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BACKGROUND Nephrolithiasis is one of the most common conditions affecting the kidney and is characterized by a high risk of recurrence. Thiazide diuretic agents are widely used for prevention of the recurrence of kidney stones, but data regarding the efficacy of such agents as compared with placebo are limited. Furthermore, dose-response data are also limited. METHODS In this double-blind trial, we randomly assigned patients with recurrent calcium-containing kidney stones to receive hydrochlorothiazide at a dose of 12.5 mg, 25 mg, or 50 mg once daily or placebo once daily. The main objective was to investigate the dose-response effect for the primary end point, a composite of symptomatic or radiologic recurrence of kidney stones. Radiologic recurrence was defined as the appearance of new stones on imaging or the enlargement of preexisting stones that had been observed on the baseline image. Safety was also assessed. RESULTS In all, 416 patients underwent randomization and were followed for a median of 2.9 years. A primary end-point event occurred in 60 of 102 patients (59%) in the placebo group, in 62 of 105 patients (59%) in the 12.5-mg hydrochlorothiazide group (rate ratio vs. placebo, 1.33; 95% confidence interval [CI], 0.92 to 1.93), in 61 of 108 patients (56%) in the 25-mg group (rate ratio, 1.24; 95% CI, 0.86 to 1.79), and in 49 of 101 patients (49%) in the 50-mg group (rate ratio, 0.92; 95% CI, 0.63 to 1.36). There was no relation between the hydrochlorothiazide dose and the occurrence of a primary end-point event (P = 0.66). Hypokalemia, gout, new-onset diabetes mellitus, skin allergy, and a plasma creatinine level exceeding 150% of the baseline level were more common among patients who received hydrochlorothiazide than among those who received placebo. CONCLUSIONS Among patients with recurrent kidney stones, the incidence of recurrence did not appear to differ substantially among patients receiving hydrochlorothiazide once daily at a dose of 12.5 mg, 25 mg, or 50 mg or placebo once daily. (Funded by the Swiss National Science Foundation and Inselspital; NOSTONE ClinicalTrials.gov number, NCT03057431.).

Objective To investigate the relations between caffeine-derived metabolites (methylxanthines) and plasma lipids by use of population-based data from 2 European countries. Methods Families were randomly selected from the general population of northern Belgium (FLEMENGHO), from August 12, 1985, until November 22, 1990, and 3 Swiss cities (SKIPOGH), from November 25, 2009, through April 4, 2013. We measured plasma concentrations (FLEMENGHO, SKIPOGH) and 24-hour urinary excretions (SKIPOGH) of 4 methylxanthines—caffeine, paraxanthine, theobromine, and theophylline—using ultra-high-performance liquid chromatography–tandem mass spectrometry. We used enzymatic methods to estimate total cholesterol, high-density lipoprotein cholesterol, and triglyceride levels and the Friedewald equation for low-density lipoprotein cholesterol levels in plasma. We applied sex-specific mixed models to investigate associations between methylxanthines and plasma lipids, adjusting for major confounders. Results In both FLEMENGHO (N=1987; 1055 [53%] female participants) and SKIPOGH (N=990; 523 [53%] female participants), total cholesterol, low-density lipoprotein cholesterol, and triglyceride levels increased across quartiles of plasma caffeine, paraxanthine, and theophylline (total cholesterol levels by caffeine quartiles in FLEMENGHO, male participants: 5.01±0.06 mmol/L, 5.05±0.06 mmol/L, 5.27±0.06 mmol/L, 5.62±0.06 mmol/L; female participants: 5.24±0.06 mmol/L, 5.15±0.05 mmol/L, 5.25±0.05 mmol/L, 5.42±0.05 mmol/L). Similar results were observed using urinary methylxanthines in SKIPOGH (total cholesterol levels by caffeine quartiles, male participants: 4.54±0.08 mmol/L, 4.94±0.08 mmol/L, 4.87±0.08 mmol/L, 5.27±0.09 mmol/L; female participants: 5.12±0.07 mmol/L, 5.21±0.07 mmol/L, 5.28±0.05 mmol/L, 5.28±0.07 mmol/L). Furthermore, urinary caffeine and theophylline were positively associated with high-density lipoprotein cholesterol in SKIPOGH male participants. Conclusion Plasma and urinary caffeine, paraxanthine, and theophylline were positively associated with plasma lipids, whereas the associations involving theobromine were less clear. We postulate that the positive association between caffeine intake and plasma lipids may be related to the sympathomimetic function of methylxanthines, mitigating the overall health-beneficial effect of caffeine intake.

