Association of serum albumin level and venous thromboembolic events in a large cohort of patients with nephrotic syndrome.

Background: Prior small studies have suggested an association between low serum albumin and increased risk of venous thromboembolic (VTE) events in patients with nephrotic syndrome (NS). Methods: From a nationally representative prospective cohort of over 3 million US veterans with baseline estimated glomerular filtration rate (eGFR) ≥60 mL/min/1.73 m 2 , we identified 7037 patients with NS based on ICD-9 codes. Association between serum albumin and risk of incident VTE was assessed using Cox regression analysis with adjustments for age, gender, race, comorbidities, eGFR, body mass index and anticoagulant treatment. Results: Mean age was 57 ± 11 years, patients were 96% male, 32% African-American and 60% diabetic. There were a total of 158 VTE events over a median follow-up of 8.1 years; 16 events [absolute event rate (AER) 4.1%, event rate 8.5/1000 patient-years (PY)] in patients with albumin <2.5 g/dL, 18 events (AER 3.4%, event rate 5.7/1000 patient-years) in patients with albumin 2.5-2.99 g/dL, 89 events (AER 2.5%, event rate 3.4/1000 patient-years) in patients with albumin 3-3.99 g/dL and 35 events (AER 1.4%, event rate 1.9/1000 patient-years) in patients with albumin ≥4 g/dL. Compared with patients with albumin ≥4 g/dL, those with albumin levels of 3-3.99 g/dL [adjusted hazard ratio (HR): 1.51, 95% confidence interval (CI): 1.01-2.26], 2.5-2.99 g/dL (HR: 2.24, 95% CI: 1.24-4.05) and <2.5 g/dL (HR: 2.79, 95% CI: 1.45-5.37) experienced a linearly higher risk of VTE events. Conclusions: Lower serum albumin is a strong independent predictor for VTE events in NS. The risk increases proportionately with declining albumin levels. Clinical trials are needed to determine benefit of prophylactic anticoagulation in NS patients with moderately lower serum albumin levels.

Association of Race With Mortality and Cardiovascular Events in a Large Cohort of US Veterans.

BACKGROUND: In the general population, blacks experience higher mortality than their white peers, attributed in part to their lower socioeconomic status, reduced access to care, and possibly intrinsic biological factors. Patients with kidney disease are a notable exception, among whom blacks experience lower mortality. It is unclear if similar differences affecting outcomes exist in patients with no kidney disease but with equal or similar access to health care. METHODS AND RESULTS: We compared all-cause mortality, incident coronary heart disease, and incident ischemic stroke using multivariable-adjusted Cox models in a nationwide cohort of 547 441 black and 2 525 525 white patients with baseline estimated glomerular filtration rate ≥ 60 mL·min⁻¹·1.73 m⁻² receiving care from the US Veterans Health Administration. In parallel analyses, we compared outcomes in black versus white individuals in the National Health and Nutrition Examination Survey (NHANES) 1999 to 2004. After multivariable adjustments in veterans, black race was associated with 24% lower all-cause mortality (adjusted hazard ratio, 0.76; 95% confidence interval, 0.75-0.77; P<0.001) and 37% lower incidence of coronary heart disease (adjusted hazard ratio, 0.63; 95% confidence interval, 0.62-0.65; P<0.001) but a similar incidence of ischemic stroke (adjusted hazard ratio, 0.99; 95% confidence interval, 0.97-1.01; P=0.3). Black race was associated with a 42% higher adjusted mortality among individuals with estimated glomerular filtration rate ≥ 60 mL·min⁻¹·1.73 m⁻² in NHANES (adjusted hazard ratio, 1.42; 95% confidence interval, 1.09-1.87). CONCLUSIONS: Black veterans with normal estimated glomerular filtration rate and equal access to healthcare have lower all-cause mortality and incidence of coronary heart disease and a similar incidence of ischemic stroke. These associations are in contrast to the higher mortality experienced by black individuals in the general US population.

Association of hepatitis C viral infection with incidence and progression of chronic kidney disease in a large cohort of US veterans.

