Background Hyponatremia is common in patients with conditions such as congestive heart failure, and is associated with increased mortality in hospitalized patients. Congestive heart failure is common in patients with chronic kidney disease (CKD), but the association of serum sodium concentration with mortality in such patients is not well characterized. Methods and Results We examined the association of serum sodium concentration (SeNa) with all-cause mortality in a nationally representative cohort of 655,493 US veterans with non-dialysis dependent CKD (95,961 (15%) of them with congestive heart failure). Associations were examined in time-dependent Cox models with adjustment for potential confounders. During a median follow-up of 5.5 years a total of 193,956 patients died (mortality rate, 95% confidence interval [CI]: 62.5/1000 patient-years, 62.2-62.8). The association of serum sodium level with mortality was U-shaped, with the lowest mortality seen in patients with sodium level of 140 mEq/l, and with both lower and higher levels showing significant associations with increased mortality. Patients with serum sodium levels of <130, 130-135.9, 145.1-150 and ≥150 compared to 136-145 mEq/l had multivariable adjusted mortality hazard ratios (95%CI) of 1.93 (1.83-2.03), 1.28 (1.26-1.30), 1.33 (1.28-1.38) and 1.56 (1.33-1.83), p<0.001 for all. The associations remained consistent in subgroups of patients with and without congestive heart failure. Conclusions Both lower and higher serum sodium levels are independently associated with higher mortality in patients with non-dialysis dependent CKD, irrespective of the presence of absence of congestive heart failure.

Obesity is associated with higher mortality in the general population, but this association is reversed in patients on dialysis. The nature of the relationship of obesity with adverse clinical outcomes in nondialysisdependent CKD and the putative interaction of the severity of disease with this association are unclear. We analyzed data from a nationally representative cohort of 453,946 United States veterans with eGFR,60 ml/min per 1.73 m 2 . The associations of body mass index categories (,20, 20 to ,25, 25 to ,30, 30 to ,35, 35 to ,40, 40 to ,45, 45 to ,50, and $50 kg/m 2 ) with all-cause mortality and disease progression (using multiple definitions, including incidence of ESRD, doubling of serum creatinine, and the slopes of eGFR) were examined in Cox proportional hazards models and logistic regression models. Multivariable adjustments were made for age, race, comorbidities and medications, and baseline eGFR. Body mass index showed a relatively consistent U-shaped association with clinical outcomes, with the best outcomes observed in overweight and mildly obese patients. Body mass index levels ,25 kg/m 2 were associated with worse outcomes in all patients, independent of severity of CKD. Body mass index levels $35 kg/m 2 were associated with worse outcomes in patients with earlier stages of CKD, but this association was attenuated in those patients with eGFR,30 ml/min per 1.73 m 2 . Thus, until clinical trials establish the ideal body mass index, a cautious approach to weight management is warranted in this patient population.

BACKGROUND Intraindividual blood pressure (BP) fluctuates dynamically over time. Previous studies suggested an adverse link between greater visit-to-visit variability (VVV) in systolic blood pressure (SBP) and various outcomes. However, these studies have significant limitations, such as a small size, inclusion of selected populations, and restricted outcomes. OBJECTIVES We investigated the association of increased VVV and all-cause mortality, cardiovascular events, and end-stage renal disease (ESRD) in a large cohort of U.S. veterans. METHODS From among 3,285,684 U.S. veterans with and without hypertension and normal estimated glomerular filtration rates (eGFR) during 2005 and 2006, we identified 2,865,157 patients who had 8 or more outpatient BP measurements. SBP variability (SBPV) was measured using the SD of all SBP values (normally distributed) in 1 individual. Associations of SD quartiles (<10.3, 10.3 to 12.7, 12.7 to 15.6, and ≥15.6 mm Hg) with all-cause mortality, incident coronary heart disease (CHD), stroke, and ESRD was examined using Cox models adjusted for sociodemographic characteristics, baseline eGFR, comorbidities, body mass index, SBP, diastolic BP, and antihypertensive medication use. RESULTS Several sociodemographic variables (older age, male sex, African-American race, divorced or widowed status) and clinical characteristics (lower baseline eGFR, higher SBP and DBP), and comorbidities (presence of diabetes, hypertension, cardiovascular disease, and lung disease) were all associated with higher intraindividual SBPV. The multivariable adjusted hazard ratios and 95% confidence intervals for SD quartiles 2 through 4 (compared to the first quartile) associated with all-cause mortality, CHD, stroke, and ESRD were incrementally higher. CONCLUSIONS Higher SBPV in individuals with and without hypertension was associated with increased risks of all-cause mortality, CHD, stroke, and ESRD. Further studies are needed to determine interventions that can lower SBPV and their impact on adverse health outcomes.

