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Background: Children's urinary system stones may develop from environmental, metabolic, anatomical, and other causes. Our objective is to determine the recurrence and prognosis, demographic, clinical, and etiological characteristics of children with urolithiasis., Methods: Medical records of patients were evaluated retrospectively. Patients' demographic data and medical history, serum/urine biochemical and metabolic analysis, blood gas analysis, stone analysis, imaging findings, and medical/surgical treatments were recorded., Results: The study included 364 patients (male 187). Median age at diagnosis was 2.83 (IQR 0.83-8.08) years. The most common complaints were urinary tract infection (23%) and urine discoloration (12%). Sixty-two percent had a family history of stone disease. At least one metabolic disorder was found in 120 (88%) of 137 patients having all metabolic analyses: hypercalciuria was found in 45%, hypocitraturia in 39%, and hyperoxaluria in 37%. Anatomical abnormalities were detected in 18% of patients. Of 58 stones analyzed, 65.5% were calcium and 20.6% were cystine stones. Stone recurrence rate was 15% (55/364). Older age (> 5 years), family history of stone disease, stone size (≥ 5 mm), and urinary system anatomical abnormalities were significantly associated with stone recurrence (p = 0.027, p = 0.031, p < 0.001, and p < 0.001, respectively). In adjusted logistic regression analysis, stone size ≥ 5 mm (OR 4.85, 95% CI 2.53-9.3), presence of urinary system anatomical abnormalities (OR 2.89, 95% CI 1.44-5.78), and family history of stone disease (OR 2.41, 95% CI 1.19-4.86) had increased recurrence rate., Conclusions: All children with urolithiasis should be evaluated for factors affecting stone recurrence. Children at higher risk of recurrence need to be followed carefully., (© 2024. The Author(s).)

Sex differences in kidney stone formation are well known. Females generally have slightly acidic blood and higher urine pH when compared with males, which makes them more vulnerable to calcium stone formation, yet the mechanism is still unclear. We aimed to examine the role of sex in stone formation during hypercalciuria and urine alkalinization through acetazolamide and calcium gluconate supplementation, respectively, for 4 weeks in wild-type (WT) and moderately hypercalciuric [TRPC3 knockout [KO](-/-)] male and female mice. Our goal was to develop calcium phosphate (CaP) and CaP+ calcium oxalate mixed stones in our animal model to understand the underlying sex-based mechanism of calcium nephrolithiasis. Our results from the analyses of mice urine, serum, and kidney tissues show that female mice (WT and KO) produce more urinary CaP crystals, higher [Ca 2+ ], and pH in urine compared to their male counterparts. We identified a sex-based relationship of stone-forming phenotypes (types of stones) in our mice model following urine alkalization/calcium supplementation, and our findings suggest that female mice are more susceptible to CaP stones under those conditions. Calcification and fibrotic and inflammatory markers were elevated in treated female mice compared with their male counterparts, and more so in TRPC3 KO mice compared with their WT counterparts. Together these findings contribute to a mechanistic understanding of sex-influenced CaP and mixed stone formation that can be used as a basis for determining the factors in sex-related clinical studies., (Published by Elsevier Inc.)

Introduction: To overcome the data availability hurdle of observational studies on urolithiasis, we linked claims data with 24-hour urine results from a large cohort of adults with urolithiasis. This database contains the sample size, clinical granularity, and long-term follow-up needed to study urolithiasis on a broad level., Methods: We identified adults enrolled in Medicare with urolithiasis who had a 24-hour urine collection processed by Litholink (2011 to 2016). We created a linkage of their collections results and paid Medicare claims. We characterized them across a variety of sociodemographic and clinical factors. We measured frequencies of prescription fills for medications used to prevent stone recurrence, as well as frequencies of symptomatic stone events, among these patients., Results: In total, there were 11,460 patients who performed 18,922 urine collections in the Medicare-Litholink cohort. The majority were male (57%), White (93.2%), and lived in a metropolitan county (51.5%). Results from their initial urine collections revealed abnormal pH to be the most common abnormality (77.2%), followed by low volume (63.8%), hypocitraturia (45.6%), hyperoxaluria (31.1%), hypercalciuria (28.4%), and hyperuricosuria (11.8%). Seventeen percent had prescription fills for alkali monotherapy, and 7.6% had prescription fills for thiazide diuretic monotherapy. Symptomatic stone events occurred in 23.1% at 2 years of follow-up., Conclusions: We successfully linked Medicare claims with results from 24-hour urine collections performed by adults that were processed by Litholink. The resulting database is a unique resource for future studies on the clinical effectiveness of stone prevention strategies and urolithiasis more broadly.

Regular transfusion and chelation therapy produces increased life expectancy in thalassaemic patients who may develop new complications. Since few data are available regarding hypercalciuria in β-thalassaemia major (TM), the aim of our study was to evaluate its prevalence, risk factors and clinical consequences. We enrolled 176 adult TM patients followed at the Center of Thalassemia of Ferrara. Hypercalciuria was defined by a calciuria of 4 mg/kg/day or more in a 24-h urine sample. Anamnestic, biochemical and radiological data were collected. Hypercalciuria prevalence was reported in 69.3% of patients (females 52.5%). Hypercalciuric (HC) patients used deferasirox (DFX) more often than normocalciuric (NC) patients (47.5% vs 29.6%; p < 0.05). In HC subjects plasma parathyroid hormone (PTH) (24.1 ± 10.4 vs 30.1 ± 13.2 pg/ml) and phosphate levels (3.6 ± 0.5 vs 3.8 ± 0.7 mg/dl) were lower, whereas serum calcium (9.6 ± 0.4 vs 9.4 ± 0.4 mg/dl) and urinary 24-h phosphaturia (0.9 ± 0.4 vs 0.6 ± 0.3 g/day) were higher as compared to NC patients (p < 0.05 for all comparisons). Supplementation with oral calcium and cholecalciferol was similar between the groups. A higher rate of kidney stones was present in HC (14.8%) versus NC patients (3.7%) (p < 0.05). Hypercalciuria is a frequent complication in adequately treated adult TM patients. Hypercalciuria prevalence is increased in DFX users whereas haemoglobin level or calcium supplements play no role. A significant proportion of HC patients developed kidney stones., (© 2022 The Authors. British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.)

Background: Vitamin D (VitD) supplementation is recommended by the American Academy of Pediatrics (AAP) for preterm infants to improve bone density. Complications of VitD supplementation include hypercalciuria and nephrocalcinosis (NC). NC has been reported in 7-64% infants < 32 weeks gestational age (GA) or < 1500 g birth weight (BW). The relationships between VitD supplementation, serum 25-hydroxy VitD levels, bone density, hypercalciuria and development of NC in preterm infants are not well established., Methods: Prospective, observational cohort study of 56 infants with GA ≤ 32 weeks or BW ≤ 1800 g. Demographics, dietary intakes, serum 25-hydroxy VitD levels and weekly urinalyses were collected until 40 weeks corrected GA or discharge. Bone mineral density (BMD) and content (BMC) were assessed using dual-energy X-ray absorptiometry (DEXA) scan. NC was identified by kidney ultrasound., Results: 56 infants received on average 447 IU/day of VitD with average serum 25-hydoxy VitD level 39.6 ng/mL. DEXA scan showed average BMD 0.13 g/cm 2 and BMC 35.8 g. 23/56 (41%) infants were diagnosed with NC. Infants with NC had lower GA (p < 0.01) and BW (p < 0.01) and increased presence of calcium oxalate crystals (78% vs. 36%) (p = 0.002). There were no differences in VitD intake, urine calcium/creatinine ratios or BMD and BMC in infants with versus without NC., Conclusions: VitD supplementation per AAP guidelines resulted in acceptable serum 25-hydroxyVitD levels, but no improvement in BMD or BMC compared to previously reported values. However, infants receiving recommended amounts born at earlier GA and lower BW are at increased risk of NC. VitD supplementation and serum levels should be closely monitored in this high-risk population. A higher resolution version of the Graphical abstract is available as Supplementary information., (© 2021. The Author(s), under exclusive licence to International Pediatric Nephrology Association.)

