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Adolescence is a time for rapid growth that represents an opportunity to influence peak bone mass. Prebiotic agents, such as galacto-oligosaccharides (GOS), increase Ca absorption in animal models and postmenopausal women. The objectives of the present study were to investigate the dose–response relationship of GOS supplementation on Ca absorption during growth and to assess changes in colonic microbiota to better understand the mechanism by which GOS is acting. A total of thirty-one healthy adolescent girls aged 10–13 years consumed smoothie drinks twice daily with 0, 2·5 or 5 g GOS for three 3-week periods in a random order. Fractional Ca absorption was determined from urinary Ca excretion over 48 h at the end of each 3-week period using a dual stable isotope method. Faecal microbiota and bifidobacteria were assessed by PCR–denaturing gradient gel electrophoresis and quantitative PCR. Fractional Ca absorption after the 48 h treatment with control, 5 and 10 g GOS/d was 0·393 (sd 0·092), 0·444 (sd 0·086) and 0·419 (sd 0·099), respectively. Significant improvements in Ca absorption were seen with both low and high doses of GOS compared with the control (P< 0·02), but it was not a dose–response relationship. The increase in absorption was greatest in the urine collected after 24 h, which is consistent with lower gut absorption. Faecal bifidobacteria increased (control 10·89 (sd 13·86), 5 g GOS 22·80 (sd 15·74) and 10 g GOS 11·54 (sd 14·20)) with the GOS treatment (P< 0·03). The results suggest that daily consumption of 5 g GOS increases Ca absorption, which may be mediated by the gut microbiota, specifically bifidobacteria.

Background Fractional excretion of calcium (FeCa) and urine calcium‐to‐creatinine ratios (UCaCr) estimate hypercalciuria, but more data are needed on how well they discriminate between dogs with and without CaOx urolithiasis. Objective To determine the performance of FeCa and UCaCr in predicting CaOx urolith status. Animals One hundred twenty‐one client‐owned, normocalcemic dogs: 42 CaOx stone formers (cases) and 79 controls. Methods Analytical, retrospective, cross‐sectional study. FeCa (%) and UCaCr (mg/mg) were calculated using measurements from urine and blood and were compared by urolith status with Wilcoxon rank‐sum tests. Performance was determined with receiver operating characteristic curves; “optimal” thresholds were selected to maximize sensitivity and specificity. Potential predictors of FeCa and UCaCr (e.g., urolith status, sex, breed, age) were modeled with multivariable regression. Spearman's rank correlation was run for FeCa and UCaCr. Results FeCa and UCaCr were greater in cases than controls (p < 0.001 for both); medians were 0.81 (0.12–2.47) and 0.060 (0.008–0.176) in cases and 0.50 (0.08–2.61) and 0.032 (0.005–0.131) in controls. Optimal thresholds for FeCa (0.56) and UCaCr (0.056) had moderate sensitivity (74% and 60%, respectively) and specificity (58% and 75%, respectively). FeCa and UCaCr were strongly correlated (rho = 0.94, p < 0.001) and lower in males than in females (estimate = −0.70 and −0.64, p = 0.002 and 0.005, respectively). Conclusions and Clinical Importance FeCa or UCaCr perform moderately well for identifying CaOx cases; dogs with high values might benefit from therapy to reduce hypercalciuria. Their high correlation makes the determination of both unnecessary. Lower values in males support the development of sex‐specific thresholds.

