The Effect of Thiazide Diuretics on Urinary Prostaglandin E2 Excretion and Serum Sodium in the General Population.

CONTEXT: Thiazide-induced hyponatremia is one of the most common forms of hyponatremia, but its pathogenesis is incompletely understood. Recent clinical data suggest links with prostaglandin E2 (PGE2) and a single nucleotide polymorphism (SNP) in the prostaglandin transporter gene (SLCO2A1), but it is unknown if these findings also apply to the general population. OBJECTIVE: To study the associations between serum sodium, thiazide diuretics, urinary excretions of PGE2 and its metabolite (PGEM), and the rs34550074 SNP in SLCO2A1 in the general population. DESIGN: Prospective population-based cohort study (Rotterdam Study). SETTING: General population. PARTICIPANTS: 2,178 participants (65% female, age 64 ± 8 years). INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Serum sodium levels. RESULTS: Higher urinary PGE2 excretion was associated with lower serum sodium: difference in serum sodium for each two-fold higher PGE2 -0.19 mmol/l (95%CI -0.31 to -0.06), PGEM -0.29 mmol/l (95%CI -0.41 to -0.17). This association was stronger in thiazide users (per two-fold higher PGE2 -0.73 vs. -0.12 mmol/l and PGEM -0.6 vs. -0.25 mmol/l, p for interaction < 0.05 for both). A propensity score matching analysis of thiazide vs. non-thiazide users yielded similar results. The SNP rs34550074 was not associated with lower serum sodium or higher urinary PGE2 or PGEM excretion in thiazide or non-thiazide users. CONCLUSIONS: Serum sodium is lower in people with higher urinary PGE2 and PGEM excretion and this association is stronger in thiazide users. This suggests that PGE2-mediated water reabsorption regulates serum sodium, which is relevant for the pathogenesis of hyponatremia in general and thiazide-induced hyponatremia in specific.

Urinary Prostaglandin E2 Excretion and the Risk of Cardiovascular and Kidney Disease.

BACKGROUND: Inhibition of prostaglandin synthesis by nonsteroidal anti-inflammatory drugs is associated with cardiovascular mortality and kidney disease. This study hypothesizes that urinary prostaglandin E2 (PGE2) and PGE2 metabolite (PGEM) excretions are markers of cardiovascular and kidney health, because they reflect both systemic and kidney-derived PGE2 production. METHODS AND RESULTS: PGE2 and PGEM were measured in spot urine samples from 2291 participants (≥55 years old) of the population-based Rotterdam Study. Urinary PGE2 and PGEM excretions were analyzed using linear regression analyses to identify cross-sectional associations with cardiovascular risk factors and baseline estimated glomerular filtration rate (eGFR). Longitudinal associations with cardiovascular mortality and kidney outcomes (eGFR <60 or <45 mL/min per 1.73 m2 and the composite outcome 40% eGFR loss or kidney failure) were assessed with Cox regression. Urinary PGE2 and PGEM excretions were higher with increasing age, lower eGFR, smoking, diabetes, and albuminuria. A 2-fold higher urinary PGE2 and PGEM excretion was associated with a higher risk of cardiovascular mortality (28 825 patient-years; 160 events; PGE2 hazard ratio [HR], 1.27, [95% CI, 1.06-1.54]; PGEM HR, 1.36 [95% CI, 1.10-1.67]). Higher PGE2 excretions were also associated with a higher risk of incident eGFR <60 mL/min per 1.73 m2 (31 530 person-years; 691 events; HR, 1.13 [95% CI, 1.02-1.25]) with similar HRs for the other kidney outcomes. CONCLUSIONS: Urinary PGE2 and PGEM excretions are novel markers for the presence and progression of cardiovascular and kidney disease. Future studies should address whether these associations are causal and can be targeted to improve cardiovascular and kidney outcomes.

Circulating metabolites associated with kidney function decline and incident CKD: a multi-platform population-based study.