Background Autosomal dominant polycystic kidney disease (ADPKD) is characterized by a unique bone and mineral phenotype. The impact of tolvaptan treatment on mineral metabolism and bone mineral density (BMD) is unknown. Methods We conducted an analysis in the Bern ADPKD Registry, a prospective observational cohort study. Mineral metabolism parameters were measured at baseline and every 12 months thereafter. BMD was determined by dual-energy X-ray absorptiometry at baseline and after 3 years. Multivariable mixed-effects regression models were applied to assess changes in mineral metabolism parameters and BMD associated with tolvaptan treatment. Results A total of 189 participants (122 without and 67 with subsequent tolvaptan treatment) were included in the analysis. During follow-up, tolvaptan treatment was associated with increased BMD at the femoral neck {β = 0.092 [95% confidence interval (CI) 0.001–0.183], P = .047}. In addition, tolvaptan treatment was associated with higher plasma magnesium [β = 0.019 (95% CI 0.001–0.037), P = .037], bicarbonate [β = 0.972 (95% CI 0.242–1.702), P = .009] and urine pH [β = 0.214 (95% CI 0.056–0.372), P = .008] and lower parathyroid hormone [β = −0.191 (95% CI −0.328 to −0.053), P = .006], 1,25(OH)D3 [β = −0.126 (95% CI −0.235 to −0.164), P = .024] and fractional urinary magnesium excretion [β = −0.473 (95% CI −0.622 to −0.324), P Conclusions Chronic tolvaptan treatment is associated with increased femoral BMD and significant changes in both mineral metabolism and acid–base parameters in ADPKD patients.

Zusammenfassung. Das Wissen um den Steintyp ist für Therapie, Prophylaxe und Verlauf eines Nierensteinleidens zentral. Der Steintyp kann sich im Verlauf eines Steinleidens komplett ändern und Nierensteine sollten daher ausnahmslos einer Analyse zugeführt werden. Dieser Artikel behandelt einige Aspekte der Analysemethoden und Typen von Nierensteinen, die Häufigkeit einzelner Steintypen sowie allgemeine und spezifische Mechanismen der Nierensteinbildung und soll zu einer vertieften Beschäftigung mit dieser Thematik anregen.

Objectives: Urinary biochemistry is used to detect and monitor conditions associated with recurrent kidney stones. There are no predictive machine learning (ML) tools for kidney stone type or recurrence. We therefore aimed to build and validate ML models for these outcomes using age, gender, 24-hour urine biochemistry and stone composition. Materials and Methods: Data from 3 cohorts were used, Southampton, UK (n=3013), Newcastle, UK (n=5984) and Bern, Switzerland (n=794). Of these 3130 had available 24-hour urine biochemistry measurements (calcium, oxalate, urate, pH, volume), and 1684 had clinical data on kidney stone recurrence. Two predictive models were constructed (UK and Swiss) using two ML techniques (Partitioning and Random Forests [RF]) and validated internally with a subset of the same dataset (e.g UK model/UK test set), and externally with the other dataset (UK model/Swiss test set). Results and Limitations: For kidney stone type, on external validation accuracy of UK RF model=0.79 (95% CI: 0.73-0.84), sensitivity: calcium oxalate=0.99 and calcium phosphate/urate=0.00. Specificity: calcium oxalate=0.00 and calcium phosphate/urate=0.99. For the Swiss RF model accuracy=0.87 (95% CI: 0.83-0.89), sensitivity: calcium oxalate=0.99 and calcium phosphate/urate=0.00. Specificity: calcium oxalate=0.00, calcium phosphate=0.00 and urate=1.00. For stone recurrence, on external validation accuracy of UK RF model=0.22 (95% CI: 0.19-0.25), sensitivity=0.93 and specificity=0.09. Swiss RF model accuracy=0.42 (95% CI: 0.39-0.47), sensitivity=0.03 and specificity=0.97. Conclusions: Neither kidney stone type nor kidney stone recurrence can be accurately predicted using modelling tools built using specific 24-hour urinary biochemistry values alone. Further studies to delineate accurate predictive tools should be undertaken using both known and novel risk factors.