Efficacy of sodium-glucose cotransporter 2 inhibitors for kidney stone prevention in nondiabetic patients is unknown. In a double-blind, placebo-controlled, single-center, crossover phase 2 trial, 53 adults (≥18 and <75 years) with calcium ( n  = 28) or uric acid (UA; n  = 25) kidney stones (at least one previous kidney stone event) without diabetes (HbA1c < 6.5%, no diabetes treatment) were randomized to once daily empagliflozin 25 mg followed by placebo or reverse (2 weeks per treatment). Randomization and analysis were performed separately for both stone types. Primary analyses were conducted in the per protocol set. Primary outcomes were urine relative supersaturation ratios (RSRs) for calcium oxalate (CaOx), calcium phosphate (CaP) and UA—validated surrogates for stone recurrence. Prespecified RSR reductions (≥15%) were met in both groups of stone formers. In patients with calcium stones, empagliflozin reduced RSR CaP (relative difference to placebo, −36%; 95% confidence interval, −48% to −21%; P  < 0.001), but not RSRs CaOx and UA. In patients with UA stones, empagliflozin reduced RSR UA (−30%; 95% confidence interval, −44% to −12%; P  = 0.002) but not RSRs CaOx and CaP. No serious or prespecified adverse events occurred. Thus, empagliflozin substantially reduced RSRs in nondiabetic adults with calcium and UA kidney stones. ClinicalTrials.gov registration: NCT04911660 . As part of the SWEETSTONE trial, the authors report the ability of the sodium-glucose cotransporter 2 inhibitor empagliflozin to reduce the likelihood of kidney stone formation in individuals without diabetes.

Patients with chronic kidney disease (CKD) are given calcium carbonate to bind dietary phosphorus, reduce phosphorus retention, and prevent negative calcium balance; however, data are limited on calcium and phosphorus balance during CKD to support this. Here, we studied eight patients with stage 3 or 4 CKD (mean estimated glomerular filtration rate 36ml/min) who received a controlled diet with or without a calcium carbonate supplement (1500mg/day calcium) during two 3-week balance periods in a randomized placebo-controlled cross-over design. All feces and urine were collected during weeks 2 and 3 of each balance period and fasting blood, and urine was collected at baseline and at the end of each week. Calcium kinetics were determined using oral and intravenous 45calcium. Patients were found to be in neutral calcium and phosphorus balance while on the placebo. Calcium carbonate supplementation produced positive calcium balance, did not affect phosphorus balance, and produced only a modest reduction in urine phosphorus excretion compared with placebo. Calcium kinetics demonstrated positive net bone balance but less than overall calcium balance, suggesting soft-tissue deposition. Fasting blood and urine biochemistries of calcium and phosphate homeostasis were unaffected by calcium carbonate. Thus, the positive calcium balance produced by calcium carbonate treatment within 3 weeks cautions against its use as a phosphate binder in patients with stage 3 or 4 CKD, if these findings can be extrapolated to long-term therapy.

Background Reference values for urinary calcium (Ca) and other solutes/creatinine (Cr) ratios in infants and young children are scarce. Its variation with type of lactation administered, breastfed (BF) or formula (F), is incompletely known. Methods A total of 511 spot urine samples from 136 children, aged 6 days to < 5 years, was collected. Urine was collected no fasting in infants < 18 months and first morning fasting in children aged 2.5–4 years. Urinary osmolality, Cr, urea, Ca, phosphate (P), magnesium (Mg), and uric acid (UA) were determined. Values are expressed as solute-to-Cr ratio. Results Urinary values were grouped according to the child’s age: 6–17 days (G1), 1–5 months (G2), 6–12 months (G3), 13–18 months (G4), and 2.5–4 years (G5). G1 was excluded; Ca/Cr and UA/Cr (95th percentile) decreased with age (G2 vs. G5) from 1.64 to 0.39 and 2.33 to 0.83 mg/mg, respectively. The P/Cr median rises significantly with age from 0.31 (G2) to 1.66 mg/mg (G5). Mg/Cr was similar in all groups (median 0.20, 95th percentile 0.37 mg/mg). Ca/Cr (95th percentile) of BF infants was 1.80 mg/mg (< 3 months) and 1.63 mg/mg (3–5 months), much higher than F infants (0.93 and 0.90 mg/mg, respectively). P/Cr and P/Ca were lower in BF infants. Conclusions Values for urinary Ca/Cr, P/Cr, Mg/Cr, and UA/Cr in infants and children < 5 years were updated. BF infants < 6 months showed higher Ca/Cr and lower P/Cr than F infants. New cutoff values to diagnose hypercalciuria in infants < 6 months, according to the type of lactation, are proposed. Graphical abstract A higher resolution version of the Graphical abstract is available as Supplementary information