UNLABELLED: An estimated 4 million Americans have been exposed to the hepatitis C virus (HCV). The risks of incident and progressive chronic kidney disease and of mortality in patients with normal kidney function infected with HCV are unclear. 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/1.73 m(2) and 25% decrease in eGFR), (3) end-stage renal disease, and (4) rate of kidney function decline. Associations were examined in naive 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. The patients' age was 54.5 ± 13.1 (mean ± standard deviation) years, 22% were black, 92% were male, and the baseline eGFR was 88 ± 16 mL/min/1.73 m(2) . In multivariable adjusted models HCV infection was associated with a 2.2-fold higher mortality (fully adjusted hazard ratio = 2.17, 95% confidence interval [CI] 2.13-2.21), a 15% higher incidence of decreased kidney function (adjusted hazard ratio = 1.15, 95% CI 1.12-1.17), a 22% higher risk of steeper slopes of eGFR (adjusted odds ratio = 1.22, 95% CI 1.19-1.26), and a 98% higher hazard of end-stage renal disease (adjusted hazard ratio = 1.98, 95% CI 1.81-2.16). Quantitatively similar results were found in propensity-matched cohort analyses. CONCLUSIONS: Infection with HCV 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 chronic kidney disease and improve patient outcomes.

Association of incident restless legs syndrome with outcomes in a large cohort of US veterans.

Restless legs syndrome is a common sleep disorder, but there is a paucity of large cohort studies examining the association of restless legs syndrome with clinical outcomes, including all-cause mortality, incident coronary heart disease, stroke and chronic kidney disease. From a nationally representative prospective cohort of over 3 million US veterans [93% male, median follow-up time of 8.1 years (interquartile range: 7.0-8.5 years)] with baseline estimated glomerular filtration rate ≥ 60 mL min(-1) 1.73 m(-2), a propensity-matched cohort of 7392 patients was created, and the association between incident restless legs syndrome and the following was examined: (1) all-cause mortality; (2) incident coronary heart disease; (3) incident strokes; and (4) incident chronic kidney disease defined as estimated glomerular filtration rate <60 mL min(-1) 1.73 m(-2). Associations were examined using Cox models. The mean ± SD age of the propensity-matched cohort at baseline was 59 ± 12 years; 89 and 8% of patients were white and black, respectively; 31% of the patients were diabetic; and the mean baseline estimated glomerular filtration rate was 83.9 ± 15.1 mL min(-1) 1.73 m(-2). Propensity matching resulted in a balanced cohort, with the disappearance in baseline differences in comorbidities. Compared with restless legs syndrome-negative patients, incident restless legs syndrome was associated with 88% higher mortality risk [hazard ratio and 95% confidence interval: 1.88 (1.70-2.08)], and almost four times higher risk of coronary heart disease and stroke [hazard ratio: 3.97 (3.26-4.84) and 3.89 (3.07-4.94), respectively]. The risk of incident chronic kidney disease was also significantly higher in incident restless legs syndrome patients [hazard ratio: 3.17 (2.74-3.66)] compared with restless legs syndrome-negative counterparts. In this large and contemporary cohort of US veterans, incident restless legs syndrome was associated with higher risk of mortality, incident coronary heart disease, stroke and chronic kidney disease.

Age, Race and Cardiovascular Outcomes in African American Veterans.

