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.

Low potassium excretion but not high sodium excretion is associated with increased risk of developing chronic kidney disease.

It is unclear whether sodium and potassium intake is relevant to the development of chronic kidney disease (CKD) in the general population. Our aim was to examine the associations of urinary sodium (UNaV) and potassium excretion (UKV), as estimates of intake, with risk of developing CKD in a population-based cohort. We studied 5315 individuals free of CKD at baseline of the Prevention of Renal and Vascular End-Stage Disease (PREVEND) study, a prospective, population-based cohort of Dutch men and women aged 28 to 75 years. UNaV and UKV were measured in two 24-hour urine specimens at baseline (1997-1998) and midway during follow-up (2001-2003). CKD was defined as de novo development of eGFR under 60 ml/min per 1.73 m(2) or albuminuria over 30 mg/24 hours, or both. Baseline UNaV and UKV were 135 mmol/24 hours (interquartile range: 106-169 mmol/24 hours) and 70 mmol/24 hours (interquartile range, 57-85 mmol/24 hours), respectively. During a median follow-up of 10.3 years, 872 patients developed CKD. After multivariable adjustment for important covariables, no association was observed between UNaV and risk of CKD (hazard ratio per 50 mmol/24 hours [1 SD] increment, 0.97; 95% confidence interval, 0.89-1.06). Each 21 mmol/24 hours (1 SD) decrement in UKV was significantly associated with a 16% higher risk of developing CKD (multivariable-adjusted hazard ratio, 1.16; 95% confidence interval, 1.06-1.28). Thus, low UKV, and not high UNaV, was associated with an increased risk of developing CKD in a population-based cohort with normal kidney function.

Intake of n-3 fatty acids and long-term outcome in renal transplant recipients: a post hoc analysis of a prospective cohort study.

Supplementation with n-3 fatty acids may improve long-term outcomes of renal transplant recipients (RTR). Recent evidence suggests that EPA and DHA have different outcomes compared with α-linolenic acid (ALA). We examined the prospective associations of EPA-DHA and ALA intakes with graft failure and all-cause mortality in 637 RTR. During 3·1 years (interquartile range 2·7, 3·8) of follow-up, forty-one developed graft failure and sixty-seven died. In age- and sex-adjusted analyses, EPA-DHA and ALA intakes were not associated with graft failure. EPA-DHA intake was not significantly associated with mortality (hazard ratio (HR) 0·79; 95% CI 0·54, 1·15 per 0·1 energy% difference). ALA intake was significantly associated with mortality (HR 1·17; 95% CI 1·04, 1·31 per 0·1 energy% difference). This association remained following adjustments for BMI, proteinuria and intakes of fat, carbohydrate and protein. RTR in the highest tertile of ALA intake exhibited about 2-fold higher mortality risk (HR 2·21; 95% CI 1·23, 3·97) compared with the lowest tertile. In conclusion, ALA intake may be associated with increased mortality in RTR. Future RCT are needed to confirm these results.

Sodium excretion and risk of developing coronary heart disease.

BACKGROUND: Despite compelling evidence for sodium's adverse effects on blood pressure, it remains uncertain whether excess sodium intake is a risk factor for coronary heart disease (CHD) in the overall population and in potentially more susceptible subgroups. METHODS AND RESULTS: We prospectively followed 7543 adults aged 28 to 75 years and free of cardiovascular and kidney disease in 1997/1998 of the Prevention of Renal and Vascular End-stage Disease (PREVEND) study. Sodium excretion was measured in two 24-hour urine collections at baseline. Potential susceptibility factors were blood pressure and plasma N-terminal pro-B-type natriuretic peptide (NT-proBNP). Median 24-hour sodium excretion was 137 mmol (Q1-Q3, 106-171 mmol). During a median follow-up of 10.5 (Q1-Q3: 9.9-10.8) years, 452 CHD events occurred. In the entire cohort, there was no association between each 1-g/d (43 mmol/24 h) increment in sodium excretion and CHD risk (adjusted hazard ratio, 1.07; 95% confidence interval, 0.98-1.18; P=0.15). However, the association of sodium excretion with CHD risk tended to be modified by mean arterial pressure (Pinteraction=0.08) and was modified by NT-proBNP (Pinteraction=0.002). When stratified, each 1-g/d increment in sodium excretion was associated with an increased risk for CHD in subjects with hypertension (adjusted hazard ratio, 1.14; 95% confidence interval, 1.01-1.28; n=2363) and in subjects with NT-proBNP concentrations above the sex-specific median (adjusted hazard ratio, 1.16; 95% confidence interval, 1.03-1.30; n=3771). CONCLUSIONS: Overall, there was no association between sodium excretion and risk of CHD. The association between sodium excretion and CHD risk was modified by NT-proBNP. Higher sodium excretion was associated with an increased CHD risk among subjects with increased NT-proBNP concentrations or with hypertension.

