Sodium and potassium intake as determinants of cardiovascular and renal health

Worldwide, there is an increase in the prevalence of cardiovascular disease and chronic kidney disease. Intake of dietary minerals, in particular sodium and potassium, might play an important role in the prevention of these chronic diseases. However, the evidence on the potential beneficial effects of these dietary interventions is inconsistent. The discrepancies in literature might partly be explained by methodological issues of studies, including varying – and often inaccurate– methods used for the assessment of dietary sodium and potassium intake, including dietary questionnaires. In the studies included in this thesis, the intake of sodium and potassium was determined by measuring the excretion in 24-hour urine collections, which is considered the most accurate characterization of an individual’s mean sodium and potassium intake. Results of thesis suggest that a low sodium intake is associated with an increased risk of stroke in the general population. Despite the effect of sodium on blood pressure, we could not identify an association between sodium intake and risk of developing chronic kidney disease. Furthermore, the results suggest an important role of sufficient potassium intake in the prevention of a high blood pressure and chronic kidney disease in a population-based cohort, and also with poor long-term outcome in renal transplant recipients, including renal graft failure and all-cause mortality. Despite these findings, we could not identify an association between potassium intake and risk of cardiovascular disease

Kidney Age Index (KAI):A novel age-related biomarker to estimate kidney function in patients with diabetic kidney disease using machine learning

BACKGROUND AND OBJECTIVE: With aging, patients with diabetic kidney disease (DKD) show progressive decrease in kidney function. We investigated whether the deviation of biological age (BA) from the chronological age (CA) due to DKD can be used (denoted as Kidney Age Index; KAI) to quantify kidney function using machine learning algorithms. METHODS: Three large datasets were used in this study to develop KAI. The machine learning algorithms were trained on PREVEND dataset with healthy subjects (N = 7963) using 13 clinical markers to predict the CA. The trained model was then used to predict the BA of patients with DKD using RENAAL (N = 1451) and IDNT (N = 1706). The performance of four traditional machine learning algorithms were evaluated and the KAI = BA-CA was estimated for each patient. RESULTS: The neural network model achieved the best performance and predicted the CA of healthy subjects in PREVEND dataset with a mean absolute deviation (MAD) = 6.5 ± 3.5 years and pearson correlation = 0.62. Patients with DKD showed a significant higher KAI of 15.4 ± 11.8 years and 13.6 ± 12.3 years in RENAAL and IDNT datasets, respectively. CONCLUSIONS: Our findings suggest that for a given CA, patients with DKD shows excess BA when compared to their healthy counterparts due to disease severity. With further improvement, the proposed KAI can be used as a complementary easy-to-interpret tool to give a more inclusive idea into disease state

Circulating Total Bilirubin and Future Risk of Hypertension in the General Population: The Prevention of Renal and Vascular End-Stage Disease (PREVEND) Prospective Study and a Mendelian Randomization Approach

BACKGROUND: Circulating total bilirubin is known to be inversely and independently associated with future risk of cardiovascular disease. However, the relationship of circulating total bilirubin with incident hypertension is uncertain. We aimed to assess the association of total bilirubin with future hypertension risk and supplemented this with a Mendelian randomization approach to investigate any causal relevance to the association. METHODS AND RESULTS: Plasma total bilirubin levels were measured at baseline in the PREVEND (Prevention of Renal and Vascular End-Stage Disease) prospective study of 3989 men and women without hypertension. Hazard ratios (95% confidence intervals) of total bilirubin with incident hypertension were assessed. New-onset hypertension was recorded in 1206 participants during a median follow-up of 10.7 years. Baseline total bilirubin was approximately log-linearly associated with hypertension risk. Age- and sex-adjusted hazard ratio for hypertension per 1-SD increase in loge total bilirubin was 0.86 (0.81-0.92; P0.05 for all), arguing against a strong causal association of circulating bilirubin with blood pressure. CONCLUSIONS: The weak and inverse association of circulating total bilirubin with future hypertension risk may be driven by biases such as unmeasured confounding and/or reverse causation. Further evaluation is warranted.The Dutch Kidney Foundation supported the infrastructure of the PREVEND program from 1997 to 2003 (Grant E.033). The University Medical Center Groningen supported the infrastructure from 2003 to 2006. Dade Behring, Ausam, Roche, and Abbott financed laboratory equipment and reagents by which various laboratory determinations could be performed. The Dutch Heart Foundation supported studies on lipid metabolism (Grant 2001‐005). The funding sources had no role in study design; in data collection, analysis, or interpretation of the data; in writing of the report; or in the decision to submit for publication

Educational level and risk of chronic kidney disease:longitudinal data from the PREVEND study

