Novel Variant of SLC34A3 in a Compound Heterozygous Brazilian Girl with Hereditary Hypophosphatemic Rickets with Hypercalciuria.

Hereditary hypophosphatemic rickets with hypercalciuria (HHRH) is a rare FGF23-independent disorder caused by biallelic variants in the SLC34A3 gene. The disease severity varies, and patients have an increased risk of developing renal complications. Phosphate supplementation is standard of care and active vitamin D analogs are not indicated as they could worsen the hypercalciuria. We report a Brazilian girl with HHRH who presented with knee pain and progressive genu valgum deformity that became apparent later in childhood (at age 8). Nephrocalcinosis was also identified at age 13. Next-generation sequencing (NGS) target panel directed to inherited forms of rickets detected compound heterozygous pathogenic variants in SLC34A3, including a novel missense variant c.1217G>T (p.Gly406Val). Compliance to oral phosphorus therapy was suboptimal and adjunctive chlorthalidone therapy improved hypercalciuria. Our case highlights the phenotypic variability of patients with HHRH and expands the growing list of SLC34A3 variants associated with this disorder. An accurate diagnosis is crucial for proper treatment, and a thiazide diuretic may be useful as adjunctive therapy for controlling hypercalciuria.

Clinical Findings and Genetic Analysis of Nine Mexican Families with Bartter Syndrome.

BACKGROUND: Bartter's syndrome (BS) is a group of salt-wasting tubulopathies characterized by hypokalemia, metabolic alkalosis, hypercalciuria, secondary hyperaldosteronism, and low or normal blood pressure. Loss-of-function variants in genes encoding for five proteins expressed in the thick ascending limb of Henle in the nephron, produced different genetic types of BS. AIM: Clinical and genetic analysis of families with Antenatal Bartter syndrome (ABS) and with Classic Bartter syndrome (CBS). METHODS: Nine patients from unrelated non-consanguineous Mexican families were studied. Massive parallel sequencing of a gene panel or whole-exome sequencing was used to identify the causative gene. RESULTS: Proband 1 was homozygous for the pathogenic variant p.Arg302Gln in the SLC12A1 gene encoding for the sodium-potassium-chloride NKCC2 cotransporter. Proband 3 was homozygous for the nonsense variant p.Cys308* in the KCNJ1 gene encoding for the ROMK potassium channel. Probands 7, 8, and 9 showed variants in the CLCKNB gene encoding the chloride channel ClC-Kb: proband 7 was compound heterozygous for the deletion of the entire gene and the missense change p.Arg438Cys; proband 8 presented a homozygous deletion of the whole gene and proband 9 was homozygous for the nonsense mutation p.Arg595*. A heterozygous variant of unknown significance was detected in the SLC12A1 gene in proband 2, and no variants were found in SLC12A1, KCNJ1, BSND, CLCNKA, CLCNKB, and MAGED2 genes in probands 4, 5, and 6. CONCLUSIONS: Genetic analysis identified loss-of-function variants in the SLC12A1, KCNJ1, and CLCNKB genes in four patients with ABS and in the CLCNKB gene in two patients with CBS.

Bartter-like Syndrome Induced By Tacrolimus in a Renal Transplanted Boy: A Case Report.

BACKGROUND: Losing-salt tubulopathies, such as Bartter syndrome, are rare and usually inherited due to mutations of tubular reabsorption channels of the nephrons. Despite its scarcity, some cases of acquired losing-salt tubulopathies have been described. In this case report, we discuss the main aspects of Bartter syndrome and present a rare pediatric case of probable tacrolimusinduced Bartter-like syndrome in a renal transplanted boy. CASE PRESENTATION: A ten-year-old male patient with end-stage renal disease due to endo and extra capillary glomerulonephritis was submitted to renal transplantation from a deceased donor. The post-operatory evolution was satisfactory with normalization of serum creatinine levels, mild hypertension, and the absence of metabolic disorders. The immunosuppression protocol included tacrolimus (0.3 mg/kg/day), mycophenolate (455 mg/m2/day) and prednisone (0.5 mg/kg/day). Two months later, the patient was hospitalized due to vomiting, dehydration, intense hypokalemia (1.3 mEq/L), hyponatremia (125 mEq/L), and hypochloremia (84 mmol/L). During hospitalization, he evolved with polydipsia (3000 mL/day) and polyuria (120-160 mL/m2/h) associated with major elevation of urinary potassium excretion, hypercalciuria, mild metabolic alkalosis, hyperfiltration, and proteinuria. The tacrolimus dose was reduced under the suspicion of tubular dysfunction, leading to a better metabolic profile. However, the patient developed a Banff IIb graft rejection, which required pulse therapy and elevation of tacrolimus and mycophenolate doses. Recovery of renal function parameters occurred, but the metabolic disorders worsened following tacrolimus dose elevation. The patient required chronic potassium, chloride, and sodium replacement. CONCLUSION: After administering immunosuppressive medications, physicians should be aware of the possibility of Bartter-like or other losing-salt tubulopathies syndromes that can affect metabolic homeostasis. The suspicion must always be considered in the case of a transplanted patient who presents dehydration and hydroelectrolytic disorders right after the commencement of nephrotoxic immunosuppressive drugs, including tacrolimus and cyclosporine.

