Excessive dietary lipid intake provokes an acquired form of lysosomal lipid storage disease in the kidney.

Obesity and dyslipidaemia are features of the metabolic syndrome and risk factors for chronic kidney disease. The cellular mechanisms connecting metabolic syndrome with chronic kidney disease onset and progression remain largely unclear. We show that proximal tubular epithelium is a target site for lipid deposition upon overnutrition with a cholesterol-rich Western-type diet. Affected proximal tubule epithelial cells displayed giant vacuoles of lysosomal or autophagosomal origin, harbouring oxidised lipoproteins and concentric membrane layer structures (multilamellar bodies), reminiscent of lysosomal storage diseases. Additionally, lipidomic analysis revealed renal deposition of cholesterol and phospholipids, including lysosomal phospholipids. Proteomic profiles of renal multilamellar bodies were distinct from those of epidermis or lung multilamellar bodies and of cytoplasmic lipid droplets. Tubular multilamellar bodies were observed in kidney biopsies of obese hypercholesterolaemic patients, and the concentration of the phospholipidosis marker di-docosahexaenoyl (22:6)-bis(monoacylglycerol) phosphate was doubled in urine from individuals with metabolic syndrome and chronic kidney disease. The enrichment of proximal tubule epithelial cells with phospholipids and multilamellar bodies was accompanied by enhanced inflammation, fibrosis, tubular damage markers, and higher urinary electrolyte content. Concomitantly to the intralysosomal lipid storage, a renal transcriptional response was initiated to enhance lysosomal degradation and lipid synthesis. In cultured proximal tubule epithelial cells, inhibition of cholesterol efflux transport or oxysterol treatment induced effects very similar to the in vivo situation, such as multilamellar body and phospholipid amassing, and induction of damage, inflammatory, fibrotic, and lipogenic molecules. The onset of phospholipidosis in proximal tubule epithelial cells is a novel pathological trait in metabolic syndrome-related chronic kidney disease, and emphasises the importance of healthy lysosomes and nutrition for kidney well-being. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

The fibroblast hormone endotrophin is a biomarker of mortality in chronic diseases.

Fibrosis, driven by fibroblast activities, is an important contributor to morbidity and mortality in most chronic diseases. Endotrophin, a signaling molecule derived from processing of type VI collagen by highly activated fibroblasts, is involved in fibrotic tissue remodeling. Circulating levels of endotrophin have been associated with an increased risk of mortality in multiple chronic diseases. We conducted a systematic literature review collecting evidence from original papers published between 2012 and January 2023 that reported associations between circulating endotrophin (PRO-C6) and mortality. Cohorts with data available to the study authors were included in an Individual Patient Data (IPD) meta-analysis that evaluated the association of PRO-C6 with mortality (PROSPERO registration number: CRD42023340215) after adjustment for age, sex and BMI, where available. In the IPD meta-analysis including sixteen cohorts of patients with different non-communicable chronic diseases (NCCDs) (N=15,205) the estimated summary hazard ratio for 3-years all-cause mortality was 2.10 (95% CI 1.75-2.52) for a 2-fold increase in PRO-C6, with some heterogeneity observed between the studies (I2=70%). This meta-analysis is the first study documenting that fibroblast activities, as quantified by circulating endotrophin, are independently associated with mortality across a broad range of NCCDs. This indicates that, irrespective of disease, interstitial tissue remodeling, and consequently fibroblast activities, has a central role in adverse clinical outcomes, and should be considered with urgency from drug developers as a target to treat.

Dairy consumption and incident prediabetes: prospective associations and network models in the large population-based Lifelines Study.