Alcohol consumption is inversely associated with the risk of developing chronic kidney disease.

There are few reports of associations between alcohol consumption and risk of chronic kidney disease (CKD). To investigate this further, we studied 5476 participants aged 28-75 years in the Prevention of Renal and Vascular End-Stage Disease (PREVEND) study, a prospective population-based cohort, who were free of CKD at baseline (1997/1998). Alcohol consumption was self-reported on a questionnaire validated against serum high-density lipoprotein cholesterol. The primary outcome was de novo CKD defined as a combination of a creatinine-cystatin C-based estimated glomerular filtration rate (eGFR) under 60 ml/min per 1.73 m(2) and/or the mean of two consecutive 24-h urinary albumin excretions over 30 mg. During four serial follow-up examinations (median 10.2 years until February 2012), 903 participants developed CKD. Compared with those abstaining from alcohol, the multivariable-adjusted hazard ratios (95% confidence interval) for CKD risk were 0.85 (0.69-1.04) for occasional (under 10 g/week), 0.82 (0.69-0.98) for light (10-69.9 g/week), 0.71 (0.58-0.88) for moderate (70-210 g/week), and 0.60 (0.42-0.86) for heavier (over 210 g/week) alcohol consumers (significant trend). Similar inverse associations for alcohol consumption were found when CKD was defined as eGFR <60 ml/min per 1.73 m(2) or as 24-h urinary albumin excretion over 30 mg. Thus, in this population-based cohort, alcohol consumption was inversely associated with the risk of developing CKD.

Vitamin K status and mortality after kidney transplantation: a cohort study.

BACKGROUND: Vitamin K modulates calcification by activating calcification inhibitors such as matrix Gla protein (MGP). In kidney transplant recipients, vitamin K insufficiency is common, but implications for long-term outcomes are unclear. STUDY DESIGN: Single-center observational study with a longitudinal design. SETTING & PARTICIPANTS: 518 stable kidney transplant recipients; 56% men; mean age, 51±12 (SD) years; and a median of 6 (IQR, 3-12) years after kidney transplantation. FACTOR: Plasma desphosphorylated-uncarboxylated MGP (dp-ucMGP) levels, reflecting vitamin K status. OUTCOMES: All-cause mortality and transplant failure. RESULTS: At inclusion, median dp-ucMGP level was 1,038 (IQR, 733-1,536) pmol/L, with 473 (91%) patients having vitamin K insufficiency (defined as dp-ucMGP>500pmol/L). During a median follow-up of 9.8 (IQR, 8.5-10.2) years, 152 (29%) patients died and 54 (10%) developed transplant failure. Patients in the highest quartile of dp-ucMGP were at considerably higher mortality risk compared with patients in the lowest quartile (HR, 3.10; 95% CI, 1.87-5.12; P for trend<0.001; P for quartile 1 [Q1] vs Q4<0.001). After adjustment for potential confounders, including kidney function and exclusion of patients treated with a vitamin K antagonist, this association remained significant. Patients in the highest quartile also were at higher risk of developing transplant failure (HR, 2.61; 95% CI, 1.22-5.57; P for trend=0.004; P for Q1 vs Q4=0.01), but this association was lost after adjustment for baseline kidney function (HR, 1.20; 95% CI, 0.52-2.75; P for trend=0.6; P for Q1 vs Q4=0.7). LIMITATIONS: Although MGP exists as various species, only dp-ucMGP was measured. No data were available for vascular calcification as an intermediate end point. CONCLUSIONS: Vitamin K insufficiency, that is, a high circulating level of dp-ucMGP, is highly prevalent in stable kidney transplant recipients and is associated independently with increased risk of mortality. Future studies should address whether vitamin K supplementation may lead to improved outcomes after kidney transplantation.