Use of Teriparatide in Hyperphosphatemic Familial Tumor Calcinosis: Evaluating the Interaction Between FGF23 and PTH on the Phosphaturic Effect.

Hyperphosphatemic familial tumor calcinosis (HFTC) is a rare disease characterized by hyperphosphatemia and calcium and phosphorus crystal deposition. It occurs due to the loss of function of FGF23. Herein, we report a case of a 50-year-old woman diagnosed with HFTC (homozygous variant in the GALNT3 gene, c.803_804 C insertion) with a history of ectopic calcifications in the past 30 years. Laboratory tests on admission were as follows: phosphate (P) 7.1 mg/dL (Normal range (NR) 2.5-4.5 mg/dL), FGF23 c-terminal 2050 RU/mL (NR < 150 RU/mL), and intact FGF23 (iFGF23) 18.93 pg/mL (NR 12.0-69.0 pg/mL). Treatment with acetazolamide, sevelamer, and a phosphorus-restricted diet was started, but phosphatemia remained high and calcifications continued to progress. In an attempt to further decrease P, a 36-day cycle of teriparatide (TPTD) 20 mcg twice daily was added, decreasing P from 6.2 to 5.2 mg/dL and increasing the 1.25(OH)2 vitamin D by 34.2%. As urinalysis was not feasible at the end of the 36-day cycle, a second cycle was performed for another 28 days, producing a similar decrease in P (from 6.4 to 5.5 mg/mL) and an evident decrease in the rate of tubular reabsorption of P (from 97.2 to 85.3%), however, accompanied by a worrying increase in calciuria. The use of TPTD 20 mcg twice daily in a patient with genetic resistance to FGF23 (HFTC) was associated with consistent increase in phosphaturia and reduction in phosphatemia, in addition to an increase in calcitriol. The resulting hypercalciuria precludes the therapeutic use of TPTD in HFTC and suggests an important role of FGF23, not only in phosphate homeostasis but also in avoiding any excess of calcitriol.

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.

High Prevalence of Hypocitraturia in Stone Formers from the Maya Region of Yucatan, Mexico.

BACKGROUND: Urinary Stone Disease (USD) arises from an interaction of genetic and environmental factors. Urinary metabolic abnormalities are well described as risk factors. In Mexico, the Maya region holds the highest prevalence of USD. Treatment of these abnormalities lowers the risk of recurrences. AIM: Assess the underlying metabolic abnormalities of patients with USD to provide a rationale to lead further prevention strategies. METHODS: Clinical and demographical data from patients coming to the Stone Clinic were prospectively collected along with a 24 h urinary panel to identify metabolic abnormalities. All participants signed consent and the study was approved by the hospital's institutional review board. RESULTS: A total of 126 patients were included, with a mean age of 47.2 ± 13 years, 75.4% were female. A positive family history of stones was observed in 40 and 87.3% were overweight/obese. The frequency of hypocitraturia, hypercalciuria, hypomagnesuria, hyperoxaluria, and hyperuricosuria was 91.3, 68.5, 42.1, 36.5, and 26.6%, respectively. Median urinary citrate was 79.5 (37.5-160) mg/24 h and was inversely correlated to glycemia. Urine Calcium/Creatinine index was correlated with Hounsfield units (HU) (p = 0.01). Oxalate was correlated with HU and stone burden. Interestingly, dietary distribution of macro- and micronutrients were similar between groups. Patients with a single kidney had lower citrate and higher urinary calcium. CONCLUSIONS: Interestingly, a shortage of inhibitors such as citrate and magnesium are highly prevalent in patients with USD from the Maya region and seems to be influenced by other metabolic conditions as malnutrition next to the genetic component.