BACKGROUND: Evidence on associations between dairy consumption and incident prediabetes is inconsistent. One potential explanation for heterogeneity is that health behavior and food intake covary with the consumption of various high-fat and low-fat dairy types. OBJECTIVE: The objective was to investigate the associations of total dairy and dairy types with incident prediabetes and to assess how dairy intake is linked with metabolic risk factors, lifestyle behaviors, and foods, as potential explanations for these associations. METHODS: Overall, 74,132 participants from the prospective population-based Lifelines study were included (mean age, 45.5 ± 12.3 y; 59.7% female). Baseline dairy intake was measured using a validated food frequency questionnaire. Prediabetes at follow-up was defined based on the World Health Organization/International Expert Committee criteria as fasting plasma glucose of 110-125 mg/dL or glycated hemoglobin concentrations of 6.0%-6.5%. Associations were analyzed using Poisson regression models adjusted for social demographics, lifestyle behaviors, family history of diabetes, and food group intake. Interconnections were assessed with mixed graphical model networks. RESULTS: At a mean follow-up of 4.1 ± 1.1 y, 2746 participants developed prediabetes (3.7%). In regression analyses, neutral associations were found for most dairy types. Intake of plain milk and low-fat milk were associated with a higher risk of prediabetes in the top compared with bottom quartiles (relative risk [RR]: 1.17; 95% confidence interval [CI]: 1.05, 1.30; P-trend = 0.04 and RR: 1.18; 95% CI: 1.06, 1.31; P-trend =0.01). Strong but nonsignificant effect estimates for high-fat yogurt in relation to prediabetes were found (RRservings/day: 0.80; 95% CI: 0.64, 1.01). The network analysis showed that low-fat milk clustered with energy-dense foods, including bread, meat, and high-fat cheese, whereas high-fat yogurt had no clear link with lifestyle risk factors and food intake. CONCLUSIONS: In this large cohort of Dutch adults, low-fat milk intake was associated with higher prediabetes risk. Heterogeneous associations by dairy type and fat content might partly be attributed to confounding caused by behaviors and food intake related to dairy intake.

Effect of Intravenous Ferric Carboxymaltose on Exercise Capacity After Kidney Transplantation (EFFECT-KTx): rationale and study protocol for a double-blind, randomised, placebo-controlled trial.

INTRODUCTION: Iron deficiency (ID) is common and has been associated with an excess mortality risk in kidney transplant recipients (KTRs). In patients with chronic heart failure and ID, intravenous iron improves exercise capacity and quality of life. Whether these beneficial effects also occur in KTRs is unknown. The main objective of this trial is to address whether intravenous iron improves exercise tolerance in iron-deficient KTRs. METHODS AND ANALYSIS: The Effect of Ferric Carboxymaltose on Exercise Capacity after Kidney Transplantation study is a multicentre, double-blind, randomised, placebo-controlled clinical trial that will include 158 iron-deficient KTRs. ID is defined as plasma ferritin <100 µg/L or plasma ferritin 100-299 µg/L with transferrin saturation <20%. Patients are randomised to receive 10 mL of ferric carboxymaltose (50 mg Fe3+/mL, intravenously) or placebo (0.9% sodium chloride solution) every 6 weeks, four dosages in total. The primary endpoint is change in exercise capacity, as quantified by the 6 min walk test, between the first study visit and the end of follow-up, 24 weeks later. Secondary endpoints include changes in haemoglobin levels and iron status, quality of life, systolic and diastolic heart function, skeletal muscle strength, bone and mineral parameters, neurocognitive function and safety endpoints. Tertiary (explorative) outcomes are changes in gut microbiota and lymphocyte proliferation and function. ETHICS AND DISSEMINATION: The protocol of this study has been approved by the medical ethical committee of the University Medical Centre Groningen (METc 2018/482;) and is being conducted in accordance with the principles of the Declaration of Helsinki, the Standard Protocol Items: Recommendations for Interventional Trials checklist and the Good Clinical Practice guidelines provided by the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use. Study results will be disseminated through publications in peer-reviewed journals and conference presentations. TRIAL REGISTRATION NUMBER: NCT03769441.

Rationale and design of the CORE (COrticosteroids REvised) study: protocol.

INTRODUCTION: Corticosteroids are an important pillar in many anti-inflammatory and immunosuppressive treatment regimens and are available in natural and synthetic forms, which are considered equipotent if clinical bioequivalence data are used. Current clinical bioequivalence data are however based on animal studies or studies with subjective endpoints. Furthermore, advancement in steroid physiology with regard to metabolism, intracellular handling and receptor activation have not yet been incorporated. Therefore, this study aims to re-examine the clinical bioequivalence and dose effects of the most widely used synthetic corticosteroids, prednisolone and dexamethasone. METHODS AND ANALYSIS: In this double-blind, randomised cross-over clinical trial, 24 healthy male and female volunteers aged 18-75 years, will be included. All volunteers will randomly receive either first a daily dose of 7.5 mg prednisolone for 1 week, immediately followed by a daily dose of 30 mg prednisolone for 1 week, or first a presumed clinical bioequivalent dose of 1.125 mg dexamethasone per day, immediately followed by 4.5 mg of dexamethasone per day for 1 week. After a wash-out period of 4-8 weeks, the other treatment will be applied. The primary study endpoint is the difference in free cortisol excretion in 24 hours urine. Secondary endpoints will include differences in immunological parameters, blood pressure and metabolic measurements. ETHICS AND DISSEMINATION: This study has been approved by the Medical Ethics Committee of the University Medical Center Groningen (METC 2020.398). The results of this study will be submitted for publication in peer-reviewed journals. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov (Identifier: NCT04733144), and in the Dutch trial registry (NL9138).