BACKGROUND: The longitudinal association between low education and chronic kidney disease (CKD) and its underlying mechanisms is poorly characterized. We therefore examined the association of low education with incident CKD and change in kidney function, and explored potential mediators of this association. METHODS: We analysed data on 6078 participants from the community-based Prevention of Renal and Vascular End-stage Disease study. Educational level was categorized into low, medium and high ( secondary schooling, respectively). Kidney function was assessed by estimating glomerular filtration rate (eGFR) by serum creatinine and cystatin C at five examinations during ∼11 years of follow-up. Incident CKD was defined as new-onset eGFR <60 mL/min/1.73 m2 and/or urinary albumin ≥30 mg/24 h in those free of CKD at baseline. We estimated main effects with Cox regression and linear mixed models. In exploratory causal mediation analyses, we examined mediation by several potential risk factors. RESULTS: Incident CKD was observed in 861 (17%) participants. Lower education was associated with higher rates of incident CKD [low versus high education; hazard ratio (HR) (95% CI) 1.25 (1.05-1.48), Ptrend = 0.009] and accelerated eGFR decline [B (95% CI) -0.15 (-0.21 to -0.09) mL/min/1.73 m2/year, Ptrend < 0.001]. The association between education and incident CKD was mediated by smoking, potassium excretion, body mass index (BMI), waist-to-hip ratio (WHR) and hypertension. Analysis on annual eGFR change in addition suggested mediation by magnesium excretion, protein intake and diabetes. CONCLUSIONS: In the general population, we observed an inverse association of educational level with CKD. Diabetes and the modifiable risk factors smoking, poor diet, BMI, WHR and hypertension are suggested to underlie this association. These findings provide support for targeted preventive policies to reduce socioeconomic disparities in kidney disease

Proenkephalin and risk of developing chronic kidney disease:The Prevention of Renal and Vascular End-stage Disease study

BACKGROUND: Proenkephalin (pro-ENK) was recently found to be associated with low estimated glomerular filtration rate (eGFR). The association of pro-ENK with urinary albumin excretion (UAE), another marker for chronic kidney disease (CKD), has not been investigated. We examined the association of pro-ENK with eGFR and UAE as markers of CKD. METHODS: We included 4375 subjects of the Prevention of Renal and Vascular End-Stage Disease (PREVEND) study. CKDeGFR was defined as development of eGFR <60 ml/min/1.73 m2 and CKDUAE as albuminuria >30 mg/24 h. RESULTS: Baseline median pro-ENK was 52.2 (IQR: 44.9-60.5) pmol/L. After a median follow-up of 8.4 (IQR: 7.9-8.9) years, 183 subjects developed CKDeGFR and 371 developed CKDUAE. The association of pro-ENK with CKDeGFR was modified by sex (Pinteraction < 0.1), in such a way that after adjustment, the association only remained significant in men (adjusted hazard ratio per SD increase in 10log-transformed pro-ENK, 1.65; 95% CI: 1.15-2.36) and not in women (0.83; 0.58-1.20). No significant association was observed between pro-ENK and CKDUAE risk (0.83; 0.58-1.20). CONCLUSIONS: High pro-ENK is associated with increased risk of CKDeGFR in men, but not in women. No association of pro-ENK with CKDUAE was observed. These results should be interpreted with caution, since residual confounding and potential overfitting of models could have influenced the results

Separating the effects of 24-hour urinary chloride and sodium excretion on blood pressure and risk of hypertension:Results from PREVEND

OBJECTIVE:Research into dietary factors associated with hypertension has focused on the sodium component of salt. However, chloride has distinct physiological effects that may surpass the effect of sodium on blood pressure. This study aims to separate the specific effects of chloride and sodium intake on blood pressure. METHODS:We studied 5673 participants from the Prevention of Renal and Vascular End-Stage Disease(PREVEND) study. Urinary chloride(uCl) and sodium(uNa) were measured in two 24-hour collections. We used generalized-linear-regression to evaluate the relation of uCl and uNa with baseline blood pressure and Cox-proportional-hazards-analysis to assess the association with hypertension. Multicollinearity was assessed with Ridge regression. RESULTS:Baseline 24-hour uCl was 135±39mmol and uNa was 144±54mmol. The correlation between uCl and uNa was high (Pearson's r = 0.96). UCl and uNa had similar non-significant positive and linear associations with blood pressure. In 3515 normotensive patients, 1021 patients developed hypertension during a median follow-up of 7.4 years. UCl and uNa had a comparable but non-significant J-shaped effect on the risk of hypertension. Adding both uCl and uNa to the same model produced instability, demonstrated by Ridge coefficients that converged or changed sign. The single index of uNa minus uCl showed a non-significant higher risk of hypertension of 2% per 10mmol/24-hour difference (HR1.02, 95%CI 0.98-1.06). CONCLUSION:UCl and uNa had similar positive but non-significant associations with blood pressure and risk of hypertension and their effects could not be disentangled. Hence, the alleged adverse effects of high salt intake could be due to sodium, chloride or both. This encourages further study into the effect of chloride in order to complement dietary recommendations currently focused on sodium alone

