Jun Ling Lu

Hyponatremia, Hypernatremia, and Mortality in Patients With Chronic Kidney Disease With and Without Congestive Heart Failure

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, 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 with all-cause mortality in a nationally representative cohort of 655 493 US veterans with non–dialysis-dependent chronic kidney disease (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, 62.5/1000 patient-years; 95% confidence interval, 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 to 135.9, 145.1 to 150, and ≥150 mEq/L compared with 136 to 145 mEq/L had multivariable-adjusted mortality hazard ratios (95% confidence interval) 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 chronic kidney disease, irrespective of the presence or absence of congestive heart failure.

Association of Body Mass Index with Outcomes in Patients with CKD

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 nondialysis-dependent 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.

Association of age and BMI with kidney function and mortality: a cohort study

BACKGROUND Compared with normal weight, obesity might be associated with worse clinical outcomes, including chronic kidney disease. Whether this association is modified by age is not known. We investigated the association of BMI with progressive loss of kidney function and all-cause mortality in US veterans. METHODS In a national cohort of 3,376,187 US veterans with an estimated glomerular filtration rate (eGFR) of more than 60 mL/min per 1·73 m(2), we assessed the association of BMI in patients of different ages (<40 years, 40 years to <50 years, 50 years to <60 years, 60 years to <70 years, 70 years to <80 years, and ≥80 years) with loss of kidney function and with all-cause mortality in logistic regression models and Cox proportional hazards models adjusted for ethnic origin, sex, comorbidities, medications, and baseline eGFR. FINDINGS 274,764 (8·1%) of 3,376,187 veterans had a rapid decline in kidney function (decrease in slope of >5 mL/min per 1·73 m(2)). The lowest risk for loss of kidney function was noted in patients with BMI of at least 25 kg/m(2) but less than 30 kg/m(2). A generally consistent U-shaped association was noted between BMI and rapid loss of kidney function that was more prominent with increasing age, except in the patients younger than 40 years, in whom BMI did not seem to be predictive of renal function impairment. 672,341 veterans died (28·7 per 1000 patient-years, 95% CI 28·6-28·7) over a median follow-up of 6·8 years (IQR 6·5-7·7). BMI also showed a U-shaped association with mortality, which was similar in all age groups. INTERPRETATION A BMI of 30 kg/m(2) or more is associated with rapid loss of kidney function in patients with eGFR of at least 60 mL/min per 1·73 m(2), and this association is accentuated in older patients. A BMI of 35 kg/m(2) or more is also associated with high mortality. A BMI of at least 25 kg/m(2) but less than 30 kg/m(2) is associated with the best clinical outcomes. FUNDING National Institute of Health, Memphis VA Medical Center, Long Beach VA Healthcare System, Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development, Health Services Research and Development, and VA Information Resource Center.

Outcomes associated with microalbuminuria: effect modification by chronic kidney disease.

OBJECTIVES This study sought to compare the association of microalbuminuria with outcomes in patients with different comorbidities. BACKGROUND The risk of adverse outcomes associated with lower levels proteinuria has been found to be linearly decreasing with even low-normal levels of microalbuminuria. It is unclear whether comorbid conditions change these associations. METHODS We examined the association of urine microalbumin-creatinine ratio (UACR) with mortality and the slopes of estimated glomerular filtration rate (eGFR) in a nationally representative cohort of 298,875 U.S. veterans. Associations of UACR with all-cause mortality overall and in subgroups of patients with and without diabetes mellitus, hypertension, cardiovascular disease, congestive heart failure, and advanced chronic kidney disease (CKD) were examined in Cox models, and with the slopes of eGFR in linear and logistic regression models. RESULTS Very low levels of UACR were linearly associated with decreased mortality and less progression of CKD overall: adjusted mortality hazard ratio and estimated glomerular filtration rate slope (95% confidence interval [CI]) associated with UACR ≥200 μg/mg, compared to <5 μg/mg were 1.53 (95% CI: 1.38 to 1.69, p < 0.001) and -1.59 (95% CI: -1.83 to -1.35, p < 0.001). Similar linearity was present in all examined subgroups, except in patients with CKD in whom a U-shaped association was present and in whom a UACR of 10 to 19 was associated with the best outcomes. CONCLUSIONS The association of UACR with mortality and with progressive CKD is modified in patients with CKD, who experience higher mortality and worse progression of CKD with the lowest levels of UACR. Proteinuria-lowering interventions in patients with advanced CKD should be implemented cautiously, considering the potential for adverse outcomes.