Adverse socioeconomic circumstances negatively affect the functioning of biological systems, but the underlying mechanisms remain only partially understood. Here, we explore the associations between life-course socioeconomic factors and four markers of epigenetic aging in a population-based setting.We used data from a population-based study conducted in Switzerland (SKIPOGH) to assess the association between childhood, adulthood, and life-course socioeconomic indicators, and blood-derived markers of epigenetic aging (Levine’s, DunedinPoAm38, GrimAge epigenetic age acceleration (EAA) and the mortality risk score (MS)). We used mixed regression to explore the associations between socioeconomic indicators and markers of epigenetic aging independently, and counterfactual mediation to investigate the mechanisms underlying the life-course socioeconomic gradient in epigenetic aging.Individuals reporting a low father’s occupation, adverse financial conditions in childhood, a low income, having financial difficulties, or experiencing unfavorable socioeconomic trajectories were epigenetically older than their more advantaged counterparts. Specifically, this corresponded to an average increase of 1.0-1.5 years for Levine’s epigenetic age when compared to chronological age, 1.1-1.5 additional years for GrimAge, 5%-8% higher DunedinPoAm38 EAA, and 2%-5% higher MS score. By exploring the life-course mechanisms underlying the socioeconomic gradient in epigenetic aging, we found that both childhood and adulthood socioeconomic factors contributed to epigenetic aging, and that detrimental lifestyle factors mediated the relation between socioeconomic circumstances in adulthood and EAA.Our study provides novel empirical evidence for a “sensitive-period” life-course model, whereby adverse socioeconomic circumstances in childhood and adulthood negatively affected epigenetic aging. Counterfactual mediation analyses further showed that the effect of socioeconomic factors in adulthood operated through detrimental lifestyle factors, whereas associations involving early-life socioeconomic factors were less clear.

Adverse socioeconomic circumstances negatively affect the functioning of biological systems, but the underlying mechanisms remain only partially understood. Here, we explore the associations between life-course socioeconomic factors and four markers of epigenetic aging in a population-based setting. We included 684 participants (52 % women, mean age 52.6 ± 15.5 years) from a population and family-based Swiss study. We used nine life-course socioeconomic indicators as the main exposure variables, and four blood-derived, second generation markers of epigenetic aging as the outcome variables (Levine's DNAmPhenoAge, DunedinPoAm38, GrimAge epigenetic age acceleration (EAA), and the mortality risk score (MS)). First, we investigated the associations between socioeconomic indicators and markers of epigenetic aging via mixed-effect linear regression models, adjusting for age, sex, participant's recruitment center, familial structure (random-effect covariate), seasonality of blood sampling, and technical covariates. Second, we implemented counterfactual mediation analysis to investigate life-course and intermediate mechanisms underlying the socioeconomic gradient in epigenetic aging. Effect-size estimates were assessed using regression coefficients and counterfactual mediation parameters, along with their respective 95 % confidence intervals. Individuals reporting a low father's occupation, adverse financial conditions in childhood, a low income, having financial difficulties, or experiencing unfavorable socioeconomic trajectories were epigenetically older and had a higher mortality risk score than their more advantaged counterparts. Specifically, this corresponded to an average increase of 1.1-1.5 years for Levine's epigenetic age (β and 95 %CI range, β (minimum and maximum): 1.1-1.5 95 %CI[0.0-0.2; 2.3-3.0]), 1.1-1.5 additional years for GrimAge (β: 1.1-1.5 95 %CI[0.2-0.6; 1.9-3.0]), a 1-3 % higher DunedinPoAm38 age acceleration (β: 0.01-0.03 95 %CI[0.00; 0.03-0.04]), and a 10-50 % higher MS score (β: 0.1-0.4 95 %CI[0.0-0.2; 0.3-0.4]) for the aforementioned socioeconomic indicators. By exploring the life-course mechanisms underlying the socioeconomic gradient in epigenetic aging, we found that both childhood and adulthood socioeconomic factors contributed to epigenetic aging, and that detrimental lifestyle factors mediated the relation between socioeconomic circumstances in adulthood and EAA (31-89 % mediated proportion). This study provides emerging evidence for an association between disadvantaged life-course socioeconomic circumstances and detrimental epigenetic aging patterns, supporting the "sensitive-period" life-course model. Counterfactual mediation analyses further indicated that the effect of socioeconomic factors in adulthood operates through detrimental lifestyle factors, whereas associations involving early-life socioeconomic factors were less clear.

