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Background and objectives Atrial fibrillation (AF) is common in CKD and associated with poor kidney and cardiovascular outcomes. Prediction models developed using novel methods may be useful to identify patients with CKD at highest risk of incident AF. We compared a previously published prediction model with models developed using machine learning methods in a CKD population. Design, setting, participants, & measurements We studied 2766 participants in the Chronic Renal Insufficiency Cohort study without prior AF with complete cardiac biomarker (N-terminal pro-B-type natriuretic peptide and high-sensitivity troponin T) and clinical data. We evaluated the utility of machine learning methods as well as a previously validated clinical prediction model (Cohorts for Heart and Aging Research in Genomic Epidemiology [CHARGE]-AF, which included 11 predictors, using original and re-estimated coefficients) to predict incident AF. Discriminatory ability of each model was assessed using the ten-fold cross-validated C-index; calibration was evaluated graphically and with the Gronnesby and Borgan test. Results Mean (SD) age of participants was 57 (11) years, 55% were men, 38% were Black, and mean (SD) eGFR was 45 (15) ml/min per 1.73 m2; 259 incident AF events occurred during a median of 8 years of follow-up. The CHARGE-AF prediction equation using original and re-estimated coefficients had C-indices of 0.67 (95% confidence interval, 0.64 to 0.71) and 0.67 (95% confidence interval, 0.64 to 0.70), respectively. A likelihood-based boosting model using clinical variables only had a C-index of 0.67 (95% confidence interval, 0.64 to 0.70); adding N-terminal pro-B-type natriuretic peptide, high-sensitivity troponin T, or both biomarkers improved the C-index by 0.04, 0.01, and 0.04, respectively. In addition to N-terminal pro-B-type natriuretic peptide and high-sensitivity troponin T, the final model included age, non-Hispanic Black race/ethnicity, Hispanic race/ethnicity, cardiovascular disease, chronic obstructive pulmonary disease, myocardial infarction, peripheral vascular disease, use of angiotensin-converting enzyme inhibitor/angiotensin receptor blockers, calcium channel blockers, diuretics, height, and weight. Conclusions Using machine learning algorithms, a model that included 12 standard clinical variables and cardiac-specific biomarkers N-terminal pro-B-type natriuretic peptide and high-sensitivity troponin T had moderate discrimination for incident AF in a CKD population.

BACKGROUND: Recent work suggests that dysregulated cellular metabolism may play a key role in the pathogenesis of autosomal dominant polycystic kidney disease (ADPKD). The TAME-PKD clinical trial is testing the safety, tolerability, and efficacy of metformin, a regulator of cell metabolism, in patients with ADPKD. This study investigates the cross-sectional association of urinary metabolic biomarkers with ADPKD severity among TAME-PKD trial participants at baseline. METHODS: Concentrations of total protein, targeted metabolites (lactate, pyruvate, succinate, and cAMP), and key glycolytic enzymes (pyruvate kinase M2 [PKM2], lactate dehydrogenase A [LDHA], and pyruvate dehydrogenase kinase 1 [PDK1]) were measured by ELISA, enzymatic assays, and immunoblotting in baseline urine specimens of 95 TAME-PKD participants. These analytes, normalized by urinary creatinine or osmolality to estimate excretion, were correlated with patients’ baseline height-adjusted total kidney volumes (htTKVs) by MRI and eGFR. Additional analyses were performed, adjusting for participants’ age and sex, using multivariable linear regression. RESULTS: Greater htTKV correlated with lower eGFR (r=−0.39; P=0.0001). Urinary protein excretion modestly correlated with eGFR (negatively) and htTKV (positively). Urinary cAMP normalized to creatinine positively correlated with eGFR. Among glycolytic enzymes, PKM2 and LDHA excretion positively correlated with htTKV, whereas PKM2 excretion negatively correlated with eGFR. These associations remained significant after adjustments for age and sex. Moreover, in adjusted models, succinate excretion was positively associated with eGFR, and protein excretion was more strongly associated with both eGFR and htTKV in patients

BACKGROUND: Autosomal dominant polycystic kidney disease (ADPKD) has been associated with metabolic disturbances characterized by downregulation of AMP-activated protein kinase (AMPK), a critical sensor of the cellular energy status. Therapeutic activation of AMPK by metformin could inhibit cyst enlargement by inhibition of both the mammalian target of rapamycin pathway and fluid secretion via the CFTR chloride channel. METHODS: We designed a phase-2, randomized, placebo-controlled, clinical trial to assess the safety, tolerability, and efficacy of metformin on total kidney volume in adults without diabetes (age 18–60 years) with ADPKD and eGFR of ≥50 ml/min per 1.73 m(2). There were no eligibility criteria relating to kidney volume. In addition to demographics and clinical/family history, baseline parameters included eGFR, total kidney and liver volumes measured by MRI, and patient-reported outcomes were ascertained by the Medical Outcomes Study Short Form-36, the Gastrointestinal Safety Rating Scale, and the HALT-PKD pain questionnaire. RESULTS: We successfully randomized 97 participants recruited from two university-based clinical sites in Baltimore and Boston. The mean age of participants was 41.9 years, 72% were female, and 94% of participants were White. The majority of study participants had early stage disease, with a mean eGFR of 86.8±19.0 ml/min per 1.73 m(2). Approximately half of the study participants (48%) were classified as high risk for progression (Mayo imaging classes 1C, 1D, or 1E). There was no correlation between kidney and/or liver size and health-related quality of life (HRQoL) or gastrointestinal symptom severity. CONCLUSIONS: We report successful recruitment in this ongoing, novel, clinical trial of metformin in ADPKD, with a study sample comprising patients with early stage disease and nearly a half of participants considered at high estimated risk for progression. Participants reported a low gastrointestinal symptom burden at baseline, and HRQoL similar to that of the general population, with no differences in symptoms or HRQoL related to organomegaly. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: Metformin as a Novel Therapy for Autosomal Dominant Polycystic Kidney Disease (TAME), NCT02656017

Background: A malignant subphenotype of left ventricular hypertrophy (LVH) has been described, in which minimal elevations in cardiac biomarkers identify individuals with LVH at high risk for developing heart failure (HF). We tested the hypothesis that a higher prevalence of malignant LVH among blacks may contribute to racial disparities in HF risk. Methods: Participants (n=15 710) without prevalent cardiovascular disease were pooled from 3 population-based cohort studies, the ARIC Study (Atherosclerosis Risk in Communities), the DHS (Dallas Heart Study), and the MESA (Multi-Ethnic Study of Atherosclerosis). Participants were classified into 3 groups: those without ECG-LVH, those with ECG-LVH and normal biomarkers (hs-cTnT (high sensitivity cardiac troponin-T) Results: Over the 10-year follow-up period, HF occurred in 512 (3.3%) participants, with 5.2% in black men, 3.8% in white men, 3.2% in black women, and 2.2% in white women. The prevalence of malignant LVH was 3-fold higher among black men and women versus white men and women. Compared with participants without LVH, the adjusted hazard ratio for HF was 2.8 (95% CI, 2.1–3.5) in those with malignant LVH and 0.9 (95% CI, 0.6–1.5) in those with LVH and normal biomarkers, with similar findings in each race/sex subgroup. Mediation analyses indicated that 33% of excess hazard for HF among black men and 11% of the excess hazard among black women was explained by the higher prevalence of malignant LVH in blacks. Of black men who developed HF, 30.8% had malignant LVH at baseline, with a corresponding population attributable fraction of 0.21. The proportion of HF cases occurring among those with malignant LVH, and the corresponding population attributable fraction, were intermediate and similar among black women and white men and lowest among white women. Conclusions: A higher prevalence of malignant LVH may in part explain the higher risk of HF among blacks versus whites. Strategies to prevent development or attenuate risk associated with malignant LVH should be investigated as a strategy to lower HF risk and mitigate racial disparities.