Background: Investigation of circulating metabolites associated with kidney function and chronic kidney disease (CKD) risk could enhance our understanding of underlying pathways and identify new biomarkers for kidney function. Methods: We selected participants from the population-based Rotterdam Study with data on circulating metabolites and estimated glomerular filtration rate based on serum creatinine (eGFRcreat) available at the same time point. Data on eGFR based on serum cystatin C (eGFRcys) and urine albumin-to-creatinine ratio (ACR) were also included. CKD was defined as eGFRcreat <60 ml/min per 1.73 m2. Data on circulating metabolites (ntotal = 1381) was obtained from the Nightingale and Metabolon platform. Linear regression, linear mixed, and Cox proportional-hazards regression analyses were conducted to study the associations between metabolites and kidney function. We performed bidirectional two-sample Mendelian randomization analyses to investigate causality of the identified associations. Results: We included 3337 and 1540 participants with data from Nightingale and Metabolon, respectively. A total of 1381 metabolites (243 from Nightingale and 1138 from Metabolon) were included in the analyses. A large number of metabolites were significantly associated with eGFRcreat, eGFRcys, ACR, and CKD, including 16 metabolites that were associated with all four outcomes. Among these, C-glycosyltryptophan (HR 1.50, 95%CI 1.31;1.71) and X-12026 (HR 1.46, 95%CI 1.26;1.68) were most strongly associated with CKD risk. We revealed sex differences in the associations of 11-ketoetiocholanolone glucuronide and 11-beta-glucuronide with the kidney function assessments. No causal associations between the identified metabolites and kidney function were observed. Conclusion: Our study indicates that several circulating metabolites are associated with kidney function which are likely to have potential as biomarkers, rather than as molecules involved in the pathophysiology of kidney function decline.

Effects of correcting metabolic acidosis on muscle mass and functionality in chronic kidney disease: a systematic review and meta-analysis.

Metabolic acidosis unfavourably influences the nutritional status of patients with non-dialysis dependent chronic kidney disease (CKD) including the loss of muscle mass and functionality, but the benefits of correction are uncertain. We investigated the effects of correcting metabolic acidosis on nutritional status in patients with CKD in a systematic review and meta-analysis. A search was conducted in MEDLINE and the Cochrane Library from inception to June 2023. Study selection, bias assessment, and data extraction were independently performed by two reviewers. The Cochrane risk of bias tool was used to assess the quality of individual studies. We applied random effects meta-analysis to obtain pooled standardized mean difference (SMD) and 95% confidence intervals (CIs). We retrieved data from 12 intervention studies including 1995 patients, with a mean age of 63.7 ± 11.7 years, a mean estimated glomerular filtration rate of 29.8 ± 8.8 mL/min per 1.73 m2 , and 58% were male. Eleven studies performed an intervention with oral sodium bicarbonate compared with either placebo or with standard care and one study compared veverimer, an oral HCl-binding polymer, with placebo. The mean change in serum bicarbonate was +3.6 mEq/L in the intervention group and +0.4 mEq/L in the control group. Correcting metabolic acidosis significantly improved muscle mass assessed by mid-arm muscle circumference (SMD 0.35 [95% CI 0.16 to 0.54], P < 0.001) and functionality assessed with the sit-to-stand test (SMD -0.31 [95% CI -0.52 to 0.11], P = 0.003). We found no statistically significant effects on dietary protein intake, handgrip strength, serum albumin and prealbumin concentrations, and blood urea nitrogen. Correcting metabolic acidosis in patients with CKD improves muscle mass and physical function. Correction of metabolic acidosis should be considered as part of the nutritional care for patients with CKD.

Trajectories of kidney function and risk of mortality.

BACKGROUND: We aimed to identify patterns within the rate of kidney function decline, determinants of these patterns and their association with all-cause mortality risk in the general population. METHODS: Participants aged ≥ 45 years with at least one assessment of creatinine-based estimated glomerular filtration rate (eGFR) taken between 1997 and 2018 were selected from a population-based cohort study. Analyses were performed using several distinct latent class trajectory modelling methods. Cumulative incidences were calculated with 45 years of age as the starting point. RESULTS: In 12 062 participants (85 922 eGFR assessments, mean age 67.0 years, 58.7% women, median follow-up 9.6 years), four trajectories of eGFR change with age were identified: slow eGFR decline [rate of change in mL/min/1.73 m2 per year (RC), -0.9; 95% CI, -0.9 to -0.9; reference group], intermediate eGFR decline (RC, -2.5; 95% CI, -2.7 to -2.5) and fast eGFR decline (RC, -4.3; 95% CI, -4.4 to -4.1), and an increase/stable eGFR (RC, 0.3; 95% CI, 0.3 to 0.4). Women were more likely to have an increase/stable eGFR [odds ratio (OR), 1.94; 95% CI, 1.53 to 2.46] whereas men were more likely to have a fast eGFR decline (OR, 1.86; 95% CI, 1.33 to 2.60). Participants with diabetes, cardiovascular disease (CVD) or hypertension were more likely to have an intermediate or fast eGFR decline. All-cause mortality risks (cumulative incidence at age of 70 years) were 32.3% (95% CI, 21.4 to 47.9, slow eGFR decline), 6.7% (95% CI, 3.5 to 12.4, intermediate eGFR decline), 68.8% (95% CI, 44.4 to 87.8, fast eGFR decline) and 9.5% (95% CI, 5.5 to 15.7, increase/stable eGFR). CONCLUSION: Sex, hypertension, diabetes and CVD were identified as trajectory membership determinants. Having fast eGFR decline was associated with the highest risk of all-cause mortality, highlighting the need for extensive monitoring and prevention of kidney function decline in individuals at risk of having fast eGFR decline.

