted diet had been indicated. We divided them, according to the response, into a dependent diet and an independent diet. We considered 122 patients with diagnosis of hypercalciuria diet dependent (105 women and 17 men), which were followed with dietary control (800 mg of calcium, around 1 g of animal proteins and < 100 mEq sodium a day). The appearance of stones, or the recurrence of stones, was not considered, nor was bone involvement. After an average of 17 months, everyone had their calciuria controlled and there were even 16 (13%) who, after 42 months of follow-up, continued to be normocalciuric only on a diet. We conclude that the division of the hypercalciurias is fundamental, according to their response to a restricted diet, in order to avoid or postpone the use of diuretics and its adverse effects, with an adequate management of the diet.

Hipercalciuria hidiopática como factor predisponente de infección urinaria / Idiopathic hypercalciuria as predisposing factor of urinary infection

Introducción: La hipercalciuria idiopática es una alteración metabólica relativamente frecuente y existen escasas publicaciones de su relación con la infección del tracto urinario. Objetivos: Precisar si existe asociación entre la infección urinaria e hipercalciuria idiopática para determinar si esta alteración metabólica constituye un factor de riesgo de infección urinaria. Métodos: Estudio descriptivo longitudinal prospectivo en pacientes de edad pediátrica con diagnóstico de infección urinaria atendidos en el Hospital Pediátrico Universitario William Soler entre 1ro. enero de 2016 y 31 de diciembre de 2017. Dos semanas después de controlada la infección se recogió muestra de orina de la primera micción del día para determinación de índice calcio/creatinina y precisar la excreción de calcio en 24 horas. Si esta prueba arroja resultados positivos, entre dos y cuatro semanas posteriores, se repite la muestra y si ambas son positivas y el calcio en sangre es normal se diagnostica hipercalciuria idiopática. Resultados: Se incluyeron en el estudio 130 pacientes. En 43,8 por ciento se encontró hipercalciuria idiopática. En su primer episodio infeccioso se estudiaron 52,3 por ciento y los restantes con antecedentes de infección o recurrencia. En 86,2 por ciento la infección fue catalogada como pielonefrítica. La distribución por sexo de la hipercalciuria no mostró diferencia y el síntoma hematuria con dolor abdominal recurrente resultó sugestivo de infección asociada a hipercalciuria (p < 0,05). El germen infectante no contribuye a pensar en hipercalciuria. Conclusión: La hipercalciuria idiopática constituye un factor predisponente de infección del tracto urinario(AU)

Introduction: Idiopathic hypercalciuria is a relatively frequent metabolic alteration and there are scarce publications on its relation with the urinary tract´s infection. Objective: To specify if there is a relation between urinary infection and idiopathic hypercalciuria, in order to determine if this last one constitutes a risk factor of urinary infection. Methods: Prospective, descriptive and longitudinal study in pediatric age's patients with a diagnosis of urinary infection that were attended in William Soler University Pediatric Hospital from January 1st, 2016 to December 31st, 2017. After two weeks of the infection being controlled, a urine sample from the first micturition of the day was collected to determine calcium/creatinine index and to specify calcium excretion in 24 hours. If this test shows positive results, after two to four weeks the sample is repeated, and if both are positive and calcium level in blood is normal, so idiopathic hypercalciuria is diagnosed. Results: 130 patients were included in the study. In 43.8 percent idiopathic hypercalciuria was found. 52.3 percent were studied during the first infectious episode, and there is presented a history of infection or recurrence. In 86.2 percent of the patients, the infection was catalogued as pyelonephritis. Hypercalciuria´s gender distribution didn't show any differences, and the symptom called hematuria with recurrent abdominal pain was suggestive to an infection related to hypercalciuria (p < 0.05). The infectious germ does not induce to think in hypercalciuria. Conclusions: Idiopathic hypercalciuria constitutes a predisposing factor of urinary tract's infection(AU)

[Current concepts on the pathogenesis of urinary stones]. / Aktuelle Konzepte zur Pathogenese von Harnsteinen.

