Plasma Kidney Injury Molecule 1 in CKD: Findings From the Boston Kidney Biopsy Cohort and CRIC Studies.

RATIONALE & OBJECTIVE: Plasma kidney injury molecule 1 (KIM-1) is a sensitive marker of proximal tubule injury, but its association with risks of adverse clinical outcomes across a spectrum of kidney diseases is unknown. STUDY DESIGN: Prospective, observational cohort study. SETTING & PARTICIPANTS: 524 individuals enrolled into the Boston Kidney Biopsy Cohort (BKBC) Study undergoing clinically indicated native kidney biopsy with biopsy specimens adjudicated for semiquantitative scores of histopathology by 2 kidney pathologists and 3,800 individuals with common forms of chronic kidney disease (CKD) enrolled into the Chronic Renal Insufficiency Cohort (CRIC) Study. EXPOSURE: Histopathologic lesions and clinicopathologic diagnosis in cross-sectional analyses, baseline plasma KIM-1 levels in prospective analyses. OUTCOMES: Baseline plasma KIM-1 levels in cross-sectional analyses, kidney failure (defined as initiation of kidney replacement therapy) and death in prospective analyses. ANALYTICAL APPROACH: Multivariable-adjusted linear regression models tested associations of plasma KIM-1 levels with histopathologic lesions and clinicopathologic diagnoses. Cox proportional hazards models tested associations of plasma KIM-1 levels with future kidney failure and death. RESULTS: In the BKBC Study, higher plasma KIM-1 levels were associated with more severe acute tubular injury, tubulointerstitial inflammation, and more severe mesangial expansion after multivariable adjustment. Participants with diabetic nephropathy, glomerulopathies, and tubulointerstitial disease had significantly higher plasma KIM-1 levels after multivariable adjustment. In the BKBC Study, CKD in 124 participants progressed to kidney failure and 85 participants died during a median follow-up time of 5 years. In the CRIC Study, CKD in 1,153 participants progressed to kidney failure and 1,356 participants died during a median follow-up time of 11.5 years. In both cohorts, each doubling of plasma KIM-1 level was associated with an increased risk of kidney failure after multivariable adjustment (hazard ratios of 1.19 [95% CI, 1.03-1.38] and 1.10 [95% CI, 1.06-1.15] for BKBC and CRIC, respectively). There was no statistically significant association of plasma KIM-1 levels with death in either cohort. LIMITATIONS: Generalizability and unmeasured confounding. CONCLUSIONS: Plasma KIM-1 is associated with underlying tubulointerstitial and mesangial lesions and progression to kidney failure in 2 cohort studies of individuals with kidney diseases.

Risk of Potentially Inappropriate Medications in Adults With CKD: Findings From the Chronic Renal Insufficiency Cohort (CRIC) Study.

RATIONALE & OBJECTIVE: Adults with chronic kidney disease (CKD) may be at increased risk of adverse effects from use of potentially inappropriate medications (PIMs). Our objective was to assess whether PIM exposure has an independent association with CKD progression, hospitalizations, mortality, or falls. STUDY DESIGN: Retrospective observational study. SETTING & PARTICIPANTS: Chronic Renal Insufficiency Cohort (CRIC) study; 3,929 adults with CKD enrolled 2003-2008 and followed prospectively until December 2011. EXPOSURE: PIM exposure was defined as prescriptions for any medications to be avoided in older adults as defined by the 2015 American Geriatrics Society Beers Criteria. OUTCOME: Hospitalization count, death, a composite kidney disease end point of CKD progression or initiation of kidney replacement therapy (KRT), KRT, and fall events assessed 1 year after PIM exposure. ANALYTICAL APPROACH: Logistic regression and Poisson regression to estimate the associations of PIM exposure with each outcome. RESULTS: The most commonly prescribed PIMs were proton pump inhibitors and α-blockers. In unadjusted models, any PIM exposure (compared to none) was associated with hospitalizations, death, and fall events. After adjustment, exposure to 1, 2, or≥3 PIMs had a graded association with a higher hospitalization rate (rate ratios of 1.09 [95% CI, 1.01-1.17], 1.18 [95% CI, 1.07-1.30], and 1.35 [95% CI, 1.19-1.53], respectively) and higher odds of mortality (odds ratios of 1.19 [95% CI, 0.91-1.54], 1.62 [95% CI, 1.21-2.17], and 1.65 [95% CI, 1.14-2.41], respectively). In a cohort subset reporting falls (n=1,109), prescriptions for≥3 PIMs were associated with an increased risk of falls (adjusted OR, 2.85 [95% CI, 1.54-5.26]). PIMs were not associated with CKD progression or KRT. Age did not modify the association between PIM count and outcomes. LIMITATIONS: Measurement bias; confounding by indication. CONCLUSIONS: Adults of any age with CKD who are prescribed PIMs have an increased risk of hospitalization, mortality, and falls with the greatest risk occurring after more than 1 PIM prescription.