Causal path analyses of the association of protein intake with risk of mortality and graft failure in renal transplant recipients.

The effect of a low protein intake on survival in renal transplant recipients (RTR) is unknown. A low protein intake may increase risks of malnutrition, low muscle mass, and death. We aimed to study associations of protein intake with mortality and graft failure and to identify potential intermediate factors. Protein intake was estimated from 24-h urinary urea excretion (24-h UUE). Graft failure was defined as return to dialysis or retransplantation. We used Cox regression analyses to analyze associations with outcome and potential intermediate factors in the causal path. In 604 RTR, mean ± SD 24-h UUE was 380 ± 114 mmol/24-h. During median follow-up for 7.0 yr (interquartile range: 6.2-7.5 yr), 133 RTR died and 53 developed graft failure. In univariate analyses, 24-h UUE was associated with lower risk of mortality (HR [95% CI] = 0.80 [0.69-0.94]) and graft failure (HR [95% CI] = 0.72 [0.56-0.92]). These associations were independent of potential confounders. In causal path analyses, the association of 24-h UUE with mortality disappeared after adjustment for muscle mass. Low protein intake is associated with increased risk of mortality and graft failure in RTR. Causal path analyses reveal that the association with mortality is explained by low muscle mass. These findings suggest that protein intake restriction should not be advised to RTR.

Total adiponectin and risk of symptomatic lower extremity peripheral artery disease in men.

OBJECTIVE: Lower concentrations of adiponectin have been linked to subsequent risk of coronary heart disease in healthy individuals. Whether similar relationships exist for the development of systemic atherosclerosis, such as peripheral artery disease (PAD), is uncertain. We investigated the association between total adiponectin and risk of lower extremity PAD. APPROACH AND RESULTS: We performed a prospective, nested case-control study among 18,225 male participants of the Health Professionals Follow-up Study who were free of diagnosed cardiovascular disease at the time of blood draw (1993-1995). During 14 years of follow-up, 143 men developed PAD. Using risk set sampling, controls were selected in a 3:1 ratio and matched on age, smoking status, fasting status, and date of blood draw (n=429). Median (interquartile range) adiponectin concentrations at baseline were lower among cases compared with controls (4.1 [3.2-5.5] versus 5.4 [3.8-7.5] µg/mL; P<0.001). A log-linear inverse association was evident over the full spectrum of adiponectin concentrations with PAD risk after controlling for baseline cardiovascular risk factors using restricted spline conditional logistic regression. Adiponectin was associated with a 42% lower risk of PAD per SD increase in natural log-transformed adiponectin (relative risk, 0.58; 95% confidence interval, 0.45-0.74) after adjustment for cardiovascular risk factors. The relative risk was attenuated (relative risk, 0.68; 95% confidence interval, 0.51-0.92) after further accounting for high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, C-reactive protein, and cystatin C. Additional adjustment for hemoglobin A(1c), triglycerides, and γ-glutamyltransferase had little impact on this association (relative risk, 0.68; 95% confidence interval, 0.50-0.92). CONCLUSIONS: Total adiponectin is inversely associated with risk of symptomatic lower extremity PAD in men.

Moderate alcohol consumption alters both leucocyte gene expression profiles and circulating proteins related to immune response and lipid metabolism in men.