The process of kidney stone formation is complex and still not completely understood. Supersaturation and crystallization are the main drivers for the etiopathogenesis of uric acid, xanthine and cystine stones but this physicochemical concept fails to adequately explain the formation of calcium-based nephrolithiasis, which represents the majority of kidney stones. Contemporary concepts of the pathogenesis of calcium-based nephrolithiasis focus on a nidus-associated stone formation of calcium-based nephrolithiasis on Randall's plaques or on plugs of Bellini's duct. Randall's plaques originate from the interaction of interstitial calcium supersaturation in the renal papilla, vascular and interstitial inflammatory processes and mineral deposits of calcifying nanoparticles on the basal membrane of the thin ascending branch of the loop of Henle; however, plugs of Bellini's duct are assumed to be caused by mineral deposits on the wall of the collecting ducts. Aggregation and overgrowth are influenced by the interaction of matrix proteins with calcium supersaturated urine, by an imbalance between promoters and inhibitors of stone formation in the calyceal urine. Current research has elucidated many factors contributing to stone formation by revealing novel insights into the physiology of nephron and papilla, by analyzing vascular, inflammatory and calcifying processes in the renal medulla, by examining the proteome, the microbiome, promoters and inhibitors of stone formation in the urine and by conducting the first genome-wide association studies; however, more future research is mandatory to fill the gap of knowledge and hopefully, to obtain novel prophylactic, therapeutic and metaphylactic tools beyond the current state of knowledge.

The idiopathic hypercalciuria reviewed. Metabolic abnormality or disease? / La hipercalciuria idiopática revisada. ¿Anomalía metabólica o enfermedad?

Idiopathic hypercalciuria (IH) is defined as that clinical situation in which an increase in urinary calcium excretion is observed, in the absence of hypercalcemia and other known causes of hypercalciuria. In recent years, its diagnosis in pediatric age has been more frequent because it has been known that it can debut with very different symptoms, in the absence of kidney stone formation. The discovery of genetic hypercalciuric stone-forming rats has allowed us to glimpse the pathophysiological mechanism of IH since they show many data in common with humans with IH as normal levels of blood calcium, intestinal calcium hyperabsorption, increased bone resorption and a defect in the renal tubular calcium reabsorption. In 1993, it was shown that in these animals there is an increase in the number of vitamin D receptors (VDR) in the intestine, which favors an increase in the functional capacity of calcitriol-VDR complexes that explains the increase in intestinal transport of calcium. The same happens at the bone level producing a greater resorption. In our opinion, IH is a 'metabolic anomaly' or, better, an inheritable constitutive metabolic characteristic. In this sense, what patients with IH would inherit is the availability of having a greater number of VDRs in their cells than those with normal urinary calcium excretion. IH cannot be considered a sensu stricto disease, so pharmacological treatment must be individualized.

Etiología de la hematuria monosintomática en pediatría / Etiology of monosymptomatic hematuria in Pediatrics

Introducción: La hematuria es el hallazgo clínico más frecuente entre las enfermedades genitourinarias, después de las infecciones del tracto urinario a cualquier edad. Objetivo: Identificar las características generales y etiología de la hematuria monosintomática en pacientes pediátricos. Métodos: Investigación descriptiva longitudinal y prospectiva con los pacientes atendidos con hematuria monosintomática en el Servicio de Nefrología del Hospital Pediátrico Docente William Soler entre el primero de enero de 2014 y 31 de diciembre de 2015. Resultados: Se reclutaron 45 pacientes. Predominó en escolares (40 por ciento) y adolescentes (40 por ciento), sexo masculino (55,5 por ciento). Se recogió el antecedente personal o familiar de hematuria en 44,5 por ciento y 55,5 por ciento, respectivamente. La urolitiasis familiar estuvo presente en 37,7 por ciento. El tipo de hematuria más frecuente fue la macroscópica (75,8 por ciento), no glomerular (71,2 por ciento), sin proteinuria (77,8 por ciento), y hematíes eumórficos (62,2 por ciento). La causa más frecuente fue la hipercalciuria idiopática (51,1 por ciento) y el 80 por ciento de todos los pacientes solo recibió tratamiento higieno-dietético. En 20 por ciento de los pacientes no se pudo precisar la causa etiológica. Conclusiones: La causa más frecuente de hematuria fue no glomerular (hipercalciuria idiopática) y en aquellos con hematuria cuya causa etiológica no se pudo precisar, es obligado mantener un seguimiento prolongado(AU)

