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Rationale & Objective: Kidney disease negatively affects cognition. We assessed the effect of kidney transplantation (KT) on different cognitive domains., Study Design: Prospective cohort study., Setting & Participants: We examined pre- versus post-KT cognition in patients waitlisted for KT at an academic center., Predictors: Transplant status. We measured cognitive function before KT (n=101), 3 months after KT (n=78), and 1 year after KT (n = 83)., Outcomes: Our primary outcome was change in cognitive function before versus after KT. We used standard neuropsychological tests to assess global cognition (Mini-Mental State Exam [MMSE]), episodic/declarative memory (Logical Memory), psychomotor speed/visuospatial function (Digit Symbol Substitution Test [DSST], Trail Making Test [TMT] A), working memory/attention (Digit Span), executive function (TMT B), and semantic memory/verbal fluency/language (Category Fluency)., Analytical Approach: Using linear mixed model analysis, we evaluated the changes in neuropsychological test scores adjusted for age, sex, race, education, and number of assessments., Results: Before KT, Logical Memory I and II, DSST, MMSE, Category Fluency (animal naming), and Digit Span backward scores were low compared with normative values from the National Alzheimer's Coordinating Center data. Logical Memory I and II scores improved after KT (pre- vs post-KT, estimated group difference [d]=3.3, P<0.001 for Logical Memory I; d=4.27, P<0.001 for Logical Memory II), such that post-KT scores were similar to normative values (post-KT vs normative values, d = -0.37, P=0.06 for Logical Memory I; d = -0.89, P=0.08 for Logical Memory II). Category Fluency (animal naming; d=2.4, P<0.001) and DSST (d=3.12, P=0.01) scores also improved with KT, but post-KT DSST scores remained lower than normative values (post-KT vs normative values, d = -5.17, P<0.001). MMSE, Digit Span, and TMT A and B scores did not change after KT., Limitations: Single-center study., Conclusions: Episodic and verbal declarative memory normalize after KT. Semantic memory, verbal fluency, language, psychomotor speed, and visuospatial function show partial improvement. Cognitive impairment in kidney disease is therefore at least partly reversible with KT., Plain-Language Summary: Cognitive impairment in kidney disease affects self-esteem, vocational abilities, quality of life, health care costs, and mortality. It is not clear whether kidney transplantation (KT) improves cognition and whether the improvement is uniform across cognitive domains. The distinction between reversible and irreversible cognitive impairment has important implications in the clinical care of patients before and after KT. We assessed cognition before KT and 3 months and 12 months after KT and discovered that episodic and verbal declarative memory normalized with KT. Semantic memory, verbal fluency, language, psychomotor speed, and visuospatial function also improved with KT but did not reach normal levels. Cognitive impairment in kidney disease is therefore at least partly reversible., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Heart failure with preserved ejection fraction (HFpEF) comprises approximately one-half of all diagnoses of heart failure. There is significant overlap of this clinical syndrome with chronic kidney disease (CKD), with many shared comorbid conditions. The presence of CKD in patients with HFpEF is one of the most powerful risk factors for adverse clinical outcomes, including death and heart failure hospitalization. The pathophysiology linking HFpEF and CKD remains unclear, but it is postulated to consist of numerous bidirectional pathways, including endothelial dysfunction, inflammation, obesity, insulin resistance, and impaired sodium handling. The diagnosis of HFpEF requires certain criteria to be satisfied, including signs and symptoms consistent with volume overload caused by structural or functional cardiac abnormalities and evidence of increased cardiac filling pressures. There are numerous overlapping metabolic clinical syndromes in patients with HFpEF and CKD that can serve as targets for intervention. With an increasing number of therapies available for HFpEF and CKD as well as for obesity and diabetes, improved recognition and diagnosis are paramount for appropriate management and improved clinical outcomes in patients with both HFpEF and CKD., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Rationale & Objective: Both hypervolemia and hypovolemia are associated with chronic kidney disease (CKD) progression. Although longitudinal monitoring of B-type natriuretic peptide (BNP) may aid physicians' decision making about the optimization of volume status, its clinical benefit remains uncertain in CKD. This study assessed the association between BNP monitoring and the risk of incident kidney replacement therapy (KRT)., Study Design: Retrospective cohort study., Setting & Participants: A total of 2,998 outpatients with stages 3-5 of nondialyzed CKD referred to the department of nephrology at an academic hospital., Exposure: BNP monitoring., Outcome: KRT, acute kidney injury (AKI), and heart failure hospitalization., Analytical Approach: Marginal structural models, which create a balanced pseudo population at each time point, were applied to account for potential time-dependent confounders. Inverse probability weighted pooled logistic regression models were employed to estimate hazard ratios., Results: At baseline, the median age and estimated glomerular filtration rate were 66 years and 38.1mL/min/1.73m 2 , respectively. During the follow-up period (median, 5.9 [IQR, 2.8-9.9] years), 449 patients required KRT, 765 had AKI, and 236 were hospitalized for heart failure. After adjustment for time-updated clinical characteristics and physician-specific practice styles, BNP monitoring was associated with lower risks of KRT (HR, 0.44 [95% CI, 0.21-0.92]), AKI (HR, 0.36 [95% CI, 0.18-0.72]), and heart failure hospitalization (HR, 0.37 [95% CI, 0.14-0.95]). The association between BNP monitoring and KRT was attenuated after additional adjustment for AKI or heart failure hospitalization as a time-varying covariate., Limitations: Residual confounding by measured and unmeasured variables or indications for BNP measurements., Conclusions: BNP monitoring was associated with a lower risk of KRT among patients with CKD that did not require dialysis. This association is potentially mediated through a reduced risk of AKI or heart failure hospitalization., Plain-Language Summary: Both volume overload and volume depletion are deleterious to kidney function. B-type natriuretic peptide (BNP) is a biomarker that reflects volume status not only in heart failure but also in nondialysis chronic kidney disease (CKD). Although longitudinal BNP monitoring may aid physicians' decision making about the optimization of volume status, its clinical benefit remains uncertain in CKD. In this cohort study analyzing 2,998 patients with nondialyzed CKD, BNP monitoring was associated with a lower risk of kidney replacement therapy, acute kidney injury, and heart failure hospitalization over the follow-up period. The association with kidney replacement therapy may be mediated through a reduced risk of acute kidney injury or heart failure hospitalization. BNP monitoring may aid physicians in optimal fluid management, potentially conferring better kidney outcomes., (Copyright © 2023 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Rationale & Objective: Hypertension is a known risk factor for dementia and cognitive impairment. There are limited data on the relation of systolic blood pressure (SBP) and diastolic blood pressure (DBP) with incident cognitive impairment in adults with chronic kidney disease. We sought to identify and characterize the relationship among blood pressure, cognitive impairment, and severity of decreased kidney function in adults with chronic kidney disease., Study Design: Longitudinal cohort study., Setting & Participants: 3,768 participants in the Chronic Renal Insufficiency Cohort (CRIC) Study., Exposure: Baseline SBP and DBP were examined as exposure variables, using continuous (linear, per 10-mm Hg higher), categorical (SBP<120 [reference], 120 to 140,>140mm Hg; DBP<70 (reference), 70 to 80, > 80mm Hg) and nonlinear terms (splines)., Outcome: Incident cognitive impairment defined as a decline in Modified Mini-Mental State Examination (3MS) score to greater than 1 standard deviation below the cohort mean., Analytical Approach: Cox proportional hazard models adjusted for demographics as well as kidney disease and cardiovascular disease risk factors., Results: The mean age of participants was 58±11 (SD) years, estimated glomerular filtration rate (eGFR) was 44mL/min/1.73m 2 ± 15 (SD), and the median follow-up time was 11 (IQR, 7-13) years. In 3,048 participants without cognitive impairment at baseline and with at least 1 follow-up 3MS test, a higher baseline SBP was significantly associated with incident cognitive impairment only in the eGFR>45mL/min/1.73m 2 subgroup (adjusted hazard ratio [AHR], 1.13 [95% CI, 1.05-1.22] per 10mm Hg higher SBP]. Spline analyses, aimed at exploring nonlinearity, showed that the relationship between baseline SBP and incident cognitive impairment was J-shaped and significant only in the eGFR>45mL/min/1.73m 2 subgroup (P=0.02). Baseline DBP was not associated with incident cognitive impairment in any analyses., Limitations: 3MS test as the primary measure of cognitive function., Conclusions: Among patients with chronic kidney disease, higher baseline SBP was associated with higher risk of incident cognitive impairment specifically in those individuals with eGFR>45mL/min/1.73m 2 ., Plain-Language Summary: High blood pressure is a strong risk factor for dementia and cognitive impairment in studies of adults without kidney disease. High blood pressure and cognitive impairment are common in adults with chronic kidney disease (CKD). The impact of blood pressure on the development of future cognitive impairment in patients with CKD remains unclear. We identified the relationship between blood pressure and cognitive impairment in 3,076 adults with CKD. Baseline blood pressure was measured, after which serial cognitive testing was performed over 11 years. Fourteen percent of participants developed cognitive impairment. We found that a higher baseline systolic blood pressure was associated with an increased risk of cognitive impairment. We found that this association was stronger in adults with mild-to-moderate