BACKGROUND: In the general population, compared wtih their White peers, African Americans suffer premature all-cause and cardiovascular (CV) deaths, attributed in part to reduced access to care and lower socioeconomic status. Prior reports indicated younger (aged 35 to 44 years) African Americans had a signficantly greater age-adjusted risk of death. Recent studies suggest that in a more egalitarian health care structure than typical United States (US) health care structures, African Americans may have similar or even better CV outcomes, but the impact of age is less well-known. METHODS: We examined age stratified all-cause mortality, and incident coronary heart disease (CHD) and ischemic stroke in 3,072,966 patients (547,441 African American and 2,525,525 White) with an estimated glomerular filtration rate (eGFR)>60 mL/min/1.73m(2) receiving care from the US Veterans Health Administration. Outcomes were examined in Cox models adjusted for demographics, comorbidities, kidney function, blood pressure, socioeconomics and indicators of the quality of health care delivery. RESULTS: African Americans had an overall 30% lower all-cause mortality (P<.001) and 29% lower incidence of CHD (P<.001) and higher incidence of ischemic stroke (aHR, 95%CI: 1.16, 1.13-1.18, P<.001). The lower rates of mortality and CHD were strongest in younger African Americans and attenuated across patients aged ≥70 years. Stroke rates did not differ by race in persons aged <70 years. CONCLUSIONS: Among patients with normal eGFR and receiving care in the Veterans Health Administration, younger African Americans had lower all-cause mortality and incidence of CHD and similar rates of stroke, independent of demographic, comorbidity and socioeconomic differences. The lower all-cause mortality persisted but attenuated with increasing age and the lower incidence of CHD ended at aged ≥80 years. The higher incidence of ischemic stroke in African Americans was driven by increasing risk in patients aged ≥70 years suggesting that the improved cardiovascular outcomes were most dramatic for younger African Americans.

Association of incident obstructive sleep apnoea with outcomes in a large cohort of US veterans.

RATIONALE: There is a paucity of large cohort studies examining the association of obstructive sleep apnoea (OSA) with clinical outcomes including all-cause mortality, coronary heart disease (CHD), strokes and chronic kidney disease (CKD). OBJECTIVES: We hypothesised 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/1.73 m(2), we examined the association between the diagnosis of incident OSA, treated and untreated with CPAP, and: (1) all-cause mortality, (2) incident CHD, (3) incident strokes, (4)incident CKD defined as eGFR<60 mL/min/1.73 m(2), and (5) slopes of eGFR. MAIN RESULTS: Compared with OSA-negative patients, untreated and treated OSA was associated with 86% higher mortality risk, (adjusted HR and 95% CI 1.86 (1.81 to 1.91) and 35% (1.35 (1.21 to 1.51)), respectively. Similarly, untreated and treated OSA was associated with 3.5 times (3.54 (3.40 to 3.69)) and 3 times (3.06 (2.62 to 3.56)) higher risk of incident CHD; 3.5 times higher risk of incident strokes (3.48 (3.28 to 3.64) and 3.50 (2.92 to 4.19)) for untreated and treated OSA, respectively. The risk of incident CKD was also significantly higher in untreated (2.27 (2.19 to 2.36)) and treated (2.79 (2.48 to 3.13)) patients with OSA. The median (IQR) of the eGFR slope was -0.41 (-2.01 to 0.99), -0.61 (-2.69 to 0.93) and -0.87 (-3.00 to 0.70) mL/min/1.73 m(2) in OSA-negative patients, untreated OSA-positive patients 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.

Impact of Non-Adherence on Renal and Cardiovascular Outcomes in US Veterans.