Using a novel concept to measure outcomes in solid organ recipients provided promising results.

OBJECTIVES: Efforts to evaluate the health of solid organ transplant recipients are hampered by the lack of adequate patient-reported outcome measures (PROMs) targeting this group. We developed the Transplant ePROM (TXP), which is based on a novel measurement model and administered through a mobile application to fill this gap. The main objective of this article is to elucidate how we derived the weights for different items, and to report initial empirical results. STUDY DESIGN AND SETTING: The nine health items in the TXP were fatigue, skin, worry, self-reliance, activities, weight, sexuality, stooling, and memory. Via an online survey solid organ recipient participating in the TransplantLines Biobank and Cohort study (NCT03272841) were asked to describe and then compare their own health state with six other health states. Coefficients for item levels were obtained using a conditional logit model. RESULTS: A total of 232 solid organ transplant recipients (mean age: 54 years) participated. The majority (106) were kidney recipients, followed by lung, liver, and heart recipients. Fatigue was the most frequent complaint (54%). The strongest negative coefficients were found for activities and worry, followed by self-reliance and memory. CONCLUSION: A set of coefficients and values were developed for TXP. The TXP score approximated an optimal health state for the majority of respondents and recipients of different organs reported comparable health states.

Meat intake and risk of mortality and graft failure in kidney transplant recipients.

BACKGROUND: It is unknown whether meat intake is beneficial for long-term patient and graft survival in kidney transplant recipients (KTR). OBJECTIVES: We first investigated the association of the previously described meat intake biomarkers 1-methylhistidine and 3-methylhistidine with intake of white and red meat as estimated from a validated food frequency questionnaire (FFQ). Second, we investigated the association of the meat intake biomarkers with long-term outcomes in KTR. METHODS: We measured 24-h urinary excretion of 1-methylhistidine and 3-methylhistidine by validated assays in a cohort of 678 clinically stable KTR. Cross-sectional associations were assessed by linear regression. We used Cox regression analyses to prospectively study associations of log2-transformed biomarkers with mortality and graft failure. RESULTS: Urinary 1-methylhistidine and 3-methylhistidine excretion values were median: 282; interquartile range (IQR): 132-598 µmol/24 h and median: 231; IQR: 175-306 µmol/24 h, respectively. Urinary 1-methylhistidine was associated with white meat intake [standardized ß (st ß): 0.20; 95% CI: 0.12, 0.28; P < 0.001], whereas urinary 3-methylhistidine was associated with red meat intake (st ß: 0.30; 95% CI: 0.23, 0.38; P < 0.001). During median follow-up for 5.4 (IQR: 4.9-6.1) y, 145 (21%) died and 83 (12%) developed graft failure. Urinary 3-methylhistidine was inversely associated with mortality independently of potential confounders (HR per doubling: 0.55; 95% CI: 0.42, 0.72; P < 0.001). Both urinary 1-methylhistidine and urinary 3-methylhistidine were inversely associated with graft failure independent of potential confounders (HR per doubling: 0.84; 95% CI: 0.73, 0.96; P = 0.01; and 0.59; 95% CI: 0.41, 0.85; P = 0.004, respectively). CONCLUSIONS: High urinary 3-methylhistidine, reflecting higher red meat intake, is independently associated with lower risk of mortality. High urinary concentrations of both 1- and 3-methylhistidine, of which the former reflects higher white meat intake, are independently associated with lower risk of graft failure in KTR. Future intervention studies are warranted to study the effect of high meat intake on mortality and graft failure in KTR, using these biomarkers.

A novel haemocytometric COVID-19 prognostic score developed and validated in an observational multicentre European hospital-based study.

COVID-19 induces haemocytometric changes. Complete blood count changes, including new cell activation parameters, from 982 confirmed COVID-19 adult patients from 11 European hospitals were retrospectively analysed for distinctive patterns based on age, gender, clinical severity, symptom duration, and hospital days. The observed haemocytometric patterns formed the basis to develop a multi-haemocytometric-parameter prognostic score to predict, during the first three days after presentation, which patients will recover without ventilation or deteriorate within a two-week timeframe, needing intensive care or with fatal outcome. The prognostic score, with ROC curve AUC at baseline of 0.753 (95% CI 0.723-0.781) increasing to 0.875 (95% CI 0.806-0.926) on day 3, was superior to any individual parameter at distinguishing between clinical severity. Findings were confirmed in a validation cohort. Aim is that the score and haemocytometry results are simultaneously provided by analyser software, enabling wide applicability of the score as haemocytometry is commonly requested in COVID-19 patients.