Moderate alcohol consumption has various effects on immune and inflammatory processes, which could accumulatively modulate chronic disease risk. So far, no comprehensive, integrative profiling has been performed to investigate the effects of longer-term alcohol consumption. Therefore, we studied the effects of alcohol consumption on gene expression patterns using large-scale profiling of whole-genome transcriptomics in blood cells and on a number of proteins in blood. In a randomised, open-label, cross-over trial, twenty-four young, normal-weight men consumed 100 ml vodka (30 g alcohol) with 200 ml orange juice or only orange juice daily during dinner for 4 weeks. After each period, blood was sampled for measuring gene expression and selected proteins. Pathway analysis of 345 down-regulated and 455 up-regulated genes revealed effects of alcohol consumption on various signalling responses, immune processes and lipid metabolism. Among the signalling processes, the most prominently changed was glucocorticoid receptor signalling. A network on immune response showed a down-regulated NF-κB gene expression together with increased plasma adiponectin and decreased pro-inflammatory IL-1 receptor antagonist and IL-18, and acute-phase proteins ferritin and α1-antitrypsin concentrations (all P < 0.05) after alcohol consumption. Furthermore, a network of gene expression changes related to lipid metabolism was observed, with a central role for PPARα which was supported by increased HDL-cholesterol and several apo concentrations (all P < 0.05) after alcohol consumption. In conclusion, an integrated approach of profiling both genes and proteins in blood showed that 4 weeks of moderate alcohol consumption altered immune responses and lipid metabolism.

Associations between conventional cardiovascular risk factors and risk of peripheral artery disease in men.

CONTEXT: Previous studies have examined the associations of individual clinical risk factors with risk of peripheral artery disease (PAD), but the combined effects of these risk factors are largely unknown. OBJECTIVE: To estimate the degree to which the 4 conventional cardiovascular risk factors of smoking, hypertension, hypercholesterolemia, and type 2 diabetes are associated with the risk of PAD among men. DESIGN, SETTING, AND PARTICIPANTS: Prospective study of 44,985 men in the United States without a history of cardiovascular disease at baseline in 1986; participants in the Health Professionals Follow-up Study were followed up for 25 years until January 2011. The presence of risk factors was updated biennially during follow-up. MAIN OUTCOME MEASURE: Clinically significant PAD defined as limb amputation or revascularization, angiogram reporting vascular obstruction of 50% or greater, ankle-brachial index of less than 0.90, or physician-diagnosed PAD. RESULTS: During a median follow-up of 24.2 years (interquartile range, 20.8-24.7 years), there were 537 cases of incident PAD. Each risk factor was significantly and independently associated with a higher risk of PAD after adjustment for the other 3 risk factors and confounders. The age-adjusted incidence rates were 9 (95% CI, 6-14) cases/100,000 person-years (n = 19 incident cases) for 0 risk factors, 23 (95% CI, 18-28) cases/100,000 person-years (n = 99 incident cases) for 1 risk factor, 47 (95% CI, 39-56) cases/100,000 person-years (n = 176 incident cases) for 2 risk factors, 92 (95% CI, 76-111) cases/100,000 person-years (n = 180 incident cases) for 3 risk factors, and 186 (95% CI, 141-246) cases/100,000 person-years (n = 63 incident cases) for 4 risk factors. The multivariable-adjusted hazard ratio for each additional risk factor was 2.06 (95% CI, 1.88-2.26). Men without any of the 4 risk factors had a hazard ratio of PAD of 0.23 (95% CI, 0.14-0.36) compared with all other men in the cohort. In 96% of PAD cases (95% CI, 94%-98%), at least 1 of the 4 risk factors was present at the time of PAD diagnosis. The population-attributable risk associated with these 4 risk factors was 75% (95% CI, 64%-87%). The absolute incidence of PAD among men with all 4 risk factors was 3.5/1000 person-years. CONCLUSION: Among men in this cohort, smoking, hypertension, hypercholesterolemia, and type 2 diabetes account for the majority of risk associated with development of clinically significant PAD.