Sex Differences in the Association Between Serum Testosterone and Kidney Function in the General Population.

Introduction: Testosterone might prevent kidney function decline, although evidence is limited in men and lacking in women from the general population. We investigated the association between serum testosterone and kidney function in men and women from a large population-based cohort study. Methods: Participants aged ≥45 years with available measurements of serum testosterone, sex hormone-binding globulin (SHBG), creatinine, and cystatine C were included. Assessments of kidney function included baseline assessments of the estimated glomerular filtration rate (eGFR) based on serum creatinine (eGFRcreat) or serum cystatin C (eGFRcys), and the urine albumin-to-creatinine ratio (ACR), and repeated assessments of eGFRcreat. Linear regression and linear mixed models were used to assess the associations of serum free and total testosterone with kidney function, stratified for sex. Results: A total of 4095 men and 5389 women (mean age 65.2 years) were included. In men, higher free testosterone was associated with lower eGFRcreat (beta -0.63, 95% confidence interval [CI]: -1.05; -0.21), higher eGFRcys (beta 0.56, 95% CI: 0.07; 1.05), and lower ACR (beta -0.25, 95% CI: -0.35; -0.16) at baseline. Higher total testosterone was associated with higher baseline and follow-up eGFRcreat, and with lower eGFRcreat when additionally adjusted for SHBG. In women, higher free testosterone was associated with lower baseline eGFRcreat and eGFRcys (beta -1.03, 95% CI: -1.36; -0.71; beta -1.07, 95% CI: -1.44; -0.70; respectively) and lower eGFRcreat over time (beta -0.78, 95% CI: -1.10; -0.46), but not with ACR. Conclusions: eGFRcys might be a better parameter than eGFRcreat for the association of testosterone with kidney function, although further studies investigating this are needed. Furthermore, we identified sex differences in the association between testosterone and kidney function, with a positive association in men and a negative association in women.

Serum sodium, cognition and incident dementia in the general population.

BACKGROUND: Low serum sodium may be associated with cognitive impairment and dementia in the general population, but the data remain inconclusive. Therefore, we aimed to determine the association of low serum sodium with cognitive function and incident dementia in the general population. METHODS: Participants from a prospective population-based cohort were eligible if data on serum sodium (collected between 1997 and 2008), dementia prevalence and dementia incidence were available (follow-up until 2018). Global cognitive function was assessed with the Mini-Mental State Examination (MMSE) and the general cognitive factor (G-factor, derived from principal component analysis of individual tests). Linear regression and Cox proportional-hazards models were used to assess associations of standardised continuous and categorised low serum sodium (mean - 1.96*SD: cut-off of 137 mmol/L) with overall cognitive function and incident dementia, respectively. RESULTS: In all, 8,028 participants free of dementia at baseline (mean age 63.6 years, 57% female, serum sodium 142 ± 2 mmol/L), including 217 participants with low serum sodium, were included. Cross-sectionally, continuous serum sodium and/or low serum sodium were not associated with the MMSE or G-factor. However, participants with low serum sodium performed worse on the Stroop and Purdue Pegboard tests. During a median follow-up of 10.7 years, 758 subjects developed dementia. Continuous serum sodium (hazard ratio (HR) 0.98, 95% confidence interval (CI) 0.92;1.05) and low serum sodium (HR 1.27, 95% CI 0.90;1.79) were not associated with a higher risk of incident dementia. CONCLUSION: We identified no significant associations of low serum sodium with overall cognitive functioning and risk of dementia. However, low serum sodium-including levels above the clinical cut-off for hyponatremia-was associated with impairments in selected cognitive domains including attention and psychomotor function.