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., Competing Interests: Declaration of Competing Interest Mario Basulto-Martínez declares that he has no conflict of interest. Barbara I Peña-Espinoza that she has no conflict of interest. Rafael Valdez-Ortiz that he has no conflict of interest. Rachel Escalante-Sosa that she has no conflict of interest. Juan P. Flores-Tapia that he has no conflict of interest. Marta Menjivar that she has no conflict of interest., (Copyright © 2021. Published by Elsevier Inc.)

Antibiotics can alter the gut microbiome (GMB), which may be associated with stone disease. We sought to determine the effect that antibiotics have on the GMB, urine ion excretion and stone formation in genetic hypercalciuric stone-forming (GHS) rats. 116th generation GHS rats were fed a fixed amount of a normal calcium (1.2%) and phosphate (0.65%) diet, and divided into three groups (n = 10): control (CTL) diet, or supplemented with ciprofloxacin (Cipro, 5 mg/day) or Bactrim (250 mg/day). Urine and fecal pellets were collected over 6, 12 and 18 weeks. Fecal DNA was amplified across the 16S rRNA V4 region. At 18 weeks, kidney stone formation was visualized by Faxitron and blindly assessed by three investigators. After 18 weeks, urine calcium and oxalate decreased with Bactrim compared to CTL and Cipro. Urine pH increased with Bactrim compared to CTL and Cipro. Urine citrate increased with Cipro compared to CTL and decreased by half with Bactrim. Calcification increased with Bactrim compared to CTL and Cipro. Increased microbial diversity correlated with decreased urinary oxalate in all animals (R = - 0.46, p = 0.006). A potential microbial network emerged as significantly associated with shifts in urinary pH. Bactrim and Cipro differentially altered the GMB of GHS rats. The Bactrim group experienced a decrease in urine calcium, increased CaP supersaturation and increased calcification. The GMB is likely a contributing factor to changes in urine chemistry, supersaturation and stone risk. Further investigation is required to fully understand the association between antibiotics, the GMB and kidney stone formation.

Background & Aims: Abnormalities of parathyroid hormone (PTH) and fibroblast growth factor 23 (FGF23) secretion may cause calcium-phosphate (Ca-P) metabolism disorders in nephrolithiasis. Post-phosphate-load alterations in serum Ca, P and PTH, phosphaturia and calciuria enable monitoring hormonal regulation of Ca-P homeostasis. Our study aimed to determine differences in: 1.selected Ca-P metabolism parameters between healthy and kidney-stone-forming individuals, 2.PTH and FGF23 secretion induced by sodium-phosphate-load(NaP-load) in patients with/without hypercalciuria, 3.secretion of Ca-P related hormones in patients with low and normal/high serum concentrations of 25-hydroxyvitamin D 3 (25OHD 3 )., Methods: Sodium phosphates NaH 2 PO 4 /Na 2 HPO 4 -100mmol were administered orally for five days in 19 hypercalciuric [urinary Ca(U-Ca) 6.5 ± 1.7 mmol/d]-HSF, 35 normocalciuric (2.5±1 mmol/d)-NSF stone-forming patients and 19 controls (U-Ca 2.5 ± 1.4 mmol/d)-CG. On days 1 and 5 PTH-,FGF23-,Ca-,P were determined before and after NaP-load. The areas under PTH, FGF23 curves (AUC) were calculated. U-Ca, urinary phosphate (U-P) and sodium (U-Na) were also determined., Results: Following NaP-load, patients and controls exhibited expected alterations in Ca-P homeostasis. Despite changes in phosphate and PTH, no differences in FGF23 concentrations were observed. Patients differed from controls in having higher AUCPTH, calciuria and natriuresis, taking longer for PTH and P to normalize and lack of correlation between AUCPTH and phosphaturia. Post-NaP-load hypocalciuric effect of PTH secretion in NSF was less pronounced than in CG. In the HSFs, the hypocalciuric effect was more pronounced than in NSFs, but insufficient to correct hypercalciuria. In all stone-formers with low 25OHD 3 concentrations, the AUCFGF23 was significantly increased on first (1215 ± 605vs766 ± 315 p = 0.0457) and fifth days (1211 ± 641vs777 ± 299 p = 0.041) of NaP-load, compared to normal/high 25OHD 3 -patients. Hypercalciuric patients with low 25OHD 3 concentrations had greater AUCPTH5 than those with normal/high 25OHD 3 (1005 ± 401vs835 ± 220 p = 0.0341)., Conclusions: Compared to controls, kidney-stone-forming patients exhibited enhanced PTH secretion after NaP-load. The HSFs showed a more pronounced hypocalciuric effect than NSFs, but insufficient to correct hypercalciuria. In hypercalciuric stone-formers with low 25OHD 3 , FGF23 engagement in hyperphosphatemia reduction increased., Competing Interests: Conflict of Interest All authors of this publication declare no conflicts of interests., (Copyright © 2020 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.)

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 .

The major risk factor for kidney stone disease is idiopathic hypercalciuria. Recent evidence implicates a role for defective calcium reabsorption in the renal proximal tubule. We hypothesized that claudin-2, a paracellular cation channel protein, mediates proximal tubule calcium reabsorption. We found that claudin-2-null mice have hypercalciuria due to a primary defect in renal tubule calcium transport and papillary nephrocalcinosis that resembles the intratubular plugs in kidney stone formers. Our findings suggest that a proximal tubule defect in calcium reabsorption predisposes to papillary calcification, providing support for the vas washdown hypothesis. Claudin-2-null mice were also found to have increased net intestinal calcium absorption, but reduced paracellular calcium permeability in the colon, suggesting that this was due to reduced intestinal calcium secretion. Common genetic variants in the claudin-2 gene were associated with decreased tissue expression of claudin-2 and increased risk of kidney stones in 2 large population-based studies. Finally, we describe a family in which males with a rare missense variant in claudin-2 have marked hypercalciuria and kidney stone disease. Our findings indicate that claudin-2 is a key regulator of calcium excretion and a potential target for therapies to prevent kidney stones.

Background: The incidence of nephrolithiasis in children and adolescents is increasing and appears to double every 10 years. The most important role of the pediatric nephrologist is to diagnose and modify various metabolic and non-metabolic risk factors, as well as prevent long-term complications especially in the case of recurrent nephrolithiasis., Objective: The purpose of this review is to summarize the existing literature on the etiology and management of pediatric nephrolithiasis., Results: The incidence of kidney stones is increasing; dietary and environmental factors are probably the main causes for this increased incidence. In most pediatric patients, the etiology for the kidney stones can be identified. Metabolic factors, such as hypercalciuria and hypocitraturia, urinary tract infection, and urinary stasis, constitute leading causes. Herein, we review the etiologies, diagnostic work-up, and treatment options for the most prevalent causes of kidney stones. The detrimental effects of excessive dietary sodium, reduced fluid intake, and the benefits of plant-based over animal-based protein consumption on urinary crystal formation are discussed. We also review the long-term complications., Conclusions: Pediatric nephrologists have an important role in the diagnostic work-up and prevention of recurring nephrolithiasis.

Introduction and Purpose: Distal renal tubular acidosis (DRTA) is a metabolic disorder that associates urolithiasis and urinary pH > 6. The prevalence of DRTA in patients with calcium phosphate stones is not well known. The objective is to determine the prevalence of DRTA in patients with calcium phosphate stones and urinary pH above 6 based on the furosemide test., Methods: A total of 54 patients with calcium phosphate stones and urinary pH above 6.0 were submitted to the furosemide test. The association of DRTA with age, sex, type of stone, stone recurrence, stone bilaterality, 24-h urine biochemistry, and adverse effects of the furosemide test were examined., Results: The furosemide test indicated that 19 of 54 patients (35.2%) had DRTA. The sex ratio was similar in the two groups (p < 0.776). The DRTA group was significantly younger (p < 0.001), and had a higher prevalence of bilateral stones (p < 0.001), a higher prevalence of recurrent stones (p < 0.04), a lower plasma potassium level (p < 0.001), a higher urinary Ca level (p ≤ 0.05), and a lower urinary citrate level (p < 0.001). None of the patients reported adverse effects from the furosemide test., Conclusions: There was a high prevalence of DTRA in patients with urinary pH above 6 and calcium phosphate stones. Young age, bilateral stones, stone recurrence, hypercalciuria, hypocitraturia, and plasma hypokalemia were associated with DRTA. None of the patients reported adverse effects of the furosemide test.