CKD compared with those with advanced CKD., (Copyright © 2023 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Rationale & Objective: Acute decreases in glomerular filtration rate (GFR) occur commonly during intensive blood pressure (BP) lowering. Our objective was to determine the relationship between acute decreases in estimated GFR and patient outcomes., Study Design: Retrospective observational study., Setting & Participants: Participants from 4 randomized controlled trials of intensive BP lowering in chronic kidney disease (Modification of Diet in Renal Disease study, African American Study of Kidney Disease and Hypertension, Systolic Blood Pressure Intervention Trial, and Action to Control Cardiovascular Risk in Diabetes trial)., Exposure: A 4-category exposure defined by the level of acute decrease in estimated GFR (defined as>15% vs≤15% between baseline and month 4) and the randomization to intensive versus usual BP control., Outcomes: Risk of kidney replacement therapy (primary outcome), defined as the need for dialysis or transplant except in the Action to Control Cardiovascular Risk in Diabetes trial, which defined its kidney outcome as a composite occurrence of serum creatinine concentration>3.3mg/dL, kidney failure, or kidney replacement therapy., Analytical Approach: Multivariable Cox models., Results: We included 4,473 individuals randomly assigned to intensive versus usual BP control who had a total of 351 kidney outcomes and 304 deaths during median follow-up durations of 22 and 24 months, respectively. Approximately 14% of participants exhibited an acute decrease in eGFR, 11.0% in the usual BP treatment arm and 17.8% in the intensive BP treatment arm. In adjusted models, compared with a≤15% eGFR decrease in the usual BP arm, a≤15% eGFR decrease in the intensive BP control arm was associated with lower risk of the kidney outcome (HR, 0.75; 95% CI, 0.57-0.98). In contrast, a>15% decrease in eGFR was associated with a higher risk of the kidney outcome in the usual (HR, 2.47; 95% CI, 1.80-3.38) and intensive BP treatment arms (HR, 1.99; 95% CI, 1.45-2.73) compared with a≤15% decrease in the usual BP arm., Limitations: Observational study, residual confounding., Conclusions: Decreases in eGFR of>15% in the usual and intensive BP treatment arms were associated with a higher risk of kidney outcomes compared with a≤15% decrease in the usual BP arm and may be a harbinger of adverse outcomes., (Copyright © 2023 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Rationale & Objective: Cardiovascular disease (CVD) is a major cause of mortality among people with diabetic kidney disease (DKD). The pathophysiology is inadequately explained by traditional CVD risk factors. The uremic solutes trimethylamine-N-oxide (TMAO) and asymmetric and symmetric dimethylarginine (ADMA, SDMA) have been linked to CVD in kidney failure with replacement therapy (KFRT), but data are limited in populations with diabetes and less severe kidney disease., Study Design: Observational cohort., Settings & Participants: Random subcohort of 555 REGARDS (Reasons for Geographic and Racial Differences in Stroke) study participants with diabetes and estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m 2 at study entry., Exposure: ADMA, SDMA, and TMAO assayed by liquid chromatography-mass spectrometry in plasma and urine., Outcome: Cardiovascular mortality (primary outcome); all-cause mortality and incident KFRT (secondary outcomes)., Analytical Approach: Plasma concentrations and ratios of urine to plasma concentrations of ADMA, SDMA, and TMAO were tested for association with outcomes. Adjusted Cox regression models were fitted and hazard ratios of outcomes calculated per standard deviation and per doubling, and as interquartile comparisons., Results: The mean baseline eGFR was 44 mL/min/1.73 m 2 . Cardiovascular death, overall mortality, and KFRT occurred in 120, 285, and 89 participants, respectively, during a mean 6.2 years of follow-up. Higher plasma ADMA and SDMA (HRs of 1.20 and 1.28 per 1-SD greater concentration), and lower ratios of urine to plasma concentrations of ADMA, SDMA, and TMAO (HRs per halving of 1.53, 1.69, and 1.38) were associated with cardiovascular mortality. Higher plasma concentrations of ADMA, SDMA, and TMAO (HRs of 1.31, 1.42, and 1.13 per 1-SD greater concentration) and lower urine to plasma ratios of ADMA, SDMA, and TMAO (HRs per halving of 1.34, 1.37, and 1.26) were associated with all-cause mortality. Higher plasma ADMA and SDMA were associated with incident KFRT by categorical comparisons (HRs of 2.75 and 2.96, comparing quartile 4 to quartile 1), but not in continuous analyses., Limitations: Single cohort, restricted to patients with diabetes and eGFR < 60 mL/min/1.73 m 2 , potential residual confounding by GFR, no dietary information., Conclusions: Higher plasma concentrations and lower ratios of urine to plasma concentrations of uremic solutes were independently associated with cardiovascular and all-cause mortality in DKD. Associations of ratios of urine to plasma concentrations with mortality suggest a connection between renal uremic solute clearance and CVD pathogenesis., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Rationale & Objective: Achievement of decongestion in acute heart failure (AHF) is associated with improved survival and cardiovascular outcomes but can be associated with acute declines in estimated glomerular filtration rate (eGFR). We examined whether the rate of in-hospital decongestion is associated with longer term kidney function decline., Study Design: Post hoc analysis of trial data., Settings & Participants: Patients with ≥2 measures of kidney function (n = 3,500) from the Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study With Tolvaptan (EVEREST) trial., Exposure: In-hospital rate of change in assessments of volume overload, including B-type natriuretic peptide (BNP), N-terminal pro-B-type natriuretic peptide (NT-proBNP), and clinical congestion score (0-12); and rate of change in hemoconcentration including measures of hematocrit, albumin, and total protein., Outcome: Incident chronic kidney disease GFR category 4 or worse (chronic kidney disease [CKD] categories G4-G5; defined by a new eGFR of <30 mL/min/1.73 m 2 ) and eGFR decline of >40%., Analytical Approach: Multivariable cause-specific hazards models., Results: Over median 10-month follow-up period, faster decreases in volume overload and more rapid increases in hemoconcentration were associated with a decreased risk of incident CKD G4-G5 and eGFR decline of >40%. In adjusted analyses, for every 6% faster decline in BNP per week, there was a 32% lower risk of both incident CKD G4-G5 (HR, 0.68 [95% CI, 0.58-0.79]) and eGFR decline of >40% (HR, 0.68 [95% CI, 0.57-0.80]). For every 1% faster increase per week in absolute hematocrit, there was a lower risk for both incident CKD G4-G5 (HR, 0.73 [95% CI, 0.64-0.84]) and eGFR decline of >40% (HR, 0.82 [95% CI, 0.71-0.95]), with results consistent for other biomarkers., Limitations: Possibility of residual confounding., Conclusions: These results provide reassurance that more rapid decongestion in patients with AHF does not increase the risk of adverse kidney outcomes in patients with heart failure., (Copyright © 2021 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Rationale & Objective: Most circulating biomarkers of chronic kidney disease (CKD) progression focus on factors reflecting glomerular filtration. Few biomarkers capture nonglomerular pathways of kidney injury or damage, which may be particularly informative in populations at high risk for CKD progression such as individuals with diabetes., Study Design: Cohort study., Setting & Participants: 594 participants (mean age, 70 years; 53% women) of the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study who had diabetes and an estimated glomerular filtration rate (eGFR)<60mL/min/1.73m 2 at baseline., Exposures: Plasma biomarkers of inflammation/fibrosis (TNFR1 and TNFR2, suPAR, MCP-1, YKL-40) and tubular injury (KIM-1) measured at the baseline visit., Outcomes: Incident kidney failure with replacement therapy (KFRT)., Analytical Approach: Cox proportional hazards regression and least absolute shrinkage and selection operator regression adjusted for established risk factors for kidney function decline, baseline eGFR, and urinary albumin-creatinine ratio (UACR)., Results: A total of 98 KFRT events were observed over a mean of 6.2±3.5 (standard deviation) years of follow-up. Plasma biomarkers were modestly associated with baseline eGFR (correlation coefficients ranging from-0.08 to-0.65) and UACR (0.14 to 0.56). In individual biomarker models adjusted for eGFR, UACR, and established risk factors, hazard ratios for incident KFRT per 2-fold higher biomarker concentrations were 1.52 (95% CI, 1.25-1.84) for plasma KIM-1, 1.54 (95% CI, 1.08-2.21) for TNFR1, 1.91 (95% CI, 1.16-3.14) for TNFR2, and 1.39 (95% CI, 1.05-1.84) for YKL-40. In least absolute shrinkage and selection operator regression models accounting for biomarkers in parallel, plasma KIM-1 and TNFR1 remained associated with incident KFRT., Limitations: Single biomarker measurement, lack of follow-up eGFR assessments., Conclusions: Individual plasma markers of inflammation/fibrosis (TNFR1, TNFR2, YKL-40) and tubular injury (KIM-1) were associated with risk of incident KFRT in adults with diabetes and an eGFR<60mL/min/1.73m 2 after adjustment for established risk factors., (Copyright © 2021 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Rationale & Objective: Angiotensin-converting enzyme (ACE) inhibitors are beneficial in heart failure with reduced ejection fraction (HFrEF). We sought to describe longitudinal trends in estimated glomerular filtration rate (eGFR) in HFrEF and how ACE-inhibitor therapy influences these changes., Study Design: Post hoc analysis of trial data., Settings & Participants: Symptomatic (Treatment Trial, n=2,423) and asymptomatic (Prevention Trial, n=4,094) patients from the Studies of Left Ventricular Dysfunction (SOLVD)., Exposure: Enalapril versus placebo., Outcomes: Early and long-term eGFR slope (ie, within and after the first 6 weeks) and 4 kidney end points: (1) serum creatinine level increase by≥0.3mg/dL, (2)>30% eGFR decline, (3)>40% eGFR decline, and (4) incident eGFR<30mL/min/1.73m 2 ., Analytical Approach: Shared parameter models, multivariable Cox regression models., Results: Baseline mean eGFR was lower in the Treatment Trial than in the Prevention Trial, 69.5±19.8 (SD) versus 76.2±18.6mL/min/1.73m 2 . Following randomization, an early