Association of habitual coffee consumption and kidney function: A prospective analysis in the Rotterdam Study.

BACKGROUND & AIMS: Population-based studies have suggested a protective effect of coffee against development of chronic kidney disease (CKD), possibly through coffee's anti-inflammatory and antioxidant compounds. Studies on coffee and kidney function decline in the general population are scarce. We studied associations of habitual coffee consumption with repeated assessments of estimated glomerular filtration rate (eGFR) and urinary albumin-to-creatinine ratio (ACR). METHODS: We used data from 7,914 participants of the population-based Rotterdam Study. Baseline coffee consumption data (cups/day) were obtained from home interviews and validated food frequency questionnaires (1997-2008). Repeated assessments of eGFR (ml/min per 1.73 m2, 1997-2014) were calculated according to the creatinine-based CKD Epidemiology Collaboration equation of 2012. Repeated assessments of urinary albumin and creatinine were used to estimate ACR (mg/g, 2006-2014). Data were analyzed by applying linear mixed models, adjusted for sociodemographic, lifestyle and dietary factors, and cardiovascular disease risk factors. Predefined subgroup analyses were performed stratified by CKD risk factors. RESULTS: Participants' mean (SD) baseline age was 66 (10) years, 57% were women and median [IQR] coffee consumption was 3.0 [2.0, 5.0] cups/day. Those drinking more coffee were more likely to smoke, and to have type 2 diabetes (T2D) and obesity. Mean eGFR was 79 (15) ml/min per 1.73 m2. In the total study population, coffee was not associated with longitudinal eGFR during a median of 5.4 years of follow-up (ß = 0.04 ml/min per 1.73 m2 per one cup/day [95% CI: -0.10,0.18]). However, among those aged >70 years, one additional coffee cup/day was associated with on average 0.84 (0.51,1.18) ml/min per 1.73 m2 higher longitudinal eGFR. Among obese participants this estimate was 0.32 (0.01,0.63). A protective trend was also observed among former smokers (0.17 [-0.03,0.39]) and those with T2D (0.42 [-0.05,0.88]). Coffee was not associated with longitudinal ACR (0.01 mg/ml [-0.01,0.02]). CONCLUSION: While coffee was not associated with eGFR and ACR in the total population, more coffee consumption was associated with higher longitudinal eGFR among those at higher risk for CKD, i.e., among those aged 70+ and obese participants. These findings require confirmation in other prospective cohort studies.

Kidney function and the risk of sudden cardiac death in the general population.

Background: Chronic kidney disease increases sudden cardiac death (SCD) risk, but the association between kidney function and SCD in a general population is largely unknown. Therefore, we investigated the association between kidney function and SCD in a general middle-aged and elderly population. Methods: We included individuals aged ≥45 years from a prospective population-based cohort study. The association between kidney function assessments [estimated glomerular filtration rate based on serum creatinine (eGFRcreat), cystatin C (eGFRcys) or both (eGFRcreat-cys)] and SCD was investigated using Cox proportional-hazards and joint models. Absolute 10-year risks were computed using competing risk analyses. Mediation analyses were performed using a four-way decomposition method. Results: We included 9687 participants (median follow-up 8.9 years; mean age 65.3 years; 56.7% women; 243 SCD cases). Lower eGFRcys and eGFRcreat-cys were associated with increased SCD risk [hazard ratio (HR) 1.23, 95% confidence interval (CI) 1.12-1.34 and HR 1.17, 95% CI 1.06-1.29, per 10 mL/min/1.73 m2 eGFR decrease]. A significant trend (P = 0.001) across eGFRcys categories was found, with an HR of 2.11 (95% CI 1.19-3.74) for eGFRcys <60 compared with eGFRcys >90 mL/min/1.73 m2. Comparing eGFRcys of 90 to 60 mL/min/1.73 m2, absolute 10-year risk increased from 1.0% to 2.5%. Identified subgroups at increased risk included older participants and participants with atrial fibrillation. The associations were not mediated by coronary heart disease, hypertension or diabetes. Conclusions: Reduced kidney function is associated with increased SCD risk in the general population, especially with eGFRcys. eGFRcys could be added to prediction models and screening programmes for SCD prevention.

The role of serum testosterone and dehydroepiandrosterone sulfate in kidney function and clinical outcomes in chronic kidney disease: a systematic review and meta-analysis.