Association between vascular access creation and deceleration of estimated glomerular filtration rate decline in late-stage chronic kidney disease patients transitioning to end-stage renal disease

Background Prior studies have suggested that arteriovenous fistula (AVF) or graft (AVG) creation may be associated with slowing of estimated glomerular filtration rate (eGFR) decline. It is unclear if this is attributable to the physiological benefits of a mature access on systemic circulation versus confounding factors. Methods We examined a nationwide cohort of 3026 US veterans with advanced chronic kidney disease (CKD) transitioning to dialysis between 2007 and 2011 who had a pre-dialysis AVF/AVG and had at least three outpatient eGFR measurements both before and after AVF/AVG creation. Slopes of eGFR were estimated using mixed-effects models adjusted for fixed and time-dependent confounders, and compared separately for the pre- and post-AVF/AVG period overall and in patients stratified by AVF/AVG maturation. In all, 3514 patients without AVF/AVG who started dialysis with a catheter served as comparators, using an arbitrary 6-month index date before dialysis initiation to assess change in eGFR slopes. Results Of the 3026 patients with AVF/AVG (mean age 67 years, 98% male, 75% diabetic), 71% had a mature AVF/AVG at dialysis initiation. eGFR decline accelerated in the last 6 months prior to dialysis in patients with a catheter (median, from -6.0 to -16.3 mL/min/1.73 m2/year, P < 0.001), while a significant deceleration of eGFR decline was seen after vascular access creation in those with AVF/AVG (median, from -5.6 to -4.1 mL/min/1.73 m2/year, P < 0.001). Findings were independent of AVF/AVG maturation status and were robust in adjusted models. Conclusions The creation of pre-dialysis AVF/AVG appears to be associated with eGFR slope deceleration and, consequently, may delay the onset of dialysis initiation in advanced CKD patients.

Survival advantage in black versus white men with CKD: effect of estimated GFR and case mix.

BACKGROUND Black dialysis patients have significantly lower mortality compared with white patients, in contradistinction to the higher mortality seen in blacks in the general population. It is unclear whether a similar paradox exists in patients with non-dialysis-dependent chronic kidney disease (CKD), and if it does, what its underlying reasons are. STUDY DESIGN Historical cohort. SETTING & PARTICIPANTS 518,406 white and 52,402 black male US veterans with non-dialysis-dependent CKD stages 3-5. PREDICTOR Black race. OUTCOMES & MEASUREMENTS We examined overall and CKD stage-specific all-cause mortality using parametric survival models. The effect of sociodemographic characteristics, comorbid conditions, and laboratory characteristics on the observed differences was explored in multivariable models. RESULTS During a median follow-up of 4.7 years, 172,093 patients died (mortality rate, 71.0 [95% CI, 70.6-71.3] per 1,000 patient-years). Black race was associated with significantly lower crude mortality (HR, 0.95; 95% CI, 0.94-0.97; P < 0.001). The survival advantage was attenuated after adjustment for age (HR, 1.14; 95% CI, 1.12-1.16), but was magnified after full multivariable adjustment (HR, 0.72; 95% CI, 0.70-0.73; P < 0.001). The unadjusted survival advantage of blacks was more prominent in those with more advanced stages of CKD, but CKD stage-specific differences were attenuated by multivariable adjustment. LIMITATIONS Exclusively male patients. CONCLUSIONS Black patients with CKD have lower mortality compared with white patients. The survival advantage seen in blacks is accentuated in patients with more advanced stages of CKD, which may be explained by changes in case-mix and laboratory characteristics occurring during the course of kidney disease.

Association of depression and antidepressant use with mortality in a large cohort of patients with nondialysis-dependent CKD.

BACKGROUND AND OBJECTIVES Depression is common and is associated with higher mortality in patients with ESRD or CKD (stage 5). Less information is available on earlier stages of CKD. This study aimed to determine the prevalence of depression and any association with all-cause mortality in patients with varying severity of nondialysis-dependent CKD. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS This is a retrospective study of a national cohort of 598,153 US veterans with nondialysis-dependent CKD stages 1-5 followed for a median of 4.7 years in the US Department of Veterans Affairs Health System. Diagnosis of depression was established as a result of systematic screening and administration of antidepressants. Association of depression with all-cause mortality overall and stratified by CKD stages were examined with the Kaplan-Meier method and in Cox models. RESULTS There were 179,441 patients (30%) with a diagnosis of depression. Over median follow-up of 4.7 years, depression was associated with significantly higher age-adjusted mortality overall (hazard ratio, 1.55; 95% confidence interval, 1.54-1.57; P<0.001). Sequential adjustments for sociodemographic characteristics and especially for comorbid conditions attenuated this association, which nevertheless remained significant (hazard ratio, 1.25; 95% confidence interval, 1.23-1.26). CONCLUSIONS In this large cohort of predominantly elderly male patients with CKD, prevalence of depression and antidepressant use is high (30%) and is associated with significantly higher all-cause mortality independent of comorbid conditions.