BACKGROUND: Adherence is paramount in treating hypertension; however, no gold standard method is available for non-adherence screening, delineating high-risk patients. An International Classification of Diseases 9th Edition non-adherence diagnostic code (V15.81) has been available for decades; but, its utility is poorly studied. We examined the association between the V15.81 code assigned prior to the initiation of anti-hypertensive drugs (AHDs) and renal and cardiovascular outcomes. METHODS: This was a historical prospective cohort study involving 312,489 newly treated hypertensive individuals (mean age 53.8 years, 90.9% males, 20.3% black, median follow-up 8.0 years). We used crude and Cox models adjusted for baseline socio-demographic characteristics, estimated glomerular filtration rate (eGFR), body mass index, blood pressure, comorbidities, and prospective AHD adherence (measured as proportion of days covered, PDC). RESULTS: In the unadjusted analysis, the V15.81 code was associated with higher risks for faster eGFR decline (hazard ratio, HR 1.22, 95% CI 1.11-1.33), incident CKD (HR 1.17, 95% CI 1.09-1.27), end-stage renal disease (ESRD) (HR 2.53, 95% CI 1.72-3.72), incident coronary artery disease (CAD) (HR 1.26, 95% CI 1.15-1.38), and stroke (HR 1.55, 95% CI 1.38-1.73). In the adjusted model, the V15.81 code remained predictive of increased risk of CKD (HR 1.33, 95% CI 1.22-1.45), ESRD (HR 1.81, 95% CI 1.18-2.78), incident CAD (HR 1.26, 95% CI 1.14-1.40), and stroke (HR 1.46, 95% CI 1.29-1.65). Additional adjustment for PDC did not alter adverse associations between V15.81 code and studied outcomes. CONCLUSIONS: Assignment of V15.81 code prior to AHD therapy was associated with higher risks of renal and cardiovascular outcomes in incident hypertensive US veterans. Previous history of non-adherence is a poor prognostic marker in hypertensive individuals; therefore, patients with V15.81 code may require close monitoring. The observational nature of this study limits our ability to make firm recommendations for clinical practice.

The relationship between thyroid function and estimated glomerular filtration rate in patients with chronic kidney disease.

BACKGROUND: Recent studies have shown an increasing risk of hypothyroidism with incrementally lower estimated glomerular filtration rate (eGFR) in cohorts comprised of patients with normal to mildly impaired kidney function. We sought to confirm these findings in a nationally representative cohort of Veterans Affairs patients with moderate-to-severe chronic kidney disease (CKD). METHODS: This study examined the association between kidney function and hypothyroidism among 461 607 veterans with Stage 3 to 5 CKD who underwent repeated measurements of serum creatinine and thyrotropin (TSH) at identical time points between October 2004 and September 2006. Kidney function was defined by eGFR using the Chronic Kidney Disease Epidemiology Collaboration formula. In primary analyses, the association between eGFR and hypothyroidism (defined as serum TSH > 5 mIU/L and/or receipt of thyroid hormone supplementation) was estimated using multivariable random effects logistic regression. In secondary analyses, the association between eGFR and serum TSH level was estimated using multivariable random effects linear regression. RESULTS: At baseline, 68.9, 25.5, 5.3 and 0.3% of patients had Stage 3A, 3B, 4 and 5 CKD, respectively. For every 10 mL/min/1.73 m(2) lower eGFR, there was an 18% higher risk of hypothyroidism: adjusted odds ratio 1.18 [95% confidence interval (CI) 1.17-1.20, P < 0.001]. In secondary analyses, we observed that a 10 mL/min/1.73 m(2) lower eGFR was associated with a 0.11 mIU/L higher serum TSH (95% CI 0.10-0.11 mIU/L higher serum TSH, P < 0.001). CONCLUSIONS: In a nationally representative cohort of patients with moderate-to-severe CKD, there is an inverse association between eGFR and risk of hypothyroidism.

Paricalcitol versus ergocalciferol for secondary hyperparathyroidism in CKD stages 3 and 4: a randomized controlled trial.

BACKGROUND: The efficacy of 25-hydroxyvitamin D (25[OH]D) supplementation versus vitamin D receptor activators for the treatment of secondary hyperparathyroidism (SHPT) in patients with chronic kidney disease (CKD) stages 3 or 4 and vitamin D deficiency is unclear. STUDY DESIGN: Randomized controlled trial. SETTING & PARTICIPANTS: 80 patients with CKD stages 3 or 4, 25(OH)D level <30 ng/mL, and SHPT in a single medical center. INTERVENTION: Ergocalciferol, 50,000 units, titrated to achieve serum levels ≥30 ng/mL versus paricalcitol, 1 or 2 µg/d, for 16 weeks. OUTCOMES: The occurrence of 2 consecutive parathyroid hormone (PTH) levels decreased by at least 30% from baseline. All analyses were intention to treat. RESULTS: Baseline characteristics in the 2 groups were similar. 21 patients (53%) on paricalcitol and 7 patients (18%) on ergocalciferol treatment achieved the primary outcome measure (P = 0.002). After 16 weeks, PTH levels did not decrease significantly in patients receiving ergocalciferol, but were decreased significantly in those treated with paricalcitol (mean estimate of between-group difference over 16 weeks of therapy, 43.9 pg/mL; 95% CI, 11.2-76.6; P = 0.009). Serum 25(OH)D levels increased significantly after 16 weeks in only the ergocalciferol group, but not the paricalcitol group (mean estimate of between-group difference over 16 weeks of therapy, 7.08 ng/mL; 95% CI, 4.32-9.85; P < 0.001). Episodes of hyperphosphatemia and hypercalcemia were not significantly different between the 2 groups. LIMITATIONS: Lack of blinding and use of surrogate end points. CONCLUSIONS: Paricalcitol is more effective than ergocalciferol at decreasing PTH levels in patients with CKD stages 3 or 4 with vitamin D deficiency and SHPT.