In stone formers (SFs) with idiopathic hypercalciuria, urine pH governs the mineral phase of stones. Calcium phosphate (CaP) SFs have higher urine pH than calcium oxalate (CaOx) SFs. Normal women have higher urine pH than men on fixed diets, accompanied by greater absorption of food alkali. Female CaP and male CaOx SFs have similar urine pH as same sex normal individuals, but male CaP and female CaOx SFs may have abnormal acid-base handling. We studied 25 normal individuals (13 men and 12 women), 17 CaOx SFs (11 men and 6 women), and 15 CaP SFs (8 men and 7 women) on fixed diets. Urine and blood samples were collected under fasting and fed conditions. Female CaOx SFs had lower urine pH and lower alkali absorption, fed, compared with normal women; their urine NH 4 was higher and urine citrate excretion lower than in normal women, consistent with their higher net acid excretion. Male CaOx SFs had higher urine citrate excretion and higher serum ultrafilterable citrate levels than normal men. Both male and female CaP SFs had higher urine pH fasting than same sex normal individuals, but only men were higher in the fed period, and there were no differences from normal in gut alkali absorption. CaP SFs of both sexes had higher urine NH 4 and lower urine citrate than same sex normal individuals. The lower urine pH of female CaOx SFs seems related to decreased gut alkali absorption, while the higher pH of CaP SFs, accompanied by higher urine NH 4 and lower urine citrate, suggests a proximal tubule disorder.

The expression of vitamin D receptor (VDR) and 1,25-dihydroxyvitamin D 3 [1,25(OH)D] levels exceed the values of controls in some but not all hypercalciuric stone formers (HSF). We aimed to evaluate serum 1,25(OH)D levels, the expression of VDR, CYP27B1, and CYP24A1 hydroxylases in HSF in comparison with normocalciuric stone formers (NSF) and healthy subjects (HS). Blood samples, 24-h urine collections and a 3-day dietary record were obtained from 30 participants from each of the groups. The expression of VDR, CYP27B1, and CYP24A1 was measured by flow cytometry. HSF presented significantly higher urinary volume, sodium, magnesium, oxalate, uric acid, and phosphorus than NSF and HS. Calcium intake was lower in HSF versus NSF and HS (442 ± 41 vs 594 ± 42 and 559 ± 41 mg/day, respectively, p = 0.027). Ionized calcium was significantly lower in HSF than NSF (1.29 ± 0.0 vs 1.31 ± 0.0 mmol/L, p < 0.01). Serum 1,25(OH)D was significantly higher in HSF and NSF than HS (22.5 ± 1.2; 22.2 ± 1.2 vs 17.4 ± 1.2 pg/ml, p = 0.007) but serum 25(OH)D, PTH, klotho and plasma FGF-23 did not differ between groups. VDR expression was higher in HSF and NSF than HS (80.8 ± 3.2; 78.7 ± 3.3 vs 68.6 ± 3.2%, p = 0.023). Although CYP27B1 and CYP24A1 expressions were similar among all groups, the ratio of 1,25(OH)D/CYP24A1 was higher in HSF and NSF than in HS (1.43 ± 0.25 and 0.56 ± 0.10 vs 0.34 ± 0.06, p = 0.00). Stone formers, regardless of urinary calcium excretion, had higher VDR expression and 1,25(OH)D levels than HS, even in ranges considered normal. Higher 1,25(OH)D/CYP24A1 ratio suggested a lower degradation of 1,25(OH)D by CYP24A1 in HSF and NSF.

Calcineurin inhibitors (CNIs) are immunosuppressive drugs used to prevent graft rejection after organ transplant. Common side effects include renal magnesium wasting and hypomagnesemia, which may contribute to new-onset diabetes mellitus, and hypercalciuria, which may contribute to post-transplant osteoporosis. Previous work suggested that CNIs reduce the abundance of key divalent cation transport proteins, expressed along the distal convoluted tubule, causing renal magnesium and calcium wasting. It has not been clear, however, whether these effects are specific for the distal convoluted tubule, and whether these represent off-target toxic drug effects, or result from inhibition of calcineurin. The CNI tacrolimus can inhibit calcineurin only when it binds with the immunophilin, FKBP12; we previously generated mice in which FKBP12 could be deleted along the nephron, to test whether calcineurin inhibition is involved, these mice are normal at baseline. Here, we confirmed that tacrolimus-treated control mice developed hypomagnesemia and urinary calcium wasting, with decreased protein and mRNA abundance of key magnesium and calcium transport proteins (NCX-1 and Calbindin-D 28k ). However, qPCR also showed decreased mRNA expression of NCX-1 and Calbindin-D 28k , and TRPM6. In contrast, KS-FKBP12 -/- mice treated with tacrolimus were completely protected from these effects. These results indicate that tacrolimus affects calcium and magnesium transport along the distal convoluted tubule and strongly suggests that inhibition of the phosphatase, calcineurin, is directly involved., (© 2020 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society.)

Study Question: Can whole exome sequencing (WES) reveal a novel pathogenic variant in asthenozoospermia in a multiplex family including multiple patients?, Summary Answer: Patients were discovered to be homozygous for a rare 2-bp deletion in the ADCY10 coding region (c.1205&#95;1206del, rs779944215)., What Is Known Already: ADCY10 encodes for soluble adenylyl cyclase (sAC), which is the predominant adenylate cyclase in sperm. It is already established that proper sAC activity and a constant supply of cAMP are crucial to sperm motility regulation, and knockout mouse models have been reported as severely asthenozoospermic. ADCY10 is a susceptibility gene for dominant absorptive hypercalciuria (OMIM#143870); however, no ADCY10 variations have been confirmed to cause human asthenozoospermia to date., Study Design, Size, Duration: This was a retrospective genetics study of a highly consanguineous pedigree of asthenozoospermia. The subject family was recruited in Iran in 2016., Participants/materials, Setting, Methods: The two patients were diagnosed as asthenozoospermic through careful clinical investigations. Both patients, respective parents, and an unaffected brother were subjected to WES. The discovered variant was validated by Sanger sequencing and segregated with the phenotype. To confirm the pathogenicity of the variant, sperm samples from both patients, 10 normozoospermic men and 10 asthenozoospermic patients not representing the variation, were treated with a cAMP analogue dissolved in human tubal fluid medium, followed by computer-assisted sperm analysis and statistical analyses., Main Results and the Role of Chance: The discovered homozygous variant occurs at 10 amino acids upstream of the ADCY10 nucleotide binding site leading to a premature termination (p.His402Argfs*41). Treatment of the patients' sperm samples with a cell-permeable cAMP analogue resulted in a significant increase in sperm motility, indicating the pathogenic role of the variant. Moreover, absorptive hypercalciuria, segregating within the family, was also associated with the same variant following a dominant inheritance., Limitations, Reasons for Caution: Though nonsense-mediated decay is highly likely to occur in the mutated transcripts, we were not able to confirm this due to low RNA levels in mature sperm., Wider Implications of the Findings: Our finding enlarges the phenotypic spectrum associated with the ADCY10 gene, previously described as a susceptibility gene for dominant absorptive hypercalciuria., Study Funding/competing Interest(s): This study was supported by grants from the Royan Institute, Tehran, Iran, and San Raffaele Hospital, Milan, Italy. The authors have no conflict of interest., Trial Registration Number: N/A., (© The Author(s) 2019. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objective: Considering the predictive role of the relatively low urinary citrate for stone formation, especially in hypercalciuric patients, this study is aimed at comparing urine calcium to citrate (Ca/Cit) ratio in 3 groups of children, including patients with idiopathic hypercalciuria with and without renal stone as well as the healthy children., Methods: This study was carried out on 96 children (2 to 12 years old) referred to a pediatric nephrology clinic in the city of Ahvaz, Southwest Iran. All the children underwent renal ultrasonography, urinalysis, and measurement of random nonfasting urine Ca, Cr, and citrate. Those with secondary hypercalciuria, urinary tract malformations, and/or functional abnormalities of the gastrointestinal tract were excluded from the study., Results: The mean Ca/Cit. ratio (mg/mg) in the three groups, including children with hypercalciuric with and without renal stones and the healthy children (control group), was 0.44 ± 0.14, 0.39 ± 0.13, and 0.19 ± 0.08, respectively, which showed a significant difference (P < .001). There was also a significant difference in Ca/Cit ratio between the first and the control group by Tukey's range test (P < .001). Mean urinary Ca/Cit ratio in those with a positive family history of urolithiasis within three groups was 0.42 ± 0.17 and in those with a negative family history was 0.32 ± 0.16 (P = .013). Mean Ca/Cit. ratio (mg/mg) of 0.25 showed a sensitivity of 90.6% (confidence interval: 75.7-96.7%) and a specificity of 81.2% (confidence interval: 64.7-91.1%) to differentiate between the renal stone group and the control group., Conclusion: High Ca/Cit ratio can predict stones formation in hypercalciuric patients, especially in those with a positive family history of urolithiasis. The present study found the cutoff level of 0.25 for Ca/Cit. ratio as the highest prognostic value for renal stone formation., (Copyright © 2018 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