Nephrolithiasis is associated with an increased fracture risk, but predictors of bone mineral density (BMD) in stone formers (SFs) remain poorly defined.We conducted a retrospective analysis in the Bern Kidney Stone Registry (BKSR), an observational cohort of kidney SFs. Inclusion criteria were age ≥18 years and ≥1 past stone episode. Participants with non-calcium (Ca)-containing kidney stones, a history of primary hyperparathyroidism or antiresorptive or anabolic bone treatment were excluded. Multivariable linear regression analyses were used to assess the association of blood and 24-hours urine parameters and stone composition with BMD at the lumbar spine and femoral neck.In the analysis, 504 participants were included, mean age was 46 years, and 76% were male. In multivariable analyses, fasting (β: -0.031;Our study reveals distinct predictors of BMD in SFs. Commonly available clinical parameters, such as kidney stone composition results, can be used to identify SFs at risk for low BMD.

Introduction Lipoprotein(a) [Lp(a)] is an LDL-like molecule that is likely causally related to cardiovascular events. Lp(a) levels are highly variable, by more two orders of magnitude, and most of this variability appears to be of genetic origin. Exogenous hormones (hormone replacement therapy) seem to influence Lp(a) levels, but the impact of the variation of endogenous hormone levels on Lp(a) is unknown. Purpose To investigate the association between Lp(a) levels and non-genetic factors, as endogenous steroid hormone levels, in contrast to genetic factors. Methods We investigated the association of 28 endogenous steroids with Lp(a) levels and compared the association to other non-genetic and genetic variables in a prospective, population-based sample (N=1,021). Results The average age of the participants was 51 years and 53% were female. Median Lp(a) levels were 62 (±204) mg/l and the 90th and 99th percentile of Lp(a) was 616mg/l and 1035 mg/l respectively. The prevalence of a Lp(a) elevation ≥700mg/l was 3.2% and Lp(a) varied greatly from undetectable to 1,690mg/l. Age explained 2.0% of Lp(a) variability (p Conclusion Our results confirm previous findings demonstrating that the majority of the Lp(a) variation in the general population is of genetic origin. Age and LDL-levels explain a further small part of Lp(a) variability. Endogenous hormone levels do not contribute significantly to the wide range of variability. Funding Acknowledgement Type of funding sources: None. Coefficient plot Lp(a) and variables