Body fat estimates from bioelectrical impedance equations in cardiovascular risk assessment: The PREVEND cohort study.

AIMS: To investigate prospectively the association of body fat percentage (BF%) estimates using various equations from bioelectrical impedance analysis (BIA) with cardiovascular events, compared with body mass index (BMI) and waist circumference. METHODS AND RESULTS: We used data of 34 BIA-BF%-equations that were used for estimation of BF% in 6486 (men = 3194, women = 3294) subjects. During a median follow-up of 8.3 years, 510 (7.9%) cardiovascular events (363 in men; 147 in women) occurred. In men, the crude hazard ratio (95% confidence interval) for BF% from the best predicting BIA-BF%-equation was 3.97 (3.30-4.78) against 2.13 (1.85-2.45) for BF% from the BIA device's BIA-BF%-equation, 1.34 (1.20-1.49) for BMI and 1.49 (1.40-1.73) for waist circumference per log-1-SD increase of all. In women, the hazard ratios for best predicting BIA-BF%-equation, BIA device estimation, BMI and waist circumference were 3.80 (2.85-4.99), 1.89 (1.57-2.28), 1.35 (1.21-1.51) and 1.52 (1.31-1.75), respectively. After adjustments for age, Framingham cardiovascular disease risk score and creatinine excretion - a marker of muscle mass - BF%s and BMI remained independently associated with cardiovascular events in both men and women, while waist circumference was independently associated with cardiovascular events in men, but not in women. According to discrimination ability (C-index) and additive predictive value (net reclassification index and integrated discrimination index) on obesity measures to the Framingham cardiovascular disease risk score, BF% was superior to BMI and waist circumference in both men and women. CONCLUSIONS: BF% was independently associated with future cardiovascular events. Body fat estimates from the best-predicting BIA-BF%-equations can be a more predictive measurement in cardiovascular risk assessment than BMI or waist circumference.

Plasma copeptin and chronic kidney disease risk in 3 European cohorts from the general population.

BACKGROUND: The prevalence of chronic kidney disease (CKD) is increasing worldwide. The identification of factors contributing to its progression is important for designing preventive measures. Previous studies have suggested that chronically high vasopressin is deleterious to renal function. Here, we evaluated the association of plasma copeptin, a surrogate of vasopressin, with the incidence of CKD in the general population. METHODS: We studied 3 European cohorts: DESIR (n = 5,047; France), MDCS-CC (n = 3,643; Sweden), and PREVEND (n = 7,684; the Netherlands). Median follow-up was 8.5, 16.5, and 11.3 years, respectively. Pooled data were analyzed at an individual level for 4 endpoints during follow-up: incidence of stage 3 CKD (estimated glomerular filtration rate [eGFR] < 60 ml/min/1.73 m2); the KDIGO criterion "certain drop in eGFR"; rapid kidney function decline (eGFR slope steeper than -3 ml/min/1.73 m2/yr); and incidence of microalbuminuria. RESULTS: The upper tertile of plasma copeptin was significantly and independently associated with a 49% higher risk for stage 3 CKD (P < 0.0001); a 64% higher risk for kidney function decline, as defined by the KDIGO criterion (P < 0.0001); a 79% higher risk for rapid kidney function decline (P < 0.0001); and a 24% higher risk for microalbuminuria (P = 0.008). CONCLUSIONS: High copeptin levels are associated with the development and the progression of CKD in the general population. Intervention studies are needed to assess the potential beneficial effect on kidney health in the general population of reducing vasopressin secretion or action. FUNDING: INSERM and Danone Research Centre for Specialized Nutrition.

Dried blood spot validation of five immunosuppressants, without hematocrit correction, on two LC-MS/MS systems.

AIM: Hematocrit (Ht) effects remain a challenge in dried blood spot (DBS) sampling. The aim was to develop an immunosuppressant DBS assay on two LC-MS/MS systems covering a clinically relevant Ht range without Ht correction. RESULTS: The method was partially validated for tacrolimus, sirolimus, everolimus, cyclosporin A and fully validated for mycophenolic acid on an Agilent and Thermo LC-MS/MS system. Bias caused by Ht effects were within 15% for all immunosuppressants between Ht levels of 0.23 and 0.48 l/l. Clinical validation of DBS versus whole blood samples for tacrolimus and cyclosporin A showed no differences between the two matrices. CONCLUSION: A multiple immunosuppressant DBS method without Ht correction, has been validated, including a clinical validation for tacrolimus and cyclosporin A, making this procedure suitable for home sampling.