Principais distúrbios metabólicos em adolescentes portadores de nefrolitíase / Main metabolic disorders in adolescents with nephrolithiasis

Introdução: Os cálculos renais compreendem uma das mais comuns patologias do trato urinário e têm apresentado maior incidência em adolescentes nos últimos anos. Objetivos: Identificar os distúrbios metabólicos causadores de cálculo renal mais prevalentes em adolescentes. Métodos: Foram analisados os prontuários de 135 indivíduos portadores de nefrolitíase, com idade entre 12 e 18 anos, de ambos os sexos. Na análise laboratorial, incluiu-se: duas amostras de urina de 24 horas, contendo cálcio, citrato, oxalato e ácido úrico; uma amostra sanguínea, contendo creatinina, paratormônio, ácido úrico e cálcio; pH urinário após 12 horas de restrição hídrica e jejum; urocultura e cistinúria qualitativa. Resultados: 88 pacientes apresentaram hipercaIciúria (65,2%), 42 apresentaram hipocitratúria (31,1%) e 29 hiperuricosúria (21,5%). As demais alterações observadas foram: volume urinário reduzido (14,8%), infecções do trato urinário (9,6%), hiperoxalúria (5,2%), hiperparatireoidismo (1,5%) e acidose tubular renal (1,5%). Os distúrbios metabólicos mais frequentemente observados nos adolescentes portadores de cálculo renal foram hipercalciúria, hipocitratúria e hiperuricosúria

Introduction: Kidney stones are one of the most common pathologies of the urinary tract and have had a higher incidence in adolescents in recent years. Objectives: To identify the most prevalent metabolic disorders that cause kidney stones in adolescents. Methods: The medical records of 135 individuals with nephrolithiasis, aged between 12 and 18 years, of both sexes, were analyzed. The laboratory analysis included: two 24-hour urine samples containing calcium, citrate, oxalate and uric acid; a blood sample, containing creatinine, parathyroid hormone, uric acid, and calcium; urinary pH after 12 hours of fluid restriction and fasting; uroculture and qualitative cystinuria. Results: 88 patients had hyperuricosuria (65.2%), 42 had hypocitraturia (31.1%) and 29 had hyperuricosuria (21.5%). The other changes observed were: reduced urinary volume (14.8%), urinary tract infections (9.6%), hyperoxaluria (5.2%), hyperparathyroidism (1.5%) and renal tubular acidosis (1.5 %). Conclusions: The metabolic disorders most frequently observed in adolescents with kidney stones were hypercalciuria, hypocitraturia and hyperuricosuria.

Beyond kidney stones: Why pediatricians should worry about hypercalciuria.

The incidence of urolithiasis (UL) is increasing, and it has become more common in children and adolescents over the past few decades. Hypercalciuria is the leading metabolic risk factor of pediatric UL, and it has high morbidity, with or without lithiasis as hematuria and impairment of bone mass. The reduction in bone mineral density has already been described in pediatric idiopathic hypercalciuria (IH), and the precise mechanisms of bone loss or failure to achieve adequate bone mass gain remain unknown. A current understanding is that hypercalciuria throughout life can be considered a risk of change in bone structure and low bone mass throughout life. However, it is still not entirely known whether hypercalciuria throughout life can compromise the quality of the mass. The peak bone mass is achieved by late adolescence, peaking at the end of the second decade of life. This accumulation should occur without interference in order to achieve the peak of optimal bone mass. The bone mass acquired during childhood and adolescence is a major determinant of adult bone health, and its accumulation should occur without interference. This raises the critical question of whether adult osteoporosis and the risk of fractures are initiated during childhood. Pediatricians should be aware of this pediatric problem and investigate their patients. They should have the knowledge and ability to diagnose and initially manage patients with IH, with or without UL.

Trastornos metabólicos urinarios en pacientes urolitiásicos con enfermedad renal poliquística y sin ella / Urinary metabolic disorders in urolithiasis patients with and without polycystic kidney disease

Introducción: La urolitiasis se ha incrementado en las últimas décadas. La enfermedad renal poliquística autosómica dominante (ERPAD), enfermedad renal hereditaria más frecuente, ocupa un lugar preponderante. Objetivos: Identificar la frecuencia de presentación de los trastornos metabólicos urinarios en pacientes litiásicos cubanos con ERPAD y sin ella Métodos: Estudio descriptivo, transversal. Fueron estudiados 579 pacientes adultos sin ERPAD, seleccionados por muestreo simple aleatorio y los 21 pacientes con ERPAD, del total de pacientes con litiasis urinaria que se realizó estudio metabólico renal en el Laboratorio de Fisiopatología Renal del Instituto de Nefrología, en el periodo 2010-2015. Los datos fueron tomados de la historia clínica y del informe de estudio metabólico renal. La información se procesó de forma automatizada (SPSS 22.0). Se utilizó el promedio, desviación estándar, análisis de distribución de frecuencias y el test de homogeneidad. Resultados: En los pacientes con ERPAD predominó el sexo femenino (57,1 por ciento), mientras que en los pacientes sin ERPAD, el masculino (63,4 por ciento). Los trastornos más frecuentes en la población no poliquística fueron hipercalciuria (45,3 por ciento) e hipofosfatemia (17,1 por ciento). En los poliquísticos, aclaramiento aumentado de ácido úrico (38,1 por ciento) e hipercalciuria (23,8 por ciento). Se encontraron diferencias estadísticamente significativas para aumento del aclaramiento de ácido úrico (p = 0,01) e hiperfosfatemia (p = 0,04). Conclusiones: Los principales trastornos metabólicos de los pacientes litiásicos, tanto poliquísticos como no poliquísticos, son el aclaramiento de ácido úrico aumentado, hipercalciuria, hiperuricosuria e hipofosfatemia, aunque el orden de presentación es diferente. El aclaramiento de ácido úrico aumentado y la hiperfosfatemia se presentan con mayor frecuencia en los pacientes litiásicos poliquísticos(AU)