Background The secretion of organic solutes by the proximal tubules is an essential intrinsic kidney function. However, the clinical significance of the kidney's clearance of tubular secretory solutes is uncertain. Methods In this prospective cohort study, we evaluated 3416 participants with CKD from the Chronic Renal Insufficiency Cohort (CRIC) study. We measured plasma and 24-hour urine concentrations of endogenous candidate secretory solutes at baseline, using targeted liquid chromatography-tandem mass spectrometry. The study defined CKD progression by a ≥50% decline in the eGFR, initiation of maintenance dialysis, or kidney transplantation. We used Cox proportional hazards regression to test associations of secretory-solute clearances with CKD progression and mortality, adjusting for eGFR, albuminuria, and other confounding characteristics. Results Participants in this ancillary study had a mean age of 58 years and 41% were black; the median eGFR was 43 ml/min per 1.73 m2. After adjustment, lower kidney clearances of six solutes-kynurenic acid, pyridoxic acid, indoxyl sulfate, xanthosine, isovalerylglycine, and cinnamoylglycine-were associated with significantly greater risks of CKD progression, with clearance of kynurenic acid, a highly protein-bound solute, having the strongest association. Lower clearances of isovalerylglycine, tiglylglycine, hippurate, and trimethyluric acid were significantly associated with all-cause mortality after adjustment. Conclusions We found lower kidney clearances of endogenous secretory solutes to be associated with CKD progression and all-cause mortality, independent of eGFR and albuminuria. This suggests that tubular clearance of secretory solutes provides additional information about kidney health beyond measurements of glomerular function alone.

Background: Risk for atherosclerotic cardiovascular disease was a novel consideration for antihypertensive medication initiation in the 2017 American College of Cardiology/American Heart Association Blood Pressure (BP) guideline. Whether biomarkers of chronic myocardial injury (high-sensitivity cardiac troponin T ≥6 ng/L] and stress (N-terminal pro-B-type natriuretic peptide [NT-proBNP] ≥100 pg/mL) can inform cardiovascular (CV) risk stratification and treatment decisions among adults with elevated BP and hypertension is unclear. Methods: Participant-level data from 3 cohort studies (Atherosclerosis Risk in Communities Study, Dallas Heart Study, and Multiethnic Study of Atherosclerosis) were pooled, excluding individuals with prevalent CV disease and those taking antihypertensive medication at baseline. Participants were analyzed according to BP treatment group from the 2017 American College of Cardiology/American Heart Association BP guideline and those with high BP (120 to 159/ Results: The study included 12 987 participants (mean age, 55 years; 55% women; 21.5% with elevated high-sensitivity cardiac troponin T; 17.7% with elevated NT-proBNP) with 825 incident CV events over 10-year follow-up. Participants with elevated BP or hypertension not recommended for antihypertensive medication with versus without either elevated high-sensitivity cardiac troponin T or NT-proBNP had a 10-year CV incidence rate of 11.0% and 4.6%, with a 10-year number needed to treat to prevent 1 event for intensive BP lowering of 36 and 85, respectively. Among participants with stage 1 or stage 2 hypertension recommended for antihypertensive medication with BP Conclusions: Elevations in high-sensitivity cardiac troponin T or NT-proBNP identify individuals with elevated BP or hypertension not currently recommended for antihypertensive medication who are at high risk for CV events. The presence of nonelevated biomarkers, even in the setting of stage 1 or stage 2 hypertension, was associated with lower risk. Incorporation of biomarkers into risk assessment algorithms may lead to more appropriate matching of intensive BP control with patient risk.

BACKGROUND AND OBJECTIVES: In autosomal dominant polycystic kidney disease (ADPKD), the GFR often remains normal despite significant nephron loss. Proximal tubular secretory clearance may be reduced in ADPKD before detectable changes in GFR. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We used targeted mass spectrometry to quantify secretory solutes from blood and urine samples from 31 patients with ADPKD and preserved GFR (mean eGFR =111±11 ml/min per 1.73 m(2)) and 25 healthy control individuals as well as from 95 patients with ADPKD and reduced GFR (mean eGFR =53±21 ml/min per 1.73 m(2)) and 92 individuals with non-ADPKD CKD. We used linear regression to compare the fractional excretion of each solute between ADPKD and control groups. Among 112 patients with ADPKD, we used linear regression to determine associations of solute fractional excretion with height-adjusted total kidney volume. RESULTS: After adjusting for demographics, clinical characteristics, and kidney function measures, the fractional excretions of three secretory solutes were lower in patients with ADPKD and preserved GFR compared with healthy individuals: 52% lower cinnamoylglycine excretion (95% confidence interval, 24% to 70%), 53% lower tiglylglycine excretion (95% confidence interval, 23% to 71%), and 91% lower xanthosine excretion (95% confidence interval, 83% to 95%). In addition to lower excretions of tiglylglycine and xanthosine, patients with ADPKD and reduced GFR also demonstrated 37% lower dimethyluric acid excretion (95% confidence interval, 21% to 50%), 58% lower hippurate excretion (95% confidence interval, 48% to 66%), 48% lower isovalerylglycine excretion (95% confidence interval, 37% to 56%), and 31% lower pyridoxic acid excretion (95% confidence interval, 16% to 42%) compared with patients with non-ADPKD CKD and comparable eGFR. Among patients with ADPKD, solute fractional excretions were not associated with differences in kidney volume. CONCLUSIONS: Patients with ADPKD and preserved and reduced GFR demonstrate lower tubular secretory solute excretion compared with healthy controls and patients with non-ADPKD CKD. Our results suggest that tubular secretion is impaired in ADPKD independent of GFR.

Introduction: Heart failure (HF) is a leading contributor of cardiovascular morbidity and mortality in the chronic kidney disease (CKD) population. While risk equations such as the pooled cohort equations to prevent HF (PCP-HF) have been validated in the general population, no such tools have been evaluated in CKD-specific cohorts. Strategies for identification of individuals with CKD at higher risk of HF are needed. Methods: Among black and white participants with CKD stages 2-4 enrolled in the CRIC Study, we included individuals between the ages of 30-79 without baseline cardiovascular disease. We assessed model performance of the PCP-HF to predict incident HF and recalibrated the PCP-HF in the CKD population (PCP-HF CKD ). Given that indices of kidney function are associated with HF, we examined the contribution of estimated glomerular filtration rate (eGFR) and urinary albumin-to-creatinine ratio (UACR) to PCP-HF CKD by change in C-statistic, net reclassification index (NRI) and integrated discrimination index (IDI). Results: Among 2328 participants, mean (SD) baseline eGFR was 46 (15) ml/min/1.73m2 and median (IQR) UACR was 37 (7, 381) mg/g. Over 9.5 years of follow-up, 336 incident HF events occurred. The PCP-HF equations systematically under-predicted HF risk in participants with CKD (C-statistic CKD had good discrimination and calibration (C-statistic 0.75-0.78), except in black women (0.61). Addition of UACR, but not eGFR, to the PCP-HF CKD improved model calibration (Figure) and performance in all race-sex groups (delta C-statistic 0.03-0.11, NRI and IDI values p Conclusions: Routinely available clinical data in patients with CKD can reliably predict incident HF. Further study is needed to examine whether implementation of the modified PCP-HF CKD risk prediction equation into clinical practice can improve HF prevention and patient outcomes.

Background Current strategies for cardiovascular disease ( CVD ) risk assessment focus on 10‐year or longer timeframes. Shorter‐term CVD risk is also clinically relevant, particularly for high‐risk occupations, but is under‐investigated. Methods and Results We pooled data from participants in the ARIC (Atherosclerosis Risk in Communities study), MESA (Multi‐Ethnic Study of Atherosclerosis), and DHS (Dallas Heart Study), free from CVD at baseline (N=16 581). Measurements included N‐terminal pro‐B‐type natriuretic peptide (>100 pg/mL prospectively defined as abnormal); high‐sensitivity cardiac troponin T (abnormal >5 ng/L); high‐sensitivity C‐reactive protein (abnormal >3 mg/L); left ventricular hypertrophy by ECG (abnormal if present); carotid intima‐media thickness, and plaque (abnormal >75th percentile for age and sex or presence of plaque); and coronary artery calcium (abnormal >10 Agatston U). Each abnormal test result except left ventricular hypertrophy by ECG was independently associated with increased 3‐year risk of global CVD (myocardial infarction, stroke, coronary revascularization, incident heart failure, or atrial fibrillation), even after adjustment for traditional CVD risk factors and the other test results. When a simple integer score counting the number of abnormal tests was used, 3‐year multivariable‐adjusted global CVD risk was increased among participants with integer scores of 1, 2, 3, and 4, by ≈2‐, 3‐, 4.5‐ and 8‐fold, respectively, when compared with those with a score of 0. Qualitatively similar results were obtained for atherosclerotic CVD (fatal or non‐fatal myocardial infarction or stroke). Conclusions A strategy incorporating multiple biomarkers and atherosclerosis imaging improved assessment of 3‐year global and atherosclerotic CVD risk compared with a standard approach using traditional risk factors.