eGFR decline occurred in the enalapril group; however, slopes during the median 3-year follow-up were not statistically different by randomization arm in either the Treatment Trial (-0.84 in enalapril vs-1.36mL/min/1.73m 2 per year in placebo; P=0.08) or Prevention Trial (-1.27 in enalapril vs-1.36mL/min/1.73m 2 per year in placebo; P=0.7). Random assignment to enalapril treatment increased the risk for all 4 outcomes in the Treatment Trial in the first 6-week period (HRs were 1.48 [95% CI, 1.10-1.99] for creatinine increase by≥0.3mg/dL; 1.38 [95% CI, 0.98-1.94] for eGFR decline> 30%; 2.60 [95% CI, 1.30-5.21] for eGFR decline> 40%; and 4.71 [95% CI, 1.78-12.50] for eGFR<30mL/min/1.73m 2 ), but after the first year was not significantly associated with increased risk. A similar albeit less pronounced pattern was observed in the Prevention Trial, with risks present only in the early period., Limitations: Creatinine results were not blinded, making it possible that ACE-inhibitor/placebo dosing was influenced by creatinine level., Conclusion: Kidney function decline is slow in HFrEF. Although random assignment to enalapril treatment results in a statistically increased risk for kidney surrogates, the risk is limited to the early phase and late eGFR slopes and risks are not different by randomly assigned group., (Copyright © 2019 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Patients with chronic kidney disease (CKD) are at substantially higher risk for developing cognitive impairment compared with the general population, and both lower glomerular filtration rate and the presence of albuminuria are associated with the development of cognitive impairment and poorer cognitive function. Given the excess of vascular disease seen in individuals with CKD, cerebrovascular disease is likely the predominant pathology underlying these associations, though impaired clearance of uremic metabolites, depression, sleep disturbance, anemia, and polypharmacy may also contribute. Modification of vascular disease risk factors may be helpful in limiting decline, though definite data are lacking. Specific to CKD, targeting a low blood pressure and reduction in albuminuria with angiotensin-converting enzyme inhibitors or angiotensin receptor blockers may slow cognitive decline, albeit modestly. Initiation of dialysis can improve severe impairment associated with uremia but does not appear to affect more subtle chronic cognitive impairment. In contrast, kidney transplantation appears to lead to improved cognitive function in many transplant recipients, suggesting that dialysis methods do not provide the same cognitive benefits as having a functioning kidney. Management of patients with both CKD and cognitive impairment should include a comprehensive plan including more frequent follow-up visits; involvement of family in shared decision making; measures to improve compliance, such as written instruction and pill counts; and a focus on advance directives in conjunction with an emphasis on understanding an individual patient's life goals. Further research is needed on novel therapies, including innovative dialysis methods, that aim to limit the development of cognitive impairment, slow decline in those with prevalent impairment, and improve cognitive function., (Copyright © 2019 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Rationale & Objective: Uromodulin is released by tubular epithelial cells into the serum and lower levels are associated with more severe interstitial fibrosis and tubular atrophy. Low serum uromodulin (sUMOD) levels are associated with mortality and cardiovascular disease. However, little is known about the association of sUMOD levels with long-term kidney outcomes in older adults, a population with a high prevalence of interstitial fibrosis and tubular atrophy., Study Design: Case-cohort study and case-control study., Setting & Participants: Random subcohort (n=933) and additional cases of end-stage kidney disease (ESKD) and kidney function decline (≥30% decline in estimated glomerular filtration rate [eGFR]) during follow-up of the Cardiovascular Health Study (CHS)., Predictor: sUMOD level., Outcomes: ESKD (n=14) from the random subcohort and all additional ESKD cases from outside the random subcohort (n=39) during follow-up (10 years, case-cohort study); kidney function decline of≥30% eGFR at 9 years of follow-up in individuals with repeated eGFR assessments from the random subcohort (n=56) and additional cases (n=123). 224 participants from the random subcohort served as controls (case-control study)., Analytical Approach: Modified multivariable Cox regression for ESKD and multivariable logistic regression for kidney function decline. Both analyses adjusted for demographics, eGFR, urinary albumin-creatinine ratio, and other kidney disease progression risk factors., Results: Mean age of the random subcohort was 78 years, 40% were men, 15% were black. Mean sUMOD level was 127±64ng/mL and eGFR was 63±19mL/min/1.73m 2 . In multivariable analysis, each 1-SD higher sUMOD level was associated with 63% lower risk for ESKD (HR, 0.37; 95% CI, 0.14-0.95). In demographic-adjusted analyses of kidney function decline, each 1-SD higher sUMOD level was associated with 25% lower odds of kidney function decline (OR, 0.75; 95% CI, 0.60-0.95); after multivariable adjustment, the association was attenuated and no longer significant (OR, 0.88; 95% CI, 0.68-1.14)., Limitations: Possibility of survival bias in the kidney function decline analysis., Conclusions: Higher sUMOD levels may identify elderly persons at reduced risk for ESKD., (Copyright © 2019 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Background: Random assignment to the intensive systolic blood pressure (SBP) arm (<120mmHg) in the Systolic Blood Pressure Intervention Trial (SPRINT) resulted in more rapid declines in estimated glomerular filtration rates (eGFRs) than in the standard arm (SBP<140mmHg). Whether this change reflects hemodynamic effects or accelerated intrinsic kidney damage is unknown., Study Design: Longitudinal subgroup analysis of clinical trial participants., Settings & Participants: Random sample of SPRINT participants with prevalent chronic kidney disease (CKD) defined as eGFR<60mL/min/1.73m 2 by the CKD-EPI (CKD Epidemiology Collaboration) creatinine-cystatin C equation at baseline., Outcomes & Measurements: Urine biomarkers of tubule function (β 2 -microglobulin [B2M], α 1 -microglobulin [A1M]), and uromodulin), injury (interleukin 18, kidney injury molecule 1, and neutrophil gelatinase-associated lipocalin), inflammation (monocyte chemoattractant protein 1), and repair (human cartilage glycoprotein 40) at baseline, year 1, and year 4. Biomarkers were indexed to urine creatinine concentration and changes between arms were evaluated using mixed-effects linear models and an intention-to-treat approach., Results: 978 SPRINT participants (519 in the intensive and 459 in the standard arm) with prevalent CKD were included. Mean age was 72±9 years and eGFR was 46.1±9.4mL/min/1.73m 2 at baseline. Clinical characteristics, eGFR, urinary albumin-creatinine ratio, and all 8 biomarker values were similar across arms at baseline. Compared to the standard arm, eGFR was lower by 2.9 and 3.3mL/min/1.73m 2 in the intensive arm at year 1 and year 4. None of the 8 tubule marker levels was higher in the intensive arm compared to the standard arm at year 1 or year 4. Two tubule function markers (B2M and A1M) were 29% (95% CI, 10%-43%) and 24% (95% CI, 10%-36%) lower at year 1 in the intensive versus standard arm, respectively., Limitations: Exclusion of persons with diabetes, and few participants had advanced CKD., Conclusions: Among participants with CKD in SPRINT, random assignment to the intensive SBP arm did not increase any levels of 8 urine biomarkers of tubule cell damage despite loss of eGFR. These findings support the hypothesis that eGFR declines in the intensive arm of SPRINT predominantly reflect hemodynamic changes rather than intrinsic damage to kidney tubule cells., (Published by Elsevier Inc.)

Rationale & Objectives: Lower 25-hydroxyvitamin D concentrations have been associated with risk for kidney function decline, heart failure, and mortality. However, 25-hydroxyvitamin D requires conversion to its active metabolite, calcitriol, for most biological effects. The associations of calcitriol concentrations with clinical events have not been well explored., Study Design: Case-cohort study., Setting & Participants: Well-functioning community-living older adults aged 70 to 79 years at inception who participated in the Health, Aging, and Body Composition (Health ABC) Study., Predictor: Serum calcitriol measured using positive ion electrospray ionization-tandem mass spectrometry., Outcomes: Major kidney function decline (≥30% decline in estimated glomerular filtration rate from baseline), incident heart failure (HF), and all-cause mortality during 10 years of follow-up., Analytic Approach: Baseline calcitriol concentrations were measured in a random subcohort of 479 participants and also in cases with major kidney function decline [n=397]) and incident HF (n=207) during 10 years of follow-up. Associations of serum calcitriol concentrations with these end points were evaluated using weighted Cox regression to account for the case-cohort design, while associations with mortality were assessed in the subcohort alone using unweighted Cox regression., Results: During 8.6 years of mean follow-up, 212 (44%) subcohort participants died. In fully adjusted models, each 1-standard deviation lower calcitriol concentration was associated with 30% higher risk for major kidney function decline (95% CI, 1.03-1.65; P=0.03). Calcitriol was not significantly associated with incident HF (HR, 1.16; 95% CI, 0.94-1.47) or mortality (HR, 1.01; 95% CI, 0.81-1.26). We observed no significant interactions between calcitriol concentrations and chronic kidney disease status, baseline intact parathyroid or fibroblast factor 23 concentrations., Limitations: Observational study design, calcitriol measurements at a single time point, selective study population of older adults only of white or black race., Conclusions: Lower calcitriol concentrations are independently associated with kidney function decline in community-living older adults. Future studies will be needed to clarify whether these associations reflect lower calcitriol concentrations resulting from abnormal kidney tubule dysfunction or direct mechanisms relating lower calcitriol concentrations to more rapid loss of kidney function., (Published by Elsevier Inc.)