Introduction: Urolithiasis has increased in recent decades. Autosomal dominant polycystic kidney disease (ADPKD), the most common of all hereditary kidney diseases, occupies a predominant position in terms of incidence. Objectives: Identify the frequency of occurrence of urinary metabolic disorders in Cuban urolithiasis patients with and without ADPKD. Methods: A descriptive cross-sectional study was conducted of 579 adult patients without ADPKD selected by simple random sampling, and 21 patients with ADPKD, from the total urolithiasis patients undergoing renal metabolic evaluation at the Renal Physiopathology Laboratory of the Institute of Nephrology in the period 2010-2015. Data were obtained from medical records and reports of renal metabolic studies. Information was processed with the statistical software SPSS version 22.0. Average and standard deviation were estimated and use was made of frequency distribution analysis and homogeneity testing. Results: A predominance was found of female sex among patients with ADPKD (57.1 percent) and male sex among patients without ADPKD (63.4 percent). The most common disorders were hypercalciuria (45.3 percent) and hypophosphatemia (17.1 percent) in the non-polycystic population, and increased uric acid clearance (38.1 percent) and hypercalciuria (23.8 percent) in polycystic patients. Statistically significant differences were found in uric acid clearance increase (p = 0.01) and hyperphosphatemia (p = 0.04). Conclusions: The main metabolic disorders of lithiasis patients, polycystic as well as non-polycystic, are increased uric acid clearance, hypercalciuria, hyperuricosuria and hypophosphatemia, with a varying order of presentation. Increased uric acid clearance and hyperphosphatemia are more common in polycystic lithiasis patients(AU)

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.

Should pediatric idiopathic hypercalciuria be treated with hypocalciuric agents?

BACKGROUND: Hypercalciuria is the most common metabolic risk factor for calcium urolithiasis and is associated with bone loss in adult patients. Reduced bone mineral density (BMD) was already described in idiopathic hypercalciuria (IH) children, but the precise mechanisms of bone loss or inadequate bone mass gain remain unknown. Life-long hypercalciuria might be considered a risk to change bone structure and determine low bone mass throughout life. The peak of bone mass should occur without interferences. A beneficial effect of citrate formulations and thiazides on bone mass in adult and pediatric patients with IH have been shown. AIM: To evaluate whether pharmacological therapy has a beneficial effect on bone mass in children and adolescents with IH. METHODS: This retrospective cohort study evaluated 40 hypercalciuric children non-responsive to lifestyle and diet changes. After a 2-mo run-in period of citrate formulation (Kcitrate) usage, the first bone densitometry (DXA) was ordered. In patients with sustained hypercalciuria, a thiazide diuretic was prescribed. The second DXA was performed after 12 mo. Bone densitometry was performed by DXA at lumbar spine (L2-L4). A 24-h urine (calcium, citrate, creatinine) and blood samples (urea, creatinine, uric acid, calcium, phosphorus, magnesium, chloride, hemoglobin) were obtained. Clinical data included age, gender, weight, height and body mass index. RESULTS: Forty IH children; median age 10.5 year and median time follow-up 6.0 year were evaluated. Nine patients were treated with Kcitrate (G1) and 31 with Kcitrate + thiazide (G2). There were no differences in age, gender, body mass index z-score and biochemical parameters between G1 and G2. There were no increases in total cholesterol, kalemia and magnesemia. Calciuria decreased in both groups after treatment. Lumbar spine BMD z-score increased after thiazide treatment in G2. There was no improvement in G1. CONCLUSION: Results point to a beneficial effect of thiazide on lumbar spine BMD z-score in children with IH. Further studies are necessary to confirm the results of the present study.

Caracterización clínica y metabólica de pacientes con diagnóstico de urolitiasis atendidos en una clínica de cuarto nivel de Barranquilla, Colombia / Clinical and metabolic characterization of patients with a diagnosis of urolithiasis in a four-level clinic in the city of Barranquilla