Change in Cardiac Biomarkers and Risk of Incident Heart Failure and Atrial Fibrillation in CKD: The Chronic Renal Insufficiency Cohort (CRIC) Study.

RATIONALE & OBJECTIVE: Circulating cardiac biomarkers may signal potential mechanistic pathways involved in heart failure (HF) and atrial fibrillation (AF). Single measures of circulating cardiac biomarkers are strongly associated with incident HF and AF in chronic kidney disease (CKD). We tested the associations of longitudinal changes in the N-terminal fragment of the prohormone brain natriuretic peptide (NT-proBNP), high-sensitivity troponin T (hsTnT), galectin-3, growth differentiation factor 15 (GDF-15), and soluble ST-2 (sST-2) with incident HF and AF in patients with CKD. STUDY DESIGN: Observational, case-cohort study design. SETTING & PARTICIPANTS: Adults with CKD enrolled in the Chronic Renal Insufficiency Cohort study. EXPOSURES: Biomarkers were measured at baseline and 2 years later among those without kidney failure. We created 3 categories of absolute change in each biomarker: the lowest quartile, the middle 2 quartiles, and the top quartile. OUTCOMES: The primary outcomes were incident HF and AF. ANALYTICAL APPROACH: Cox proportional hazards regression models were used to test the associations of the change categories of each cardiac biomarker with each outcome (with the middle 2 quartiles of change as the referent group), adjusting for potential confounders and baseline concentrations of each biomarker. RESULTS: The incident HF analysis included 789 participants (which included 138 incident HF cases), and the incident AF analysis included 774 participants (123 incident AF cases). In multivariable models, the top quartile of NT-proBNP change (>232pg/mL over 2years) was associated with increased risk of incident HF (HR, 1.79 [95% CI, 1.06-3.04]) and AF (HR, 2.32 [95% CI, 1.37-3.93]) compared with the referent group. Participants in the top quartile of sST2 change (>3.37ng/mL over 2years) had significantly greater risk of incident HF (HR, 1.89 [95% CI, 1.13-3.16]), whereas those in the bottom quartile (≤-3.78ng/mL over 2years) had greater risk of incident AF (HR, 2.43 [95% CI, 1.39-4.22]) compared with the 2 middle quartiles. There was no association of changes in hsTnT, galectin-3, or GDF-15 with incident HF or AF. LIMITATIONS: Observational study. CONCLUSIONS: In CKD, increases in NT-proBNP were significantly associated with greater risk of incident HF and AF, and increases in sST2 were associated with HF. Further studies should investigate whether these markers of subclinical cardiovascular disease can be modified to reduce the risk of cardiovascular disease in CKD.

Novel Risk Factors for Progression of Diabetic and Nondiabetic CKD: Findings From the Chronic Renal Insufficiency Cohort (CRIC) Study.