IntroductionKidney stones constitute a major global healthcare problem and are characterised by high recurrence rates. Thiazide and thiazide-like diuretics (thiazides) have been the standard medical treatment for the prevention of kidney stone recurrence. This clinical routine has recently been challenged by the findings of the large NOSTONE trial that failed to show superiority of hydrochlorothiazide at doses up to 50 mg daily over placebo in preventing a composite of clinical or radiological recurrence in patients at high risk of kidney stone recurrence. If these results also apply to the longer-acting and more potent thiazides indapamide and chlorthalidone remains unknown. No head-to-head comparison of different thiazides for kidney stone recurrence prevention or for the established proxies of recurrence risk, urine relative supersaturation ratios, has ever been conducted.Methods and analysisINDAPACHLOR is a single-centre, randomised, double-blind, cross-over trial evaluating the efficacy of indapamide or chlorthalidone compared with hydrochlorothiazide in lowering urine relative supersaturation ratios for calcium oxalate and calcium phosphate in individuals with idiopathic calcium kidney stones. Participants will be allocated to indapamide 2.5 mg once daily, chlorthalidone 25 mg once daily and hydrochlorothiazide 50 mg once daily in a random sequence. The three consecutive active treatment periods of 28 days each will be separated by wash-out periods of 28 days. Inclusion criteria are age ≥18 years and ≥2 stone episodes in the last 10 years with calcium-containing kidney stones (containing ≥50% of calcium oxalate, calcium phosphate or a mixture of both). Patients with secondary causes of calcium kidney stones are excluded. The primary outcomes are the changes in the relative supersaturation ratios of calcium oxalate and calcium phosphate from baseline to day 28 of each treatment period. Secondary outcomes include changes in 24 hours urine and blood parameters from baseline to day 28 of each treatment period. The study targets enrolment of 99 participants to achieve 80% power for detecting a 20% reduction in the relative supersaturation ratios of calcium oxalate and calcium phosphate when treated with indapamide or chlorthalidone and hydrochlorothiazide.Ethics and disseminationThe study was approved by the Ethics Commission Bern, Switzerland, and the Competent Authority Swissmedic. Results will be disseminated through peer-reviewed publications and conference presentations.Trial registration numbersClinicalTrials.gov (NCT06111885) and Swiss National Clinical Trials Portal (SNCTP000006156).Protocol versionVersion 4.0, 29 November 2024.

This randomized trial, involving men with recurrent calcium oxalate stones and hypercalciuria, compared the effectiveness of a low-calcium diet with one containing a normal amount of calcium but restricted amounts of animal protein and salt. After five years, only 12 of the 60 men on the diet with normal calcium, low animal protein, and low salt had recurrent stones, as compared with 23 of the 60 men on the low-calcium diet (relative risk of a recurrence among those on the normal-calcium, low-protein, low-salt diet, 0.49; 95 percent confidence interval, 0.24 to 0.98; P=0.04). This randomized trial involved men with recurrent calcium oxalate stones and hypercalciuria. Restriction of animal-protein and salt intake was more effective than restriction of calcium intake. Idiopathic hypercalciuria is an important 1 and common 2 risk factor for the formation of stones, and uncontrolled hypercalciuria is a cause of recurrences. 3 Thiazides can reduce urinary calcium excretion, 4 but since calcium excretion depends in part on diet, 5 initial attempts to decrease hypercalciuria should involve dietary modification. Since most patients with hypercalciuria have intestinal hyperabsorption of calcium, 6 it is common clinical practice to recommend a low-calcium diet. However, there are no long-term data on the efficacy of this approach. Short-term studies have shown that a low calcium intake significantly reduces urinary calcium excretion but can cause a deficiency of calcium and . . .

Clinical guidelines disagree on whether the identification of abnormal urine chemistries should occur before starting diet and medication interventions to prevent the recurrence of kidney stone events. We describe the rationale and design of the Urinary supersaturation in a Randomized trial among Individuals with Nephrolithiasis comparing Empiric versus selective therapy (URINE) study, a randomized trial comparing two multi-component interventions to improve urinary supersaturation. Participants are randomized (1:1 ratio) to the empiric or selective arm. The target sample size is 56 participants. Adults ≥ 18 years of age with idiopathic calcium stone disease and two symptomatic stone events within the previous 5 years. Exclusion criteria include systemic conditions predisposing to kidney stones and pharmacologic treatment for stone prevention at baseline. Participants in the empiric arm receive standard diet therapy recommendations, thiazide, and potassium citrate. Participants in the selective arm receive tailored diet and nutrient recommendations and medications based on baseline and 1-month follow-up of 24-h urine testing results. The primary endpoints are urinary supersaturations of calcium oxalate and calcium phosphate at 2 months of follow-up. Secondary endpoints include side effects, diet and medication adherence, and changes in 24-h urine volume, calcium, oxalate, citrate, and pH. Short-term changes in urinary supersaturation may not reflect changes in future risk of stone events. The URINE study will provide foundational data to compare the effectiveness of two prevention strategies for kidney stone disease.