Background Obesity may be associated with worse clinical outcomes, including chronic kidney disease. It is unclear if this association is modified by age. Methods In a national cohort of over 3·3 million (n=3,376,187) US veterans with estimated glomerular filtration rate (eGFR) >60ml/min/1·73m2, we examined the association of body mass index (BMI) in patients of different age (<40, 40–<50, 50–<60, 60–<70, 70–<80, and ≥80 years old) with loss of kidney function and with all-cause mortality in logistic regression models and proportional hazards models adjusted for race, gender, comorbidities, medications, and baseline eGFR. Findings A U-shaped association between BMI and loss of kidney function was somewhat consistent and more prominent with advancing age, except in the patients ≤40 years old, in whom BMI did not appear to predict renal function impairment. The lowest risk for loss of kidney function was observed in patients with BMI 25– <30 kg/m2. BMI also displayed a U-shaped association with mortality, which was similar in all age groups. Interpretation BMI ≥30 kg/m2 is associated with rapid loss of kidney function in patients with eGFR ≥60 ml/min/1·73m2, and BMI ≥35 kg/m2 is also associated with high mortality. The former association is accentuated in older patients. A BMI of 25– <30 kg/m2 is associated with optimal clinical outcomes.

Background An estimated 4 million Americans have been exposed to the hepatitis C virus (HCV) in the US population. The risk of incident and progressive chronic kidney disease and of mortality in patients with normal kidney function infected with HCV is unclear. Methods In a nationally representative cohort of 100,518 HCV+ and 920,531 HCV- US Veterans with normal baseline estimated glomerular filtration rate(eGFR), we examined the association of HCV infection with: (1)all-cause mortality, (2)incidence of decreased kidney function (defined as eGFR <60 ml/min/1.73m2 and 25% decrease in eGFR), (3)ESRD, and (4)rate of kidney function decline. Associations were examined in naïve and adjusted Cox models (for time-to-event analyses) and logistic regression models (for slopes), with sequential adjustments for important confounders. Propensity-matched cohort analysis was used in sensitivity analyses. Results The patients’ age was 54.5±13.1(mean±SD) years, 22% were black and 92% male, and the baseline eGFR was 88±16 ml/min/1.73m2. In multivariate adjusted models HCV infection was associated with 2.2 fold higher mortality (fully adjusted hazard ratio(aHR), 95%CI: 2.17(2.13–2.21)), 15% higher incidence of decreased kidney function(aHR, 95%CI: 1.15(1.12–1.17)), 22% higher risk of steeper slopes of eGFR (adjusted odds ratio, 95%CI: 1.22(1.19–1.26)) and 98% higher hazard of ESRD (aHR, 95%CI: 1.98 (1.81–2.16)). Quantitatively similar results were found in propensity-matched cohort analyses. Conclusions HCV infection is associated with higher mortality risk, incidence of decreased kidney function and progressive loss of kidney function. Randomized controlled trials are warranted to determine whether treatment of HCV infection can prevent the development and progression of CKD and improve patient outcomes.