RATIONALE & OBJECTIVE: Identification of novel risk factors for chronic kidney disease (CKD) progression may inform mechanistic investigations and improve identification of high-risk subgroups. The current study aimed to characterize CKD progression across levels of numerous risk factors and identify independent risk factors for CKD progression among those with and without diabetes. STUDY DESIGN: The Chronic Renal Insufficiency Cohort (CRIC) Study is a prospective cohort study of adults with CKD conducted at 7 US clinical centers. SETTING & PARTICIPANTS: Participants (N=3,379) had up to 12.3 years of follow-up; 47% had diabetes. PREDICTORS: 30 risk factors for CKD progression across sociodemographic, behavioral, clinical, and biochemical domains at baseline. OUTCOMES: Study outcomes were estimated glomerular filtration rate (eGFR) slope and the composite of halving of eGFR or initiation of kidney replacement therapy. ANALYTICAL APPROACH: Stepwise selection of independent risk factors was performed stratified by diabetes status using linear mixed-effects and Cox proportional hazards models. RESULTS: Among those without and with diabetes, respectively, mean eGFR slope was-1.4±3.3 and-2.7±4.7mL/min/1.73m2 per year. Among participants with diabetes, multivariable-adjusted hazard of the composite outcome was approximately 2-fold or greater with higher levels of the inflammatory chemokine CXCL12, the cardiac marker N-terminal pro-B-type natriuretic peptide (NT-proBNP), and the kidney injury marker urinary neutrophil gelatinase-associated lipocalin (NGAL). Among those without diabetes, low serum bicarbonate and higher high-sensitivity troponin T, NT-proBNP, and urinary NGAL levels were all significantly associated with a 1.5-fold or greater rate of the composite outcome. LIMITATIONS: The observational study design precludes causal inference. CONCLUSIONS: Strong associations for cardiac markers, plasma CXCL12, and urinary NGAL are comparable to that of systolic blood pressure≥140mm Hg, a well-established risk factor for CKD progression. This warrants further investigation into the potential mechanisms that these markers indicate and opportunities to use them to improve risk stratification.

Association of circulating cardiac biomarkers with electrocardiographic abnormalities in chronic kidney disease.

BACKGROUND: Among patients with chronic kidney disease (CKD), the circulating cardiac biomarkers soluble ST2 (SST2), galectin-3, growth differentiation factor-15 (GDF-15), N-terminal pro-B-type natriuretic peptide (NT-proBNP) and high-sensitivity troponin-T (hsTnT) possibly reflect pathophysiologic processes and are associated with clinical cardiovascular disease. Whether these biomarkers are associated with electrocardiographic findings is not known. The aim of this study was to test the association between serum cardiac biomarkers and the presence of electrocardiographic changes potentially indicative of subclinical myocardial disease in patients with CKD. METHODS: We performed a cross-sectional analysis using 3048 participants from the Chronic Renal Insufficiency Cohort (CRIC) without atrial fibrillation, atrioventricular block, bundle branch block or a pacemaker at the baseline visit. Using logistic regression, we tested the association of each of the five cardiac biomarkers with baseline electrocardiogram (ECG) findings: PR interval >200 ms, QRS interval >100 ms and a prolonged QTc interval. Models were adjusted for demographic variables, measures of kidney function, prevalent cardiovascular disease and cardiovascular risk factors. RESULTS: In adjusted models, hsTnT levels associated with prolonged PR {odds ratio [OR] 1.23 [95% confidence interval (CI) 1.08-1.40]}, QRS [OR 1.28 (95% CI 1.16-1.42)] and QTc [OR 1.94 (95% CI 1.50-2.51)] intervals. NT-proBNP levels were associated with prolonged QRS [OR 1.11 (95% CI 1.06-1.16)] and QTc [OR 1.82 (95% CI 1.58-2.10)] intervals. SST2, galectin-3 and GDF-15 were not significantly associated with any of the ECG parameters. CONCLUSIONS: hsTnT and NT-proBNP were associated with ECG measures indicative of subclinical myocardial dysfunction. These results may support future research investigating the significance of myocardial ischemia and volume overload in the pathogenesis of dysfunctional myocardial conduction in CKD.