Resumen Introducción: la urolitiasis es una enfermedad frecuente de la cual en Colombia se han publicado estudios previos; sin embargo, estos no comparan las características sociodemográficas y clínicas de los pacientes con las comorbilidades y los factores predisponentes de litiasis como hiperuricemia, hipertensión arterial (HTA), obesidad y enfermedad renal crónica (ERC). Objetivos: caracterizar clínica y metabólicamente los pacientes con diagnóstico de urolitiasis atendidos en una clínica de cuarto nivel de Barranquilla, Colombia, en el año 2019. Materiales y métodos: se realizó un estudio observacional, descriptivo y transversal en 49 pacientes con base en el estudio de fichas clínicas Resultados: el 53,1 % de los participantes eran hombres y las medianas de edad y de índice de masa corporal (IMC) fueron 58 años y 26,4 kg/m2, respectivamente. Algunas de las comorbilidades identificadas fueron, en orden de frecuencia, HTA (69,4 %), ERC (36,7 %), infección de vías urinarias recurrente (24,5 %), hiperuricemia (44,9 %), hipercalcemia (16,3 %) e hiperfosfatemia (12,2 %). Los tipos de cristal encontrados fueron oxalato (20,4 %), urato (12,2 %), mezcla de oxalato y urato (4,1 %), fosfato (4,1 %), hipercalciuria e hiperoxaluria (38,8 %), hiperuricosuria e hipocalciuria (18,4 %) y hipofosfaturia o hipofosfaturia (4,1 %). Asimismo, la hiperuricemia se asoció a edad (p=0,028), ERC (p=0,026), medicamentos antihipertensivos (p=0,022), posición del cálculo en cáliz renal (p=0,012), hiperparatiroidismo (p=0,007), depuración de creatinina (p=0,046) e hipercalciuria (p=0,049). El IMC ≥30 se asoció con ERC estadio 5 (p=0,025), diálisis (p=0,025) e hiperoxaluria (p=0,021). Conclusiones: en la población analizada se evidenció una frecuencia significativa de ERC, hiperuricemia, obesidad e HTA.

Abstract Introduction: Urolithiasis is a disease with high frequency and our environment is no exception. Previous studies have been published in Colombia, however, these do not compare the sociodemographic and clinical characteristics of patients with comorbidities and predisposing factors for lithiasis such as they are hyperuricemia, high blood pressure, obesity, and chronic kidney disease (CKD). Objectives: To characterize clinically and metabolically the patients diagnosed with urolithiasis in a fourth-level clinic in the city of Barranquilla in 2019. Methods: Observational, descriptive, cross-sectional study. In 49 patients, based on the study of clinical records Results: The median age was 58 years, the male sex in 53.1 %. The median body mass index was 26.4 Kg / m2. High blood pressure was identified in 69.4 %, chronic kidney disease (CKD) in 36.7 %, recurrent urinary tract infection in 24.5 %. Hyperuricemia in 44.9 %, hypercalcemia in 16.3 % and hyperphosphatemia in 12.2 %. The crystal types were oxalate in 20.4 %, urate in 12.2 %, mixture of the previous ones in 4.1 % and in the same proportion phosphate. Hypercalciuria and hyperoxaluria in 38.8 %, hyperuricosuria and hypocalciuria in 18.4 %, while hyperphosphaturia or hypophosphaturia in 4.1 %. Hyperuricemia was associated with age (p = 0.028), CKD (p = 0.026), antihypertensive drugs (p = 0.022), the position of the stone in the renal calyx (p = 0.012), hyperparathyroidism (p = 0.007), creatinine clearance (p = 0.046) and hypercalciuria (p = 0.049). BMI ≥30 was associated with stage 5 CKD (p = 0.025), dialysis (p = 0.025), and hyperoxaluria (p = 0.021). Conclusions: A significant frequency of CKD, hyperuricemia, obesity and hypertension was evidenced in patients with urolithiasis.

Urinary Metabolic Disorders Associated with Urolithiasis in Cuban Pediatric Patients.

INTRODUCTION: Pediatric urinary lithiasis (urolithiasis) is an important health issue linked to urinary metabolic disorders. In the United States alone, annual costs associated with urolithiasis are $229 million for hospital admissions and $146 million for emergency care. OBJECTIVE: Identify urinary metabolic disorders in Cuban pediatric patients with urolithiasis and better understand the relationship of age, demographic and anthropometric variables to urinary metabolic disorders strongly associated with urolithiasis. METHODS: We carried out a descriptive, cross-sectional study. The study universe was comprised of Cuban patients aged 2 to 19 years with urinary lithiasis who underwent renal metabolic studies at the Dr Abelardo Buch López Nephrology Institute in Havana, Cuba, from 2008 through 2019. All data were obtained from reports of the aforementioned metabolic studies. We collected the following variables: age, sex, nutritional status, urinary volume, plasma and urinary creatine concentrations; and calcium, uric acid, oxalate and citrate urinary excretions collected during a 24-hour period. We included results of urinary cystine tests and urine mini-cultures. We obtained frequency distributions for categorical and qualitative variables and calculated means and standard deviations for quantitative variables. We also evaluated homogeneity of metabolic disorders between children and adolescents. RESULTS: We studied 1592 pediatric patients, of whom 67.7% (1078/1592) were adolescents. The main metabolic disorders included hypercalciuria (39.1%; 622/1592), decreased urinary flow (22.4%; 357/1592) and hypocitraturia (18.2%; 289/1592). Hypercalciuria, hypocitraturia and hyperoxaluria were more common in children, while decreased urinary flow and hyperuricosuria were more common in adolescents. Hyperuricosuria was more frequent in male patients (6.3%; 40/639 vs. 1.8%; 8/439) and had the greatest impact on lithogenesis. Hypercalciuria was more frequent in undernourished children (62.5%; 30/48) than in overweight children (21.7%; 10/46), or those with obesity (33.3%; 15/45). CONCLUSIONS: The main metabolic disorders among Cuban pediatric patients with urinary lithiasis are: hypercalciuria, decreased urinary flow and hypocitraturia. Hypercalciuria, hypocitraturia and hyperoxaluria are more common in children, and decreased urinary flow and hyperuricosuria are more common in adolescents. Identifying urinary metabolic disorders facilitates formulation of treatment plans tailored to decreasing the likelihood of urolithiasis.