Background The Kansas City Cardiomyopathy Questionnaire ( KCCQ ) is a measure of heart failure ( HF ) health status. Worse KCCQ scores are common in patients with chronic kidney disease ( CKD ), even without diagnosed heart failure ( HF ). Elevations in the cardiac biomarkers GDF‐15 (growth differentiation factor‐15), galectin‐3, sST2 (soluble suppression of tumorigenesis‐2), hsTnT (high‐sensitivity troponin T), and NT ‐pro BNP (N‐terminal pro‐B‐type natriuretic peptide) likely reflect subclinical HF in CKD . Whether cardiac biomarkers are associated with low KCCQ scores is not known. Methods and Results We studied participants with CKD without HF in the multicenter prospective CRIC (Chronic Renal Insufficiency Cohort) Study. Outcomes included (1) low KCCQ score KCCQ score to KCCQ scores. Among 2873 participants, GDF‐15 (adjusted odds ratio 1.42 per SD ; 99% CI , 1.19–1.68) and galectin‐3 (1.28; 1.12–1.48) were significantly associated with KCCQ scores NT ‐pro BNP were not significantly associated with KCCQ scores KCCQ ≥75 at year 1, GDF‐15 (adjusted hazard ratio, 1.36 per SD ; 99% CI , 1.12–1.65), hsTnT (1.20; 1.01–1.44), and NT ‐pro BNP (1.30; 1.08–1.56) were associated with incident decline in KCCQ to KCCQ decline. Conclusions Among participants with CKD without clinical HF , GDF‐15, galectin‐3, NT ‐pro BNP , and hsTnT were associated with low KCCQ either at baseline or during follow‐up. Our findings show that elevations in cardiac biomarkers reflect early symptomatic changes in HF health status in CKD patients.

Background: Current strategies for cardiovascular disease (CVD) risk assessment among adults without known CVD are limited by suboptimal performance and a narrow focus on only atherosclerotic CVD (ASCVD). We hypothesized that a strategy combining promising biomarkers across multiple different testing modalities would improve global and atherosclerotic CVD risk assessment among individuals without known CVD. Methods: We included participants from MESA (Multi-Ethnic Study of Atherosclerosis) (n=6621) and the Dallas Heart Study (n=2202) who were free from CVD and underwent measurement of left ventricular hypertrophy by ECG, coronary artery calcium, N-terminal pro B-type natriuretic peptide, high-sensitivity cardiac troponin T, and high-sensitivity C-reactive protein. Associations of test results with the global composite CVD outcome (CVD death, myocardial infarction, stroke, coronary or peripheral revascularization, incident heart failure, or atrial fibrillation) and ASCVD (fatal or nonfatal myocardial infarction or stroke) were assessed over >10 years of follow-up. Multivariable analyses for the primary global CVD end point adjusted for traditional risk factors plus statin use and creatinine (base model). Results: Each test result was independently associated with global composite CVD events in MESA after adjustment for the components of the base model and the other test results ( P P =0.001), significant integrated discrimination improvement (0.07, 95% confidence interval [CI] 0.06–0.08, P P =0.003) were observed, and the model was well calibrated (χ 2 =12.2, P =0.20). Using a simple integer score counting the number of abnormal tests, compared with those with a score of 0, global CVD risk was increased among participants with a score of 1 (adjusted hazard ratio, 1.9; 95% CI, 1.4–2.6), 2 (hazard ratio, 3.2; 95% CI, 2.3–4.4), 3 (hazard ratio, 4.7; 95% CI, 3.4–6.5), and ≥4 (hazard ratio, 7.5; 95% CI, 5.2–10.6). Findings replicated in the Dallas Health Study were similar for the ASCVD outcome. Conclusions: Among adults without known CVD, a novel multimodality testing strategy using left ventricular hypertrophy by ECG, coronary artery calcium, N-terminal pro B-type natriuretic peptide, high-sensitivity cardiac troponin T, and high-sensitivity C-reactive protein significantly improved global CVD and ASCVD risk assessment.

Background and objectives The benefit of dual blockade of the renin-angiotensin system is limited by adverse effects. We performed a secondary analysis of the Veterans Affairs Nephropathy in Diabetes (VA NEPHRON-D) Study to describe the effect of increased intensity of renin-angiotensin system blockade on the incidence, risk factors, and outcomes of AKI. Design, setting, participants, & measurements In the VA NEPHRON-D Study, we randomized 1148 veterans receiving outpatient care with type 2 diabetes mellitus, eGFR of between 30 and 89.9 ml/min per 1.73 m 2 , and urinary albumin excretion of at least 300 μ g/mg creatinine (or a urinary total protein of at least 0.5 mg/mg creatinine) to either combination therapy with losartan and lisinopril or monotherapy with losartan. We identified hospitalized AKI events and their outcomes during a median follow-up of 2.2 years through systematic reporting of serious adverse events. Results The incidence of AKI was 12.2 (95% confidence interval, 10.5 to 14.0) versus 6.7 (95% confidence interval, 5.6 to 8.2) per 100 patient-years in the combination arm versus monotherapy arms ( P P P =0.04), lower 30-day mortality (4.7% versus 15.0%; P Conclusions Dual renin-angiotensin system blockade was associated with an increased risk of AKI compared with monotherapy, but AKI in the setting of monotherapy was associated with lower rates of recovery of kidney function, higher mortality, and higher risk of progression of kidney disease.

In the past decade, there have been increasing efforts to better define and quantify the short- and long-term risks of living kidney donation. Recent studies have expanded upon the previous literature by focusing on outcomes that are important to potential and previous donors, applying unique databases and/or registries to follow large cohorts of donors for longer periods of time, and comparing outcomes with healthy nondonor controls to estimate attributable risks of donation. Leading outcomes important to living kidney donors include kidney health, surgical risks, and psychosocial effects of donation. Recent data support that living donors may experience a small increased risk of severe CKD and ESKD compared with healthy nondonors. For most donors, the 15-year risk of kidney failure is

Background As heart failure ( HF )‐associated morbidity and mortality continue to escalate, enhanced focus on prevention is increasingly important. “Malignant” left ventricular (LV) hypertrophy ( LVH ): LVH combined with an elevated cardiac biomarker reflecting either injury (high‐sensitivity cardiac troponin T), or strain (amino‐terminal pro‐B‐type natriuretic peptide) has predicted accelerated progression to HF . We sought to determine whether malignant LVH identified community‐dwelling adults initially free of cardiovascular disease at high risk of asymptomatic decline in LV ejection fraction or a clinical cardiovascular event. Methods and Results A total of 4985 of 6814 individuals without prevalent cardiovascular disease underwent baseline cardiac magnetic resonance for LVH in combination with measurement of plasma high‐sensitivity cardiac troponin T and amino‐terminal pro‐B‐type natriuretic peptide as part of MESA (Multi‐Ethnic Study of Atherosclerosis) and were subsequently divided into 4 groups: (1) No LVH , no elevated biomarkers (n=2206; 44.3%); (2) No LVH , ≥1 elevated biomarkers (n=2275; 45.7%); (3) LVH , no elevated biomarkers (n=153; 3.0%); and (4) LVH , ≥1 elevated biomarkers (malignant LVH ; n=351; 7.0%). Cardiac magnetic resonance was repeated 10 years later (n=2831) for assessment of LV ejection fraction LVH was associated with 7.0‐, 3.5‐, and 2.6‐fold adjusted increases in incidence of HF , cardiovascular death, and asymptomatic LV dysfunction, respectively, versus group 1. New‐onset HF was predominately HF with reduced ejection fraction (9.5‐fold increase). Conclusions Malignant LVH is predictive of progression to asymptomatic LV dysfunction, HF (particularly HF with reduced ejection fraction), and cardiovascular death. Consequently, malignant LVH represents a high‐risk phenotype among individuals without known cardiovascular disease , which should be targeted for increased surveillance and more‐aggressive therapies.