Association of echocardiographic abnormalities with mortality in men with non-dialysis-dependent chronic kidney disease.

BACKGROUND: The interrelationship of left ventricular hypertrophy (LVH) with ejection fraction (EF) and their impact on mortality in non-dialysis-dependent chronic kidney disease (NDD-CKD) is unclear. METHODS: We examined the associations of EF and LVH with all-cause mortality in a historic cohort of 650 male US veterans with moderate-to-advanced NDD-CKD. EF and LVH were examined both separately and after categorizing patients according to their concomitant EF and presence/absence of LVH. Associations with mortality were examined in Cox models with adjustments for demographics, blood pressure, comorbidities, smoking status, medication use and biochemical characteristics. RESULTS: EF <30 and 30-50% were associated with higher all-cause mortality compared to EF >50% even after multivariable adjustments [multivariable adjusted hazard ratio, 95% confidence interval (CI): 2.83 (1.86-4.30) and 1.38 (1.06-1.78), P < 0.001 for linear trend]. LVH in itself was not associated with mortality [multivariable adjusted hazard ratio, 95% CI: 0.83 (0.66-1.05), P = 0.12], but the presence of LVH combined with an EF <50% was associated with the highest mortality [multivariable adjusted hazard ratios, 95% CI in patients with EF >50% + LVH, EF ≤ 50%-LVH and EF ≤ 50% + LVH, compared to EF >50%-LVH: 0.84 (0.63-1.13), 1.36 (1.00-1.83) and 1.62 (1.07-2.46)]. CONCLUSIONS: Low EF is associated with higher mortality in patients with NDD-CKD. In the presence of a low EF, LVH is also associated with higher mortality. Clinical trials are needed to determine if interventions targeting patients with low EF and LVH can lower mortality in NDD-CKD.

Association of hypo- and hyperkalemia with disease progression and mortality in males with chronic kidney disease: the role of race.

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 m(2)/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.

Outcome predictability of serum alkaline phosphatase in men with pre-dialysis CKD.

BACKGROUND: Serum alkaline phosphatase (ALP) increases in patients with chronic kidney disease (CKD) and high-turnover bone disease. ALP may represent an adjunct marker of high bone turnover devoid of drawbacks of serum parathyroid hormone (PTH), and it may also be associated with cardiovascular calcification in CKD. Higher ALP has been recently associated with increased mortality and coronary calcification in dialysis patients. In pre-dialysis CKD patients, this association is not clear. METHODS: We examined the association of baseline, time-varying and time-averaged ALP with all-cause mortality and the composite of pre-dialysis mortality or end-stage renal disease in a historical prospective cohort of 1158 male veterans with pre-dialysis CKD from a single institution by using multivariable-adjusted Cox models. RESULTS: Higher ALP was associated with increased mortality irrespective of the statistical model. Time-averaged ALP displayed a consistent linear association with mortality: a 50-U/L higher serum ALP was associated with a multivariable-adjusted death hazard ratio (95% confidence interval) of 1.17 (1.08-1.28), P < 0.001. Baseline and time-varying ALP showed non-linear associations with mortality, with serum levels above 70 U/L in all models and with lower levels in time-varying models. Associations between ALP levels and the composite outcomes were similar. However, compared to serum PTH, mortality predictability of ALP appeared more incremental. CONCLUSIONS: Elevated ALP is associated with increased mortality in patients with pre-dialysis CKD. Low ALP appears to be associated with short-term mortality.