Objective/design: Testosterone might mediate sex differences in kidney function and chronic kidney disease (CKD). However, few studies analyzing the association between testosterone and kidney function showed conflicting results. Therefore, we performed a systematic review and meta-analysis. Methods: Six electronic databases were searched from inception to March 4, 2020, for studies that investigated the association of (i) testosterone status with kidney function in the general population or (ii) testosterone status with clinical outcomes (kidney function decline, kidney failure, cardiovascular (CV) events, and cardiovascular and all-cause mortality) in CKD patients. We used random and fixed-effect models to obtain pooled effect estimates with 95% confidence intervals (CIs). Results: No randomized-controlled trials that met the inclusion criteria were identified. One study was conducted in the general population and reported an increased risk of incident CKD with low vs normal testosterone (hazard ratio (HR): 1.38, 95% CI: 1.05;1.80). Seven studies were conducted in men with CKD and included testosterone as determinant, of which six could be meta-analyzed. Low testosterone was associated with an increased risk of all-cause mortality and CV events (pooled HR: 1.98, 95% CI: 1.36;2.89; pooled HR of 2.40, 95% CI: 1.22;4.71, respectively). Two studies showed an increased risk of all-cause mortality with decreased dehydroepiandrosterone sulfate (DHEAS) in men with CKD; results regarding CV events were conflicting. Conclusions: Although literature is scarce, evidence suggests that lower testosterone may increase CKD risk in the general population and risk of all-cause mortality and CV events in men with CKD. Whether testosterone supplementation could prevent these potential detrimental outcomes should be determined in future intervention studies.

Bidirectional Association Between Kidney Function and Atrial Fibrillation: A Population-Based Cohort Study.

Background Consensus lacks concerning a bidirectional association between kidney function and atrial fibrillation (AF), but this is crucial information for prevention/treatment efforts for both chronic kidney disease and AF. Therefore, we investigated the bidirectional association between kidney function and AF. Methods and Results This study was a prospective cohort study including 9228 participants (mean age, 64.9 years; 57.2% women) with information on kidney function (estimated glomerular filtration rate [eGFR] based on serum creatinine [eGFRcreat], cystatin C [eGFRcys], or both [eGFRcreat-cys], and urine albumin-to-creatinine ratio) and AF. Reduced kidney function was defined as eGFRcreat <60 mL/min per 1.73 m2. Cox proportional-hazards, logistic regression, linear mixed, and joint models were used to investigate the association of kidney function with AF and vice versa. During follow-up (median of 8.0 years), 780 events of incident AF occurred. Lower eGFRcys and eGFRcreat-cys were associated with increased AF risk (hazard ratio [HR], 1.08 [95% CI, 1.03-1.14] and HR, 1.07 [95% CI, 1.01-1.14], respectively, per 10 mL/min per 1.73 m2 eGFR decrease). For eGFRcys and eGFRcreat-cys, 10-year cumulative incidence of AF was 16% (eGFR <60) and 6% (eGFR ≥60). Prevalent AF (versus no prevalent AF) was associated with 2.85 mL/min per 1.73 m2 lower eGFRcreat and with a faster decline of eGFRcreat with age. Prevalent AF was associated with a 1.3-fold increased risk of incident reduced kidney function. Conclusions Kidney function, especially eGFRcys, and AF are bidirectionally associated. There are currently no targeted prevention efforts for AF in patients with mild chronic kidney disease and vice versa. Our results could provide the first step to improve prediction/prevention of both conditions.

Disentangling the association between kidney function and atrial fibrillation: a bidirectional Mendelian randomization study.