Constipation and Incident CKD

Constipation is one of the most prevalent conditions in primary care settings and increases the risk of cardiovascular disease, potentially through processes mediated by altered gut microbiota. However, little is known about the association of constipation with CKD. In a nationwide cohort of 3,504,732 United States veterans with an eGFR ≥60 ml/min per 1.73 m2, we examined the association of constipation status and severity (absent, mild, or moderate/severe), defined using diagnostic codes and laxative use, with incident CKD, incident ESRD, and change in eGFR in Cox models (for time-to-event analyses) and multinomial logistic regression models (for change in eGFR). Among patients, the mean (SD) age was 60.0 (14.1) years old; 93.2% of patients were men, and 24.7% were diabetic. After multivariable adjustments, compared with patients without constipation, patients with constipation had higher incidence rates of CKD (hazard ratio, 1.13; 95% confidence interval [95% CI], 1.11 to 1.14) and ESRD (hazard ratio, 1.09; 95% CI, 1.01 to 1.18) and faster eGFR decline (multinomial odds ratios for eGFR slope <-10, -10 to <-5, and -5 to <-1 versus -1 to <0 ml/min per 1.73 m2 per year, 1.17; 95% CI, 1.14 to 1.20; 1.07; 95% CI, 1.04 to 1.09; and 1.01; 95% CI, 1.00 to 1.03, respectively). More severe constipation associated with an incrementally higher risk for each renal outcome. In conclusion, constipation status and severity associate with higher risk of incident CKD and ESRD and with progressive eGFR decline, independent of known risk factors. Further studies should elucidate the underlying mechanisms.

Early Mortality Associated with Inpatient versus Outpatient Hemodialysis Initiation in a Large Cohort of US Veterans with Incident End-Stage Renal Disease

Background: Mortality in the immediate post-hemodialysis transition period is extremely high. Many end-stage renal disease (ESRD) patients in the US start dialysis in an inpatient setting, but the characteristics of patients starting dialysis as inpatients, and the association of inpatient hemodialysis transition with mortality remain unclear. Methods: We examined 48,261 US veterans who transitioned to hemodialysis between October 2007 and September 2011. Associations of inpatient hemodialysis starting with all-cause mortality were examined in Cox proportional hazard models, with adjustments for demographics, comorbidities, vascular access type, pre-dialysis nephrology care and medication use, and last pre-ESRD estimated glomerular filtration rate and hemoglobin. Results: A total of 22,338 (46.3%) patients received the first hemodialysis treatment in an inpatient setting. Inpatient hemodialysis transition was associated with older age, presence of a tunneled catheter, higher comorbidity burden, and lack of pre-dialysis nephrology care. A total of 8,674 patients died (mortality rate 405/1,000 patient-years, 95% CI 397-413) during the first 6 months after transition to hemodialysis. The starting of inpatient vs. outpatient hemodialysis was associated with significantly higher crude all-cause mortality, but this association was attenuated after multivariable adjustments. Conclusions: Transition to hemodialysis in an inpatient setting is more common in older and sicker individuals, and in patients without pre-dialysis nephrology care and those who used a catheter for vascular access. Future studies are needed to determine if a higher proportion of patients could start hemodialysis treatment in outpatient clinics, through interventions targeting modifiable risk factors such as timely vascular access placement or earlier nephrology referrals.

Changes in Albuminuria and Subsequent Risk of Incident Kidney Disease

BACKGROUND AND OBJECTIVES Albuminuria is a robust predictor of CKD progression. However, little is known about the associations of changes in albuminuria with the risk of kidney events outside the settings of clinical trials. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS In a nationwide cohort of 56,946 United States veterans with an eGFR≥60 ml/min per 1.73 m2, we examined the associations of 1-year fold changes in albuminuria with subsequent incident CKD (>25% decrease in eGFR reaching <60 ml/min per 1.73 m2) and rapid eGFR decline (eGFR slope <-5 ml/min per 1.73 m2 per year) assessed using Cox models and logistic regression, respectively, with adjustment for confounders. RESULTS The mean age was 64 (SD, 10) years old; 97% were men, and 91% were diabetic. There was a nearly linear association between 1-year fold changes in albuminuria and incident CKD. The multivariable-adjusted hazard ratios (95% confidence intervals) of incident CKD associated with more than twofold decrease, 1.25- to twofold decrease, 1.25- to twofold increase, and more than twofold increase (versus <1.25-fold decrease to <1.25-fold increase) in albuminuria were 0.82 (95% confidence interval, 0.77 to 0.89), 0.93 (95% confidence interval, 0.86 to 1.00), 1.12 (95% confidence interval, 1.05 to 1.20), and 1.29 (95% confidence interval, 1.21 to 1.38), respectively. Qualitatively similar associations were present for rapid eGFR decline (adjusted odds ratios; 95% confidence intervals for corresponding albuminuria changes: adjusted odds ratio, 0.86; 95% confidence interval, 0.78 to 0.94; adjusted odds ratio, 0.98; 95% confidence interval, 0.89 to 1.07; adjusted odds ratio, 1.18; 95% confidence interval, 1.08 to 1.29; and adjusted odds ratio, 1.67; 95% confidence interval, 1.54 and 1.81, respectively). CONCLUSIONS Relative changes in albuminuria over a 1-year interval were linearly associated with subsequent risk of kidney outcomes. Additional studies are warranted to elucidate the underlying mechanisms of the observed associations and test whether active interventions to lower elevated albuminuria can improve kidney outcomes.