Litiasis renal en niños / Renal lithiasis in children

Resumen Justificación y objetivo: La litiasis renal se debe a la precipitación de cristales por un desequilibrio en la orina entre sustancias promotoras y las sustancias inhibitorias. Es una patología con una prevalencia entre 2-10% en la población pediátrica, con una incidencia que ha aumentado en los últimos 25 años; razón por la cual este estudio pretende conocer la prevalencia, las manifestaciones clínicas y metabólicas de la litiasis renal en la población pediátrica del Hospital Nacional de Niños de Costa Rica. Métodos: Es un estudio retrospectivo, descriptivo y observacional, mediante la revisión de expedientes de pacientes menores a 18 años con el diagnóstico de litiasis renal, atendidos en el Hospital Nacional de Niños, en el periodo comprendido entre enero del año 2000 al 2018. Resultados: Se incluyeron un total de 106 pacientes. El 57,5% hombres, la edad promedio al diagnóstico de 6,6 ± 3,8 años; la frecuencia de casos se ha incrementado en 5,5 veces en los últimos 5 años. Factores de riesgo detectados: anormalidades del tracto urinario 22,6% y antecedentes familiares de litiasis 17,9%. El análisis metabólico mostró un gasto urinario bajo en el 74,3%, hiperfosfaturia en un 43,2%, hipomagnesuria 39,2% e hipercalciuria 37,8%. Etiologías determinadas: metabólica 54,7%, malformaciones de las vías urinarias 16% e idiopática en un 30,9%. La litotricia intracorpórea se aplicó en un 61,2%. La recidiva se observó en el 28,5% de los casos, se encontró relación entre la incidencia de recidiva con el tamaño del lito (p = 0,001) y el tratamiento quirúrgico. (p = 0,010). Conclusiones: Existe un aumento en la frecuencia de casos de litiasis pediátrica con una etiología multifactorial en el Hospital Nacional de Niños de Costa Rica.

Abstract Background and aim: Renal lithiasis is due to the precipitation of crystals due to an imbalance in the urine between promoter substances and inhibitory substances. It is a pathology with a prevalence between 2-10% in the pediatric population, with an incidence that is increasing in the last 25 years, because of that, this study pretend to know the prevalence, the clinical and metabolic, manifestation of the renal lithiasis in the pediatric population. Methods: It is a retrospective, descriptive and observational study, by reviewing records of patients under 18 years of age with a diagnosis of renal lithiasis, treated at the Hospital Nacional de Niños, in the period of 2000 to 2018. Results: A total of 106 patients were included, 57,5% men, the average age at diagnosis of 6,6+- 3,8 years, the frequency of cases has increased 5,5 times in the last 5 years. Risk factors detected: urinary trac abnormalities 22,6% and family history of nephrolithiasis 17,9%. The metabolic analysis showed a low urinary flow rate in 74,3%, hyperphosphaturia in 43,2%, hypomagnesuria 39,2% and hypercalciuria 37,8%. Etiologies determined: metabolic 54,7%, malformations of the urinary trac 16% and idiopathic in 30,9%. Intracorporeal lithotripsy was applied in 61,2%. Recurrence was observe in 28,5 % of cases, a relationship was found between the incidence of recurrence with the size of litho (p= 0.001) and surgical treatment (p= 0.01). Conclusions: There is a significant increase in the incidence of pediatric lithiasis cases with a multifactorial etiology.