Rationale & Objective: Novel urinary biomarkers have enabled earlier detection of kidney tubular damage, but their prognostic value for adverse cardiovascular outcomes is uncertain. We hypothesized that tubular damage, measured by urine α 1 -microglobulin (A1M), amino-terminal propeptide of type III procollagen (PIIINP), and neutrophil gelatinase-associated lipocalin (NGAL), would be associated with higher risks for cardiovascular events and mortality among elders., Study Design: Case-cohort study., Setting & Participants: This study included a randomly selected subcohort (n=502), cardiovascular disease (CVD) cases (n=245), and heart failure cases (n=220) from the Health, Aging, and Body Composition (Health ABC) Study., Predictors: Baseline urine A1M, PIIINP, and NGAL concentrations., Outcomes: Incident CVD, heart failure, and all-cause mortality., Analytical Approach: Cox proportional hazards models were used to evaluate biomarker associations with each outcome., Results: At baseline, mean age was 74 years and estimated glomerular filtration rate was 73mL/min/1.73m 2 . After adjustment for demographics, estimated glomerular filtration rate, albumin-creatinine ratio, and other cardiovascular risk factors, each doubling in biomarker concentration was associated with the following adjusted HRs for CVD: A1M, 1.51 (95% CI, 1.16-1.96); PIIINP, 1.21 (95% CI, 1.00-1.46); and NGAL, 1.12 (95% CI, 1.05-1.20). There were 248 deaths in the subcohort during a median follow-up of 12.4 years. Adjusted associations of each biomarker (HR per doubling) with all-cause mortality were: A1M, 1.29 (95% CI, 1.10-1.51); PIIINP, 1.05 (95%, 0.94-1.18); and NGAL, 1.07 (95% CI, 1.02-1.12). Biomarker concentrations did not have statistically significant associations with heart failure after multivariable adjustment., Limitations: Urine biomarkers were measured at a single time point; no validation cohort available., Conclusions: Kidney tubular damage is an independent risk factor for CVD and death among elders. Future studies should investigate mechanisms by which kidney tubular damage may adversely affect cardiovascular risk., (Published by Elsevier Inc.)

Stroke risk may be more than 3-fold higher among patients with chronic kidney disease stage 5D (CKD-5D) compared to the general population, with the highest stroke rates noted among those 85 years and older. Atrial fibrillation (AF), a strong risk factor for stroke, is the most common arrhythmia and affects >7% of the population with CKD-5D. Warfarin use is widely acknowledged as an important intervention for stroke prevention with nonvalvular AF in the general population. However, use of oral anticoagulants for stroke prevention in patients with CKD-5D and nonvalvular AF continues to be debated by the nephrology community. In this National Kidney Foundation-Kidney Disease Outcomes Quality Initiative (NKF-KDOQI) controversies report, we discuss the existing observational studies that examine warfarin use and associated stroke and bleeding risks in adults with CKD-5D and AF. Non-vitamin K-dependent oral anticoagulants and their potential use for stroke prevention in patients with CKD-5D and nonvalvular AF are also discussed. Data from randomized clinical trials are urgently needed to determine the benefits and risks of oral anticoagulant use for stroke prevention in the setting of AF among patients with CKD-5D., (Copyright © 2017 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Background: Using change in estimated glomerular filtration rate (eGFR) based on creatinine concentration as a surrogate outcome in clinical trials of chronic kidney disease has been proposed. Risk for end-stage renal disease (ESRD) and all-cause mortality associated with change in concentrations of other filtration markers has not been studied in chronic kidney disease populations., Study Design: Observational analysis of 2 clinical trials., Setting & Participants: Participants in the MDRD (Modification of Diet in Renal Disease; n=317) Study and AASK (African American Study of Kidney Disease and Hypertension; n=373)., Predictors: Creatinine, cystatin C, β-trace protein (BTP), and β 2 -microglobulin (B2M) were measured in serum samples collected at the 12- and 24-month follow-up visits, along with measured GFR (mGFR) at these time points., Outcomes: ESRD and all-cause mortality., Measurements: Poisson regression was used to estimate incidence rate ratios and 95% CIs for ESRD and all-cause mortality during long-term follow-up (10-16 years) per 30% decline in mGFR or eGFR for each filtration marker and the average of all 4 markers., Results: 1-year decline in mGFR, eGFR cr , eGFR BTP , and the average of the 4 filtration markers was significantly associated with increased risk for incident ESRD in both studies (all P≤0.02). Compared to mGFR, only decline in eGFR BTP was statistically significantly more strongly associated with ESRD risk in both studies (both P≤0.03). Decline in eGFR cr , but not mGFR or the other filtration markers, was significantly associated with risk for all-cause mortality in AASK only (incidence rate ratio per 30% decline, 4.17; 95% CI, 1.78-9.74; P<0.001), but this association was not significantly different from decline in mGFR (P=0.2)., Limitations: Small sample size., Conclusions: Declines in mGFR, eGFR cr , eGFR BTP , and the average of 4 filtration markers (creatinine, cystatin C, BTP, and B2M) were consistently associated with progression to ESRD., (Copyright © 2017 National Kidney Foundation, Inc. All rights reserved.)

Background: Cognitive impairment is common in patients treated with hemodialysis. The trajectory of cognitive function and risk factors for cognitive decline remain uncertain in this population., Study Design: Longitudinal cohort., Setting & Participants: 314 prevalent hemodialysis patients., Predictors: Age, sex, race, education level, hemodialysis vintage, cause of end-stage renal disease, and baseline history of cardiovascular disease., Outcomes: Cognitive function as determined by a comprehensive neurocognitive battery, administered at baseline and yearly when possible. Individual cognitive test results were reduced into 2 domain scores using principal components analysis, representing memory and executive function, which were used as our coprimary outcomes and by definition have a mean of zero and SD of 1., Results: Mean age was 63 years; 54% were men, 22% were black, and 90% had at least a high school education. During a median follow-up of 2.1 (IQR, 0.9-4.2) years, 196 had at least 1 follow-up test, 156 died, and 43 received a kidney transplant. Linear mixed models and joint models, which accounted for competing risks from death, dropout, or kidney transplantation, showed nearly identical results. The joint model demonstrated a decline in executive function (-0.09 [95% CI, -0.13 to -0.05] SD per year), whereas memory improved slightly (0.05 [95% CI, 0.02 to 0.08] SD per year). A significant yearly decline was also seen in the Mini-Mental State Examination score (median change, -0.41; 95% CI, -0.57 to -0.25). Older age was the only significant risk factor for steeper executive function decline (-0.04 [95% CI, -0.06 to -0.02] SD steeper annual decline for each 10 years of age)., Limitations: Prevalent hemodialysis patients only, limited follow-up testing due to high mortality rate, and exclusion of participants with severe cognitive deficits or dementia., Conclusions: Prevalent hemodialysis patients demonstrate significant cognitive decline, particularly within tests of executive function. Older age was the only statistically significant risk factor for steeper cognitive decline, which may have important clinical consequences for patient management and education. Future studies should evaluate strategies to maintain or improve cognitive function., (Copyright © 2017 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Background: Laboratory studies suggest that urinary uromodulin, the most common protein in the urine of healthy adults, may protect against urinary tract infection (UTI). Epidemiologic studies evaluating this relationship in humans are lacking., Study Design: Prospective longitudinal cohort study., Setting & Participants: 953 participants enrolled in the Cardiovascular Health Study., Predictor: Uromodulin assayed using enzyme-linked immunosorbent assay in spot urine samples., Outcomes: Composite of outpatient UTI events or UTI-related hospitalizations and each of them individually identified using International Classification of Diseases, Ninth Revision (ICD-9) codes using negative binomial regression with robust standard errors adjusted for age, race, sex, body mass index, diabetes, estimated glomerular filtration rate, and urinary albumin and urinary creatinine excretion., Results: Median uromodulin level was 25.9 (IQR, 17.3-38.9) μg/mL, mean age of participants was 78 years, 61% were women, and 15% were black. There were 331 outpatient UTI events and 87 UTI-related hospitalizations among 186 participants during a median 9.9 years of follow-up. Persons in the highest quartile (>38.93μg/mL) of uromodulin concentration had a significantly lower risk for the composite outcome (incidence rate ratio [IRR], 0.47; 95% CI, 0.29-0.79) compared with those in the lowest quartile (≤17.26μg/mL). This association remained significant for outpatient UTI events (highest vs lowest quartile even after excluding those with prior UTI: IRR, 0.42; 95% CI, 0.23-0.77). The direction of association with UTI hospitalization was similar, but not statistically significant (IRR, 0.78; 95% CI, 0.39-1.58)., Limitations: Use of ICD-9 codes to identify outcomes and lack of generalizability to younger populations., Conclusions: High urinary uromodulin levels are associated with lower risk for UTI in older community-dwelling adults independent of traditional UTI risk factors. This finding supports prior laboratory data indicating a protective role of uromodulin against UTI. Further