Heart Failure Increases the Risk of Adverse Renal Outcomes in Patients With Normal Kidney Function.

BACKGROUND: Heart failure (HF) is associated with poor cardiac outcomes and mortality. It is not known whether HF leads to poor renal outcomes in patients with normal kidney function. We hypothesized that HF is associated with worse long-term renal outcomes. METHODS AND RESULTS: Among 3 570 865 US veterans with estimated glomerular filtration rate (eGFR) ≥60 mL min-1 1.73 m-2 during October 1, 2004 to September 30, 2006, we identified 156 743 with an International Classification of Diseases, Ninth Revision, diagnosis of HF. We examined the association of HF with incident chronic kidney disease (CKD), the composite of incident CKD or mortality, and rapid rate of eGFR decline (slopes steeper than -5 mL min-1 1.73 m-2 y-1) using Cox proportional hazard analyses and logistic regression. Adjustments were made for various confounders. The mean±standard deviation baseline age and eGFR of HF patients were 68±11 years and 78±14 mL min-1 1.73 m-2 and in patients without HF were 59±14 years and 84±16 mL min-1 1.73 m-2, respectively. HF patients had higher prevalence of hypertension, diabetes mellitus, cardiac, peripheral vascular and chronic lung diseases, stroke, and dementia. Incidence of CKD was 69.0/1000 patient-years in HF patients versus 14.5/1000 patient-years in patients without HF, and 22% of patients with HF had rapid decline in eGFR compared with 8.5% in patients without HF. HF patients had a 2.12-, 2.06-, and 2.13-fold higher multivariable-adjusted risk of incident CKD, composite of CKD or mortality, and rapid eGFR decline, respectively. CONCLUSIONS: HF is associated with significantly higher risk of incident CKD, incident CKD or mortality, and rapid eGFR decline. Early diagnosis and management of HF could help reduce the risk of long-term renal complications.

Synergistic association of combined glycemic and blood pressure level with risk of complications in US veterans with diabetes.

OBJECTIVES: Hemoglobin A1c levels less than 7.0% and systolic blood pressure (SBP) less than 140 mmHg are each associated with lower risk of vascular complications in patients with diabetes mellitus. Associations between combined A1c level and SBP categories and risk of mortality and morbidity in diabetic patients are not well characterized. METHODS: We examined 891 670 US diabetic veterans with baseline estimated glomerular filtration rates more than 60 ml/min per 1.73 m (mean age 67 ±â€Š11 years, 97% men, 17% African-Americans). The associations of mutually exclusive combined categories of A1c (<6.5, 6.5-6.9, 7.0-7.9, 8.0-8.9, 9.0-9.9, and ≥10%) and SBP (<100, 100-119, 120-139, 140-159, 160-179, and ≥180 mmHg) with the risk of all-cause mortality and incident chronic kidney disease (CKD), coronary heart disease, and stroke were examined in Cox models adjusted for baseline characteristics using patients with concomitant A1c 6.5-6.9% and SBP of 120-139 mmHg as the referent group. RESULTS: A total of 221 529 (25%) patients died, and 178 588 (20%), 43 373 (5%) and 36 935 (4%) developed CKD, coronary heart disease and stroke, respectively, during a median follow-up of 7.4 years. SBP displayed a J-shaped association with each outcome except CKD risk that was linearly associated with SBP across all A1c categories. A1c above 7.0% was associated with monotonically worse outcomes for all end points in all SBP categories. Patients with the combined highest A1c and SBP levels experienced the worst outcomes. CONCLUSION: SBP greater than 120-139 mmHg and A1c greater than 7.0% are associated with higher mortality and vascular complications in diabetic patients, independent of each other. Combined efforts to improve both glycemic and blood pressure control may synergistically improve outcomes in patients with normal kidney function.