Vitamin B-6 deficiency is common and associated with poor long-term outcome in renal transplant recipients.

Background: Previous studies have reported low circulating concentrations of pyridoxal-5-phospate (PLP) in renal transplant recipients (RTRs). It is unknown whether this is because of low intake or altered handling, and it is also unknown whether variation in circulating concentrations of PLP influences long-term outcome.Objective: We compared vitamin B-6 intake and circulating PLP concentrations of RTRs with those of healthy controls and investigated long-term clinical implications of vitamin B-6 deficiency in stable outpatient RTRs.Design: In a longitudinal cohort of 687 stable RTRs (57% male; mean ± SD age: 53 ± 13 y) with a median (IQR) follow-up of 5.3 y (4.8-6.1 y) and 357 healthy controls (47% male; age 54 ± 11 y), baseline vitamin B-6 was measured as plasma PLP by high-performance liquid chromatography (HPLC). Vitamin B-6 deficiency was defined as PLP <20 nmol/L, and insufficiency as PLP 20-30 nmol/L. Dietary intake was assessed by validated food-frequency questionnaires.Results: At inclusion [5.3 y (1.8-12.1 y) after transplantation], the mean vitamin B-6 intakes in RTRs and healthy controls were 1.77 ± 0.49 and 1.85 ± 0.56 mg/d, respectively (P = 0.23). In these groups, the median plasma PLP concentrations were 29 nmol/L (17-50 nmol/L) and 41 nmol/L (29-60 nmol/L), respectively (P < 0.001). Accordingly, deficiency was present in 30% of RTRs compared with 11% of healthy controls. PLP concentrations were inversely associated with glucose homeostasis variables and inflammation variables (all P < 0.01). During follow-up, 149 (21%) RTRs died and 82 (12%) developed graft failure. In RTRs, vitamin B-6 deficiency was associated with considerably higher mortality risk (HR 2.14; 95% CI: 1.48, 3.08) than a sufficient vitamin B-6 status, independent of potential confounders. No associations were observed for graft failure (P = 0.18).Conclusions: Vitamin B-6 deficiency is common in RTRs and does not seem to be a consequence of inadequate intake. In addition, this deficient state is clinically relevant and independently associated with an increased risk of mortality in RTRs. The cohort on which the study was based [TransplantLines Food and Nutrition Biobank and Cohort Study (TxL-FN)] was registered at clinicaltrials.gov as NCT02811835.

Functional vitamin B-6 status and long-term mortality in renal transplant recipients.

Background: Low plasma concentrations of pyridoxal 5'-phosphate (PLP) are common in renal transplant recipients (RTRs) and confer increased risk of long-term mortality. To our knowledge, it is not known whether low plasma PLP concentrations have functional (i.e., intracellular) consequences and, if so, whether such consequences are associated with increased risk of mortality.Objectives: We assessed the association of plasma PLP with functional vitamin B-6 status and explored the potential association of functional vitamin B-6 status with long-term mortality in RTRs.Design: In a longitudinal cohort of 678 stable RTRs with a median follow-up of 5.3 y (IQR: 4.8-6.1 y) and 297 healthy controls, PLP, plasma 3-hydroxykynurenine (3-HK), and xanthurenic acid (XA) were analyzed via validated assays. PLP was used as direct biomarker for vitamin B-6 status, and the 3-HK:XA ratio was used as functional biomarker of vitamin B-6 status with a higher ratio reflecting worse functional vitamin B-6 status.Results: Median PLP, 3-HK, and XA concentrations were 41 nmol/L (IQR: 29-60 nmol/L), 40.1 nmol/L (IQR: 33.0-48.0 nmol/L), and 19.1 nmol/L (IQR: 14.5-24.9 nmol/L), respectively, in healthy controls compared with 29 nmol/L (IQR: 17-50 nmol/L), 61.5 nmol/L (IQR: 45.6-86.5 nmol/L), and 25.5 nmol/L (IQR: 17.2-40.0 nmol/L), respectively, in RTRs (all P < 0.001). RTRs had a higher median 3-HK:XA ratio (2.38; IQR: 1.68-3.49) than did healthy controls (2.13; IQR: 1.63-2.71) (P < 0.05). In RTRs, the 3-HK:XA ratio was inversely associated with plasma PLP (ß = -0.21, P < 0.001). Moreover, a higher 3-HK:XA ratio was independently associated with increased risk of all-cause mortality (HR per SD increment: 1.30; 95% CI: 1.13, 1.49), cancer mortality (HR per SD increment: 1.47; 95% CI: 1.12, 1.95), and infectious disease mortality (HR per SD increment: 1.50; 95% CI: 1.21, 1.86) in RTRs.Conclusions: Vitamin B-6-deficient RTRs have a worse functional vitamin B-6 status than do healthy controls and vitamin B-6-sufficient RTRs. Worse functional vitamin B-6 status in RTRs is independently associated with an increased risk of mortality particularly because of cancer and infectious disease. This trial was registered at clinicaltrials.gov as NCT02811835.