In the last decades, proteomics has been largely applied to the Nephrology field, with the double aim to (1) elucidate the biological processes underlying renal diseases; (2) identify disease-specific biomarkers, predictor factors of therapeutic efficacy and prognostic factors of disease progression. Kidney stone disease, and in particular, inherited nephrolithiasis (INL) are not an exception. Given the multifactorial origin of these disorders, the combination of genomics and proteomics studies may complement each other, with the final objective to give a global and comprehensive mechanistic view. In this review, we summarize the results of recent proteomic studies which have expanded our knowledge about INL, focusing the attention on monogenic forms of nephrolithiasis (cystinuria, Dent's disease, Bartter syndrome, distal renal tubular acidosis and primary hyperoxaluria), on polygenic hypercalciuria and on medullary sponge kidney disease.

Introduction: Whether administrating of vitamin D supplements increases the risk of hypercalciuria is still unanswered. The aim of the present study was to determine whether use of vitamin D supplementation might increase the risk of hypercalciuria., Methods and Materials: This interventional study was conducted on 30 who suffered from vitamin D insufficiency and deficiency and also had a history of nephrolithiasis. The patients were treated with vitamin D supplement (50000 units per week for 2 months and then every 2 weeks until the end of the 3rd month). Serum and urinary biomarkers were measured at baseline and 3 months after start of vitamin D therapy., Results: Administrating vitamin D supplement for 3 months led to a significant increase in serum level of 25-hydroxyvitamin D from 10.4 ± 4.2 ng/mL to 44.0 ± 10.7 ng/mL (P < .001). Also, the median level of serum parathyroid hormone was significantly reduced from 53 ng/L (interquartile range, 22 ng/L to 163 ng/L) to 38 ng/L (interquartile range, 16 ng/L to 102 ng/L; P < .001). There was also a significant increase in urinary citrate after using vitamin D supplement compared with the baseline from 341 mg (interquartile range, 90 mg to 757 mg) to 411 mg (interquartile range, 115 mg to 1295 mg; P = .045). Comparing biochemical parameters between the groups who developed 15% and greater and less than 15% increase in urinary calcium showed no significant difference after treatment., Conclusions: The use of vitamin D supplements in conventional dose in patients with vitamin D deficiency may not lead to increased risk of hypercalciuria.

Introduction: Both dietary restriction of sodium chloride (NaCl) and treatment with thiazides have been used in hypercalciuric patients., Objectives: To calculate regular salt intake and investigate the correlation between natriuresis and urinary calcium with usual diet (B) and after changing the amount of NaCl intake and administration of thiazides., Material and Methods: Nineteen healthy young individuals had their diet replaced by 2l of Nutrison ® Low Sodium (500mg sodium/day) daily for two days. Then, 5g of NaCl were added every two days («5», «10» and «15»), administering 50mg (H50) and 100mg (H100) of Higroton ® on the last two days. Blood sodium, plasma renin activity (PRA) and aldosterone were determined in venous blood samples, as were urinary sodium and calcium., Statistical Analysis: Wilcoxon t-test and the Pearson linear correlation were calculated., Results: Urinary Na (mEq/24h): 210.3±87.6 («B»); 42.7±20.4 («5»); 135.5±50.6 («10»); 225.5±56.7 («15»). Urinary calcium (mg/24h): 207.8±93.6 («B»); 172.8±63.1 («5»); 206.2±87.7 («10»); 227.4±84.1 («15»). A positive correlation was observed between natriuresis and urinary calcium in «10» (r=0.47) and «15» (r=0.67). After Higroton ® , natriuresis: 232.3±50.7; 377±4 (H50); 341.1±68.4 (H100); Ca in urine: 209.8±57.4; 213.2±67.6 (H50); 159.1±52.2 (H100)., Conclusions: Salt intake in the population studied was estimated to be 14.9±4.9g/day with a positive correlation found between sodium and calcium urine output with daily intakes of 11.25 and 16.25g of salt. With the usual intake, for each gram of salt, urinary calcium increased by 5.46 mg/24 h and with 100mg of Higroton ® it decreased by 50.7mg/24h. These data could be useful for the management of patients with excretory hypercalciuria or hypoparathyroidism., (Copyright © 2018 Sociedad Española de Nefrología. Published by Elsevier España, S.L.U. All rights reserved.)

Objective: It is anticipated that an intake of vitamin D found acceptable by Endocrine Society Guidelines (10 000 IU/day) with co-administered calcium supplements may result in frequent hypercalciuria and hypercalcaemia. This combination may be associated with kidney stones. The objective of this study was to compare the episodes of hypercalciuria and hypercalcaemia from calcium supplements co-administered with 10 000 IU or 600 IU vitamin D daily. This design allows a comparison of the Institute of Medicine recommendation for the RDA of vitamin D along with the upper limit of calcium intake with the high intake of vitamin D suggested by the Endocrine Society., Context: Harms of currently recommended high intake of vitamin D have not been studied., Design: The design was a randomized controlled trial with 2 groups with evaluation every 3 months for one year: (a) CaCO 3 1200 mg/day with 10 000 IU vitamin D 3 /day or (b) CaCO 3 1200 mg/day with 600 IU vitamin D 3 /day., Patients: This study was conducted in an ambulatory research centre in healthy, white postmenopausal women., Measurements: Serum and 24-hour urine calcium were measured., Results: Hypercalcaemia and hypercalciuria occurred in both groups. At the final visit, 19/48 in the high dose D group had hypercalciuria. The odds of developing hypercalciuria were 3.6 [OR = 3.6(1.39, 9.3)] times higher in the high dose D group. The odds of developing hypercalcaemia did not differ between groups., Conclusions: The safe upper level of vitamin D recommended by the Endocrine Society when accompanied by calcium supplements results in frequent hypercalciuria. The risk of kidney stones at these levels should be investigated., (© 2018 John Wiley & Sons Ltd.)

Purpose: Kidney stone disease is characterized by a relatively high rate of recurrence. In our study we analyzed the association between relative supersaturation and the risk of stone recurrence. Additionally, we examined the association between the risk of recurrence and changes in relative supersaturation and urinary composition after 1 week of medical treatment., Materials and Methods: We performed a post hoc analysis of data from a previously published randomized controlled trial comparing the effect of 2 diets in 120 men with recurrent calcium oxalate stones and hypercalciuria. Baseline and followup 24-hour urine parameters were used to calculate the relative supersaturation of calcium oxalate, calcium phosphate and uric acid using the EQUIL2, JESS and LithoRisk computer programs. Cox models were used to calculate the estimated association between each baseline relative supersaturation, and 1-week changes and the risk of recurrence during followup., Results: During a 5-year followup 35 patients (34%) experienced recurrence. A reduction in calcium oxalate relative supersaturation at 1 week was significantly associated with a lower risk of recurrence using the EQUIL2 calculation (for every 10% reduction from baseline HR 0.92, 95% CI 0.86-1.00, p = 0.044). However, there was no association for relative supersaturation calculated by other methods or for the relative supersaturation of other salts. Changes in the 24-hour urine excretion of citrate, potassium and magnesium were significantly associated with a risk of recurrence., Conclusions: In recurrent stone formers with hypercalciuria baseline values and changes in the relative supersaturation of calcium oxalate may be associated with the risk of recurrence. Changes in urinary citrate, potassium and magnesium following dietary intervention may also be predictive., (Copyright © 2018 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