Thiazide and thiazide-like diuretics in nephrolithiasis / Diuréticos tiazídicos e tiazídicos-like na nefrolitíase

Abstract Thiazide and thiazide-like diuretics are widely used for the management of hypercalciuria among stone-forming patients. Although the effects of different thiazides should be relatively similar in terms of prevention of stone recurrence, their potency and side effects may differ. However, there is scarce data concerning the metabolic and bone effects of these agents among recurrent nephrolithiasis patients with hypercalciuria. The aim of this update article was to compare our experience in the use of thiazide and thiazide- like diuretics with that of the current literature, concerning their anticalciuric properties and consequent reduction of recurrent stone formation. Their impact on bone mass and potential side effects were also discussed.

Resumo Diuréticos tiazídicos e tiazídicos-like são amplamente usados para o tratamento da hipercalciúria em pacientes com formação de cálculos. Embora os efeitos dos diferentes tiazídicos devam ser relativamente semelhantes em termos de prevenção da recorrência do cálculo, sua potência e efeitos colaterais podem ser diferentes. No entanto, há poucos dados sobre os efeitos metabólicos e ósseos desses agentes em pacientes com nefrolitíase recorrente com hipercalciúria. O objetivo deste artigo de atualização foi comparar nossa experiência quanto ao uso de tiazídicos e tiazídicos-like com a publicada na literatura atual, no que diz respeito às suas propriedades anticalciúricas e consequente redução da formação de cálculos recorrentes. Discutimos também seu impacto na massa óssea e potenciais efeitos colaterais.

Bartter's syndrome: clinical findings, genetic causes and therapeutic approach.

BACKGOUND: Bartter's syndrome (BS) is a rare group of salt losing tubulopathies due to the impairment of transport mechanisms at the thick ascending limb of the Henle's loop. DATA SOURCES: Literature reviews and original research articles were collected from database, including PubMed and Scopus. RESULTS: According to the time of onset and symptoms, BS can be classified into antenatal and classic BS. Molecular studies have identified different subtypes of BS. BS types I, II and III are caused by mutations on genes encoding the luminal Na+-K+-2Cl- co-transporter, the luminal K+ channel ROMK, and the basolateral chloride channel ClC-Kb (CLCNKB), respectively. Loss-of-function mutations of Barttin CLCNK type accessory beta subunit cause BS type IVa. Simultaneous mutations of CLCNKB and CLCNKA cause BS type IVb. BS type V consists in a novel transient form characterized by antenatal presentation due to mutations in the MAGE family member D2. Severe gain-of-function mutations of the extracellular calcium sensing receptor gene can result in an autosomal dominant condition of BS. Main clinical and biochemical alterations in BS include polyuria, dehydration, hypokalemia, hypochloremic metabolic alkalosis, hyperreninemia, high levels of prostaglandins, normal or low blood pressure, hypercalciuria and failure to thrive. Treatment focuses mainly at correcting dehydration and electrolyte disturbances and in measures to reduce polyuria, including the use of nonsteroidal anti-inflammatory medications to control excessive renal prostaglandin E2 production. CONCLUSIONS: Early diagnosis and treatment of BS may prevent long-term consequences such as growth failure, nephrocalcinosis and end-stage renal disease.

Association between dietary pattern and metabolic disorders in children and adolescents with urolithiasis / Associação entre o padrão alimentar e distúrbios metabólicos em crianças e adolescentes com urolitíase

Abstract Objective: To describe the dietary patterns and occurrence of metabolic disorders in children and adolescents with urolithiasis treatment at a referral hospital in southern Brazil in order to learn the features of urolithiasis in this population to better develop preventive actions. Methods: Descriptive study conducted between 2016 and 2017 in a tertiary care referral hospital. Fourty patients aged 2-19 years old with urolithiasis proven by imaging were included. Clinical and dietary data were obtained through interviews and medical records. For statistical analyses, the chi-squared test was performed. Results: 40 individuals were analyzed. Mean age at diagnosis was 7.2 ± 4 years. 25% were overweight or obese. 95% had metabolic disorders, hypocitraturia being the predominant type. Protein intake was adequate in all participants and carbohydrate intake, in 70% of them; 37.5% had lipid intake above recommended and 65% had low fiber intake. The mean daily sodium intake was 2.64 g (±1.74), with 55% of participants ingesting more than the recommended amount. A total of 52.5% had low potassium intake, with a mean of 4.79 g/day (±2.49). Calcium intake was adequate in 27.5%. No significant differences were identified in relation to mean daily consumption among participants with or without the various metabolic disorders. Conclusion: Pediatric urolithiasis is often accompanied by metabolic disorders; therefore, metabolic evaluation should be part of the diagnostic process and subsequent analysis of these patients' dietary patterns, helping to optimize treatment and prevent recurrences and complications.