research is needed to understand if this may lead to new treatments to prevent or treat UTI., (Copyright © 2016 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Background: Low urine potassium excretion, as a surrogate for dietary potassium intake, is associated with higher risk for hypertension and cardiovascular disease in a general population. Few studies have investigated the relationship of urine potassium with clinical outcomes in chronic kidney disease (CKD)., Study Design: Longitudinal cohort study., Setting & Participants: The MDRD (Modification of Diet in Renal Disease) Study was a randomized controlled trial (N = 840) conducted in 1989 to 1993 to examine the effects of blood pressure control and dietary protein restriction on kidney disease progression in adults aged 18 to 70 years with CKD stages 2 to 4. This post hoc analysis included 812 participants., Predictor: The primary predictor variable was 24-hour urine potassium excretion, measured at baseline and at multiple time points (presented as time-updated average urine potassium excretion)., Outcomes: Kidney failure, defined as initiation of dialysis therapy or transplantation, was determined from US Renal Data System data. All-cause mortality was assessed using the National Death Index., Results: Median follow-up for kidney failure was 6.1 (IQR, 3.5-11.7) years, with 9 events/100 patient-years. Median all-cause mortality follow-up was 19.2 (IQR, 10.8-20.6) years, with 3 deaths/100 patient-years. Baseline mean urine potassium excretion was 2.39±0.89 (SD) g/d. Each 1-SD higher baseline urine potassium level was associated with an adjusted HR of 0.95 (95% CI, 0.87-1.04) for kidney failure and 0.83 (95% CI, 0.74-0.94) for all-cause mortality. Results were consistent using time-updated average urine potassium measurements., Limitations: Analyses were performed using urine potassium excretion as a surrogate for dietary potassium intake. Results are obtained from a primarily young, nondiabetic, and advanced CKD population and may not be generalizable to the general CKD population., Conclusions: Higher urine potassium excretion was associated with lower risk for all-cause mortality, but not kidney failure., (Copyright © 2016 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Background: Diabetes mellitus and hypertension are risk factors for acute kidney injury (AKI). Whether estimated glomerular filtration rate (eGFR) and urine albumin-creatinine ratio (ACR) remain risk factors for AKI in the presence and absence of these conditions is uncertain., Study Design: Meta-analysis of cohort studies., Setting & Population: 8 general-population (1,285,045 participants) and 5 chronic kidney disease (CKD; 79,519 participants) cohorts., Selection Criteria for Studies: Cohorts participating in the CKD Prognosis Consortium., Predictors: Diabetes and hypertension status, eGFR by the 2009 CKD Epidemiology Collaboration creatinine equation, urine ACR, and interactions., Outcome: Hospitalization with AKI, using Cox proportional hazards models to estimate HRs of AKI and random-effects meta-analysis to pool results., Results: During a mean follow-up of 4 years, there were 16,480 episodes of AKI in the general-population and 2,087 episodes in the CKD cohorts. Low eGFRs and high ACRs were associated with higher risks of AKI in individuals with or without diabetes and with or without hypertension. When compared to a common reference of eGFR of 80mL/min/1.73m(2) in nondiabetic patients, HRs for AKI were generally higher in diabetic patients at any level of eGFR. The same was true for diabetic patients at all levels of ACR compared with nondiabetic patients. The risk gradient for AKI with lower eGFRs was greater in those without diabetes than with diabetes, but similar with higher ACRs in those without versus with diabetes. Those with hypertension had a higher risk of AKI at eGFRs>60mL/min/1.73m(2) than those without hypertension. However, risk gradients for AKI with both lower eGFRs and higher ACRs were greater for those without than with hypertension., Limitations: AKI identified by diagnostic code., Conclusions: Lower eGFRs and higher ACRs are associated with higher risks of AKI among individuals with or without either diabetes or hypertension., (Copyright © 2015 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Background: Acute kidney injury (AKI) is a serious global public health problem. We aimed to quantify the risk of AKI associated with estimated glomerular filtration rate (eGFR), albuminuria (albumin-creatinine ratio [ACR]), age, sex, and race (African American and white)., Study Design: Collaborative meta-analysis., Setting & Population: 8 general-population cohorts (1,285,049 participants) and 5 chronic kidney disease (CKD) cohorts (79,519 participants)., Selection Criteria for Studies: Available eGFR, ACR, and 50 or more AKI events., Predictors: Age, sex, race, eGFR, urine ACR, and interactions., Outcome: Hospitalized with or for AKI, using Cox proportional hazards models to estimate HRs of AKI and random-effects meta-analysis to pool results., Results: 16,480 (1.3%) general-population cohort participants had AKI over a mean follow-up of 4 years; 2,087 (2.6%) CKD participants had AKI over a mean follow-up of 1 year. Lower eGFR and higher ACR were strongly associated with AKI. Compared with eGFR of 80mL/min/1.73m(2), the adjusted HR of AKI at eGFR of 45mL/min/1.73m(2) was 3.35 (95% CI, 2.75-4.07). Compared with ACR of 5mg/g, the risk of AKI at ACR of 300mg/g was 2.73 (95% CI, 2.18-3.43). Older age was associated with higher risk of AKI, but this effect was attenuated with lower eGFR or higher ACR. Male sex was associated with higher risk of AKI, with a slight attenuation in lower eGFR but not in higher ACR. African Americans had higher AKI risk at higher levels of eGFR and most levels of ACR., Limitations: Only 2 general-population cohorts could contribute to analyses by race; AKI identified by diagnostic code., Conclusions: Reduced eGFR and increased ACR are consistent strong risk factors for AKI, whereas associations of AKI with age, sex, and race may be weaker in more advanced stages of CKD., (Copyright © 2015 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Background: Elevated fibroblast growth factor 23 (FGF-23) concentrations are associated with greater risk of cardiovascular events and mortality, especially among people with chronic kidney disease (CKD). Because individuals with CKD are at an increased risk of sudden cardiac death (SCD), we sought to understand whether FGF-23 level is a stronger risk factor for SCD versus non-SCD., Study Design: Cohort study., Setting & Participants: 3,244 participants 65 years or older in the community-based Cardiovascular Health Study., Predictor: Plasma FGF-23 concentrations., Outcomes: We assessed SCD and non-SCD in these analyses. SCD was adjudicated rigorously and was defined as a sudden pulseless condition of cardiac origin in a previously stable person occurring out of hospital or in the emergency department., Measurements: We estimated associations of baseline FGF-23 concentrations with SCD and non-SCD using Cox proportional hazards models after adjustment for demographics, cardiovascular risk factors, comorbid conditions, and kidney function. We also tested whether associations differed by CKD status., Results: During a median follow-up of 8.1 years, there were 118 adjudicated SCD and 570 non-SCD events. After multivariable adjustment for demographics, cardiovascular risk factors, comorbid conditions, and parameters of kidney function, higher FGF-23 concentrations were an independent risk factor for non-SCD (HR [per doubling], 1.17; 95% CI, 1.06-1.30). However, elevated FGF-23 concentrations were not associated independently with SCD (HR [per doubling], 1.07; 95% CI, 0.85-1.35). In stratified analysis by CKD status (36.5% of cohort), doubling of FGF-23 concentrations was associated independently with non-SCD (adjusted HR, 1.26; 95% CI, 1.10-1.45). A similar magnitude of association was observed between FGF-23 level and SCD in the CKD subgroup; however, it was not significant (HR, 1.20; 95% CI, 0.89-1.62)., Limitations: Limited power to detect moderate-sized effects between FGF-23 level and SCD in both the primary and stratified analyses., Conclusions: In this population-based study, FGF-23 level elevations were associated independently with non-SCD. Among individuals with CKD, the associations between FGF-23 level and SCD and non-SCD were similar., (Copyright © 2015 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Blood pressure (BP) is one of the key modifiable risk factors for cardiovascular disease (CVD) both in primary and secondary prevention of disease. In this review, we discuss BP treatment in prevalent CVD and heart failure. Evidence for specific agents based on their neurohormonal effects and evidence for target values for systolic or diastolic BP are covered. The potential adverse effects of overtreatment of BP are also discussed. BP targets for those with CVD should generally be less than 140/90 mm Hg but require individualization of therapy for any further reduction based on the clinical setting., (Copyright © 2015 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