BACKGROUND: The potential bidirectional causal association between kidney function and atrial fibrillation (AF) remains unclear. METHODS: We conducted a bidirectional two-sample Mendelian randomization (MR) analysis. From multiple genome-wide association studies (GWAS), we retrieved genetic variants associated with kidney function (estimated glomerular filtration rate based on creatinine (eGFRcreat), blood urea nitrogen (BUN), chronic kidney disease (CKD stage ≥G3): n = 1,045,620, eGFR based on cystatin C: n = 24,063-32,861, urine albumin-to-creatinine ratio (UACR), and microalbuminuria: n = 564,257), and AF (n = 1,030,836). The inverse-variance weighted method was used as our main analysis. RESULTS: MR analyses supported a causal effect of CKD (n = 9 SNPs, odds ratio (OR): 1.10, 95% confidence interval (CI): 1.04-1.17, p-value = 1.97 × 10-03), and microalbuminuria (n = 5 SNPs, OR: 1.26, 95% CI: 1.10-1.46, p-value = 1.38 × 10-03) on AF risk. We also observed a causal effect of AF on eGFRcreat (n = 97 SNPs, OR: 1.00, 95% CI: 1.00-1.00, p-value = 6.78 × 10-03), CKD (n = 107 SNPs, OR: 1.06, 95% CI: 1.03-1.09, p-value = 2.97 × 10-04), microalbuminuria (n = 83 SNPs, OR: 1.07, 95% CI: 1.04-1.09, p-value = 2.49 × 10-08), and a suggestive causal effect on eGFRcys (n = 103 SNPs, OR: 0.99, 95% CI: 0.99-1.00, p-value = 4.61 × 10-02). Sensitivity analyses, including weighted median estimator, MR-Egger, the MR pleiotropy residual sum and outlier test, and excluding genetic variants associated with possible confounders and/or horizontal mediators (myocardial infarction/coronary artery disease, heart failure) indicated that these findings were robust. CONCLUSIONS: Our results supported a bidirectional causal association between kidney function and AF. The shared genetic architecture between kidney dysfunction and AF might represent potential important therapeutic targets to prevent both conditions in the general population.

Thyroid Function and the Risk of Prediabetes and Type 2 Diabetes.

CONTEXT: Thyroid hormones are important regulators of glucose metabolism, and studies investigating the association between thyroid function and type 2 diabetes incidence have shown conflicting results. OBJECTIVE: We aimed to combine the evidence from prospective studies addressing the association between thyroid function and type 2 diabetes risk. METHODS: We systematically searched in Embase, Medline (Ovid), Web of Science, Cochrane, and Google Scholar for prospective studies assessing the association of thyroid function and incident type 2 diabetes. Data extraction was performed using a standardized protocol by 2 independent reviewers. We assessed study quality using the Newcastle-Ottawa Scale and pooled hazard ratios (HRs) and 95% CI using random-effects models. RESULTS: From the 4574 publications identified, 7 met our inclusion criteria and were included in the qualitative synthesis. Six publications were included in the meta-analysis. Studies assessed hypothyroidism (6 studies), hyperthyroidism (5 studies), thyrotropin (TSH) in the reference range (4 studies), and free thyroxine (FT4) in the reference range (3 studies) in relation to incident type 2 diabetes. The pooled HR for the risk of type 2 diabetes was 1.26 (95% CI, 1.05-1.52) for hypothyroidism, 1.16 (95% CI, 0.90-1.49) for hyperthyroidism, 1.06 (95% CI, 0.96-1.17) for TSH in the reference range, and 0.95 (95% CI, 0.91-0.98) for FT4 in the reference range. CONCLUSION: Current evidence suggests an increased type 2 diabetes risk in people with hypothyroidism and lower FT4 levels in the reference range. Further population-based studies are needed to address this association given the limited evidence.

Determinants of the Evolution of Kidney Function With Age.

INTRODUCTION: Kidney function declines with age, but its determinants in the general population remain incompletely understood. We investigated the rate and determinants of kidney function decline in the general population. METHODS: Participants with information on kidney function were selected from a population-based cohort study. Joint models were used to investigate the evolution of the estimated glomerular filtration rate (eGFR, expressed in ml/min per 1.73 m2 per year) and the urine albumin-to-creatinine ratio (ACR, expressed in mg/g per year) with age. We stratified for 8 potential determinants of kidney function decline, including sex, cardiovascular risk factors, and cardiovascular disease. RESULTS: We included 12,062 participants with 85,922 eGFR assessments (mean age 67.0 years, 58.7% women) and 3522 participants with 5995 ACR measurements. The annual eGFR decline was 0.82 and the ACR increase was 0.05. All determinants appeared detrimental for eGFR and ACR, except for prediabetes and higher body mass index which proved only detrimental for ACR. In participants without the determinants, eGFR decline was 0.75 and ACR increase was 0.002. Higher baseline eGFR but faster eGFR decline with age was detected in men (0.92 vs. 0.75), smokers (0.90 vs. 0.75), and participants with diabetes (1.07 vs. 0.78). CONCLUSION: We identify prediabetes, smoking, and blood pressure as modifiable risk factors for kidney function decline. As with diabetes, hyperfiltration seems important in accelerated kidney function decline in men and smokers. The interpretation of kidney function decline may require adjustment for age and sex to prevent overdiagnosis of chronic kidney disease in aging populations.