Increased Risk of Incident Chronic Kidney Disease, Cardiovascular Disease, and Mortality in Patients With Diabetes With Comorbid Depression.

OBJECTIVE: It is not known if patients with diabetes with depression have an increased risk of chronic kidney disease (CKD). We examined the association between depression and incident CKD, mortality, and incident cardiovascular events in U.S. veterans with diabetes. RESEARCH DESIGN AND METHODS: Among a nationally representative prospective cohort of >3 million U.S. veterans with baseline estimated glomerular filtration rate (eGFR) ≥60 mL/min/1.73 m2, we identified 933,211 patients with diabetes. Diabetes was ascertained by an ICD-9-CM code for diabetes, an HbA1c >6.4%, or receiving antidiabetes medication during the inclusion period. Depression was defined by an ICD-9-CM code for depression or by antidepressant use during the inclusion period. Incident CKD was defined as two eGFR levels <60 mL/min/1.73 m2 separated by ≥90 days and a >25% decline in baseline eGFR. The associations between depression and outcomes were assessed using Cox proportional regression. RESULTS: Depression was present in 340,806 patients at enrollment. Depressed patients were younger (61 ± 11 vs. 65 ± 11 years), had higher eGFR (84 ± 15 vs. 81 ± 14 mL/min/1.73 m2), but had more comorbidities. Incident CKD developed in 180,343 patients. Depression was associated with 20% higher risk of incident CKD (adjusted hazard ratio [aHR] and 95% CI: 1.20 [1.19-1.21]). Similarly, depression was associated with increased all-cause mortality (aHR and 95% CI: 1.25 [1.24-1.26]). CONCLUSIONS: The presence of depression in patients with diabetes is associated with higher risk of developing CKD compared with nondepressed patients. Intervention studies should determine if effective treatment of depression in patients with diabetes would prevent major renal and cardiovascular complications.

Association of Systolic Blood Pressure Variability With Mortality, Coronary Heart Disease, Stroke, and Renal Disease.

BACKGROUND: Intraindividual blood pressure (BP) fluctuates dynamically over time. Previous studies suggested an adverse link between greater visit-to-visit variability 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: This study investigated the association of increased visit-to-visit variability 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. Systolic blood pressure 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 diastolic BP), 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 with 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.

Association of Pre-Operative Albuminuria with Post-Operative Outcomes after Coronary Artery Bypass Grafting.

The effect on post-operative outcomes after coronary artery bypass graft (CABG) surgery is not clear. Among 17,812 patients who underwent CABG during October 1,2006-September 28,2012 in any Department of US Veterans Affairs (VA) hospital, we identified 5,968 with available preoperative urine albumin-creatinine ratio (UACR) measurements. We examined the association of UACR<30, 30-299 and >=300 mg/g with 30/90/180/365-day and overall all-cause mortality, and hospitalization length >10 days, and with acute kidney injury(AKI). Mean ± SD baseline age and eGFR were 66 ± 8 years and 77 ± 19 ml/min/1.73 m(2), respectively. 788 patients (13.2%) died during a median follow-up of 3.2 years, and 26.8% patients developed AKI (23.1%-Stage 1; 2.9%-Stage 2; 0.8%-Stage 3) within 30 days of CABG. The median lengths of stay were 8 days (IQR: 6-13 days), 10 days (IQR: 7-14 days) and 12 days (IQR: 8-19 days) for groups with UACR < 30 mg/g, 30-299 mg/g and ≥300 mg/g, respectively. Higher UACR conferred 72 to 85% higher 90-, 180-, and 365-day mortality compared to UACR<30 mg/g (odds ratio and 95% confidence interval for UACR≥300 vs. <30 mg/g: 1.72(1.01-2.95); 1.85(1.14-3.01); 1.74(1.15-2.61), respectively). Higher UACR was also associated with significantly longer hospitalizations and higher incidence of all stages of AKI. Higher UACR is associated with significantly higher odds of mortality, longer post-CABG hospitalization, and higher AKI incidence.