Background and objectives Elevations in N-terminal pro–B-type natriuretic peptide and high-sensitivity troponin T are associated with poor cardiovascular outcomes. Whether elevations in these cardiac biomarkers are associated with decline in kidney function was evaluated. Design, setting, participants, & measurements N-terminal pro–B-type natriuretic peptide and troponin T were measured at baseline in 3752 participants free of heart failure in the Cardiovascular Health Study. eGFR was determined from the Chronic Kidney Disease Epidemiology Collaboration equation using serum cystatin C. Rapid decline in kidney function was defined as decline in serum cystatin C eGFR≥30%, and incident CKD was defined as the onset of serum cystatin C eGFR n =2786). Cox regression models were used to examine the associations of each biomarker with kidney function decline adjusting for demographics, baseline serum cystatin C eGFR, diabetes, and other CKD risk factors. Results In total, 503 participants had rapid decline in serum cystatin C eGFR over a mean follow-up time of 6.41 (1.81) years, and 685 participants developed incident CKD over a mean follow-up time of 6.41 (1.74) years. Participants in the highest quartile of N-terminal pro–B-type natriuretic peptide (>237 pg/ml) had an 67% higher risk of rapid decline and 38% higher adjusted risk of incident CKD compared with participants in the lowest quartile (adjusted hazard ratio for serum cystatin C eGFR rapid decline, 1.67; 95% confidence interval, 1.25 to 2.23; hazard ratio for incident CKD, 1.38; 95% confidence interval, 1.08 to 1.76). Participants in the highest category of troponin T (>10.58 pg/ml) had 80% greater risk of rapid decline compared with participants in the lowest category (adjusted hazard ratio, 1.80; 95% confidence interval, 1.35 to 2.40). The association of troponin T with incident CKD was not statistically significant (hazard ratio, 1.17; 95% confidence interval, 0.92 to 1.50). Conclusions Elevated N-terminal pro–B-type natriuretic peptide and troponin T are associated with rapid decline of kidney function and incident CKD. Additional studies are needed to evaluate the mechanisms that may explain this association.

PURPOSE OF REVIEW: This review presents the role of combination therapy of renin-angiotensin-aldosterone system blockade on cardiovascular and kidney disease. RECENT FINDINGS: Three large randomized controlled trials comparing combination therapy of renin-angiotensin-aldosterone system blockade to monotherapy in individuals with increased cardiovascular risk, chronic kidney disease, or diabetic nephropathy have been reported. These trials - ONTARGET, ALTITUDE, and VA NEPHRON-D - demonstrated an excess risk of adverse effects [especially acute kidney injury (AKI) and hyperkalemia] with combination therapy, without significant benefit in reducing cardiovascular and renal morbidity. SUMMARY: Current evidence supports avoiding dual renin-angiotensin-aldosterone system blockade in patients with chronic kidney disease. Subsequent studies of dual renin-angiotensin-aldosterone system blockade should examine adverse event risks and renal progression endpoints.

Purpose of review Both cognitive and physical function are commonly impaired in individuals with chronic kidney disease (CKD), resulting in important impacts on their quality of life and overall health. This review summarizes the burden of cognitive and physical impairment in CKD, focusing on recent research that highlights a possible unifying microvascular cause among these shared comorbid conditions. Recent findings Multiple small studies have been published recently evaluating cognitive and physical functioning in people with CKD. These studies overall demonstrate a high burden of comorbid conditions in people with CKD, including microvascular disease, that may result in cognitive impairment. Additionally, studies demonstrate that physical function is substantially worse than expected in individuals with CKD, that decreased physical activity is associated with worse outcomes, that frailty is very common and associated with an increased risk of death, and that structured exercise programs have small but tangible short-term effects on markers of physical performance. Summary Impaired cognitive function and physical performance are important factors impacting the lives of people with CKD. Further research is necessary to better treat these important comorbid conditions in people with CKD.

Patients with CKD represent a vulnerable population where the risks of atrial fibrillation, ischemic stroke, and bleeding are all heightened. Although large randomized, controlled trials in the general population clearly demonstrate that the benefits of warfarin and direct-acting oral anticoagulants outweigh the risks of bleeding, no such studies have been conducted in patients when their creatinine clearance falls below 25–30 ml/min. Without randomized, controlled trial data, the role of anticoagulation in patients with CKD with atrial fibrillation remains unclear and our practice is informed by a growing body of imperfect literature such as observational and pharmacokinetic studies. This article aims to present a contemporary literature review of the benefits versus harms of anticoagulation in atrial fibrillation for patients with CKD stages 3, 4, 5, and 5 on dialysis. Although unanswered questions and areas of clinical equipoise remain, this piece serves to assist physicians in interpreting the complex body of literature and applying it to their clinical care.

Conventional creatinine-based glomerular filtration rate (GFR) equations are insufficiently accurate for estimating GFR in cirrhosis. The Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) recently proposed an equation to estimate GFR in subjects without cirrhosis using both serum creatinine and cystatin C levels. Performance of the new CKD-EPI creatinine-cystatin C equation (2012) was superior to previous creatinine- or cystatin C-based GFR equations. To evaluate the performance of the CKD-EPI creatinine-cystatin C equation in subjects with cirrhosis, we compared it to GFR measured by non-radiolabeled iothalamate plasma clearance (mGFR) in 72 subjects with cirrhosis. We compared the “bias”, “precision” and “accuracy” of the new CKD-EPI creatinine-cystatin C equation to that of 24-hour urinary creatinine clearance (CrCl), Cockcroft-Gault (CG) and previously reported creatinine- and/or cystatin C-based GFR-estimating equations. Accuracy of CKD-EPI creatinine-cystatin C equation as quantified by root mean squared error of difference scores [differences between mGFR and estimated GFR (eGFR) or between mGFR and CrCl, or between mGFR and CG equation for each subject] (RMSE=23.56) was significantly better than that of CrCl (37.69, P=0.001), CG (RMSE=36.12, P=0.002) and GFR-estimating equations based on cystatin C only. Its accuracy as quantified by percentage of eGFRs that differed by greater than 30% with respect to mGFR was significantly better compared to CrCl (P=0.024), CG (P=0.0001), 4-variable MDRD (P=0.027) and CKD-EPI creatinine 2009 (P=0.012) equations. However, for 23.61% of the subjects, GFR estimated by CKD-EPI creatinine-cystatin C equation differed from the mGFR by more than 30%. CONCLUSIONS The diagnostic performance of CKD-EPI creatinine-cystatin C equation (2012) in patients with cirrhosis was superior to conventional equations in clinical practice for estimating GFR. However, its diagnostic performance was substantially worse than reported in subjects without cirrhosis.

The incidence of stroke is substantially higher among hemodialysis patients than among patients with earlier stages of CKD, but to what extent the initiation of dialysis accelerates the risk for stroke is not well understood. In this cohort study, we analyzed data from incident hemodialysis and peritoneal dialysis patients in 2009 who were at least 67 years old and had Medicare as primary payer. We noted whether each of the 20,979 hemodialysis patients initiated dialysis as an outpatient (47%) or inpatient (53%). One year before initiation, the baseline stroke rate was 0.15%-0.20% of patients per month (ppm) for both outpatient and inpatient initiators. Among outpatient initiators, stroke rates began rising approximately 90 days before initiation, reached 0.5% ppm during the 30 days before initiation, and peaked at 0.7% ppm (8.4% per patient-year) during the 30 days after initiation. The pattern was similar among inpatient initiators, but the stroke rate peaked at 1.5% ppm (18% per patient-year). For both hemodialysis groups, stroke rates rapidly declined by 1-2 months after initiation, fluctuated, and stabilized at approximately twice the baseline rate by 1 year. Among the 620 peritoneal dialysis patients, stroke rates were slightly lower and variable, but approximately doubled after initiation. In conclusion, these data suggest that the process of initiating dialysis may cause strokes. Further studies should evaluate methods to mitigate the risk for stroke during this high-risk period.