Purpose: To study (1) the differences in the relative abundance of urinary proteins between children with kidney stones (RS) and hypercalciuria, hypocitraturia, normal metabolic work-up, and healthy controls (HC); (2) the association of these proteins with various diseases., Methods: Quantitative proteomic comparison of pooled urine from RS (N = 30, 24 females, mean age 12.95 ± 4.03 years) versus age- and gender-matched HC, using mass spectrometry. Relative protein abundance was estimated using spectral counting. Proteins of interest were selected using the following criteria: (1) ≥ 5 spectral counts; (2) ≥ twofold difference in spectral counts; and (3) ≤ 0.05 p value for the Fisher's Exact Test., Results: Of the 1813 proteins identified, 229 met the above criteria, with 162 proteins up-regulated in the RS group and 67 up-regulated in HC. The largest group of proteins (30 out of 229) was found to be associated with cardiovascular disease (CVD). Of those, 16 were involved in coagulation, fibrinolysis, and adhesion, 10 in inflammation, 5 in lipid transport and metabolism, and 4 in oxidative stress. All except two were exclusively found in children with hypercalciuria and hypocitraturia, and were not seen in children with normal metabolic work-up., Conclusion: Using a proteomic approach, we found a significant association between hypercalciuric and hypocitraturic nephrolithiasis and CVD in children. The shared risk factors among both diseases are endothelial dysfunction and atherosclerosis caused by abnormal coagulation, adhesion, disturbance of lipid transport and metabolism, oxidative stress and inflammation. Further understanding of the pathophysiological link between nephrolithiasis and CVD is necessary for developing new therapeutic targets.

Background: Molecular and cellular pathophysiological events occurring in the majority of rare kidney diseases remain to be elucidated. Familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC) is a rare autosomal recessive disorder caused by mutations in either CLDN16 or CLDN19 genes. This disease is characterized by massive urinary wasting of magnesium and calcium, osmosis deregulation and polyuria. Patients with p.G20D homozygous mutation in CLDN19 gene exhibit different progression to kidney failure suggesting that beyond the pathogenic mutation itself, other molecular events are favoring disease progression. Due to the fact that biopsy is not clinically indicated in these patients, urinary exosome-like vesicles (uEVs) can be envisioned as a valuable non-invasive source of information of events occurring in the kidney. Exosome research has increased notably to identify novel disease biomarkers but there is no consensus standardized protocols for uEVs isolation in patients with polyuria. For this reason, this work was aimed to evaluate and refine different uEVs isolation methods based on differential centrifugation, the gold standard method., Results: Characterization by NTA, cryo-TEM and immunoblotting techniques identified the most appropriate protocol to obtain the highest yield and purest uEVs enriched fraction possible from urine control samples and FHHNC patients. Moreover, we tested five different RNA extraction methods and evaluated the miRNA expression pattern by qRT-PCR., Conclusions: In summary, we have standardized the conditions to proceed with the identification of differentially expressed miRNAs in uEVs of FHHNC patients, or other renal diseases characterized by polyuria.

Nephrolithiasis is a common urological disease and could be secondary to primary hyperparathyroidism (PHPT). PHPT is traditionally characterised with hypercalcaemia. Recently, a normocalcemic PHPT has been officially recognised at the International Workshops. Regarding this new phenotype, nephrolithiasis is frequently found in studies that evaluate low bone mass. However, until now, no study on aetiology of nephrolithiasis considered normocalcemic PHPT. Hypercalciuria related to PHPT is considered as an important risk factor of stone formation in hypercalcemic PHPT, but the precise relationships between hypercalcemic PHPT and nephrolithiasis and between normocalcemic PHPT and nephrolithiasis remain unclear. In patients with hypercalcemic PHPT, after a surgical cure of PHPT, the renal calcium excretion and stone recurrence rate reduce but remain higher above health controls. This finding implies that abnormalities not caused by PHPT also probably affect stone formation. According to the new guideline, the presence of stones indicates the need for parathyroidectomy in patients with either hypercalcemic or normocalcemic PHPT unless contraindications exist. Patients with contraindications for parathyroidectomy or those who do not want to receive parathyroidectomy should be monitored for signs of disease progression and given of medical management. Moreover, due to decreased but significantly higher frequency of nephrolithiasis above those of healthy controls, patients with nephrolithiasis associated with PHPT after parathyroidectomy still should be motivated to explore strategies to prevent stone occurrence.

Purpose: The aim of the study was assessment of four selected macromolecules level: osteopontin, calgranulin, uromodulin and bikunin in fresh morning urine sample in children with nephrolithiasis in the course of idiopathic hypercalciuria., Materials and Methods: The study included 90 subjects aged from 12 months to 18 years. The study group comprised 57 subjects- children with urinary tract lithiasis in the course of idiopathic hypercalciuria and the control group - 33 healthy children with no history of urolithiasis. Determinations of osteopontin, calgranulin, uromodulin and bikunin levels in the first morning urine were performed., Results: The study group had a significantly decreased osteopontin excretion and significantly increased bikuninexcretion, and increased, however statistically nonsignificant, calgranulin excretion in comparison with the control group. Uromodulin excretion did not differ between groups. In both groups a statistically significant positive correlation was observed between uromodulin and bikunin levels., Conclusion: Children with urinary tract lithiasis in the course of idiopathic hypercalciuria reveal a different distribution of the study proteins than a healthy population.

Introduction and Objectives: Studies have demonstrated associations between nephrolithiasis and systemic conditions, including low bone mineral density (BMD), which may correlate with hypercalciuria in kidney stone formers (KSFs). Traditionally, low BMD is diagnosed with dual-energy X-ray absorptiometry. As a noncontrast CT (NCCT) scan is typically part of a stone evaluation, our objective was to evaluate the association of NCCT-based vertebral BMD with 24-hour urine parameters in KSF., Materials and Methods: This is a retrospective analysis of 99 KSFs who had CT imaging and 24-hour urine studies. For each patient, BMD was estimated at the L1 vertebral body and CT attenuation measured in HU. A threshold of 160 HU was chosen to distinguish normal from low BMD. Univariate and multivariate logistic regression analysis was performed to compare patients with low and normal BMD. Multivariate linear regression was performed to assess for variables associated with 24-hour urine parameters., Results: Patients with low BMD had higher 24-hour urine calcium (219 vs 147 mg/day, p < 0.0001) and larger stone volume (259 vs 78.4 mm 3 , p = 0.009). Multivariate analysis demonstrated age >60 years (odds ratio [OR] 9.3, p < 0.0001) and hypercalciuria (OR 4.34, p = 0.004) correlated with low BMD. Linear regression demonstrated that lower BMD was associated with higher urinary calcium (β-coefficient -0.268, p = 0.009) and lower urinary citrate (β-coefficient 0.332, p = 0.01)., Conclusions: CT-based diagnosis of low mineral bone density is associated with derangement in 24-hour urine calcium and citrate in KSFs, as well as larger stone volumes.

The incidence of urinary tract stones in infancy has been increasing in Turkey. Risk factors and vitamin D receptor (VDR) gene polymorphisms were investigated in infants aged < 1 year who had stones. Forty infants with urinary tract stones and 80 infants without stones, aged < 1 year were enrolled in this study. Detailed surveys were taken of all infants, metabolic parameters and ApaI and FokI VDR gene polymorphisms were investigated. Infants with stones tended to be more commonly fed formula and multivitamins (vitamins A, C, D) (p < 0.05). Positive family history came into prominence in the stony group (p < 0.05). There were no significant differences in ApaI and FokI VDR gene polymorphisms between the groups with stones and the control groups. However, CA genotype of ApaI polymorphism was associated with family history and C allele of ApaI was related with family history and hypercalciuria (p < 0.05). Hypercalciuria emerged as an underlying metabolic abnormality in the etiology of stones, and was observed at a rate of 38%. Infants who are given formula and multivitamins for vitamin D supplementation are at increased risk for the formation of urinary tract stones. VDR gene polymorphisms cause the formation of urinary tract stones and affect calcium (Ca) metabolism.