Association of medical treatment nonadherence with all-cause mortality in newly treated hypertensive US veterans.

Nonadherence to antihypertensive drugs is associated with adverse outcomes; however, mediators of this relationship are poorly understood. We examined the association between the International Classification of Diseases-Ninth Revision code for medical treatment nonadherence (V15.81) assigned before initiation of antihypertensive drug therapy and all-cause mortality in a large cohort of incident hypertensive US veterans. A propensity score-matched cohort of 18 822 patients (9411 patients with and without a V15.81 code) was generated based on variables predictive of the presence of the V15.81 code to assess its independent association with all-cause mortality during 3.8 years of follow-up. We used Cox models before and after adjustment for antihypertensive drug adherence (measured as the proportion of days covered) and for measures of blood pressure to determine whether the association of nonadherence with mortality was mediated through consequences of not following prescribed antihypertensive drugs. At baseline, the mean age of patients was 50.0 years, 91.4% were men, and 33.2% were blacks. The V15.81 code presence was associated with higher all-cause mortality (hazard ratio, 1.38, 95% confidence interval, 1.26-1.52; P<0.001). Adjustment for medication adherence, blood pressure levels, and blood pressure variability during follow-up did not alter the association between the V15.81 code and all-cause mortality (hazard ratio, 1.35; 95% confidence interval, 1.20-1.52; P<0.001). In conclusion, assignment of a V15.81 code before antihypertensive drug therapy was associated with higher all-cause mortality in incident hypertensive US veterans and can be useful to identify high-risk patients in administrative databases. This association was not mediated by worse adherence to antihypertensive drugs or differences in follow-up blood pressure.

Observational modeling of strict vs conventional blood pressure control in patients with chronic kidney disease.

IMPORTANCE: The effect of strict blood pressure control on clinical outcomes in patients with chronic kidney disease (CKD) is unclear. OBJECTIVE: To compare the outcomes associated with a treated systolic blood pressure (SBP) of less than 120 mm Hg vs those associated with the currently recommended SBP of less than 140 mm Hg in a national CKD database of US veterans. DESIGN, SETTING, AND PARTICIPANTS: Historical cohort study using a nationwide cohort of US veterans with prevalent CKD, estimated glomerular filtration rate less than 60 mL/min/1.73 m(2), and uncontrolled hypertension, who then received 1 or more additional blood pressure medications with evidence of a decrease in SBP. Propensity scores were calculated to reflect each individual's probability for future SBP less than 120 vs 120 to 139 mm Hg. MAIN OUTCOMES AND MEASURES: The effect of SBP on all-cause mortality was evaluated by the log-rank test, and in Cox models adjusted for propensity scores. RESULTS: Using a database of 651,749 patients with CKD, we identified 77,765 individuals meeting the inclusion criteria. A total of 5760 patients experienced follow-up treated SBP of less than 120 mm Hg and 72,005 patients had SBP of 120 to 139 mm Hg. During a median follow-up of 6.0 years, 19,517 patients died, with 2380 deaths in the SBP less than 120 mm Hg group (death rate, 80.9/1000 patient-years [95% CI, 77.7-84.2/1000 patient-years]) and 17,137 deaths in the SBP 120 to 139 mm Hg group (death rate, 41.8/1000 patient-years [95% CI, 41.2-42.4/1000 patient-years]; P < .001). The mortality hazard ratio (95% CI) associated with follow-up SBP less than 120 vs 120 to 139 mm Hg was 1.70 (1.63-1.78) after adjustment for propensity scores. CONCLUSIONS AND RELEVANCE: Our results suggest that stricter SBP control is associated with higher all-cause mortality in patients with CKD. Confirmation of these findings by ongoing clinical trials would suggest that modeling of therapeutic interventions in observational cohorts may offer useful guidance for the treatment of conditions that lack clinical trial data.