The Effects of Osteoporotic and Non-osteoporotic Medications on Fracture Risk and Bone Mineral Density.

Osteoporosis is a highly prevalent bone disease affecting more than 37.5 million individuals in the European Union (EU) and the  United States of America (USA). It is characterized by low bone mineral density (BMD), impaired bone quality, and loss of structural and biomechanical properties, resulting in reduced bone strength. An increase in morbidity and mortality is seen in patients with osteoporosis, caused by the approximately 3.5 million new osteoporotic fractures occurring every year in the EU. Currently, different medications are available for the treatment of osteoporosis, including anti-resorptive and osteoanabolic medications. Bisphosphonates, which belong to the anti-resorptive medications, are the standard treatment for osteoporosis based on their positive effects on bone, long-term experience, and low costs. However, not only medications used for the treatment of osteoporosis can affect bone: several other medications are suggested to have an effect on bone as well, especially on fracture risk and BMD. Knowledge about the positive and negative effects of different medications on both fracture risk and BMD is important, as it can contribute to an improvement in osteoporosis prevention and treatment in general, and, even more importantly, to the individual's health. In this review, we therefore discuss the effects of both osteoporotic and non-osteoporotic medications on fracture risk and BMD. In addition, we discuss the underlying mechanisms of action.

Determinants of Serum Immunoglobulin Levels: A Systematic Review and Meta-Analysis.

Background: An up-to-date overview of determinants of serum immunoglobulins in adults is pivotal for clinical practice and research, but currently lacking. We therefore performed a systematic review and meta-analysis to identify determinants of serum immunoglobulin levels. Methods: Embase, Web of Science, Medline, Cochrane, and Google Scholar were searched from inception to July 11th, 2019 for articles reporting on determinants of serum immunoglobulin A, G or M (IgA, IgG or IgM) in adult humans. Random and fixed effect models were applied to obtain pooled mean differences (MDs) and 95% confidence intervals (CIs) for the association of age and sex with serum immunoglobulins. Results: We retrieved 117 articles reporting on determinants of serum immunoglobulins, of which 28 could be meta-analyzed. Older compared to younger individuals had higher IgA (MD: 0.38; CI: 0.18 - 0.58), but lower IgM levels (MD: -0.40; 95%: -0.66 - -0.14). Men had higher IgA (MD: 0.22; CI: 0.03 - 0.42), but lower IgM levels (MD: -0.21; CI: -0.32 - -0.10) than women. Age and sex did not influence IgG. Caucasian ethnicity was associated with lower IgA, IgG, and IgM. Smoking and corticosteroid use were associated with lower IgG. Positive associations were reported of probiotics with IgG, alcohol with IgA, hypertension with IgA and IgG, and acute psychological stress with IgA, IgG, and IgM. Conclusions: Older age and male sex are associated with higher IgA, but lower IgM, and urge investigation of age- and sex-specific reference ranges of immunoglobulins. Other identified determinants were ethnicity, diet, lifestyle and cardio-metabolic factors.

The impact of thiazide diuretics on bone mineral density and the trabecular bone score: the Rotterdam Study.

The decreased risk of osteoporotic fractures in thiazide diuretics (TD) users is possibly not only caused by an increase in bone mineral density (BMD), but by an increase in other determinants of bone strength as well, such as the trabecular bone score (TBS). To test this hypothesis, we studied the association between TD use and both lumbar spine BMD (LS-BMD) and lumbar spine TBS (LS-TBS) cross-sectionally in 6096 participants from the Rotterdam Study, as well as the association between TD use and bone turnover estimated by serum osteocalcin levels. We found that past and current use of TD were associated with an increase of LS-BMD (ß = 0.021 g/cm2 (95% CI: 0.006;0.036) and ß = 0.016 g/cm2 (95% CI: 0.002;0.031), respectively). Use of ≥1 defined daily dose (DDD) (ß = 0.028, 95% CI: 0.010;0.046; p for trend within DDD of use <0.001) and use of >365 days (ß = 0.033, 95% CI: 0.014;0.052; p for trend within duration of use <0.001) were positively associated with LS-BMD. No significant association between TD use and LS-TBS was observed. Mean serum osteocalcin levels were significantly different between users and non-users of TD (20.2 ng/ml (SD 8.3) and 22.5 ng/ml (SD 17.0), respectively, p < 0.001). Furthermore, linear regression analysis showed that the use of TD was associated with a 3.2 ng/l (95% CI: -4.4.; -2.0) lower serum osteocalcin level compared to non-use of TD, when adjusted for Rotterdam Study cohort, age, and sex. Our results may implicate that the decreased fracture risk in TD users is explained by increased bone mass rather than by improved bone microarchitecture. Alternatively, changes in bone microarchitecture might not be detected through TBS and more sophisticated techniques are possibly needed to study a potential effect of TD on bone microarchitecture.