Hypercalciuria is a main risk factor for kidney stone  formation. TRPV5 is the gatekeeper protein for mediating calcium transport and reabsorption in the kidney. In the present study, we tested the effect of TRPV5 activation with small activating RNA (saRNA), which could induce gene expression by targeting the promoter of the gene, on ethylene glycol (EG)-induced calcium oxalate (CaOx) crystals formation in rat kidney. Five pairs of RNA activation sequences targeting the promoter of rat TRPV5 were designed and synthesized. The synthesized saRNA with the strongest activating effect was selected, and transcellular calcium transportation was tested by Fura-2 analysis. Subsequently, Sprague-Dawley rats were equally divided into three groups and fed with water, 1% EG for 28 days after injecting the negative control saRNA, 1% EG for 28 days after injecting the selected TRPV5-saRNA, respectively. The CaOx crystal formation and the 24-h urine components were assessed. In vitro study, saRNA ds-320 could significantly activate the expression of TRPV5 and transcellular calcium transportation. In vivo study, after 28 days treatment of EG, rats pre-infected with saRNA ds-320 had lower urinary calcium excretion and renal CaOx crystals formation as compared to that pre-infected with negative control saRNA. Activation of TRVP5 with saRNA ds-320 could inhibit EG-induced calcium oxalate crystals formation via promoting urine calcium reabsorption and decreasing urine calcium excretion in rats.

Purpose: The paper focuses on the relationship of risk factors and metabolic disorders with mineralogical composition of calculi, age and gender of calcium oxalate stone formers., Materials and Methods: Stone mineralogical composition, 24 hour biochemistry and pH-profile of urine were examined for sixty four stone formers using powder X-ray diffraction, spectrophotometric and potentiometric techniques., Results: The analysis indicated that 44 % of calculi were composed of pure calcium oxalate monohydrate, whereas other 56 % contained both monohydrate and dihydrate or usually their mixtures with hydroxyl apatite. Hypocitraturia, hypercalciuria and hyperuricosuria were identified as the most frequent disorders. Patients with pure calcium oxalate stones and calcium oxalate mixed with apatite revealed different patterns including age, acid-base balance of urine, calcium, citrate excretion etc.Conclusions: Our results demonstrate that most patients simultaneously reveal several risk factors. The special attention should be paid to normalize the daily citrate, calcium and urate excretion. High risk patients, such as postmenopausal females or stone formers with a high apatite content require a specific metabolic evaluation towards in highlighting abnormalities associated with stone formation.

The formation of urinary stone, urolithiasis, is one the oldest known disease affecting human throughout different civilizations and times. The exact pathophysiological mechanism of urolithiasis is not yet clear, as these calculi are of various types and too complex for simple understanding. A single theory cannot explain its formation; therefore, different theories are presented in various times for its explanation like free particle, fixed particle, Randall's plaque theory. In addition, various factors and components are identified that play an important role in the formation of these urinary calculi. In this review, composition of kidney stones, its prevalence/incidence, explanation of pathophysiological mechanisms and role of various factors; urinary pH, uric acid, parathyroid hormone, citrate, oxalate, calcium and macromolecules; osteopontin, matrix Gla protein, kidney injury molecules, urinary prothrombin fragment-1, Tamm-Horsfall protein, inter-α-inhibitors, have been discussed in detail.

The estimated lifetime risk of nephrolithiasis is growing nowadays, and the formation of kidney stones is frequently promoted by hypercalciuria. Vitamin D, and especially its active metabolite calcitriol, increase digestive calcium absorption-as urinary calcium excretion is directly correlated with digestive calcium absorption, vitamin D metabolites could theoretically increase calciuria and promote urinary stone formation. Nevertheless, there was, until recently, low evidence that 25-hydroxyvitamin D serum levels would be correlated with kidney stone formation, even if high calcitriol concentrations are frequently observed in hypercalciuric stone formers. Low 25-hydroxyvitamin D serum levels have been associated with a broad spectrum of diseases, leading to a huge increase in vitamin D prescription in the general population. In parallel, an increased frequency of kidney stone episodes has been observed in prospective studies evaluating vitamin D alone or in association with calcium supplements, and epidemiological studies have identified an association between high 25-hydroxyvitamin D serum levels and kidney stone formation in some groups of patients. Moreover, urinary calcium excretion has been shown to increase in response to vitamin D supplements, at least in some groups of kidney stone formers. It seems likely that predisposed individuals may develop hypercalciuria and kidney stones in response to vitamin D supplements., Competing Interests: The authors declare no conflict of interest.

Background: Proton pump inhibitor (PPI) induced hypomagnesemia is a completely unexplained issue and cases are still being reported. Long-term use is the main factor, but there are a few articles stating that it may also emerge with short-term use. We aimed to evaluate the changes of serum and urine magnesium levels during shortterm high dose pantoprazol treatment., Methods: The serum and 24-hour urine magnesium levels of 58 patients were evaluated during the course of 2 days. Of 58 patients, 25 were allowed oral intake on the 3rd day of hospitalization and thus, 24-hour urine for 3 days was collected from 33 patients., Results: There were no significant differences in the mean levels of serum magnesium and the median levels of urine magnesium. When the magnesium levels were evaluated by age over and under 60 years, the baseline serum magnesium level was significantly higher than the 1st level in patients aged ≥ 60 years (p = 0.029). The 3rd day serum magnesium level was significantly higher than the baseline and 1st day levels in those aged < 60 years (p = 0.049)., Conclusions: We showed that plasma levels and urinary excretion of magnesium did not change significantly during high-dose pantoprazol treatment. It can be hypothesized that magnesium levels are not affected by PPIs in short-term usage. Age and other contributing factors may have more impact on PPI induced hypomagnesemia. Patients aged over 60 years might be handled carefully under proton pump inhibitors treatment.

Objectives: To characterize the stone risk and the impact of parathyroidectomy on the metabolic profile of patients with primary hyperparathyroidism (PHPT) and urolithiasis., Patients and Methods: We analysed the prospectively collected charts of patients treated at our stone clinic between January 2001 and January 2016 searching for patients with PHPT and urolithiasis. Imaging evaluation of the kidneys, bones and parathyroid glands was assessed. We analysed the demographic data, serum and urinary variables before and after parathyroidectomy. We used a paired t-test, Fisher's test, Spearman's test and anova in the statistical analysis., Results: A total of 51 patients were included. The mean patient age was 57.1 ± 12.1 years and 82.4% were women. Before parathyroidectomy, mean calcium and parathyroid hormone (PTH) levels were 11.2 ± 1.0 mg/dL and 331 ± 584 pg/dL, respectively. Hypercalcaemia was present in 84.3% of patients. All eight patients with normal calcium levels had elevated PTH levels. Only two patients did not have PTH above the normal range, although both had elevated calcium levels. The most common urinary disorders were low urinary volume (64.7%), hypercalciuria (60.8%), high urinary pH (41.2%) and hypocitraturia (31.4%). After parathyroidectomy, the number of patients with hypercalcaemia (n = 4; 7.8%), elevated PTH (n = 17; 33.3%) and hypophosphataemia (n = 3; 5.9%) significantly decreased (P < 0.001). The number of urinary abnormalities decreased and there was a reduction in urinary calcium (P < 0.001), pH (P = 0.001) and citrate levels (P = 0.003)., Conclusion: Individuals with PHPT and nephrolithiasis frequently have elevated baseline PTH and calcium levels. Low volume, hypercalciuria, high urinary pH, and hypocitraturia are the most frequent urinary disorders. Parathyroidectomy is effective in normalizing serum calcium and PTH levels, although other urinary metabolic may persist. Patients should be monitored for the need for citrate supplementation., (© 2017 The Authors BJU International © 2017 BJU International Published by John Wiley & Sons Ltd.)

Introduction: Nephrolithiasis is one of the most common urinary tract diseases. After the first episode of urinary calculus, the risk of recurrence is nearly 40% to 50% at 5 years. Nephrolithiasis is a systemic disease that is associated with some metabolic disorders. This study aimed to provide a picture of the frequency of metabolic abnormalities in patients with nephrolithiasis from west part of Iran., Materials and Methods: Patients with recurrent urinary tract calculi referred to the Nephrology-Urology Clinics in Khorramabad city were recruited. After collection of demographic data of all the patients, 24-hour urine and blood samples were taken to measure biochemical factors., Results: Of the 232 participants, 125 were males and 107 were females. Hyperoxaluria was seen in 93 (40.1%) of the participants, hypercalciuria in 55 (23.7%), hypocitraturia in 58 (25%), and hyperuricosuria in 33 (14.9%). Hyperoxaluria in the males was significantly more frequent than in the female patients. There were no significant differences between the two groups in other urinary metabolic disorders., Conclusions: Patients with nephrolithiasis from Lorestan province may have metabolic characteristics varying from those of regions; ethnicity may be a possible reason. Variation of dietary regimens, such as the amount of meat or vegetable in the diet that can change oxalate, calcium, or citrate of urine, might have influenced the results. Time of sampling is another factor. Population-specific studies are helpful to health care providers for preventive planning for nephrolithiasis.