Long-term magnesium supplementation improves arterial stiffness in overweight and obese adults: results of a randomized, double-blind, placebo-controlled intervention trial.

BACKGROUND: Epidemiologic studies have suggested a protective effect of magnesium intake on cardiovascular disease risk. However, intervention trials of magnesium supplementation on blood pressure and conventional cardiometabolic risk markers are inconsistent. Effects on vascular function markers related to cardiovascular disease risk have rarely been studied. OBJECTIVE: The objective was to evaluate the effects of long-term magnesium supplementation on arterial stiffness. DESIGN: We performed a 24-wk, randomized, double-blind, placebo-controlled intervention study. Fifty-two overweight and slightly obese individuals (30 men and 22 postmenopausal women, mean ± SD age: 62 ± 6 y) were randomly allocated to receive either 3 times daily magnesium (3 × 117 mg or 350 mg/d) or placebo capsules. Twenty-four-hour urine collections and 24-h ambulatory blood pressure assessments were performed at the start and end of the study. Carotid-to-femoral pulse wave velocity (PWVc-f) was assessed at baseline, after 12 wk, and at week 24. RESULTS: Serum magnesium concentrations did not differ after 12 wk but tended to increase after 24-wk magnesium supplementation compared with placebo by 0.02 mmol/L (95% CI: 0.00, 0.04 mmol/L; P = 0.09). Twenty-four-hour urinary magnesium excretion increased by 2.01 mmol (95% CI: 1.22, 2.93 mmol; P < 0.001) at week 24. PWVc-f was not changed after 12 wk (0.0 m/s; 95% CI: -0.6, 0.5 m/s; P = 0.90) but was improved in the magnesium compared with the placebo group by 1.0 m/s (95% CI: 0.4, 1.6 m/s; P = 0.001) after 24 wk. Office and 24-h ambulatory blood pressure levels were not changed. No adverse events were observed. CONCLUSION: Our data indicate that a daily magnesium supplement of 350 mg for 24 wk in overweight and obese adults reduces arterial stiffness, as estimated by a decrease in PWVc-f, suggesting a potential mechanism by which an increased dietary magnesium intake beneficially affects cardiovascular health. This trial was registered at clinicaltrials.gov as NCT02235805.

GlycA, a novel proinflammatory glycoprotein biomarker, and high-sensitivity C-reactive protein are inversely associated with sodium intake after controlling for adiposity: the Prevention of Renal and Vascular End-Stage Disease study.

BACKGROUND: The extent to which dietary sodium intake may confer alterations in the inflammatory status is unclear. GlycA is a novel proton nuclear magnetic resonance spectroscopy-measured biomarker of systemic inflammation, which is associated with the development of cardiovascular disease and diabetes. OBJECTIVE: We determined associations of the inflammatory markers GlycA and high-sensitivity C-reactive protein (hsCRP) with 24-h sodium excretion. DESIGN: A cross-sectional, population-based study was performed in 3935 subjects who were not using an antihypertensive medication, lipid-lowering drugs, or a glucose-lowering treatment. Urinary sodium excretion was calculated as the mean of two 24-h urine excretions. Linear regression models were used, with 24-h sodium excretion as an independent variable and GlycA or ln hsCRP as a dependent variable. RESULTS: The mean ± SD sodium excretion was 143.0 ± 53.4 mmol/24 h. The GlycA concentration was 343.6 ± 58.7 µmol/L, and the geometric mean of the hsCRP concentration was 1.20 mg/L (95% CI: 1.16, 1.25 mg/L). In age- and sex-adjusted analyses, GlycA and ln hsCRP were not significantly associated with 24-h sodium excretion [B: 1.23 (95% CI: -0.67, 3.13; P = 0.21) and 0.03 (95% CI: -0.004, 0.07; P = 0.08), respectively, per 1-SD increase]. After additional adjustment for body mass index (BMI), both GlycA (B: -2.76; 95% CI: -4.65, -0.86; P = 0.004) and ln hsCRP (B: -0.07; 95% CI: -0.11, -0.04; P < 0.001) were inversely associated with 24-h sodium excretion. These associations were similar if adjustment was performed for waist circumference instead of BMI or if additional adjustment was performed for relevant clinical and laboratory variables and were particularly present in men. CONCLUSIONS: The proinflammatory biomarkers GlycA and hsCRP are inversely related to higher 24-h sodium excretion when taking into account the variation in adiposity. These inverse relations remain present after taking into account other covariates.