HDL Particle Subspecies and Their Association With Incident Type 2 Diabetes:The PREVEND Study

Context: High-density lipoproteins (HDL) may be protective against type 2 diabetes (T2D) development, but HDL particles vary in size and function, which could lead to differential associations with incident T2D. A newly developed nuclear magnetic resonance (NMR)derived algorithm provides concentrations for 7 HDL subspecies. Objective: We aimed to investigate the association of HDL particle subspecies with incident T2D in the general population. Methods: Among 4828 subjects of the Prevention of Renal and Vascular End-Stage Disease (PREVEND) study without T2D at baseline, HDL subspecies with increasing size from H1P to H7P were measured by NMR (LP4 algorithm of the Vantera NMR platform). Results: A total of 265 individuals developed T2D (median follow-up of 7.3 years). In Cox regression models, HDL size and H4P (hazard ratio [HR] per 1 SD increase 0.83 [95% CI, 0.690.99] and 0.85 [95% CI, 0.75-0.95], respectively) were inversely associated with incident T2D, after adjustment for relevant covariates. In contrast, levels of H2P were positively associated with incidentT2D (HR 1.15 [95% CI, 1.01-1.32]). In secondary analyses, associations with large HDL particles and H6P were modified by body mass index (BMI) in such a way that they were particularly associated with a lower risk of incident T2D, in subjects with BMI < 30 kg/m(2). Conclusion: Greater HDL size and lower levels of H4P were associated with a lower risk, whereas higher levels of H2P were associated with a higher risk of developing T2D. In addition, large HDL particles and H6P were inversely associated with T2D in nonobese subjects

An increase in albuminuria is associated with a higher incidence of malignancies

Background. A single albuminuria measurement is reported to be an independent predictor of cancer risk. Whether change in albuminuria is also independently associated with cancer is not known. Methods. We included 64 303 subjects of the Stockholm CREAtinine Measurements( SCREAM) project without a history of cancer and with at least two urine albumin-creatinine ratio( ACR) tests up to 2 years apart. Albuminuria changes were quantified by the fold-change in ACR over 2 years, and stratified into the absence of clinically elevated albuminuria( i.e. never) , albuminuria that remained constant, and albuminuria that increased or decreased. The primary outcome was overall cancer incidence. Secondary outcomes were site-specific cancer incidences. Results. During a median follow-up of 3.7( interquartile range 3.6-3.7) years, 5126 subjects developed de novo cancer. After multivariable adjustment including baseline estimated glomerular filtration rate and baseline ACR, subjects with increasing ACR over 2 years had a 19%( hazard ratio 1.19; 95% confidence interval 1.08-1.31) higher risk of overall cancer compared with those who never had clinically elevated ACR. No association with cancer risk was seen in the groups with decreasing or constant ACR. Regarding site-specific cancer risks, subjects with increasing ACR or constant ACR had a higher risk of developing urinary tract and lung cancer. No other associations between 2-year ACR changes and site-specific cancers were found. Conclusions. Increases in albuminuria over a 2-year period are associated with a higher risk of developing overall, urinary tract and lung cancer, independent of baseline kidney function and albuminuria. These data add important weight to the link that exists between albuminuria and cancer incidence.</p

An increase in albuminuria is associated with a higher incidence of malignancies

Background. A single albuminuria measurement is reported to be an independent predictor of cancer risk. Whether change in albuminuria is also independently associated with cancer is not known. Methods. We included 64 303 subjects of the Stockholm CREAtinine Measurements( SCREAM) project without a history of cancer and with at least two urine albumin-creatinine ratio( ACR) tests up to 2 years apart. Albuminuria changes were quantified by the fold-change in ACR over 2 years, and stratified into the absence of clinically elevated albuminuria( i.e. never) , albuminuria that remained constant, and albuminuria that increased or decreased. The primary outcome was overall cancer incidence. Secondary outcomes were site-specific cancer incidences. Results. During a median follow-up of 3.7( interquartile range 3.6-3.7) years, 5126 subjects developed de novo cancer. After multivariable adjustment including baseline estimated glomerular filtration rate and baseline ACR, subjects with increasing ACR over 2 years had a 19%( hazard ratio 1.19; 95% confidence interval 1.08-1.31) higher risk of overall cancer compared with those who never had clinically elevated ACR. No association with cancer risk was seen in the groups with decreasing or constant ACR. Regarding site-specific cancer risks, subjects with increasing ACR or constant ACR had a higher risk of developing urinary tract and lung cancer. No other associations between 2-year ACR changes and site-specific cancers were found. Conclusions. Increases in albuminuria over a 2-year period are associated with a higher risk of developing overall, urinary tract and lung cancer, independent of baseline kidney function and albuminuria. These data add important weight to the link that exists between albuminuria and cancer incidence.</p