Introduction: Hematuria is the most frequent clinical finding among genitourinary diseases afterwards urinary tract infection at any age. Objective: To identify general characteristics and etiology of monosymptomatic hematuria in in pediatrics patients. Methods: Descriptive, longitudinal and prospective research of the patients by monosymptomatic hematuria attended at the Nephrology service in William Soler Teaching Pediatric Hospital from January 1, 2014 to December 31, 2015. Results: 45 patients were recruited. Schoolchildren (40 percent) were predominant and adolescents (40 percent), and males (55.5 percent). It was collected personal or familial records of hematuria in 44.5 percent and 55.5 percent, respectively. Familial urolithiasis was present in 37.7 percent. The most common type of hematuria was the macroscopic (75.8 percent), non-glomerular (71.2 percent), without proteinuria (77.8 percent) and with eumorphic hematies (62.2 percent). The most frequent etiological cause was idiopathic hypercalciuria (51.1 percent), and 80 percent of all patients only received hygiene-dietetic treatment. In the 20 percent of the patients was not possible to determine the etiological cause. Conclusions: The most frequent cause of hematuria was non-glomerular (idiopathic hypercalciuria); and in those patients with hematuria of non-precised etiological cause, it is mandatory to keep long-term follow-up(AU)

Preventive Kidney Stones: Continue Medical Education.

Nephrolithiasis is a common health problem across the globe with a prevalence of 15%-20%. Idiopathic hypercalciuria is the most common cause of nephrolithiasis, and calcium oxalate stones are the most common type of stones in idiopathic hypercalciuric patients. Calcium phosphate stones are frequently associated with other diseases such as renal tubular acidosis type 1, urinary tract infections, and hyperparathyroidism. Compared with flat abdominal film and renal sonography, a noncontrast helical computed tomography scan of the abdomen is the diagnostic procedure of choice for detection of small and radiolucent kidney stones with sensitivity and specificity of nearly 100%. Stones smaller than 5 mm in diameter often pass the urinary tract system and rarely require surgical interventions. The main risk factors for stone formation are low urine output, high urinary concentrations of calcium, oxalate, phosphate, and uric acid compounded by a lower excretion of magnesium and citrate. A complete metabolic workup to identify the risk factors is highly recommended in patients who have passed multiple kidney stones or those with recurrent disease. Calcium oxalate and calcium phosphate stones are treated by the use of thiazide diuretics, allopurinol, and potassium citrate. Strategies to prevent kidney stone recurrence should include the elimination of the identified risk factors and a dietary regimen low in salt and protein, rich in calcium and magnesium which is coupled with adequate fluid intake.

Prevalence of idiopathic hypercalciuria in children with urinary system related symptoms attending a pediatric hospital in Bandar Abbas in 2014.

BACKGROUND: Idiopathic hypercalciuria is a group of diseases which can be manifested with urinary symptoms. Its importance is due to high prevalence, recurrent infections, and stone formations which are often asymptomatic. OBJECTIVE: The objective of this study was to determine the prevalence of idiopathic hypercalciuria in children with urinary system related symptoms in Bandar Abbas in 2014. METHODS: This descriptive cross-sectional study was done in 2014 in a children's hospital in Bandar Abbas (southern Iran) on 321 children who were between 2 months to 14 years old. Random morning urine sample was obtained from all the patients, and calcium to creatinine ratio was assessed for all the patients for two times. Hypercalciuria is defined as urinary calcium excretion rate that is greater than 4 mg/kg per 24 hours in a child older than two years of age. Data was analyzed using IBM SPSS statistics 23.0 software and Chi-square and independent-samples t-test. RESULTS: Among the 321 children assessed, 153 (47.7%) had idiopathic hypercalciuria. The mean age of the children with idiopathic hypercalciuria was 55.20±43.71. Prevalence of idiopathic hypercalciuria was 48.3% in children with urinary tract infection, 54.9% and 53.6% in children with microscopic and macroscopic hematuria respectively, In children with dysuria, there were 52.1%, and 51.8% in children with frequency, 49.1% in children with kidney stone which was confirmed with sonography, 28.6% and 37.5% in children with nocturnal and daily urinary incontinency respectively. Results of this study showed no significant relationship between urinary system symptoms and idiopathic hypercalciuria (p>0.05). CONCLUSION: Hypercalciuria can be presented with different symptoms associated with urinary symptoms. Therefore, it is recommended to check the urinary calcium level in children with urinary symptoms with no definite etiology.