Serum magnesium, hepatocyte nuclear factor 1ß genotype and post-transplant diabetes mellitus: a prospective study.

BACKGROUND: Retrospective studies suggest that tacrolimus-induced hypomagnesaemia is a risk factor for post-transplant diabetes mellitus (PTDM), but prospective studies are lacking. METHODS: This was a prospective study with measurements of serum magnesium and tacrolimus at pre-specified time points in the first year after living donor kidney transplantation (KT). The role of single nucleotide polymorphisms (SNPs) in hepatocyte nuclear factor 1ß (HNF1ß) was also explored because HNF1ß regulates insulin secretion and renal magnesium handling. Repeated measurement and regression analyses were used to analyse associations with PTDM. RESULTS: In our cohort, 29 out of 167 kidney transplant recipients developed PTDM after 1 year (17%). Higher tacrolimus concentrations were significantly associated with lower serum magnesium and increased risk of hypomagnesaemia. Patients who developed PTDM had a significantly lower serum magnesium trajectory than patients who did not develop PTDM. In multivariate analysis, lower serum magnesium, age and body mass index were independent risk factors for PTDM. In recipients, the HNF1ß SNP rs752010 G > A significantly increased the risk of PTDM [odds ratio (OR) = 2.56, 95% confidence interval (CI) 1.05-6.23] but not of hypomagnesaemia. This association lost significance after correction for age and sex (OR = 2.24, 95% CI 0.90-5.57). No association between HNF1ß SNPs and PTDM was found in corresponding donors. CONCLUSIONS: A lower serum magnesium in the first year after KT is an independent risk factor for PTDM. The HNF1ß SNP rs752010 G > A may add to this risk through an effect on insulin secretion rather than hypomagnesaemia, but its role requires further confirmation.

Cost-effectiveness of extracorporeal cardiopulmonary resuscitation after in-hospital cardiac arrest: A Markov decision model.

BACKGROUND: This study aimed to estimate the cost-effectiveness of extracorporeal cardiopulmonary resuscitation (ECPR) for in-hospital cardiac arrest treatment. METHODS: A decision tree and Markov model were constructed based on current literature. The model was conditional on age, Charlson Comorbidity Index (CCI) and sex. Three treatment strategies were considered: ECPR for patients with an Age-Combined Charlson Comorbidity Index (ACCI) below different thresholds (2-4), ECPR for everyone (EALL), and ECPR for no one (NE). Cost-effectiveness was assessed with costs per quality-of-life adjusted life years (QALY). MEASUREMENTS AND MAIN RESULTS: Treating eligible patients with an ACCI below 2 points costs 8394 (95% CI: 4922-14,911) euro per extra QALY per IHCA patient; treating eligible patients with an ACCI below 3 costs 8825 (95% CI: 5192-15,777) euro per extra QALY per IHCA patient; treating eligible patients with an ACCI below 4 costs 9311 (95% CI: 5478-16,690) euro per extra QALY per IHCA patient; treating every eligible patient with ECPR costs 10,818 (95% CI: 6357-19,400) euro per extra QALY per IHCA patient. For WTP thresholds of 0-9500 euro, NE has the highest probability of being the most cost-effective strategy. For WTP thresholds between 9500 and 12,500, treating eligible patients with an ACCI below 4 has the highest probability of being the most cost-effective strategy. For WTP thresholds of 12,500 or higher, EALL was found to have the highest probability of being the most cost-effective strategy. CONCLUSIONS: Given that conventional WTP thresholds in Europe and North-America lie between 50,000-100,000 euro or U.S. dollars, ECPR can be considered a cost-effective treatment after in-hospital cardiac arrest from a healthcare perspective. More research is necessary to validate the effectiveness of ECPR, with a focus on the long-term effects of complications of ECPR.