In older adults, measurements of physical performance assess physical function and associate with mortality and disability. Muscle wasting and diminished physical performance often accompany CKD, resembling physiologic aging, but whether physical performance associates with clinical outcome in CKD is unknown. We evaluated 385 ambulatory, stroke-free participants with stage 2-4 CKD enrolled in clinic-based cohorts at the University of Washington and University of Maryland and Veterans Affairs Maryland Healthcare systems. We compared handgrip strength, usual gait speed, timed up and go (TUAG), and 6-minute walking distance with normative values and constructed Cox proportional hazards models and receiver operating characteristic curves to test associations with all-cause mortality. Mean age was 61 years and the mean estimated GFR was 41 ml/min per 1.73 m(2). Measures of lower extremity performance were at least 30% lower than predicted, but handgrip strength was relatively preserved. Fifty deaths occurred during the median 3-year follow-up period. After adjustment, each 0.1-m/s decrement in gait speed associated with a 26% higher risk for death, and each 1-second longer TUAG associated with an 8% higher risk for death. On the basis of the receiver operating characteristic analysis, gait speed and TUAG more strongly predicted 3-year mortality than kidney function or commonly measured serum biomarkers. Adding gait speed to a model that included estimated GFR significantly improved the prediction of 3-year mortality. In summary, impaired physical performance of the lower extremities is common in CKD and strongly associates with all-cause mortality.

Background and Purpose— Because of its association with atrial fibrillation and heart failure, we hypothesized that amino terminal pro–B-type natriuretic peptide (NT-proBNP) would identify a subgroup of patients from the Warfarin–Aspirin Recurrent Stroke Study, diagnosed with inferred noncardioembolic ischemic strokes, where anticoagulation would be more effective than antiplatelet agents in reducing risk of subsequent events. Methods— NT-proBNP was measured in stored serum collected at baseline from participants enrolled in Warfarin–Aspirin Recurrent Stroke Study, a previously reported randomized trial. Relative effectiveness of warfarin and aspirin in preventing recurrent ischemic stroke or death over 2 years was compared based on NT-proBNP concentrations. Results— About 95% of 1028 patients with assays had NT-proBNP below 750 pg/mL, and among them, no evidence for treatment effect modification was evident. For 49 patients with NT-proBNP >750 pg/mL, the 2-year rate of events per 100 person-years was 45.9 for the aspirin group and 16.6 for the warfarin group, whereas for 979 patients with NT-proBNP ≤750 pg/mL, rates were similar for both treatments. For those with NT-proBNP >750 pg/mL, the hazard ratio was 0.30 (95% confidence interval: 0.12–0.84; P =0.021) significantly favoring warfarin over aspirin. A formal test for interaction of NT-proBNP with treatment was significant ( P =0.01). Conclusions— For secondary stroke prevention, elevated NT-proBNP concentrations may identify a subgroup of ischemic stroke patients without known atrial fibrillation, about 5% based on the current study, who may benefit more from anticoagulants than antiplatelet agents. Clinical Trial Registration— This trial was not registered because enrollment began before 2005.

Background Soluble ST 2 ( sST 2), a marker of myocyte stretch and fibrosis, has prognostic value in many cardiovascular diseases. We hypothesized that sST 2 levels are associated with incident heart failure (HF), including subtypes of preserved ( HF p EF ) and reduced ( HF r EF ) ejection fraction, and cardiovascular death. Methods and Results Baseline serum sST 2 was measured in 3915 older, community‐dwelling subjects from the Cardiovascular Health Study without prevalent HF. sST 2 levels were associated with older age, male sex, black race, traditional cardiovascular risk factors, other biomarkers of inflammation, cardiac stretch, myocardial injury, and fibrosis, and abnormal echocardiographic parameters. In longitudinal analysis, greater sST 2 was associated with a higher risk of incident HF and cardiovascular death; however, in multivariate models adjusting for other cardiac risk factors and the cardiac‐specific biomarker, N‐terminal pro–type B natriuretic peptide, these associations were attenuated. In these models, an sST 2 level above the US Food and Drug Administration–approved cut‐off value (>35 ng/mL) was significantly associated with incident HF (hazard ratio [ HR ], 1.20; 95% CI , 1.02–1.43) and cardiovascular death ( HR , 1.21; 95% CI , 1.02–1.44), and greater sST 2 was continuously associated with cardiovascular death (per 1‐ln increment: HR , 1.24; 95% CI , 1.02–1.50). sST 2 was not associated with the HF subtypes of HF p EF and HF r EF in adjusted analysis. Addition of sST 2 to existing risk models of HF and cardiovascular death modestly improved discrimination and reclassification into a higher risk. Conclusions The predictive value of sST 2 for HF of all subtypes and cardiovascular death is modest in an elderly population despite strong cross‐sectional associations with risk factors and underlying cardiac pathology.

Background— Repeated myocardial microinjuries lead to collagen deposition and fibrosis, thereby increasing the risk of clinical heart failure. Little is known about the longitudinal association between increases in myocardial injury and the biology of collagen synthesis and deposition. Methods and Results— Repeated measures of highly sensitive cardiac troponin T (cTnT) were obtained in participants of the Cardiovascular Health Study (N=353; mean age, 74±6 years; 52% women) at baseline and at 3 years follow-up. Biomarkers of collagen metabolism were obtained at follow-up and included carboxyterminal propeptide of procollagen type I, carboxyterminal telopeptide of type I collagen, and aminoterminal propeptide of procollagen III. Multivariable linear regression analyses were used to examine the association between baseline cTnT and changes in cTnT with collagen metabolism markers at follow-up adjusting for demographics, heart failure status, and cardiovascular risk factors. Results indicated that cTnT increases over 3-years were significantly associated with higher levels of carboxyterminal telopeptide of type I collagen (β=0.22, P P =0.035) at follow-up when adjusting for demographic, clinical, and biochemical covariates including baseline cTnT. These associations were stronger in patients with heart failure than in control subjects. Conclusions— Increases in myocardial microinjury measured by changes in cTnT adversely affect markers of collagen metabolism. These findings are important to the biology of myocardial fibrosis and tissue repair. Serial evaluation of cTnT combined with collagen metabolism markers may further elucidate the pathophysiology of heart failure.

Summary Background and objectives Depression is a risk indicator for adverse outcomes in dialysis patients, but its prognostic impact in individuals who are not yet on dialysis is unknown. This study examines whether depressive symptoms are longitudinally associated with renal function decline, new-onset chronic kidney disease (CKD), ESRD, or hospitalization with acute kidney injury (AKI). Design, setting, participants, & measurements Depressive symptoms were measured in a longitudinal cohort study with the 10-item Centers for Epidemiologic Studies Depression scale using a previously validated cut-off value (8). CKD at study entry and during follow-up was defined as an estimated GFR (eGFR) 60 ml/min per m 2 . Outcomes were rapid decline in eGFR (3 ml/min per m 2 per year), new-onset CKD, ESRD (U.S. Renal Data System-based), and AKI (based on adjudicated medical record review). The median follow-up duration was 10.5 years. Results Depressed participants (21.2%) showed a higher prevalence of CKD at baseline compared with nondepressed participants in multivariable analysis. Depression was associated with a subsequent risk of rapid decline in eGFR, incident ESRD, and AKI, but not incident CKD in unadjusted models. In multivariable analyses, only associations of depressive symptoms with AKI remained significant. Conclusions Elevated depressive symptoms are associated with subsequent adverse renal disease outcomes. The depression-related elevated risk of AKI was independent of traditional renal disease risk factors and may in part be explained by the predictive value of depression for acute coronary syndromes and heart failure hospitalizations that can be complicated by AKI. Clin J Am Soc Nephrol 6: ●●● –●●● , 2011. doi: 10.2215/CJN.03840510

Cognitive impairment is common among persons with chronic kidney disease, but the extent to which nontraditional vascular risk factors mediate this association is unclear.We conducted cross-sectional analyses of baseline data collected from adults with chronic kidney disease participating in the Chronic Renal Insufficiency Cohort study. Cognitive impairment was defined as a Modified Mini-Mental State Exam score1 SD below the mean score.Among 3591 participants, the mean age was 58.2±11.0 years, and the mean estimated GFR (eGFR) was 43.4±13.5 ml/min per 1.73 m2. Cognitive impairment was present in 13%. After adjustment for demographic characteristics, prevalent vascular disease (stroke, coronary artery disease, and peripheral arterial disease) and traditional vascular risk factors (diabetes, hypertension, smoking, and elevated cholesterol), an eGFR30 ml/min per 1.73 m2 was associated with a 47% increased odds of cognitive impairment (odds ratio 1.47, 95% confidence interval 1.05, 2.05) relative to those with an eGFR 45 to 59 ml/min per 1.73 m2. This association was attenuated and no longer significant after adjustment for hemoglobin concentration. While other nontraditional vascular risk factors including C-reactive protein, homocysteine, serum albumin, and albuminuria were correlated with cognitive impairment in unadjusted analyses, they were not significantly associated with cognitive impairment after adjustment for eGFR and other confounders.The prevalence of cognitive impairment was higher among those with lower eGFR, independent of traditional vascular risk factors. This association may be explained in part by anemia.