Short-term oral exposure to white wine transiently lowers serum free fatty acids.

In humans little is known as to whether oral sensory stimulation with alcohol elicits cephalic phase responses. This study sought to determine whether oral alcohol exposure, in the form of white wine, provokes cephalic phase responses in normal-weight and overweight women. In a semi-randomized, crossover trial, eleven normal-weight and eleven overweight women sham-fed, after an overnight fast under three separate conditions 4 weeks apart, cake (750kJ), 25cL white wine (750kJ; approximately 26g alcohol) and 25cL water. Blood was drawn prior to and for 30min after two 3-min episodes of modified sham-feeding (MSF). Blood samples were analyzed for free fatty acid (FFA), triglyceride, glucose, pancreatic polypeptide (PP), insulin and alcohol concentrations. Incremental area under the curves (IAUC) of FFA concentrations differed significantly between the three treatments but not between BMI categories. After MSF with wine, FFA concentrations dropped to a minimum of 77+/-3% of baseline concentrations at t=12+/-2min after baseline and returned to baseline after approximately 30min, whereas after MSF with cake and water, FFA concentrations gradually increased. In conclusion, short-term oral white wine exposure substantially and temporarily decreases FFA concentrations suggesting a cephalic phase response of alcohol. This effect occurred regardless of BMI.

Magnesium and Blood Pressure: A Physiology-Based Approach.

Hypertension is an important public health challenge because of its high prevalence and strong association with cardiovascular disease and premature death. Hypertension is a major cause of CKD, is present in more than 80% of CKD patients, and contributes to CKD progression. Risk factors for hypertension include, but are not limited to, age, race, family history, obesity, physical inactivity, tobacco use, and inadequate intake of minerals such as calcium, potassium, and magnesium. Magnesium is the second most abundant intracellular cation in the human body and plays an important role in insulin and adenosine triphosphate metabolism. Low dietary magnesium intake has been associated with an increased risk of developing hypertension in prospective cohort studies. Moreover, clinical trials suggest that magnesium supplementation has blood pressure-lowering effects. In addition, emerging data reveal potential mechanisms by which magnesium may influence blood pressure. Here, we will review these mechanisms, using a physiology-based approach, focusing on the effects of magnesium on total peripheral resistance and cardiac output.

Association of Low Urinary Sodium Excretion With Increased Risk of Stroke.

The positive relationship between sodium intake and blood pressure is well established. However, results of observational studies on dietary sodium intake and risk of stroke are inconsistent. Moreover, prospective studies with multiple 24-hour urine samples for accurate estimation of habitual sodium intake are scarce. We examined the association of urinary sodium excretion (UNaV) as an accurate estimate of intake with risk of stroke. We studied 7330 individuals free of cardiovascular events at baseline in the Prevention of Renal and Vascular End-stage Disease (PREVEND) study, a prospective, population-based cohort of Dutch men and women. The UNaV was measured in two 24-hour urine specimens at baseline (1997-1998) and two specimens during follow-up (2001-2003). Baseline median UNaV was 137 mmol/24 h (interquartile range, 106-171 mmol/24 h). During a median follow-up of 12.5 years (interquartile range, 11.9-12.9 years), a total of 183 stroke events occurred. An inverse association between UNaV and risk of stroke was observed after adjustment for age and sex (hazard ratio [HR] per 1-SD [51 mmol/24 h] decrement, 1.36; 95% CI, 1.11-1.65), which remained independent of additional adjustment for anthropometric, dietary, lifestyle, and other potential confounding factors (HR, 1.44; 95% CI, 1.14-1.82). After adjustment for potential mediators (systolic blood pressure and antihypertensive medication, plasma renin, aldosterone, and sodium levels), the association of UNaV with risk of stroke remained unchanged, with HRs (95% CIs) of 1.44 (1.14-1.82), 1.50 (1.18-1.90), 1.54 (1.21-1.97), and 1.49 (1.17-1.90), respectively. This prospective study revealed an association of low UNaV with an increased risk of stroke.