While vitamin D (vitD) deficiency is thought to contribute to poor health in a variety of ways and should be corrected, there is still concern about giving vitD supplements to patients with a history of nephrolithiasis. The aim is to study the prevalence of vitD deficiency and the effect on stone risk of cholecalciferol (vitD3) supplementation in a cohort of idiopathic stone formers (ISF). We screened for vitD deficiency and urinary measures of stone risk, comparing vitD deficient (serum 25-OH vitD ≤30 nmol/L; ≤12 ng/mL) with vitD insufficient (31-75 nmol/L; 13-30 ng/mL) or vitD replete (>75 nmol/L; >30 ng/mL); we investigated the effect of giving vitD3 (20,000 IU orally, weekly for 4 months) to 37 of the vitD deficients. Thirty-one percent (142/456) were vitD deficient, 57% (259/456) vitD insufficient, and the rest (12%) vitD replete (55/456). Comparison among the groups showed that baseline 24-h urinary measures related to stone risk expressed as concentration ratios over urine creatinine (Cr), such as U. Calcium/Cr, U. Oxalate/Cr, U. Citrate/Cr, and U. Uric acid/Cr were not significantly different. VitD3 supplementation did significantly increase serum 25-OH vitD levels and U. Phosphate/Cr ratios, as well as reduce serum parathyroid hormone (PTH) concentrations. Following vitD3 supplementation, there was an overall rise in 24-h urine calcium excretion, but it failed to reach statistical significance (p = 0.06). U. Calcium/Cr increased in 22 out of 37 patients (average increase +0.07 mmol/mmol), decreased in 14 (average decrease -0.13 mmol/mmol), and remained unchanged in 1; 6 out of 26 initially normocalciuric ISF developed hypercalciuria; and 6 out of 9 patients who became vitD replete were hypercalciuric after supplementation. It is appropriate to monitor urinary Ca excretion in vitD-supplemented stone formers, because it may reveal underlying hypercalciuria in some treated patients.

Introduction and Objective: Despite guidelines, routine 24-hour urine testing is completed in <10% of high-risk, recurrent stone formers. Using surrogates for metabolic testing, such as key patient characteristics, could obviate the cost and burden of this test while providing information needed for proper stone prevention counseling., Methods: We performed a retrospective study of 392 consecutive patients from 2007 to 2014 with ≥2 lifetime stone episodes, >70% calcium oxalate by mineral analysis, and ≥1 24-hour urine collection. We compared mean 24-hour urine values by age in decades. We used logistic regression and receiver operating characteristic (ROC) curve analysis to assess the predictive ability of age, gender, body mass index (BMI), and comorbidities to detect abnormal 24-hour urine parameters., Results: The mean age of the cohort was 51 ± 16 years. Older age was associated with greater urinary oxalate (p-trend <0.001), lower urinary uric acid (UA) (p-trend = 0.007), and lower urinary pH (p-trend <0.001). A nonlinear association was noted between age and urinary calcium or citrate (calcium peaked at 40-49 years, p = 0.03; citrate nadired at 18-29 years, p = 0.001). ROC analysis of age, gender, and BMI to predict 24-hour urine abnormalities performed the best for hyperuricosuria (area under the curve [AUC] 0.816), hyperoxaluria (AUC 0.737), and hypocitraturia (AUC 0.740). Including diabetes mellitus or hypertension did not improve AUC significantly., Conclusions: In our recurrent calcium oxalate cohort, age significantly impacted urinary calcium, oxalate, citrate, and pH. Along with gender and BMI, age can be used to predict key 24-hour urine stone risk results. These data lay the foundation for a risk prediction tool, which could be a surrogate for 24-hour urine results in recurrent stone formers, who are unwilling or unable to complete metabolic testing. Further validation of these findings is needed in other stone populations.

Crystalluria is an imbalance between promoters and inhibitors; the first are the engine of the crystals and the second are made of substances. The biological assays make it possible to demonstrate one or more lithogenic factors observed during the lithiasis. The objective of our work was to study the impact of acidification or alkalization of the urine of lithiasic patients during a cristallurie assessment. All urine in the morning must be stored at room temperature and examined within two-three hours following voiding. 80 lithiasic patients (40 for urinary calcium and 40 for urinary uric acid) were selected from the results of cristalluria: more than 20 calcium-dependent crystals or uric acid crystal/mm 3 . For calcium and uric acid, concentration differences, after acidification and alkalization are observed: r 2 =0.43 (p<0.01) and r 2 =0.36 (p<0.01) respectively. In conclusion, in this lithiasic population with the presence of cystals, this pre-analytical stage is essential for urinary calcium and uric acid, making it possible to establish a diagnosis of certainly for the patient.

Urinary stones and urine composition are the first steps in the process of recurrence prevention, but data concerning the association between the two compositions are scarce in Chinese children with urolithiasis. We retrospectively analyzed the records of children (age range 0-18 years) with urolithiasis in our center between March 2004 and December 2013. Stone analysis was carried out in 382 children and 24-hour urine analysis in 80 children. Analysis of both stone and 24-hour urine composition was completed in 56 children. Stone samples were analyzed by Fourier transform-infrared spectrometry. The major stone constituents were calcium oxalate (78.8 %). Of 80 children with 24 h urine analysis, only 2.5 % were without urinary metabolic abnormalities. Hypocitraturia was recorded in 97.5 %, high sodium excretion in 50.0 %, cystinuria in 48.7 %, hypercalciuria in 18.8 %, small urine volumes in 12.5 %, hyperoxaluria in 5.0 % and hyperuricosuria in 1.3 %. Interestingly, higher urine volumes were recorded in girls than in boys (73.2 ± 58.5 vs 51.3 ± 45.3 mL/kg, p = 0.036). Urine sodium (p = 0.002) and oxalate (p = 0.004) were significantly higher in children >9 year old. Moreover, compared with calcium oxalate stone formers, the urine volume (p = 0.040), citrate (p = 0.007) and cystine (p = 0.004) were higher in patients with cystine stones. Hypocitraturia was the common abnormality among Chinese children with urolithiasis. The surprisingly high incidence of cystinuria is of note.

Background: Using a proteomic approach, we aimed to identify and compare the urinary excretion of proteins involved in lipid transport and metabolism in children with kidney stones and hypercalciuria (CAL), hypocitraturia (CIT), and normal metabolic work-up (NM), and in healthy controls (HCs). Additionally, we aimed to confirm these results using ELISA, and to examine the relationship between the urinary excretion of selected proteins with demographic, dietary, blood, and urinary parameters., Methods: Prospective, controlled, pilot study of pooled urine from CAL, CIT, and NM versus age- and gender-matched HCs, using liquid chromatography-mass spectrometry. Relative protein abundance was estimated using spectral counting. Results were confirmed by ELISA performed on individual samples., Results: Of the 1,813 proteins identified, 230 met the above criteria. Of those, 5 proteins (apolipoprotein A-II [APOA2]; apolipoprotein A-IV [APOA4]; apolipoprotein C-III [APOA3]; fatty acid-binding protein, liver [FABPL]; fatty acid-binding protein, adipocyte [FABP4]) involved in lipid metabolism and transport were found in the CAL group, with significant differences compared with HCs. ELISA analysis indicated statistically significant differences in the urinary excretion of APOC3, APOA4, and FABPL in the CAL group compared with HCs. Twenty-four-hour urinary calcium excretion correlated significantly with concentrations of ApoC3 (r = 0.77, p < 0.001), and FABPL (r = 0.80, p = 0.005)., Conclusions: We provide proteomic data showing increased urinary excretion of lipid metabolism/transport-related proteins in children with kidney stones and hypercalciuria. These findings suggest that abnormalities in lipid metabolism might play a role in kidney stone formation.