Background: The kidney biomarker that best reflects risk of stroke is unknown. We sought to evaluate the association of stroke with 3 kidney biomarkers: albuminuria, cystatin C, and glomerular filtration rate. Methods: These 3 biomarkers were determined in 3,287 participants without history of stroke from the Cardiovascular Health Study, a longitudinal cohort study of men and women age 65 years and older from 4 US communities. The biomarkers were albuminuria ascertained using urinary albumin-to-creatinine ratio (UACR) from morning spot urine, creatinine-based estimated glomerular filtration rate (eGFR), and cystatin C. Outcomes were incident stroke (any, ischemic, or hemorrhagic) during follow-up between 1996 and 2006. Results: A total of 390 participants had an incident stroke: 81% ischemic, 12% hemorrhagic, and 7% unclassified. In adjusted Cox regression models, UACR was more strongly related to any stroke, ischemic stroke, and hemorrhagic stroke than eGFR and cystatin C. The hazard ratio (HR) of any stroke comparing the top to bottom quintile of UACR was 2.10 (95% confidence interval [CI] 1.47–3.00), while HR for eGFR was 1.29 (95% CI 0.91–1.84) and for cystatin C was 1.22 (95% CI 0.85–1.74). When considering clinically relevant categories, elevated UACR was associated with increased hazard of any stroke and ischemic stroke regardless of eGFR or cystatin C categories. Conclusions: UACR was the kidney biomarker most strongly associated with risk of incident stroke. Results in this elderly cohort may not be applicable to younger populations. These findings suggest that measures of glomerular filtration and permeability have differential effects on stroke risk.

The severity of anemia at which to initiate erythropoiesis-stimulating agent (ESA) treatment in nondialysis chronic kidney disease (CKD) patients is unclear. Risk of mortality, hospitalizations, and blood transfusion were compared among nondialysis CKD patients with "early" versus "delayed" ESA initiation.A retrospective cohort study was conducted on CKD (estimated GFR60 ml/min/1.73m(2)) outpatients in the national Veterans Administration who were initiated on ESAs. Patients with ESRD, gastrointestinal bleeding, chemotherapy, or hematologic malignancy were excluded. Patients were characterized as having early [hemoglobin (Hb) 10.0 to 11.0 g/dl] or delayed (Hb 8.0 to 9.9 g/dl) ESA initiation. A propensity score comprising demographic, clinical, and laboratory variables was used to select a 1:1 matched cohort. Cox survival and negative binomial regression were used to compare the matched groups for all-cause mortality, hospitalizations, and blood transfusions.Of 1837 patients who met inclusion criteria, 1410 (77%) were successfully matched. The groups did not differ significantly in 31 characteristics reflecting sociodemographics, comorbidity, healthcare utilization, and renal function. There was no significant difference in mortality with early initiation. Those initiated early had a 17% lower risk of initial hospitalization and a 29% lower risk of transfusion compared with delayed initiation patients. Results did not differ between those with and without pre-ESA transfusion or hospitalization.In nondialysis CKD, ESA initiation at Hb 10.0 to 11.0 g/dl compared with 8.0 to 9.9 g/dl is associated with reduced risk of blood transfusion and initial hospitalization.

Background and objectives: Chronic kidney disease (CKD) lacks standardized patient safety indicators (PSIs); however, undetected safety events are likely to contribute to adverse outcomes in this disease. This study sought to determine the proportion of CKD patients who experience multiple potentially hazardous events from varied causes and to identify risk factors for the occurrence of “multiple hits.” Design, setting, participants, & measurements: A sample of patients with CKD (n = 70,154) in the Veterans Health Administration (VHA) were retrospectively examined for the occurrence of one or more safety events from a set of indicators defined a priori, including Agency for Healthcare Research and Quality (AHRQ) PSIs, hypoglycemia, hyperkalemia, and dosing for selected medications not accounting for CKD. Results: Approximately half of the cohort participants experienced one or two adverse safety events, whereas 7% had three or four (multiple) distinct events. Individuals with three or four of the predesignated safety events were more likely to be diabetic, non-Caucasian, have an estimated GFR (eGFR) < 30 ml/min/1.73 m2, and be ≤65 yr of age. A “Safety Risk Index” was developed using these characteristics, and those subjects that had all four traits were 25 times as likely to have three or four adverse safety events versus those with none of the characteristics. Conclusions: Patients with CKD are at a high risk for safety events pertinent to this disease and a substantial number are subject to multiple events from a diverse set of safety indicators, which could have important consequences in disease outcomes.

Within the normal range, higher serum phosphate concentrations are associated with cardiovascular events and mortality in individuals with chronic kidney disease (CKD) and in those with normal kidney function. Experimental models suggest that phosphate has a direct calcifying effect on vascular smooth muscle. We examined associations of serum phosphate concentrations with vascular and valvular calcification in 439 participants from the Multi-Ethnic Study of Atherosclerosis who had moderate CKD and no clinical cardiovascular disease. Serum phosphate concentrations were within the normal range (2.5 to 4.5 mg/dl) in 95% of study participants. The prevalence of calcification in the coronary arteries, descending thoracic aorta, aortic valve, and mitral valve was 67, 49, 25, and 20%, respectively, measured by electron-beam or multi-detector row computed tomography. After adjustment for demographics and estimated GFR, each 1-mg/dl increment in serum phosphate concentration was associated with a 21% (P = 0.002), 33% (P = 0.001), 25% (P = 0.16), and 62% (P = 0.007) greater prevalence of coronary artery, thoracic, aortic valve, and mitral valve calcification, respectively. Adjustment for traditional risk factors for atherosclerosis, parathyroid hormone, or 1,25-dihydroxyvitamin D levels did not alter these associations. In conclusion, higher serum phosphate concentrations, although still within the normal range, are associated with a greater prevalence of vascular and valvular calcification in people with moderate CKD. It remains to be determined whether lowering phosphate concentrations will impact calcification risk in the setting of kidney disease.

Background and objectives: Impaired kidney function is associated with increased risk for cardiovascular disease and may progress over time to end-stage renal disease. Abnormal lipoprotein metabolism has been implicated as a possible cause of these complications, but lipoproteins have not been described at the earliest stages of kidney disease. Design, setting, participants, & measurements: This study examined cross-sectional associations of serum cystatin C with conventional lipid measurements and detailed nuclear magnetic resonance lipoprotein measurements in the community-based Multi-Ethnic Study of Atherosclerosis. A total of 5109 participants with estimated glomerular filtration rate ≥60 ml/min per 1.73 m2 were included in analyses. Results: Adjusting for age, gender, race/ethnicity, diabetes, impaired fasting glucose, BP, smoking, medications, body mass index, and albuminuria, greater cystatin C concentrations were associated with progressively unfavorable lipid and lipoprotein concentrations, including greater triglyceride concentration (+22 mg/dl, comparing fifth versus first quintiles of cystatin C) and lesser high-density lipoprotein cholesterol concentration (−7 mg/dl) but not with low-density lipoprotein cholesterol measured using conventional methods. When low-density lipoprotein particle subclasses were examined in more detail using nuclear magnetic resonance, greater cystatin C was associated with greater concentrations of atherogenic small low-density lipoprotein particles (+63 nmol/L) and intermediate-density lipoprotein particles (+6 nmol/L) and with a decrease in mean low-density lipoprotein particle size. Conclusions: Lipoprotein abnormalities are present with milder degrees of renal impairment than previously recognized, and abnormalities in low-density lipoprotein particle distribution may not be appreciated using conventional lipid measurements. These abnormalities may contribute to kidney disease progression and/or cardiovascular disease.