Background: Lipoprotein(a) [Lp(a)] is an LDL-like molecule that is likely causal for cardiovascular events and Lp(a) variability has been shown to be mostly of genetic origin. Exogenous hormones (hormone replacement therapy) seem to influence Lp(a) levels, but the impact of endogenous hormone levels on Lp(a) is still unknown. The aim of the study was to assess the effect of endogenous steroid hormone metabolites on Lp(a). Methods: Lipoprotein(a) levels were measured in 1,021 participants from the Swiss Kidney Project on Genes in Hypertension, a family-based, multicentre, population-based prospective cohort study. Endogenous levels of 28 steroid hormone precursors were measured in 24-h urine collections from 883 individuals. Of the participants with Lp(a) data, 1,011 participants had also genotypes available. Results: The participants had an average age of 51 years and 53% were female. Median Lp(a) levels were 62 mg/L, and the 90thpercentile was 616 mg/L. The prevalence of a Lp(a) elevation ≥700 mg/L was 3.2%. Forty-three per cent of Lp(a) variability was explained respectively by: age (2%, p-16). Of the 28 endogenous steroid hormones assessed, androstenetriol, androsterone, 16α-OH-DHEA and estriol were nominatively associated with serum Lp(a) levels in univariable analyses and explained 0.4%-1% of Lp(a) variability, but none of them reached significance in multivariable models. Conclusions: In this contemporary population-based study, the prevalence of a Lp(a) elevation ≥700 mg/L was 3.2%. The effect of endogenous steroid hormone levels of Lp(a) variability was small at best, suggesting a negligible impact on the wide range of Lp(a) variability.

Context α-klotho is an integral membrane protein that serves as a coreceptor for fibroblast growth factor 23 (FGF23) in conjunction with cognate fibroblast growth factor receptors. Proteolytic cleavage sheds the ectodomain of α-klotho (soluble α-klotho) as an endocrine substance into blood, urine, and cerebrospinal fluid. Objective To study the relationship of soluble α-klotho to mineral metabolism in the general population with mainly preserved kidney function. Design Cross-sectional analysis of the associations between soluble α-klotho with laboratory markers of markers of mineral metabolism in a population-based cohort. Setting Three centers in Switzerland including 1128 participants. Measures Soluble full-length α-klotho levels by a specific immunoassay and markers of mineral metabolism. Results The median serum level of soluble α-klotho was 15.0 pmol/L. Multivariable analyses using α-klotho as the outcome variable revealed a sex-by-PTH interaction: In men, PTH was positively associated with α-klotho levels, whereas this association was negative in women. Plasma phosphate associated with soluble α-klotho levels in an age-dependent manner, changing from a positive association in young adults gradually to a negative association in the elderly. The decline of 1,25 (OH)2 vitamin D3 levels in parallel to the gradual impairment of kidney function was greatly attenuated in the setting of high circulating soluble α-klotho levels. Conclusions Soluble α-klotho level is associated with plasma phosphate in an age-dependent manner and with PTH in a sex-dependent manner. Furthermore, our data reveal soluble α-klotho as a modulator of 1,25 (OH)2 vitamin D3 levels in individuals with preserved renal function.

Sex steroid hormones exhibit anabolic effects whereas a deficiency engenders sarcopenia. Moreover, supraphysiological levels of glucocorticoids promote skeletal muscle atrophy, whereas physiologic levels of glucocorticoids may improve muscle performance. To study the relationship between both groups of steroid hormones at a physiological range with skeletal muscle mass and function in the general population. Cross-sectional analysis of the associations between urinary excreted androgens, estrogens, glucocorticoids, and steroid hormone metabolite ratios with lean mass and handgrip strength in a population-based cohort. Three centers in Switzerland including 1128 participants. Urinary steroid hormone metabolite excretion by gas chromatography-mass spectrometry, lean mass by bioimpedance analysis, and isometric handgrip strength by dynamometry. For lean mass a strong positive association was found with 11β-OH-androsterone and with most glucocorticoids. Androsterone showed a positive association in middle-aged and older adults. Estriol showed a positive association only in men. For handgrip strength, strong positive associations with androgens were found in middle-aged and older adults, whereas positive associations were found with cortisol metabolites in young to middle-aged adults. Sex steroids and glucocorticoids are strongly positively associated with skeletal muscle mass and strength in the upper limbs. The associations with muscle strength appear to be independent of muscle mass. Steroid hormones exert age-specific anabolic effects on lean mass and handgrip strength. Deficits in physical performance of aged muscles may be attenuated by androgens, whereas glucocorticoids in a physiological range increase skeletal muscle mass at all ages, as well as muscle strength in particular in younger adults.

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