Urinary potassium excretion and risk of cardiovascular events.

BACKGROUND: Observational studies on dietary potassium and risk of cardiovascular disease (CVD) have reported weak-to-modest inverse associations. Long-term prospective studies with multiple 24-h urinary samples for accurate estimation of habitual potassium intake, however, are scarce. OBJECTIVE: We examined the association between urinary potassium excretion and risk of blood pressure-related cardiovascular outcomes. DESIGN: We studied 7795 subjects free of cardiovascular events at baseline in the Prevention of Renal and Vascular End-stage Disease study, a prospective, observational cohort with oversampling of subjects with albuminuria at baseline. Main cardiovascular outcomes were CVD [including ischemic heart disease (IHD), stroke, and vascular interventions], IHD, stroke, and new-onset heart failure (HF). Potassium excretion was measured in two 24-h urine specimens at the start of the study (1997-1998) and midway through follow-up (2001-2003). RESULTS: Baseline median urinary potassium excretion was 70 mmol/24 h (IQR: 56-84 mmol/24 h). During a median follow-up of 10.5 y (IQR: 9.9-10.8 y), a total of 641 CVD, 465 IHD, 172 stroke, and 265 HF events occurred. After adjustment for age and sex, inverse associations were observed between potassium excretion and risk [HR per each 26-mmol/24-h (1-g/d) increase; 95% CI] of CVD (0.87; 0.78, 0.97) and IHD (0.86; 0.75, 0.97), as well as nonsignificant inverse associations for risk of stroke (0.85; 0.68, 1.06) and HF (0.94; 0.80, 1.10). After further adjustment for body mass index, smoking, alcohol consumption, education, and urinary sodium and magnesium excretion, urinary potassium excretion was not statistically significantly associated with risk (multivariable-adjusted HR per 1-g/d increment; 95% CI) of CVD (0.96; 0.85, 1.09), IHD (0.90; 0.81, 1.04), stroke (1.09; 0.86, 1.39), or HF (0.99; 0.83, 1.18). No associations were observed between the sodium-to-potassium excretion ratio and risk of CVD, IHD, stroke, or HF. CONCLUSION: In this cohort with oversampling of subjects with albuminuria at baseline, urinary potassium excretion was not independently associated with a lower risk of cardiovascular events.

Coffee and tea consumption in relation to estimated glomerular filtration rate: results from the population-based longitudinal Doetinchem Cohort Study.

BACKGROUND: Although coffee consumption and tea consumption have been linked to diabetes, the relation with kidney function is less clear and is underresearched. OBJECTIVE: We investigated the prospective associations of coffee and tea consumption with estimated glomerular filtration rate (eGFR). DESIGN: We included 4722 participants aged 26-65 y from the Doetinchem Cohort Study who were examined every 5 y for 15 y. Coffee and tea consumption (in cups/d) were assessed at each round. eGFR was assessed by using the Chronic Kidney Disease Epidemiology Collaboration equation based on both plasma creatinine and cystatin C. We determined the association between categories of coffee and tea intake and 1) eGFR and 2) subsequent annual changes in eGFR by using generalized estimating equation analyses. RESULTS: Baseline mean ± SD eGFR was 108.0 ± 14.7 mL · min(-1) · 1.73 m(-2) Tea consumption was not associated with eGFR. Those individuals who drank >6 cups coffee/d had a 1.33 (95% CI: 0.24, 2.43) mL · min(-1) · 1.73 m(-2) higher eGFR than those who drank <1 cup/d (P-trend = 0.02). This association was most apparent among those with a median age of ≥46 y at baseline, with eGFR being 2.47 (95% CI: 0.42, 4.51) mL · min(-1) · 1.73 m(-2) higher in participants drinking >6 cups/d compared with <1 cup/d (P-trend = 0.02). Adjustment for biological risk factors and coffee constituents did not attenuate the associations. Neither coffee nor tea consumption was associated with changes in eGFR. CONCLUSIONS: Coffee consumption was associated with a slightly higher eGFR, particularly in those aged ≥46 y. The absence of an association with eGFR changes suggests that the higher eGFR among coffee consumers is unlikely to be a result of glomerular hyperfiltration. Therefore, low to moderate coffee consumption is not expected to be a concern for kidney health in the general population.