The National Kidney Foundation-Kidney Disease Outcomes Quality Initiative (NKF-KDOQI) guideline for management of dyslipidemia in chronic kidney disease (CKD) was published in 2003. Since then, considerable evidence, including randomized controlled trials of statin therapy in adults with CKD, has helped better define medical treatments for dyslipidemia. In light of the new evidence, KDIGO (Kidney Disease: Improving Global Outcomes) formed a work group for the management of dyslipidemia in patients with CKD. This work group developed a new guideline that contains substantial changes from the prior KDOQI guideline. KDIGO recommends treatment of dyslipidemia in patients with CKD primarily based on risk for coronary heart disease, which is driven in large part by age. The KDIGO guideline does not recommend using low-density lipoprotein cholesterol level as a guide for identifying individuals with CKD to be treated or as treatment targets. Initiation of statin treatment is no longer recommended in dialysis patients. To assist US practitioners in interpreting and applying the KDIGO guideline, NKF-KDOQI convened a work group to write a commentary on this guideline. For the most part, our work group agreed with the recommendations of the KDIGO guideline, although we describe several areas in which we believe the guideline statements are either too strong or need to be more nuanced, areas of uncertainty and inconsistency, as well as additional research recommendations. The target audience for the KDIGO guideline includes nephrologists, primary care practitioners, and non-nephrology specialists such as cardiologists and endocrinologists. As such, we also put the current recommendations into the context of other clinical practice recommendations for cholesterol treatment., (Copyright © 2015 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Background: Cognitive impairment is common in hemodialysis patients and is associated with significant morbidity. Limited information exists about whether cognitive impairment is associated with survival and whether the type of cognitive impairment is important., Study Design: Longitudinal cohort., Setting & Participants: Cognitive function was assessed at baseline and yearly using a comprehensive battery of cognitive tests in 292 prevalent hemodialysis patients., Predictor: Using principal component analysis, individual test results were reduced into 2 domain scores, representing memory and executive function. By definition, each score carried a mean of 0 and SD of 1., Outcomes: Association of each score with all-cause mortality was assessed using Cox proportional hazards models adjusted for demographics and dialysis and cardiovascular (CV) risk factors., Results: Mean age of participants was 63 years, 53% were men, 23% were African American, and 90% had at least a high school education. During a median follow-up of 2.1 (IQR, 1.1-3.7) years, 145 deaths occurred. Each 1-SD better executive function score was associated with a 35% lower hazard of mortality (HR, 0.65; 95% CI, 0.55-0.76). In models adjusting for demographics and dialysis-related factors, this relationship was partially attenuated but remained significant (HR, 0.81; 95% CI, 0.67-0.98), whereas adjustment for CV disease and heart failure resulted in further attenuation (HR, 0.87; 95% CI, 0.72-1.06). Use of time-dependent models showed a similar unadjusted association (HR, 0.62; 95% CI, 0.54-0.72), with the relationship remaining significant after adjustment for demographics and dialysis and CV risk factors (HR, 0.79; 95% CI, 0.66-0.94). Better memory was associated with lower mortality in univariate analysis (HR per 1 SD, 0.82; 95% CI, 0.69-0.96), but not when adjusting for demographics (HR, 1.00; 95% CI, 0.83-1.19)., Limitations: Patients with dementia were excluded from the full battery, perhaps underestimating the strength of the association., Conclusions: Worse executive function and memory are associated with increased risk of mortality. For memory, this association is explained by patient demographics, whereas for executive function, this relationship may be explained in part by CV disease burden., (Copyright © 2015 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Background: Low ankle-brachial index (ABI) is a reflection of atherosclerotic disease, and high ABI is an indicator of calcified vessels. The associations of albuminuria and cystatin C level with incidence of either low or high ABI are unknown., Study Design: Prospective longitudinal cohort study., Setting & Participants: MESA (Multi-Ethnic Study of Atherosclerosis) enrolled community-dwelling adults (N=6,814) aged 45-84 years who were free of clinical cardiovascular disease at baseline., Predictors: Baseline albumin-creatinine ratio (ACR) and serum cystatin C level., Outcomes: Development of low (<0.90), and high (>1.40) ABI using multinomial regression among persons with ABI of 0.90-1.40 at baseline., Results: During 9.8 years of follow-up, 221 and 89 participants progressed to low and high ABIs, respectively. Baseline ACR and cystatin C level were higher among progressors compared with nonprogressors. In multivariable analyses, doubling of ACR was associated with increased risk of progression to low (OR, 1.08; 95% CI, 0.99-1.20) and high (OR, 1.16; 95% CI, 1.01-1.32) ABIs. Compared to the lowest quintile, the highest quintile of ACR had a significantly increased risk of progression to low (OR, 1.79; 95% CI, 1.03-3.12) and high (OR, 2.76; 95% CI, 1.32-5.77) ABIs. Higher cystatin C levels were associated with progression to low (OR per 1-SD greater, 1.12; 95% CI, 1.00-1.26) but not high (OR per 1-SD greater, 1.01; 95% CI, 0.81-1.25) ABI, but the highest quintile of cystatin C was not associated independently with either outcome., Limitations: Single measure of albuminuria and low number of progressors to high ABI., Conclusions: In adults free of clinical cardiovascular disease, albuminuria was a strong independent risk factor for the development of both high and low ABIs, important and different measures of peripheral artery disease., (Copyright © 2014 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Background: Among populations with established chronic kidney disease (CKD), metabolic acidosis is associated with more rapid progression of kidney disease. The association of serum bicarbonate concentrations with early declines in kidney function is less clear., Study Design: Retrospective cohort study., Setting & Participants: 5,810 participants in the Multi-Ethnic Study of Atherosclerosis (MESA) with a baseline estimated glomerular filtration rate (eGFR) > 60mL/min/1.73 m(2) using the CKD-EPI (CKD Epidemiology Collaboration) creatinine-cystatin C equation., Predictors: Serum bicarbonate concentrations., Outcomes: Rapid kidney function decline (eGFR decline > 5% per year) and incident reduced eGFR (eGFR < 60mL/min/1.73 m(2) with minimum rate of eGFR loss of 1 mL/min/1.73 m(2) per year)., Results: Average bicarbonate concentration was 23.2 ± 1.8mEq/L. 1,730 (33%) participants had rapid kidney function decline, and 487 had incident reduced eGFR during follow-up. Each 1-SD lower baseline bicarbonate concentration was associated with 12% higher adjusted odds of rapid kidney function decline (95% CI, 6%-20%) and higher risk of incident reduced eGFR (adjusted incidence rate ratio, 1.11; 95% CI, 1.03-1.20) in models adjusting for demographics, baseline eGFR, albuminuria, and CKD risk factors. The OR for the associations of bicarbonate level < 21 mEq/L relative to 23-24 mEq/L was 1.35 (95% CI, 1.05-1.73) for rapid kidney function decline, and the incidence rate ratio was 1.16 (95% CI, 0.83-1.62) for incident reduced eGFR., Limitations: Cause of metabolic acidosis cannot be determined in this study., Conclusions: Lower serum bicarbonate concentrations are associated independently with rapid kidney function decline independent of eGFR or albuminuria in community-living persons with baseline eGFR > 60 mL/min/1.73 m(2). If confirmed, our findings suggest that metabolic acidosis may indicate either early kidney disease that is not captured by eGFR or albuminuria or may have a causal role in the development of eGFR < 60 mL/min/1.73 m(2)., (Copyright © 2014 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Background: In populations with prevalent chronic kidney disease (CKD), lower serum bicarbonate levels are associated with more rapid CKD progression, but whether lower bicarbonate levels also are associated with risk of incident estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m(2) and CKD progression among community-living persons with predominantly preserved kidney function is unknown., Study Design: Longitudinal observational cohort study., Setting & Participants: Well-functioning community-living elders aged 70-79 years at inception., Predictor: Serum bicarbonate level measured at the time of collection by arterialized venous blood sample using an arterial blood gas analyzer., Outcomes: Change in eGFR over 7 years, and new eGFR < 60 mL/min/1.73 m(2) with a rate of loss of at least 1 mL/min/1.73 m(2) per year., Measurements: Linear and logistic regressions were used to evaluate associations of baseline serum bicarbonate level with change in eGFR and incident eGFR < 60 mL/min/1.73 m(2)., Results: At baseline, mean eGFR was 84 ± 16 (SD)mL/min/1.73 m(2), and serum bicarbonate level was 25.2 ± 1.9 mmol/L. Compared with participants with higher bicarbonate concentrations (23.0-28.0 mmol/L), those with bicarbonate concentrations < 23 mmol/L (n = 85 [8%]) lost eGFR0.55 (95% CI, 0.13-0.97) mL/min/1.73 m(2) per year faster in models adjusted for demographics, CKD risk factors, baseline eGFR, and urine albumin-creatinine ratio. Among the 989 (92%) participants with baseline eGFRs > 60 mL/min/1.73 m(2), 252 (25%) developed incident eGFRs < 60 mL/min/1.73 m(2) at follow-up. Adjusting for the same covariates, participants with bicarbonate concentrations < 23 mmol/L had nearly 2-fold greater odds of incident eGFRs < 60 mL/min/1.73 m(2) (OR, 1.72; 95% CI, 0.97-3.07) compared with those with higher bicarbonate concentrations., Limitations: Only 2 measurements of kidney function separated by 7 years and loss to follow-up due to intervening mortality in this elderly population., Conclusions: Lower serum bicarbonate concentrations are associated independently with decline in eGFR and incident eGFR < 60 mL/min/1.73 m(2) in community-living older persons. If confirmed, serum bicarbonate levels may give insight into kidney tubule health in persons with preserved eGFRs and suggest a possible new target for intervention to prevent CKD development., (Published by Elsevier Inc.)

