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.

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.

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.

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.

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.

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.

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.

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.

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 Vitamin D Level and Change in Albuminuria and eGFR According to Sodium Intake.

BACKGROUND AND OBJECTIVES: Low circulating 25-hydroxyvitamin D [25(OH)D] and high sodium intake are both associated with progressive albuminuria and renal function loss in CKD. Both vitamin D and sodium intake interact with the renin-angiotensin-aldosterone system. We investigated whether plasma 25(OH)D or 1,25-dihydroxyvitamin D [1,25(OH)2D] is associated with developing increased albuminuria or reduced renal function and whether these associations depend on sodium intake. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Baseline plasma 25(OH)D and 1,25(OH)2D were measured by liquid chromatography tandem mass spectrometry, and sodium intake was assessed by 24-hour urine collections in the general population-based Prevention of Renal and Vascular End-Stage Disease cohort (n=5051). Two primary outcomes were development of urinary albumin excretion >30 mg/24 h and eGFR (creatinine/cystatin C-based CKD Epidemiology Collaboration) <60 ml/min per 1.73 m(2). Participants with CKD at baseline were excluded. In Cox regression analyses, we assessed associations of vitamin D with developing increased albuminuria or reduced eGFR and potential interaction with sodium intake. RESULTS: During a median follow-up of 10.4 (6.2-11.4) years, 641 (13%) participants developed increased albuminuria, and 268 (5%) participants developed reduced eGFR. Plasma 25(OH)D was inversely associated with increased albuminuria (fully adjusted hazard ratio [HR] per SD higher, 0.86; 95% confidence interval [95% CI], 0.78 to 0.95; P=0.003) but not reduced eGFR (HR, 0.99; 95% CI, 0.87 to 1.12; P=0.85). There was interaction between 25(OH)D and sodium intake for risk of developing increased albuminuria (P interaction =0.03). In participants with high sodium intake, risk of developing increased albuminuria was inversely associated with 25(OH)D (lowest versus highest quartile: adjusted HR, 1.81; 95% CI, 1.20 to 2.73, P<0.01), whereas this association was nonsignificant in participants with low sodium intake (HR, 1.29; 95% CI, 0.94 to 1.77; P=0.12). Plasma 1,25(OH)2D was not significantly associated with increased albuminuria or reduced eGFR. CONCLUSIONS: Low plasma 25(OH)D is associated with higher risk of developing increased albuminuria, particularly in individuals with high sodium intake, but not of developing reduced eGFR. Plasma 1,25(OH)2D is not associated with risk of developing increased albuminuria or reduced eGFR.

Plasma 1,25-Dihydroxyvitamin D and the Risk of Developing Hypertension: The Prevention of Renal and Vascular End-Stage Disease Study.

Previous observational studies on the vascular effects of vitamin D have predominantly relied on measurement of its inactive precursor, 25-hydroxyvitamin D, whereas the active metabolite 1,25-dihydroxyvitamin D may be of more physiological relevance. We prospectively studied the associations of 1,25-dihydroxyvitamin D and 25-hydroxyvitamin D with hypertension risk (blood pressure ≥140/90 mm Hg or initiation of blood pressure-lowering drugs) in 5066 participants aged 28 to 75 years, free of hypertension at baseline from the Prevention of Renal and Vascular End-Stage Disease Study, a well-defined cohort with serial follow-up. We measured plasma 1,25-dihydroxyvitamin D and 25-hydroxyvitamin D using liquid chromatography-tandem mass spectrometry. Mean±SD plasma concentration of 1,25-dihydroxyvitamin D was 145±47.0 pmol/L and 25-hydroxyvitamin D was 58.6±23.8 nmol/L. During a median follow-up of 6.4 years, 1036 participants (20.5%) developed hypertension. As expected, low 25-hydroxyvitamin D was associated with a higher hypertension risk; each 1-SD decrement in 25-hydroxyvitamin D was associated with a 8% higher hypertension risk (hazard ratio, 1.08; 95% confidence interval, 1.01-1.16) after adjustment for potential confounders. However, the association of 1,25-dihydroxyvitamin D was in the opposite direction; each 1-SD decrement of 1,25-dihydroxyvitamin D was associated with a 10% lower hypertension risk (hazard ratio, 0.90; 95% confidence interval, 0.84-0.96), independent of potential confounders. In contrast to the inverse association between 25-hydroxyvitamin D and hypertension risk, 1,25-dihydroxyvitamin D was positively associated with risk of hypertension. Thus, higher circulating concentrations of 1,25-dihydroxyvitamin D are associated with a higher risk of hypertension.