Association of dietary protein and dairy intakes and change in renal function: results from the population-based longitudinal Doetinchem cohort study.

BACKGROUND: Evidence has suggested that protein from dairy may be less detrimental to renal health than protein from nondairy products. However, to our knowledge, no previous studies have used cystatin C-based measures of the estimated glomerular filtration rate (eGFR). OBJECTIVE: We investigated the associations of sources of protein and dairy with the change in the eGFR in persons with a normal or mildly decreased eGFR. DESIGN: We included 3798 participants, aged 26-65 y, from the Doetinchem Cohort study who were examined ≥3 times 5 y apart. Intakes of protein and dairy and subtypes of protein and dairy were assessed at each round. With the use of the Chronic Kidney Disease Epidemiology Collaboration equation, the eGFR was estimated from cystatin C with all available samples per participant examined in one assay run. Generalized estimating equation models, which were adjusted for lifestyle, biological, and other dietary factors (monounsaturated fat, polyunsaturated fat, phosphorus, magnesium, calcium, and vitamin D) were performed. RESULTS: The mean baseline eGFR in the total cohort and in subjects with a mildly decreased eGFR (≥1 eGFR of 60-90 mL · min-1 · 1.73 m-2 during follow-up; n = 1326) was 108.6 and 95.2 mL · min-1 · 1.73 m-2, and the mean annual decline in both groups was 1.01 and 1.34 mL · min-1 · 1.73 m-2, respectively. Intakes of total, vegetable, animal, and nondairy protein, dairy protein, cheese, total dairy, high-fat dairy, and fermented dairy were not associated with eGFR changes. In individuals with a mildly decreased eGFR, higher consumption of milk, milk products, and low-fat dairy was associated with less annual decline in the eGFR (P-trend = 0.003). These associations were partially explained by dietary components of dairy (monounsaturated fat, polyunsaturated fat, phosphorus, magnesium, calcium, and vitamin D; P-trend < 0.04). CONCLUSIONS: Higher low-fat dairy consumption, but not sources of protein, is associated with less annual decline in the eGFR, particularly in individuals with a mildly decreased eGFR. These associations are partly attributable to other major components of dairy. Confirmation of these results will improve our ability to understand the role of dairy consumption in the prevention of renal dysfunction.

Urinary potassium excretion, renal ammoniagenesis, and risk of graft failure and mortality in renal transplant recipients.

BACKGROUND: Renal transplant recipients (RTRs) have commonly been urged to limit their potassium intake during renal insufficiency and may adhere to this principle after transplantation. Importantly, in experimental animal models, low dietary potassium intake induces kidney injury through stimulation of ammoniagenesis. In humans, low potassium intake is an established risk factor for high blood pressure. OBJECTIVE: We hypothesized that low 24-h urinary potassium excretion [UKV; urinary potassium concentration × volume], the gold standard for assessment of dietary potassium intake, represents a risk factor for graft failure and mortality in RTRs. In secondary analyses, we aimed to investigate whether these associations could be explained by ammoniagenesis, plasma potassium, or blood pressure. DESIGN: In a prospective cohort of 705 RTRs, we assessed dietary potassium intake by a single 24-h UKV and food-frequency questionnaires. Cox regression analyses were used to investigate prospective associations with outcome. RESULTS: We included 705 stable RTRs (mean ± SD age: 53 ± 13 y; 57% men) at 5.4 y (IQR: 1.9-12.0 y) after transplantation and 253 kidney donors. Mean ± SD UKV was 73 ± 24 mmol/24 h in RTRs compared with 85 ± 25 mmol/24 h in kidney donors. During follow-up for 3.1 y (IQR: 2.7-3.9 y), 45 RTRs developed graft failure and 83 died. RTRs in the lowest sex-specific tertile of UKV (women, <55 mmol/24 h; men, <65 mmol/24 h) had an increased risk of graft failure (HR: 3.70; 95% CI: 1.64, 8.34) and risk of mortality (HR; 2.66; 95% CI: 1.53, 4.61), independent of potential confounders. In causal path analyses, 24-h urinary ammonia excretion, plasma potassium, and blood pressure did not affect these associations. CONCLUSIONS: Our results indicate that low UKV is associated with a higher risk of graft failure and mortality in RTRs. Specific attention for adequate potassium intake after transplantation seems warranted. This trial was registered at clinicaltrials.gov as NCT02811835.