Mutations of the CYP24A1 gene, encoding for the enzyme 25(OH)D-24-hydroxylase, can cause hypercalcemia, hypercalciuria, nephrolithiasis and nephrocalcinosis. We report the case of a 22-year-old male patient with recurrent nephrolithiasis, nephrocalcinosis, hypercalcemia with low parathyroid hormone levels, hypercalciuria and low bone mass. Gene sequencing showed that the patient had compound heterozygous mutations including a novel genotype of the CYP24A1 gene. Genetic CYP24A1 testing and biochemical analyses were offered to other family members; the father was heterozygous for the same novel genotype and was also affected with recurrent nephrolithiasis.

The aim of this study was to analyze the presence of lithogenic metabolic factors in the blood and urine of patients with osteopenia versus osteoporosis. This is a cross-sectional study including 67 patients who were divided into two groups according to the presence of either osteopenia or osteoporosis as measured by bone densitometry: group 1-40 patients with osteopenia (22 men and 18 women) and group 2-27 patients with osteoporosis (13 men and 14 women). Metabolic studies were performed on the blood and urine; statistical analysis was performed comparing means and conducting linear correlation and multivariate analyses with SPSS. Statistical significance was considered to be p ≤ 0.05. The mean age of patients in group 1 was 52.9 ± 12.8 years versus 50.3 ± 11.4 in group 2; the difference was not statistically significant. In group 2, higher levels of osteocalcin, β-crosslaps, urinary calcium, fasting urine calcium/creatinine, 24 h urine calcium/creatinine and 24 h oxaluria were observed compared to group 1. In the multivariate analysis, only the β-crosslaps and urinary calcium were independently associated with osteoporosis. It would be advisable to determine the urinary calcium levels in patients with osteoporosis since altered levels may necessitate modifying the diagnostic and therapeutic approach to osteoporosis.

Objective: Hypercalciuria is a common lithogenic risk factor. The aim of this study was, first, to study the characteristics of urine biochemical factors of children with hypercalciuria (HC) and compare them with those of children without hypercalciuria. Second, to analyze the differences between children with HC and lithiasis (HCL) and children with HC and no lithiasis (HCNL)., Methods: The sample was composed by 111 cases with HC, divided into 2 groups: HCNL group, consisting of 93 cases with no personal history of kidney stones, and HCL group, 18 cases with personal history of kidney stones. As a cohort control group, 113 healthy children were used. Creatinine, urea, sodium, potassium, chlorine, uric acid, calcium, phosphorus, magnesium and osmolality: blood and 24-hour urine following parameters were determined. Oxalate and citrate were determined in urine., Results: The mean values of natriuresis, uricosuria, phosphaturia, magnesuria, citraturia, calcium oxalate and calcium phosphate saturation were higher in HCNL than in control group. The HCL group had phosphaturia, calcium oxalate and calcium phosphate saturations more elevated compared with the control group. There were no significant differences in urinary excretion of various parameters when the groups HCL and HCNL were compared., Conclusions: Our results show that children with hypercalciuria without lithiasis associated show an increase in natriuresis, phosphaturia, uricosuria, magnesuria and citraturia. We found no differences between these urinary abnormalities when compared hypercalciuric children without lithiasis with those with hypercalciuria and urolithiasis.

Background: The aim of this study was to show the presence of phosphorus and calcium metabolism disorders and the presence of urine lithogenic factors in women with osteoporotic fracture without previous urinary lithiasis., Methods: We conducted a cross-sectional study including 55 women with osteoporotic fracture surgically treated in the Trauma Department. We included women with osteoporotic fracture demonstrated by the fracture area, fracture mechanism and the presence of osteoporosis by bone densitometry. We analyzed phospho-calcium metabolism as well as the calciuria, oxaluria, citraturia and uricosuria levels with fasting and 24-hour urine study. The presence of abnormal calcium and phosphorus metabolism was compared between women with hypercalciuria and normocalciuria., Results: The 55 women had a mean age of 70.1±13.8 years and a mean body mass index of 27.9±3.8 kg/m2. Forty-percent of the patients showed hypercalciuria, 36.4% hyperoxaluria, 36.4% hypocitraturia, and 5.3% hyperuricosuria. When comparing patients with hypercalciuria and normocalciuria, the only statistically significant difference was fasting urinary calcium/creatinine levels (0.16 versus 0.08, respectively; P<0.0001)., Conclusions: Women with osteoporotic fracture showed several lithogenic factors in the urine studies, mainly fasting hypercalciuria. Although in this study hypercalciuria did not involve the presence of lithiasis, it can favor the appearance of lithiasis with other predisposing conditions. Therefore, an accurate assessment of urine calcium levels with other lithogenic factors, such as citrate and oxalate levels, may facilitate individualized management and treatment of osteoporosis without increasing the risk of nephrolithiasis.

Objectives: One of the important complications of vesicoureteral reflux (VUR) is the development of urolithiasis. Identifying factors involved in development of urolithiasis in children with VUR is immensely important. This study was conducted to determine the association between hypercalciuria and hyperuricosuria with VUR in children., Methods: One-hundred children with VUR (case group) were compared to 100 healthy children (control group) in terms of hypercalciuria and hyperuricosuria. To measure these markers, random morning fasting urine samples were used. Data were analyzed using statistical tests., Results: Hypercalciuria and hyperuricosuria frequencies, and also urine calcium/creatinine (Ca/Cr) and urine uric acid/creatinine (UA/Cr) ratios were significantly higher in the case group compared to the control group (P < 0.05). A significant difference was found between hypercalciuria and hyperuricosuria in severity of VUR (P < 0.05). A positive correlation was observed between hypercalciuria and hyperuricosuria and severity of VUR (P < 0.05)., Conclusions: The present study showed that there is association between hypercalciuria, hyperuricosuria and VUR in children. It is recommended to adopt measures to prevent the development of urolithiasis in VUR patients.

Background: Dent disease 1 is a rare cause of chronic kidney disease (CKD) in childhood secondary to mutations in the gene encoding the chloride-proton exchanger, CLC-5, which is found mainly in the proximal tubule. Clinical manifestations are variable and there are no known genotype-phenotype correlations., Case Diagnosis/treatment: The proband was identified as having a mutation in CLCN5. The extended family of the proband was invited to participate in a study of Dent disease after several males were noted to have a history of CKD. Urine retinol binding protein, urine calcium, serum creatinine, and DNA samples were collected for analysis. Ten hemizygous males and 6 heterozygous females were identified. Advanced CKD was detected in 3 males (1 child). Renal biopsies in 4 children showed both glomerular and tubulo-interstitial changes. There was no correlation between age and disease severity., Conclusions: This is the first reported family from the southern hemisphere with this condition. A novel CLCN5 mutation is described, c.1618G>C (p.Ala540Pro). The severity of renal disease varies greatly among individuals.

Aim: To evaluate the contribution of family history of stones (FHS), up to second-degree relatives, on clinical course (age of first renal colic, bilateral disease, retained calculi, recurrences, urological procedures) of idiopathic calcium nephrolithiasis (ICN) and urinary parameters of lithogenic risk, a case-control study was carried out., Method: Clinical records of 2080 patients with ICN were evaluated and categorized according to FHS. Data about clinical course of disease and urinary parameters of lithogenic risk were collected. Student's t, Chi square tests and binary logistic regression were applied to discriminate groups with vs. without FHS., Results: FHS was associated with an earlier onset of stone disease (age at first episode 32 ± 13 vs. 37 ± 15 years, p <0.001), particularly in females. After adjustment for multiple covariates, FHS was significantly associated to a higher risk of recurrence [odds ratio (OR) 1.2, 95 % confidence interval (1.1-1.4), p = 0.04], retained stones [OR 1.3, CI (1.1-1.5), p = 0.004], bilateral stones [OR 1.2, 95 % CI (1.1-1.5), p = 0.022] and urological procedures [OR 1.2, 95 % CI (1.1-1.5), p = 0.034]. FHS did not influence urinary parameters of lithogenic risk, except for calcium excretion in females., Conclusion: A positive family history influences the clinical course of ICN with some significant gender-related differences, substantially irrespective of urinary parameters of lithogenic risk.

Bartter syndrome Type III is a rare autosomal recessive disorder resulting from an inherited defect in the thick ascending limb of the loop of henle of the nephrons in kidney. The typical clinical manifestations in childhood are failure to thrive and recurrent episodes of vomiting. Typical laboratory findings which help in the diagnosis are hypokalemic metabolic alkalosis, hypomagnesemia and hypercalciuria. We report a case of Type III Bartter syndrome not responding to repeated conventional treatment of failure to thrive.