Background: Kidney damage and reduced kidney function are potent risk factors for heart failure, but existing studies are limited to assessing albuminuria or estimated glomerular filtration rate (eGFR). We evaluated the associations of levels of urinary biomarkers of kidney tubular injury (interleukin 18 [IL-18] and kidney injury molecule 1 [KIM-1]) with future risk of heart failure., Study Design: Retrospective cohort study., Setting & Participants: 2,917 participants without heart failure in the Health, Aging, and Body Composition (Health ABC) cohort., Predictors: Ratios of urine KIM-1, IL-18, and albumin to creatinine (KIM-1:Cr, IL-18:Cr, and ACR, respectively)., Outcomes: Incident heart failure over a median follow-up of 12 years., Results: Median values of each marker at baseline were 812 (IQR, 497-1,235)pg/mg for KIM-1:Cr, 31 (IQR, 19-56)pg/mg for IL-18:Cr, and 8 (IQR, 5-19) mg/g for ACR. 596 persons developed heart failure during follow-up. The top quartile of KIM-1:Cr was associated with risk of incident heart failure after adjustment for baseline eGFR, heart failure risk factors, and ACR (HR, 1.32; 95% CI, 1.02-1.70) in adjusted multivariate proportional hazards models. The top quartile of IL-18:Cr also was associated with heart failure in a model adjusted for risk factors and eGFR (HR, 1.35; 95% CI, 1.05-1.73), but was attenuated by adjustment for ACR (HR, 1.15; 95% CI, 0.89-1.48). The top quartile of ACR had a stronger adjusted association with heart failure (HR, 1.96; 95% CI, 1.53-2.51)., Limitations: Generalizability to other populations is uncertain., Conclusions: Higher urine KIM-1 concentrations were associated independently with incident heart failure risk, although the associations of higher ACR were of stronger magnitude., (Published by Elsevier Inc.)

Background: Higher urine albumin-creatinine ratio (ACR) is associated with cardiovascular disease (CVD) events, an association that is stronger than that between spot urine albumin on its own and CVD. Urine creatinine excretion is correlated with muscle mass, and low muscle mass also is associated with CVD. Whether low urine creatinine concentration in the denominator of the ACR contributes to the association of ACR with CVD is uncertain., Study Design: Prospective cohort study., Setting & Participants: 6,770 community-living individuals without CVD., Predictors: Spot urine albumin concentration, the reciprocal of the urine creatinine concentration (1/UCr), and ACR., Outcome: Incident CVD events., Results: During a mean of 7.1 years of follow-up, 281 CVD events occurred. Geometric mean values for spot urine creatinine concentration, urine albumin concentration, and ACR were 95 ± 2 (SD) mg/dL, 0.7 ± 3.7 mg/dL, and 7.0 ± 3.1 mg/g. Urine creatinine concentration was lower in older, female, and low-weight individuals. Adjusted HRs per 2-fold higher increment in each urinary measure with CVD events were similar (1/UCr: 1.07 [95% CI, 0.94-1.22]; urine albumin concentration: 1.08 [95% CI, 1.01-1.14]; and ACR: 1.11 [95% CI, 1.04-1.18]). ACR ≥10 mg/g was associated more strongly with CVD events in individuals with low weight (HR for lowest vs highest tertile: 4.34 vs 1.97; P for interaction = 0.006). Low weight also modified the association of urine albumin concentration with CVD (P for interaction = 0.06), but 1/UCr did not (P for interaction = 0.9)., Limitations: We lacked 24-hour urine data., Conclusions: Although ACR is associated more strongly with CVD events in persons with low body weight, this association is not driven by differences in spot urine creatinine concentration. Overall, the associations of ACR with CVD events appear to be driven primarily by urine albumin concentration and less by urine creatinine concentration., (Published by Elsevier Inc.)

Background: Although dialysis patients are at high risk of stroke and have a high burden of cognitive impairment, there are few reports of anatomic brain findings in the hemodialysis population. Using magnetic resonance imaging of the brain, we compared the prevalence of brain abnormalities in hemodialysis patients with that in a control population without known kidney disease., Study Design: Cross-sectional cohort., Setting & Participants: 45 maintenance hemodialysis patients and 67 controls without reported kidney disease, both without history of known stroke., Predictor: The primary predictor was dialysis status. Covariates included demographics (age, race, and sex), vascular risk factors (diabetes and hypertension), and cardiovascular disease (coronary artery disease and congestive heart failure)., Outcomes: Magnetic resonance imaging of the brain features, including severity of white matter disease and cerebral atrophy (sulcal prominence and ventricular atrophy), hippocampal size, and small-/large-vessel infarcts., Measurements: Semiquantitative scale (0-9 for white matter disease and cerebral atrophy, 0-3 for hippocampal size) and infarct prevalence., Results: Mean ages of hemodialysis patients and controls were 55 ± 17 (SD) and 53 ± 13 years, respectively. In comparison to controls, hemodialysis patients had more severe white matter disease (1.6 vs 0.7) and cerebral atrophy (sulcal prominence, 2.3 vs 0.6; ventricular enlargement, 2.3 vs 0.9; hippocampal size, 1.3 vs 1.0), with all P < 0.001. In multivariable analyses, hemodialysis status was associated independently with worse white matter disease and atrophy grades. Hemodialysis patients also had a higher prevalence of small- (17.8%) and large- (7.8%) vessel infarcts than controls (combined, 22% vs 0%; P < 0.001)., Limitations: The dialysis cohort likely is healthier than the overall US hemodialysis population, partly limiting generalizability., Conclusions: Hemodialysis patients have more white matter disease and cerebral atrophy compared with controls without known kidney disease. Hemodialysis patients also have a high prevalence of unrecognized infarcts., (Copyright © 2013 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Background: Whether elevations in levels of urinary biomarkers of tubular injury (urine neutrophil gelatinase-associated lipocalin [NGAL] and kidney injury molecule 1 [KIM-1]) are associated with future risk of kidney disease has not been investigated., Study Design: 1:1 nested case-control study., Setting & Participants: 686 participants in the Multi-Ethnic Study of Atherosclerosis (MESA)., Predictor: NGAL and KIM-1 were measured at baseline, expressed as log-transformed continuous variables, and categorized into deciles., Outcomes: Kidney function was estimated by cystatin C level using the CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) equation. Incident CKD stage 3 was defined as estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m(2) and an eGFR decrease >1 mL/min/1.73 m(2) per year, and rapid kidney function decrease was defined as decrease ≥3 mL/min/1.73 m(2) per year., Measurements: Cases were defined as persons with eGFR >60 mL/min/1.73 m(2) who subsequently developed incident CKD stage 3 and/or had rapid kidney function decrease by the MESA year-5 visit. Controls were matched for age, sex, race, diabetes, and baseline eGFR. We adjusted for age, hypertension, and presence of albuminuria (albumin-creatinine ratio ≥30 mg/g)., Results: Of 343 cases, 145 had incident CKD stage 3, 141 had rapid kidney function decrease, and 57 had both. Mean eGFR for controls was 81 ± 10 mL/min/1.73 m(2) at baseline and 80 ± 10 mL/min/1.73 m(2) at follow-up compared with 82 ± 13 and 58 ± 10 mL/min/1.73 m(2) for cases. Each doubling of KIM-1 level (in picograms per milliliter) was associated with an OR of 1.15 (95% CI, 1.02-1.29) for incident CKD stage 3 and/or rapid kidney function decrease. Compared with the lowest 90%, the highest decile of KIM-1 level was associated with an OR of 2.02 (95% CI, 1.15-3.56) for the outcome; these associations were independent of albuminuria. NGAL levels (in nanograms per milliliter) were not associated with incident CKD stage 3 and/or rapid kidney function decrease (OR, 1.04; 95% CI, 0.99-1.10). Results were similar when KIM-1 and NGAL levels were standardized for urine creatinine., Limitations: The case-control design limits the ability to account for persons who died or were not available for follow-up., Conclusions: Urinary KIM-1 level is associated with future risk of kidney disease independent of albuminuria. Urinary biomarkers of tubular injury are a promising tool for identifying persons at risk of CKD., (Copyright © 2012 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Background: Cognitive impairment is common but often undiagnosed in patients with end-stage renal disease, in part reflecting limited validated and easily administered tools to assess cognitive function in dialysis patients. Accordingly, we assessed the utility of the Kidney Disease Quality of Life Cognitive Function (KDQOL-CF) scale in comparison to an extensive neuropsychological battery, building on a prior assessment of this potential cognitive screen., Study Design: Cross-sectional cohort., Setting & Participants: Maintenance hemodialysis patients at 6 Boston area dialysis units were administered an extensive neurocognitive battery and the KDQOL-CF at the beginning of a hemodialysis session., Predictors: KDQOL-CF score, depression symptom burden, and demographic and clinical characteristics., Outcomes: Neurocognitive performance classified into executive function and memory domains, determined using principal components analysis., Measurements: Univariate and multivariable linear regression models