Resumo Objetivo: Descrever o padrão alimentar e a ocorrência de distúrbios metabólicos em crianças e adolescentes portadoras de urolitíase acompanhadas em hospital de referências no sul do Brasil a fim de conhecer as particularidades da urolitíase nessa população para melhor desenvolver ações de prevenção. Métodos: Estudo observacional descritivo realizado entre 2016 e 2017 em centro de referência em atenção terciária. Foram selecionados 40 pacientes de dois a 19 anos com urolitíase comprovada por exame de imagem. Dados clínicos e alimentares foram obtidos através de prontuário e entrevista. Para análise estatística, utilizou-se o teste qui-quadrado. Resultados: Foram analisados 40 indivíduos, 55% masculinos. Idade média ao diagnóstico 7,2 ± 4 anos; 25% tinham sobrepeso ou obesidade; 95% tinham distúrbios metabólicos, predominou a hipocitratúria. O consumo proteico e de carboidratos foi adequado em 100% e 70% dos participantes, respectivamente, 37,5% apresentaram ingestão de lipídeos acima do recomendado e 65% apresentaram ingestão de fibras alimentares abaixo do recomendado. O consumo diário médio de sódio foi de 2,64 g (± 1,74), com 55% acima do recomendado; 52,5% apresentaram baixa ingestão de potássio com média de 4,79 g/dia (± 2,49). O consumo de cálcio foi adequado em 27,5%. Não foram identificadas diferenças significativas em relação ao consumo médio diário dos nutrientes entre os participantes com ou sem os diversos distúrbios metabólicos. Conclusões: A urolitíase pediátrica é frequentemente acompanhada de distúrbios metabólicos, o que confirma a necessidade de avaliação metabólica adequada ao diagnóstico e análise do padrão alimentar a fim de identificar erros alimentares, aprimorar o tratamento desses distúrbios e prevenir recorrências e complicações.

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.

Hypomagnesemia with Hypercalciuria Leading to Nephrocalcinosis, Amelogenesis Imperfecta, and Short Stature in a Child Carrying a Homozygous Deletion in the CLDN16 Gene.

Familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC) is a rare autosomal recessive disease caused by mutations in the CLDN16 or CLDN19 gene; however, few cases develop classical amelogenesis imperfecta. Herein, we report the case of a boy with early clinical renal manifestations that started at 1 year of age and presenting with dental hypoplasia and growth delay. The patient presented with vomiting, polyuria, and polydipsia. Apart from recurrent sterile leukocyturia, erroneously treated as infectious, he was normal, except for short stature and amelogenesis imperfecta with gradually discolored teeth. Laboratory tests revealed hyperparathyroidism, hypomagnesemia, severe hypercalciuria, and hypermagnesuria on 24-h urine testing. Helical computed tomography confirmed nephrocalcinosis. We performed whole-exome sequencing (WES) to test the hypothesis of FHHNC and oligogenic inheritance of amelogenesis. Analysis of the WES binary sequence alignment/map file revealed the presence of exon 1 of the CLDN16 and absence of the other exons [c.325_c918*? (E2_E5del)]. We confirmed a CLDN16 E2_E5 homozygous deletion by multiplex ligation-dependent probe amplification and polymerase chain reaction assays. Although most mutations causing FHHNC are missense and nonsense mutations in the CLDN16 or CLDN19 gene, large deletions occur and may be misled by WES, which is generally used for genetic screening of oligogenic disorders. The patient received cholecalciferol, magnesium oxide and potassium citrate. Later, the combination with hydrochlorothiazide plus amiloride was prescribed, with a good response during follow-up. Our report broadens the phenotype of FHHNC, including severe early-onset amelogenesis and short stature, and reinforces the phenotype-genotype correlation of the large deletion found in CLDN16.

Metabolic risk factors in children with kidney stone disease: an update.

BACKGROUND: The prevalence of kidney stones in children has significantly increased in the past few decades, with concomitant increased morbidity and healthcare costs worldwide. Assessing metabolic risk factors is essential for diagnosis and specific treatment. The objective of this retrospective study is to identify the epidemiological and clinical characteristics of children under 17 years of age, as well as the metabolic risk factors of nephrolithiasis. METHODS: A total of 300 children with kidney stone disease were included to undergo several clinical tests using a standardized protocol. RESULTS: The mean age was 11.2 years, and the male:female ratio was 1.15:1.0. Biochemical abnormalities were found in 89.3% of all cases. A single urine metabolic risk factor was present in 52.6% (n = 141) of the patients, and multiple risk factors were present in 36.7% (n = 106). Idiopathic hypercalciuria (alone or in combination) and hypocitraturia (alone or in combination) were the most frequent risk factors identified in 47.0% and 39.6% of these patients, respectively. Renal colic and/or unspecified abdominal pain were the most frequent forms of presentation (76.9%), followed by hematuria in 64.4% with 97.5% of stones located in the upper urinary tract. A positive family history in first-degree and second-degree relatives was found in 64.8% of boys and 61.8% of girls. CONCLUSIONS: We conclude that specific urinary metabolic risk factors can be found in most children with kidney stones, with hypercalciuria and hypocitraturia being the most common diagnoses. Graphical abstract .