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.

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.

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.

Urinary Urea Excretion and Long-term Outcome After Renal Transplantation.

BACKGROUND: Little is known about optimal protein intake after transplantation. The aim of this study was to prospectively investigate associations of urinary urea excretion, a marker for protein intake, with graft failure and mortality in renal transplant recipients (RTR) and potential effect modification by body mass index (BMI) and estimated glomerular filtration rate (eGFR). METHODS: Urinary urea excretion was measured in repeated 24-hr urine collections between 6 and 18 months after transplantation. RESULTS: In total, 940 RTR were included. During 4.4 (2.3-7.8) years of follow-up for graft failure and 4.8 (2.5-8.3) years for all-cause mortality, 78 RTR developed graft failure and 158 RTR died. Urinary urea excretion was not associated with graft failure in the overall population, but was inversely associated with graft failure in RTR with BMI less than 25 kg/m (hazard ratio [HR], 0.64 [0.28-1.50] and 0.27 [0.09-0.83] for the second and third tertiles, respectively, P < 0.001), and in RTR with eGFR of 45 mL per min per 1.73 m or higher (HR, 0.34 [0.15-0.79], P = 0.015 and HR, 0.31 [0.11-0.86], P = 0.025 for the second and third tertiles, respectively), both independent of potential confounders. Compared to the first tertile, RTR in the second and third tertiles of urinary urea excretion were at a lower risk of all-cause mortality (HR, 0.47 [0.32-0.69]; P < 0.001 and HR, 0.42 [0.26-0.68]; P < 0.001, respectively), independent of potential confounders. Body mass index and eGFR did not influence this association. CONCLUSION: Urinary urea excretion, a marker for protein intake, was inversely related to graft failure in RTR with BMI less than 25 kg/m and in RTR with an eGFR of 45 mL per min per 1.73 m or higher. In addition, urinary urea excretion was inversely related to mortality.

Associations of 25(OH) and 1,25(OH)2 vitamin D with long-term outcomes in stable renal transplant recipients.

CONTEXT: Vitamin D deficiency is common in renal transplant recipients (RTR). The long-term implications of vitamin D deficiency in RTR remain unclear. OBJECTIVE: We investigated whether 25(OH) or 1,25(OH)2 vitamin D levels are associated with mortality, renal function decline, and graft failure in stable RTR. DESIGN: Observational study with longitudinal design. Followup was 7.0, interquartile range (IQR) 6.2-7.5 years. SETTING: Single-center outpatient clinic. PARTICIPANTS: 435 stable RTR (51% men, mean age 52 ± 12 years) were included at a median [IQR] of 6 [3-12] years after kidney transplantation. MAIN OUTCOME MEASURES: All-cause mortality, annual change of estimated glomerular filtration rate (eGFR), and graft failure. RESULTS: Mean 25-hydroxyvitamin D [25(OH)D] and 1,25-dihydroxyvitamin D [1,25(OH)2D] were 21.6 ± 9.1 ng/ml and 45.2 ± 19.0 pg/ml, respectively. During followup, 99 patients (22.8%) died and 44 patients (10.1%) developed graft failure. In univariable analysis, both 25(OH)D and 1,25(OH)2D were significantly associated with mortality (hazard ratio [HR], 0.64; 95% confidence interval (CI), 0.51-0.81; P < .001 and HR 0.69 [95% CI, 0.55-0.87], P = .002 per SD increase, respectively). The inverse association of 25(OH)D with mortality remained significant after adjustment for potential confounders (HR 0.68 [95% CI, 0.52-0.89], P = .004 per SD increase). The associations of 1,25(OH)2D with mortality and graft failure lost significance after adjustment for renal function. Severe vitamin D deficiency (25[OH]D <12 ng/ml) was independently associated with stronger annual eGFR decline. CONCLUSIONS: Low 25(OH)D is independently associated with an increased risk of all-cause mortality and 25(OH)D <12 ng/ml with a rapid eGFR decline in stable RTR. The association of low 1,25(OH)2D with mortality or graft failure depends on renal function. These results should encourage randomised controlled trials evaluating the effect of vitamin D supplementation after kidney transplantation.

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.