adjusting for age, sex, race, and end-stage renal disease cause were used to evaluate the association between KDQOL-CF score and cognitive performance, and test metrics were determined for a KDQOL-CF cutoff score of 60 or less from a maximum score of 100., Results: For 168 prevalent hemodialysis patients, KDQOL-CF score was 76 ± 19 and 40 (24%) had scores of 60 or less, consistent with self-identified worse cognitive performance. There was no significant correlation between KDQOL-CF score and either memory (P = 0.2 and P = 0.3) or executive function (P = 0.1 and P = 0.4) in univariate and multivariable models, respectively. There was a strong correlation between higher KDQOL-CF score and fewer depression symptoms (P < 0.001). Sensitivity of the KDQOL-CF was poor (range, 0.28-0.36), with modest specificity (range, 0.77-0.81) for identifying worse executive function and memory., Limitations: Cross-sectional study, modest population size, and abbreviated gold-standard cognitive battery., Conclusions: The KDQOL-CF is a poor determinant of neurocognitive performance in hemodialysis patients, with limited sensitivity. To assess cognitive impairment in hemodialysis patients, better screening tests are essential., (Copyright © 2012 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Background: The strength and direction of the associations between inflammation and coagulation biomarkers with kidney disease onset and progression remain unclear, especially in a population-based setting., Study Design: Prospective observational study., Setting & Participants: 4,966 participants from the Multi-Ethnic Study of Atherosclerosis (MESA) with a cystatin C-based estimate of glomerular filtration rate (eGFR(cys)) >60 mL/min/1.73 m(2) and at least one follow-up measurement of kidney function. All participants were free of cardiovascular disease at entry., Predictor: We evaluated the associations of C-reactive protein (CRP), interleukin 6 (IL-6), fibrinogen, factor VIII, and d-dimer levels with kidney function decrease., Outcomes & Measurements: Kidney function decrease was assessed primarily by repeated measurements of eGFR(cys) over 5 years. Rapid decrease in kidney function was defined as eGFR decrease >3 mL/min/1.73 m(2) per year. Incident low eGFR was defined as the onset of eGFR(cys) <60 mL/min/1.73 m(2) at any follow-up examination and eGFR(cys) decrease ≥1 mL/min/1.73 m(2) per year., Results: Mean age was 60 years, 39% were white, 52% were women, and 11% had diabetes. Mean eGFR(cys) was 96 mL/min/1.73 m(2) and 7% had albuminuria. Median follow-up was 4.77 years. Higher factor VIII levels (per 1 standard deviation [SD] of biomarker) had the strongest association with kidney function decrease (β = -0.25; 95% CI, -0.38 to -0.12; P < 0.001), followed by IL-6 (β = -0.16; 95% CI, -0.29 to -0.03; P = 0.01), CRP (β = -0.09; 95% CI, -0.22 to 0.03; P = 0.1), and fibrinogen levels (β = -0.09; 95% CI, -0.22 to 0.04; P = 0.2). Each 1-SD higher concentration of IL-6 (OR, 1.15; 95% CI, 1.07-1.23), factor VIII (OR, 1.11; 95% CI, 1.03-1.18), and CRP (OR, 1.09; 95% CI, 1.02-1.16) at baseline was associated significantly with rapid kidney function decrease. Only IL-6 level was associated significantly with incident low eGFR (OR, 1.09; 95% CI, 1.00-1.19)., Limitations: Observational study design and absence of measured GFR., Conclusions: Inflammation and coagulation biomarkers are associated with decreasing kidney function in ambulatory adults without established cardiovascular disease or chronic kidney disease., (Copyright © 2012 National Kidney Foundation, Inc. All rights reserved.)

Background: Moderate kidney disease may predispose to infection. We sought to determine whether decreased kidney function, estimated by serum cystatin C level, was associated with the risk of infection-related hospitalization in older individuals., Study Design: Cohort study., Setting & Participants: 5,142 Cardiovascular Health Study (CHS) participants with measured serum creatinine and cystatin C and without estimated glomerular filtration rate (eGFR) <15 mL/min/1.73 m(2) at enrollment., Predictor: The primary exposure of interest was eGFR using serum cystatin C level (eGFR(SCysC))., Outcome: Infection-related hospitalizations during a median follow-up of 11.5 years., Results: In adjusted analyses, eGFR(SCysC) categories of 60-89, 45-59, and 15-44 mL/min/1.73 m(2) were associated with 16%, 37%, and 64% greater risk of all-cause infection-related hospitalization, respectively, compared with eGFR(SCysC) ≥90 mL/min/1.73 m(2). When cause-specific infection was examined, eGFR(SCysC) of 15-44 mL/min/1.73 m(2) was associated with an 80% greater risk of pulmonary and 160% greater risk of genitourinary infection compared with eGFR(SCysC) ≥90 mL/min/1.73 m(2)., Limitations: No measures of urinary protein, study limited to principal discharge diagnosis., Conclusions: Lower kidney function, estimated using cystatin C level, was associated with a linear and graded risk of infection-related hospitalization. These findings highlight that even moderate degrees of decreased kidney function are associated with clinically significant higher risks of serious infection in older individuals., (Copyright © 2012 National Kidney Foundation, Inc. All rights reserved.)

Background: The association of subclinical vascular disease and early declines in kidney function has not been well studied., Study Design: Prospective cohort study., Setting & Participants: Multi-Ethnic Study of Atherosclerosis (MESA) participants with estimated glomerular filtration rate (eGFR) ≥60 mL/min/1.73 m(2) with follow-up of 5 years., Predictors: Pulse pressure, small (SAE) and large arterial elasticity (LAE), and flow-mediated dilation., Outcomes: Kidney function decline., Measurements: SAE and LAE were measured by pulse contour analysis of the radial artery. Kidney function was assessed by eGFR based on serum creatinine (eGFR(SCr)) and cystatin C (eGFR(SCysC))., Results: For 4,853 adults, higher pulse pressure and lower SAE and LAE had independent and linear associations with faster rates of kidney function decline. Compared with persons with pulse pressure of 40-50 mm Hg, eGFR(SCysC) declines were 0.29 (P = 0.006), 0.56 (P < 0.001), and 0.91 (P < 0.001) mL/min/1.73 m(2)/y faster in persons with pulse pressure of 50-60, 60-70, and >70 mm Hg, respectively. Compared with the highest quartile of SAE (most elastic), eGFR(SCysC) declines were 0.26 (P = 0.009), 0.35 (P = 0.001), and 0.70 (P < 0.001) mL/min/1.73 m(2)/y faster for the second, third, and fourth quartiles, respectively. For LAE, compared with the highest quartile, eGFR(SCysC) declines were 0.28 (P = 0.004), 0.58 (P < 0.001), and 0.83 (P < 0.001) mL/min/1.73 m(2)/y faster for each decreasing quartile of LAE. Findings were similar for eGFR(SCr). In contrast, for 2,997 adults with flow-mediated dilation and kidney function measures, flow-mediated dilation was not associated significantly with kidney function decline. For every 1-standard deviation greater flow-mediated dilation, eGFR(SCysC) and eGFR(SCr) changed by 0.05 (P = 0.3) and 0.06 mL/min/1.73 m(2)/y (P = 0.04), respectively., Limitations: We had no direct measure of GFR, in common with nearly all large population-based studies., Conclusions: Higher pulse pressure and lower arterial elasticity, but not flow-mediated dilation, were associated linearly and independently with faster kidney function decline in persons with eGFR ≥60 mL/min/1.73 m(2). Future studies should investigate whether treatments to decrease the stiffness of large and small arteries may slow the rate of kidney function loss., (Copyright © 2011 National Kidney Foundation, Inc. All rights reserved.)

Background: Hemodialysis patients have an elevated risk of sudden cardiac death. Although the efficacy of β-blockers for the prevention of sudden cardiac death has been proven in the general population, little evidence exists in patients with kidney failure., Study Design: Post hoc analysis of the Hemodialysis (HEMO) Study., Setting & Participants: Participants enrolled in the HEMO Study from May 1995 to February 2001., Intervention: β-Blocker use ascertained through self-reported questionnaires and dialysis clinic charts., Outcomes: Sudden cardiac death adjudicated by a committee as a secondary outcome of interest., Measurements: We used Cox proportional hazards regression models, competing risk survival analysis, propensity score matching, and covariate adjustment to study the association of β-blockers with sudden cardiac death., Results: 1,747 patients were included in this study, and 521 were on β-blocker therapy at baseline. Mean age was 58 years, 57% were women, and 39% had ischemic heart disease (IHD) at baseline. Baseline β-blocker use was not associated with lower risk of sudden cardiac death in univariate (cause-specific HR, 0.89; 95% CI, 0.64-1.24), multivariable (cause-specific HR, 0.87; 95% CI, 0.62-1.22), or propensity-matched (cause-specific HR, 0.91; 95% CI, 0.55-1.50) analyses. There was a significant interaction between β-blocker use and sudden cardiac death (interaction P = 0.03) in patients with (cause-specific HR, 0.65; 95% CI, 0.42-1.01) and without IHD (cause-specific HR, 1.61; 95% CI, 0.92-2.80)., Limitations: Observational nature of the study., Conclusions: In hemodialysis patients without preexisting IHD, β-blocker use was not associated with lower risk of sudden cardiac death. However, there was a trend toward benefit in those with IHD., (Copyright © 2011 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)