Background/Aims: Abnormal serum potassium is associated with higher mortality in dialysis patients, but its impact on outcomes in predialysis chronic kidney disease (CKD) is less clear. Furthermore, blacks with normal kidney function have lower urinary potassium excretion, but it is unclear if such differences have a bearing on race-associated outcomes in CKD. Methods: We studied predialysis mortality and slopes of estimated glomerular filtration rate, eGFR) associated with serum potassium in 1,227 males with CKD. Mortality was examined in time-dependent Cox models, and slopes of eGFR in linear mixed effects models with adjustments for case mix and laboratory values. Results: Both hypo- and hyperkalemia were associated with mortality overall and in 933 white patients, but in 294 blacks hypokalemia was a stronger death predictor. Hypokalemia was associated with loss of kidney function independent of race: a 1 mEq/l lower potassium was associated with an adjusted difference in slopes of eGFR of -0.13 ml/min/1.73 m²/year (95% CI: -0.20 to -0.07), p < 0.001. Conclusion: Hypo- and hyperkalemia are associated with higher mortality in CKD patients. Blacks appear to better tolerate higher potassium than whites. Hypokalemia is associated with faster CKD progression independent of race. Hyperkalemia management may warrant race-specific consideration, and hypokalemia correction may slow CKD progression. This is a work of the US Government and is not subject to copyright protection in the USA. Foreign copyrights may apply. Published by S. Karger AG, Basel

Rationale There is a paucity of large cohort studies examining the association of obstructive sleep apnea(OSA) with clinical outcomes including all-cause mortality, coronary heart disease(CHD), strokes and chronic kidney disease(CKD). Objectives We hypothesized that a diagnosis of incident OSA is associated with higher risks of these adverse clinical outcomes. Methods, Measurements In a nationally representative cohort of over 3 million(n=3,079,514) US veterans(93% male) with baseline estimated glomerular filtration rate (eGFR)≥60 ml/min/1.73m2, we examined the association between the diagnosis of incident OSA, treated and untreated with continuous positive airway pressure(CPAP), and: 1) all-cause mortality, 2) incident CHD, 3) incident strokes, 4)incident CKD defined as eGFR<60 ml/min/1.73m2, and 5)slopes of eGFR. Main Results Compared to OSA negative patients, untreated and treated OSA was associated with 86% higher mortality risk,(adjusted hazard ratio and 95% confidence interval: 1.86(1.81-1.91)) and 35% (1.35(1.21-1.51)), respectively. Similarly, untreated and treated OSA was associated with 3.5 times(3.54(3.40-3.69)) and 3 times(3.06(2.62-3.56)) higher risk of incident CHD; 3.5 times higher risk of incident strokes(3.48(3.28-3.64) and 3.50(2.92-4.19)) for untreated and treated OSA, respectively. The risk of incident CKD was also significantly higher in untreated(2.27(2.19-2.36)) and treated(2.79(2.48-3.13)) OSA patients. The median (interquartile range) of the eGFR slope was −0.41(−2.01 - 0.99), −0.61(−2.69 - 0.93) and −0.87(−3.00 - 0.70)ml/min/1.73m2 in OSA negative, untreated and treated OSA positive patients, respectively. Conclusions In this large and contemporary cohort of more than 3 million US veterans, a diagnosis of incident OSA was associated with higher mortality, incident CHD, stroke and CKD and with faster kidney function decline.

Objective To assess the association between ACEI/ARB use and mortality in CKD patients. Background There is insufficient evidence about the association of angiotensin converting enzyme inhibitors (ACEI) or angiotensin receptor blockers (ARBs) with mortality in chronic kidney disease (CKD) patients. Methods A logistic regression analysis was used to calculate the propensity of ACEI/ARB initiation in 141,413 US veterans with non-dialysis CKD previously unexposed to ACEI/ARB treatment. We examined the association of ACEI/ARB administration with all-cause mortality in patients matched by propensity scores, using the Kaplan-Meier method and Cox models in “intention-to-treat” analyses, and in generalized linear models with binary outcomes and inverse probability treatment weighing (IPTW) in “as-treated” analyses. Results The mean±SD age of the patients at baseline was 75±10 years, 8% of patients were black, and 22% were diabetic. ACEI/ARB administration was associated with significantly lower risk of mortality both in the intention-to-treat analysis (HR=0.81; 95%CI: 0.78-0.84, p<0.001) and in the as-treated analysis with IPTW (OR=0.37; 95%CI: 0.34-0.41, p<0.001). The association of ACEI/ARB treatment with lower risk of mortality was present in all examined subgroups. Conclusions In this large contemporary cohort of non-dialysis dependent CKD patients, ACEI/ARB administration was associated with greater survival.