Chronic kidney disease (CKD) is associated with cardiovascular (CV) disease and mortality. It is not known whether cardiac rhythm disturbances are more prevalent among individuals with CKD or whether resting electrocardiogram findings predict future CV events in the CKD setting. Data were obtained from the Cardiovascular Health Study, a community-based study of adults aged/=65 yr. After exclusions for prevalent heart disease, atrial fibrillation, implantable pacemaker, or antiarrhythmic medication use, 3238 participants were analyzed. CKD was defined by an estimated GFR60 ml/min per 1.73 m(2). Outcomes were adjudicated incident heart failure (HF), incident coronary heart disease (CHD), and mortality. Participants with CKD had longer PR and corrected QT intervals compared with those without CKD; however, differences in electrocardiographic markers were explained by traditional CV risk factors and CV medication use. After adjustment for known risk factors, each 10-ms increase in the QRS interval was associated with a 15% greater risk for incident HF (95% confidence interval [CI] 1.04 to 1.27), a 13% greater risk for CHD (95% CI 1.04 to 1.24), and a 17% greater risk for mortality (95% CI 1.09, 1.25) among CKD participants. Each 5% increase in QTI was associated with a 42% (95% CI 1.23 to 1.65), 22% (95% CI 1.07 to 1.40), and 10% (95% CI 0.98 to 1.22) greater risk for HF, CHD, and mortality, respectively. Associations seemed stronger for participants with CKD; however, no significant interactions were detected. Resting electrocardiographic abnormalities are common in CKD and independently predict future clinical CV events in this setting.

This study set out to determine whether there is a center effect on anemia management in hemodialysis patients. The US Renal Data System and Medicare standard analysis files were analyzed. Between-center variation and within-facility correlations in hematocrit values were examined in two separate data sets (years 2000 and 2001) and compared with simulated samples that were composed of random values that assumed no center effect. Mixed-effect models were used to adjust for multiple factors and quantify the within-facility correlation in hematocrit values. Expected hematocrit values were compared in patients who underwent dialysis at poor and superior performing facilities with fixed characteristics including epoetin alpha dosing. There was a wider center variation in hematocrit for the actual versus simulated data and a coefficient of variation of 4.1% for the former versus 1.7% for the latter, in both years. The within-facility correlation for hematocrit was 0.053 (95% confidence interval 0.050 to 0.056; P < 0.001) in 2000 with similar values in 2001 but no within-facility correlation in the simulated data. The impact of these findings was demonstrated with a difference in expected hematocrit for a patient who was treated with fixed-dosage epoetin alpha in the poorest versus best performing units (mean difference in expected hematocrit 3.06; 95% confidence interval 3.03 to 3.09; P < 0.001). Key attributes of a center effect on anemia management in hemodialysis have been identified. The presence of a center effect suggests that there are facility-specific processes that influence performance in dialysis anemia management and are independent of commonly titrated inputs, such as dosing of erythropoietic agents.

Kidney dysfunction is associated with bone loss, and patients with ESRD have an increased risk for hip fracture. However, the association of mild to moderate kidney disease with hip fracture has not been studied previously. The association of kidney function with incident hip fracture was examined among participants in the Cardiovascular Health Study, a community-based cohort of older individuals. The primary measure of kidney function was serum cystatin C, a measure that does not depend on lean mass. Hip fractures were identified using International Classification of Diseases, Ninth Revision codes for hospitalizations. A total of 4699 individuals had cystatin C measured in 1992 to 1993 and did not have a hip fracture before cystatin C measurement. The association of kidney function with hip fracture was analyzed with Cox proportional hazards models. Analyses were conducted separately for men and women. After a mean follow-up of 7.1 yr, 195 incident hip fractures occurred in women and 79 occurred in men. Higher cystatin C levels were associated with a higher risk for fracture in women (hazard ratio [HR] 1.26; 95% confidence interval [CI] 1.14 to 1.38 per SD) and in men (HR 1.27; 95% CI 1.11 to 1.46). After multivariable adjustment, higher cystatin C levels were significantly associated with hip fracture in women (HR 1.16; 95% CI 1.01, 1.33) but not in men (HR 1.14; 95% CI 0.86 to 1.52), although the magnitude of the association was similar. Kidney dysfunction, as assessed by cystatin C, is associated with an increased risk for hip fracture. Further studies are needed to evaluate potential mediators of this relationship and to assess whether interventions can decrease this risk.

Introduction: Chronic kidney disease (CKD) increases the risk for adverse cardiovascular events including heart failure (HF) and death. Left atrial size is an easily quantified metric that provides prognostic information in non-CKD populations. Hypothesis: We hypothesized that left atrial size would be an independent risk marker for incident HF and death in individuals with CKD. Methods: The Chronic Renal Insufficiency Cohort (CRIC) is a large, multicenter, multiracial cohort study established to understand the progression of cardiovascular and renal disease among individuals with CKD. We evaluated echocardiograms among participants without a history of heart failure. The left atrial area was measured in the apical 4-chamber view and indexed to body surface area (LAAI). Cox proportional hazards models were constructed to assess the risk between left atrial size and incident HF and death. Results: Among the 2960 CKD participants without known heart failure, higher tertiles of LAAI were associated with older age, Hispanic ethnicity, a history of stroke, myocardial infarction, atrial fibrillation, higher systolic blood pressure, hypertension, diabetes, and lower eGFR (P Conclusion: Among adults with CKD, LAAI is a stronger marker of risk for incident HF than death.

Introduction: A substantial minority of asymptomatic individuals will have very low but measurable levels of cardiac troponin T using a high sensitive assay (hs-cTnT). It is controversial if levels in this range provide physiologic and prognostic information. We hypothesized that hs-cTnT levels between the limit of blank (LOB) (3 ng/L) and limit of detection (LOD) (5 ng/L) are associated with increased incidence of heart failure (HF) and cardiovascular death compared to levels below the LOB ( Methods: hs-cTnT was measured in subjects without prevalent HF from the Cardiovascular Health Study (CHS), Atherosclerosis Risk in Communities (ARIC) study, and Dallas Heart Study (DHS). Participants were divided into two groups: levels below the LOB (n=7272) and levels between the LOB and LOD (n=3451). Cross sectional and longitudinal associations with demographics, traditional cardiovascular risk factors, and cardiovascular outcomes were made. A fixed-effect meta-analysis was performed using regression coefficients and variance estimates from fully adjusted models from all three cohorts. Results: Participants with hs-cTnT between the LOB and LOD were older, more likely to be male, and had higher prevalence of cardiovascular risk factors and structural abnormalities such as higher coronary artery calcium score and left ventricular mass. A meta-analysis of the three cohorts showed participants with hs-cTnT between the LOB and LOD were at increased risk of new-onset HF (HR=1.18, 95% CI: 1.02, 1.38) and cardiovascular death (HR=1.29, 95% CI: 1.06, 1.57) after adjusting for demographics and traditional risk factors when compared to participants with hs-cTnT below the LOB (Figure). Conclusions: hs-cTnT levels between the LOB and LOD are associated with a higher prevalence of traditional risk factors, cardiac pathology, and worse outcomes compared with levels below the LOB. Therefore, in general population cohorts, hs-cTnT should be reported down to the LOB.

Treatment with angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs) slows the progression of proteinuric diabetic kidney disease ([1][1]–[3][2]). However, the risk of progression remains high despite these medications. In the Reduction of Endpoints in NIDDM with

Subclinical brain infarcts (SBI) are common in the elderly and are associated with covert neurologic and cognitive impairment. Although renal impairment is associated with accelerated cerebrovascular disease and an increased risk for clinically apparent brain infarct, few studies have examined the relationship between renal function and SBI, and these may have been limited by the inaccuracy of creatinine as a renal function marker. A cross-sectional study was performed among older adults in the Cardiovascular Health Study to examine associations between SBI and two serum markers of renal function: Serum creatinine (SCr) and cystatin C (CysC). Patients had cranial magnetic resonance imaging and renal markers measured in 1992 to 1993. Logistic regression was used to estimate the associations between renal function (estimated by 1/SCr and 1/CysC) and SBI, controlling for potential confounding factors. SBI were present in 789 (28.7%) of 2784 participants. A linear association with SBI was observed for 1/CysC (per 1-SD decrement; odds ratio [OR] 1.20; 95% confidence interval [CI] 1.09 to 1.32; P < 0.001) but not for 1/SCr (OR 1.08; 95% CI 0.98 to 1.19; P = 0.14), for which a quadratic U-shaped association was suggested (P = 0.004). In a model with both markers, 1/CysC was linearly associated with SBI (OR 1.26; P < 0.001), whereas 1/SCr was not (OR 1.06; P = 0.3). The prevalence of SBI was directly associated with quintile of CysC, whereas the association between SCr and SBI was U-shaped, with greater prevalence at high and low levels. Compared with creatinine, CysC, a novel marker of renal function, has a stronger and more direct association with SBI in the elderly.