Plasma Proenkephalin and Poor Long-Term Outcome in Renal Transplant Recipients.

BACKGROUND: Proenkephalin (pro-ENK), a stable and reliable surrogate marker for unstable enkephalins, was found to be associated with acute kidney injury and chronic renal failure in previous studies. We aimed to investigate whether pro-ENK is linked to chronic kidney injury and poor long-term outcome in renal transplant recipients (RTR). METHODS: We included 664 stable RTR and 95 healthy kidney donors. Pro-ENK was measured in plasma with a double monoclonal sandwich immunoassay. Graft failure was defined as return to dialysis therapy or retransplantation. RESULTS: Median pro-ENK was 110 pmol/L (interquartile range [IQR], 85-148 pmol/L) in RTR and 48 pmol/L (IQR, 42-55 pmol/L) in kidney donors. Pro-ENK was correlated with estimated glomerular filtration rate (GFR) (rs = -0.80, P < 0.001) in RTR and with measured GFR (rs = -0.74, P < 0.001) in kidney donors. During a median follow-up of 3.1 years (IQR, 2.7-3.9 years), 45 RTR developed graft failure and 76 died. Pro-ENK was positively associated with risk (hazard ratio [HR] per standard deviation increment of the logarithm of pro-ENK; 95% confidence interval [CI]) of graft failure (HR, 4.80; 95% CI, 3.55-6.48) and mortality (HR, 1.50; 95% CI, 1.22-1.85). After adjustment of age, sex, and estimated GFR, the association of pro-ENK with graft failure remained significant (HR, 2.36; 95% CI, 1.37-4.06), whereas no significant association of pro-ENK with risk of all-cause mortality was observed (HR, 1.34; 95% CI, 0.90-2.09). CONCLUSIONS: Plasma pro-ENK is associated with kidney function as reflected by correlations with measured GFR in both RTR and kidney donors. In addition, pro-ENK was independently associated with increased risk of graft failure in RTR. Pro-ENK may aid in identification of RTR at risk for late graft failure.

Plasma potassium, diuretic use and risk of developing chronic kidney disease in a predominantly White population.

OBJECTIVE: Both hypokalemia and hyperkalemia are associated with disease progression in patients with chronic kidney disease (CKD). It is unclear whether similar associations are present in the general population. Our aim was to examine the association of plasma potassium with risk of developing CKD and the role of diuretics in this association in a population-based cohort. RESEARCH DESIGN AND METHODS: We studied 5,130 subjects free of CKD at baseline of the Prevention of Renal and Vascular End-Stage Disease (PREVEND) study, a prospective, population-based cohort of Dutch men and women aged 28-75 years. Hypokalemia was defined as plasma potassium <3.5 mmol/L, and hyperkalemia as plasma potassium ≥5.0 mmol/L. Risk of CKD was defined as de novo development of eGFR <60 ml/min/1.73m2 and/or albuminuria >30 mg/24h. RESULTS: Mean baseline plasma potassium was 4.4±0.3 mmol/L. The prevalences of hypokalemia and hyperkalemia were 0.5% and 3.8%, respectively; 3.0% of the subjects used diuretics. During a median follow-up of 10.3 years (interquartile range: 6.3-11.4 years), 753 subjects developed CKD. The potassium-CKD association was modified by diuretic use (Pinteraction = 0.02). Both hypokalemia without (HR, 7.74, 95% CI, 3.43-17.48) or with diuretic use (HR, 4.32, 95% CI, 1.77-10.51) were associated with an increased CKD risk as compared to plasma potassium 4.0-4.4 mmol/L without diuretic use. Plasma potassium concentrations ≥3.5 mmol/L were associated with an increased CKD risk among subjects using diuretics (Ptrend = 0.01) but not among subjects not using diuretics (Ptrend = 0.74). CONCLUSION: In this population-based cohort, hypokalemia was associated with an increased CKD risk, regardless of diuretic use. In the absence of hypokalemia, plasma potassium was not associated with an increased CKD risk, except among subjects using diuretics.