Soluble maize fibre (SCF) has been found to significantly improve bone mineral density and strength in growing rats compared with several other novel prebiotic fibres. The objective of the present study was to investigate the effect of SCF on Ca absorption and retention in pubertal children by studying the potential absorption mechanisms of the intestinal microbiota. A total of twenty-four adolescent boys and girls (12–15 years) participated in two 3-week metabolic balance studies testing 0 g/d SCF (control (CON) treatment) and 12 g/d SCF (SCF treatment) in a random order by inclusion in a low-Ca diet (600 mg/d). Fractional Ca absorption was measured at the end of the two intervention periods using a dual-stable isotope method. Diet composites and faecal and urine samples were collected daily and analysed for Ca content. Ca retention was calculated as dietary Ca intake minus Ca excretion in faeces and urine over the last 2 weeks. Microbial community composition in the faecal samples collected at the beginning and end of each session was determined by 454 pyrosequencing of the PCR-amplified 16S ribosomal RNA gene. Fractional Ca absorption was 12 % higher (41 mg/d) after the SCF treatment compared with that after the CON treatment (0·664 (sd 0·129) and 0·595 (sd 0·142), respectively; P= 0·02), but Ca retention was unaffected. The average proportion of bacteria of the phylum Bacteroidetes was significantly greater in the participants after the SCF treatment than after the CON treatment. These results suggest that moderate daily intake of SCF, a well-tolerated prebiotic fibre, increases short-term Ca absorption in adolescents consuming less than the recommended amounts of Ca.

X-linked hypophosphatemia (XLH) is the most common heritable form of rickets and osteomalacia. XLH-associated mutations in phosphate-regulating endopeptidase (PHEX) result in elevated serum FGF23, decreased renal phosphate reabsorption, and low serum concentrations of phosphate (inorganic phosphorus, Pi) and 1,25-dihydroxyvitamin D [1,25(OH)2D]. KRN23 is a human anti-FGF23 antibody developed as a potential treatment for XLH. Here, we have assessed the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and immunogenicity of KRN23 following a single i.v. or s.c. dose of KRN23 in adults with XLH. Thirty-eight XLH patients were randomized to receive a single dose of KRN23 (0.003-0.3 mg/kg i.v. or 0.1-1 mg/kg s.c.) or placebo. PK, PD, immunogenicity, safety, and tolerability were assessed for up to 50 days. KRN23 significantly increased the maximum renal tubular threshold for phosphate reabsorption (TmP/GFR), serum Pi, and 1,25(OH)2D compared with that of placebo (P<0.01). The maximum serum Pi concentration occurred later following s.c. dosing (8-15 days) compared with that seen with i.v. dosing (0.5-4 days). The effect duration was dose related and persisted longer in patients who received s.c. administration. Changes from baseline in TmP/GFR, serum Pi, and serum 1,25(OH)2D correlated with serum KRN23 concentrations. The mean t1/2 of KRN23 was 8-12 days after i.v. administration and 13-19 days after s.c. administration. Patients did not exhibit increased nephrocalcinosis or develop hypercalciuria, hypercalcemia, anti-KRN23 antibodies, or elevated serum parathyroid hormone (PTH) or creatinine. KRN23 increased TmP/GFR, serum Pi, and serum 1,25(OH)2D. The positive effect of KR23 on serum Pi and its favorable safety profile suggest utility for KRN23 in XLH patients. Trial registration. Clinicaltrials.gov NCT00830674. Funding. Kyowa Hakko Kirin Pharma, Inc.