As kidney disease progresses, patients often experience a variety of symptoms. A challenge for the nephrologist is to help determine if these symptoms are related to advancing CKD or the effect of various comorbidities and/or medications prescribed. The clinician also must decide the timing of dialysis initiation. The initiation of dialysis can have a variable effect on quality of life measures and the alleviation of uremic signs and symptoms, such as anorexia, fatigue, cognitive impairment, depressive symptoms, pruritus, and sleep disturbances. Thus, the initiation of dialysis should be a shared decision–making process among the patient, the family and the nephrology team; information should be provided, in an ongoing dialogue, to patients and their families concerning the benefits, risks, and effect of dialysis therapies on their lives.

Inflammatory and prothrombotic markers are elevated in individuals with mild to moderate renal disease. It was hypothesized that these markers may also be determinants of the progression of renal disease. The association of six markers-serum C-reactive protein (CRP), white blood cell (WBC) count, fibrinogen, factor VII, albumin, and hemoglobin-with subsequent elevations of creatinine and decline in estimated GFR in the Cardiovascular Health Study, a community-based cohort of elderly individuals, was analyzed. Linear regression was used to determine predictors of an annualized change in serum creatinine as the main outcome. Duration of follow-up was 7 yr for the original cohort and 4 yr for the more recently recruited black cohort. A total of 588 (12.7%) individuals had a decline in estimated GFR of at least 3 ml/min per yr per 1.73 m(2). Higher CRP (P < 0.001), WBC count (P < 0.001), fibrinogen (P < 0.001), and factor VII (P < 0.001) levels and lower albumin (P < 0.001) and hemoglobin levels (P < 0.001) were associated with a rise in creatinine, after adjusting for age. With additional adjustments for race, gender, baseline creatinine, systolic and diastolic BP, lipid levels, weight, and pack-years smoking, higher CRP, factor VII, fibrinogen, WBC count, and lower albumin and hemoglobin levels remained associated with a rise in creatinine. Similar results were found for decline in estimated GFR. The decline in GFR was greater with increasing number of inflammatory or prothrombotic markers that were above the median (below for hemoglobin and albumin). Inflammatory and prothrombotic markers are predictors for a change in kidney function in elderly individuals. Interventions that reduce inflammation might confer significant cardiovascular and renal benefits.

Malhotra and Siew provide a detailed and highly comprehensive review of the AKI literature that carefully delineates the major categories of AKI biomarker studies. These studies can be broadly classified as addressing questions pertaining to screening or “early detection,” prognosis, and

This comprehensive review by Agarwal and Georgianos summarizes results of numerous clinical trials of antihypertensive medications in patients on chronic dialysis ([1][1]). The authors note the unique challenges of such studies in this patient population. For example, the effect of widely used

Studies over the last 3 decades among ESRD patients on maintenance dialysis have demonstrated greatly impaired physical performance and cardiorespiratory fitness compared with the general population ([1][1]–[4][2]). Levels of habitual physical activity are also markedly lower in these patients.

Many studies of chronic renal disease have reported that men have a more rapid progression of renal insufficiency. However, other studies have found no differences between the sexes, and the true effect of sex on chronic renal disease remains a topic of controversy. There is evidence that women with non-diabetic renal diseases experience a slower progression, but in diabetic renal disease, the effect of gender is not yet established. Sex hormones may mediate the effects of gender on chronic renal disease, through alterations in the renin--angiotensin system, reduction in mesangial collagen synthesis, the modification of collagen degradation, and upregulation of nitric oxide synthesis.

Background: Kidney dysfunction leads to the retention of metabolic waste products which may subsequently impair muscle function and physical performance. Methods: We prospectively measured physical performance in 183 stroke-free older adults with stage 3-4 CKD to determine the pattern of functional impairment and the relationship of performance with severity of CKD. Functional tests included the short physical performance battery (SPPB), 4 meter walk (gait speed), 6 minute walk distance (6MWD), timed get up and go test (TGUAG), grip strength, and peak expiratory flow. Physical performance in the CKD cohort was compared to normative data obtained from 78 non-CKD controls for the TGUAG and to expected performance from published normative data for other performance measures. Among CKD subjects, associations of performance with eGFR and proteinuria were estimated using linear regression adjusting for age, sex, race, height, and weight. Results: Mean eGFR was 34.8 ±12.5 mL/min/1.73m 2 , mean BMI 30.6 ±6 kg/m 2 , and median proteinuria 240 mg/g. Mean age was 66 ±7.7years, 91% were male, 33% African American, and 40% diabetic. CKD patients had significantly worse performance compared to predicted values on the TGUAG test (36 ±41% slower), gait speed (-31.7 ±15%), 6MWD (-31 ±15%), and peak expiratory flow (-25 ±34%). Among CKD subjects, lower eGFR and greater proteinuria were associated with worse performance on the 6MWD ( Table ). In contrast, no significant associations were observed between eGFR or proteinuria with performance on the other physical performance tests. Renal Function Measure 6 Meter Walk Distance (meters) Units β * (95%CI) P value GFR MDRD (mL/min/1.73m 2) 10mL/min/1.73m 2 decrement −11.0 (-23.0, 1.1) 0.07 45-59 Ref 30-44 −7.0 (-38, 24) .044 −35 (-68, -1.3) Proteinuria (mg/g Cr) 1 ln-increment −11.0 (-21.1, -0.9) 0.033 0-299 Ref ≥300 −25.8 (-53, 1.38) 0.063 * Adjusted for age, sex, race, height, and weight Conclusions: Older adults with CKD exhibit markedly reduced physical performance, especially for tests of lower extremity function. Lower renal function and greater proteinuria are associated with worse performance on the 6-minute walk test, a measure of submaximal gait.

In the elderly, with decades of exposure to cardiovascular (CV) risk factors, CV prognosis is often considered static. We hypothesized that CV risk is dynamic reflected by changes in NTproBNP over time. We measured NTproBNP at baseline and after 2–3 years in the Cardiovascular Health Study. Long-term risk of CV death according to change in NTproBNP was estimated with the Kaplan-Meier method. We used Cox models to test if effect of change in NTproBNP was independent of demographic and CV risk factors, baseline NTproBNP, renal function, coronary disease, and CV medications. Participants were categorized at baseline as < (low) or >=190pg/mL (high) levels, based on an observed increase in risk above this level. A significant change in NTproBNP category was defined as a change of >25% to a level above or below this cut-point, based on the reported biological variability of NTproBNP. Change in NTproBNP was also evaluated as a continuous measure. Serial NTproBNP levels were measured in 2,975 (86%) of 3,469 participants (age 75±5 years) without heart failure and who had a follow-up visit. CV death was different between those with low levels that remained low (n=1,774) vs. those with low levels that became high (n=468) (1.1 vs. 2.7 per 100 person-yrs, p ). As a continuous measure, change in NTproBNP was linearly associated with CV mortality risk after adjustment (per Ln-fold increment: RR=1.47, p Proportion without Cardiovascular death, by initial and follow-up NT-proBNP

See related article, pages 55–61. Because of similarities in the vascular supply to kidney and brain, information about vascular disease in one organ may inform us about vascular disease in the other, and such knowledge may shed light on ways to treat or prevent these diseases. Unlike most organs, both kidney and brain are low resistance end-organs and are exposed to high-volume blood flow throughout the cardiac cycle, explaining their pulsating nature.1 For the kidney, impairments from vascular disease manifest as problems with glomerular filtration, detected clinically by biochemical makers such as serum creatinine, urinary albumin, and serum cystatin C. For the brain, impairments manifest with overt focal neurological deficits, such as with stroke or transient ischemic attack, or as covert global deficits affecting cognition, mobility and mood, such as has been suggested with small-vessel disease. In humans, investigation of brain vascular disease and how it causes impairment of brain function often entails looking at the structure of the brain with MRI for infarctions, white matter lesions, and volumes of brain, ventricles and sulci. Given the difficulty in getting tissue, exploration of cause usually does not include microscopic examination of brain tissue, although microinfarcts inapparent on MRI can be identified.2 For investigation of vascular disease in the kidney, structural changes detectable on imaging are limited primarily to decrements in kidney size due to chronic fibrosis and atrophy. On the other hand, tissue is more …