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.

Plasma calcidiol, calcitriol, and parathyroid hormone and risk of new onset heart failure in a population-based cohort study.

BACKGROUND: Heart failure (HF) is a major problem in the Western world, with increasing prevalence and incidence. Because HF cannot be cured, prevention of HF is of utter importance. Calcidiol, calcitriol, and parathyroid hormone (PTH) have been identified as risk factors for cardiovascular disease. However, their association with new onset HF remains to be established. We investigated whether calcidiol, calcitriol, and PTH could be used to identify those subjects at risk for new onset HF, and if they had additive predictive value over established risk predictors like N-terminal-pro Brain-type natriuretic peptide and highly sensitive Troponin-T. METHODS AND RESULTS: We examined 7470 HF-free participants in Prevention of Renal and Vascular End-stage Disease, a community-based cohort study in Groningen, the Netherlands (latitude 53°N, mean age: 49 years, 48% male). During follow-up time of 12.6 years (interquartile range: 12.3-12.9), 281 participants (4%) developed HF: 181 (66%) HF with reduced and 94 (34%) HF with preserved ejection fraction (HFrEF [left ventricular ejection fraction ≤ 40%], and HFpEF [left ventricular ejection fraction ≥ 50%], respectively). Mean (±SD) of calcidiol was 58 (±24) nmol/L, mean calcitriol 145 (±48) pmol/L, and median (interquartile range) PTH was 3.7 (3.0-4.6) pmol/L. Calcidiol levels were univariately associated with new onset HF [hazard ratio (HR) 0.82 (95% CI 0.69-0.96)], but calcitriol levels were not [HR 0.85 (95% CI 0.71-1.03)]. PTH levels kept their predictive value after adjustment for age, sex, and day of blood withdrawal (HR 1.26 [95% CI 1.04-1.53]). However, in our full model this association was lost [HR 1.10 (95% CI 0.92-1.32)]. Calcidiol, calcitriol, and PTH could not differentiate between new onset HFrEF or HFpEF. CONCLUSIONS: After adjustment for confounding factors, a single measurement of plasma calcidiol, calcitriol, or PTH was not associated with risk of developing HF. Screening for these markers to identify subjects at risk for new onset HF cannot be advocated.

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.

Socioeconomic disparities in chronic kidney disease: a systematic review and meta-analysis.

CONTEXT: Evidence on the strength of the association between low SES and chronic kidney disease (CKD; measured by low estimated glomerular filtration rate [eGFR], high albuminuria, low eGFR/high albuminuria, and renal failure) is scattered and sometimes conflicting. Therefore, a systematic review and meta-analysis was performed to summarize the strength of the associations between SES and CKD and identify study-level characteristics related to this association. EVIDENCE ACQUISITION: Studies published through January 2013 in MEDLINE and Embase were searched. From 35 studies that met the inclusion criteria, association estimates were pooled per CKD measure in the meta-analysis (performed between 2013 and 2014). Meta-regression analysis was used to identify study-level characteristics related to the strength of the SES-CKD association. EVIDENCE SYNTHESIS: Low SES was associated with low eGFR (OR=1.41, 95% CI=1.21, 1.62), high albuminuria (OR=1.52, 95% CI=1.22, 1.82), low eGFR/high albuminuria (OR=1.38, 95% CI=1.03, 1.74), and renal failure (OR=1.55, 95% CI=1.40, 1.71). Differences in SES measures across studies were not related to the strength of associations between low SES and any of the CKD measures (low GFR, p=0.63; high albuminuria, p=0.29; low eGFR/high albuminuria, p=0.54; renal failure, p=0.31). Variations in the strength of associations were related to the level of covariate adjustment for low eGFR (p<0.001) and high albuminuria (p<0.001). CONCLUSIONS: Socioeconomic disparities in CKD were fairly strong, irrespective of how SES was measured. Variations in the strength of the associations were related to the level of covariate adjustment, particularly for low eGFR and high albuminuria.