Physical activity and risk of cardiovascular events and all-cause mortality among kidney transplant recipients.

BACKGROUND: Insufficient physical activity (PA) may increase the risk of all-cause mortality and cardiovascular disease (CVD) morbidity and mortality among kidney transplant recipients (KTRs), but limited research is available. We examine the relationship between PA and the development of CVD events, CVD death and all-cause mortality among KTRs. METHODS: A total of 3050 KTRs enrolled in an international homocysteine-lowering randomized controlled trial were examined (38% female; mean age 51.8 ± 9.4 years; 75% white; 20% with prevalent CVD). PA was measured at baseline using a modified Yale Physical Activity Survey, divided into tertiles (T1, T2 and T3) from lowest to highest PA. Kaplan-Meier survival curves were used to graph the risk of events; Cox proportional hazards regression models examined the association of baseline PA levels with CVD events (e.g. stroke, myocardial infarction), CVD mortality and all-cause mortality over time. RESULTS: Participants were followed up to 2500 days (mean 3.7 ± 1.6 years). The cohort experienced 426 CVD events and 357 deaths. Fully adjusted models revealed that, compared to the lowest tertile of PA, the highest tertile experienced a significantly lower risk of CVD events {hazard ratio [HR] 0.76 [95% confidence interval (CI) 0.59-0.98]}, CVD mortality [HR 0.58 (95% CI 0.35-0.96)] and all-cause mortality [HR 0.76 (95% CI 0.59-0.98)]. Results were similar in unadjusted models. CONCLUSIONS: PA was associated with a reduced risk of CVD events and all-cause mortality among KTRs. These observed associations in a large, international sample, even when controlling for traditional CVD risk factors, indicate the potential importance of PA in reducing CVD and death among KTRs.

Impact of AKI on Urinary Protein Excretion: Analysis of Two Prospective Cohorts.

BACKGROUND: Prior studies of adverse renal consequences of AKI have almost exclusively focused on eGFR changes. Less is known about potential effects of AKI on proteinuria, although proteinuria is perhaps the strongest risk factor for future loss of renal function. METHODS: We studied enrollees from the Assessment, Serial Evaluation, and Subsequent Sequelae of AKI (ASSESS-AKI) study and the subset of the Chronic Renal Insufficiency Cohort (CRIC) study enrollees recruited from Kaiser Permanente Northern California. Both prospective cohort studies included annual ascertainment of urine protein-to-creatinine ratio, eGFR, BP, and medication use. For hospitalized participants, we used inpatient serum creatinine measurements obtained as part of clinical care to define an episode of AKI (i.e., peak/nadir inpatient serum creatinine ≥1.5). We performed mixed effects regression to examine change in log-transformed urine protein-to-creatinine ratio after AKI, controlling for time-updated covariates. RESULTS: At cohort entry, median eGFR was 62.9 ml/min per 1.73 m2 (interquartile range [IQR], 46.9-84.6) among 2048 eligible participants, and median urine protein-to-creatinine ratio was 0.12 g/g (IQR, 0.07-0.25). After enrollment, 324 participants experienced at least one episode of hospitalized AKI during 9271 person-years of follow-up; 50.3% of first AKI episodes were Kidney Disease Improving Global Outcomes stage 1 in severity, 23.8% were stage 2, and 25.9% were stage 3. In multivariable analysis, an episode of hospitalized AKI was independently associated with a 9% increase in the urine protein-to-creatinine ratio. CONCLUSIONS: Our analysis of data from two prospective cohort studies found that hospitalization for an AKI episode was independently associated with subsequent worsening of proteinuria.

Cardiac and Stress Biomarkers and Chronic Kidney Disease Progression: The CRIC Study.

BACKGROUND: Increases in cardiac and stress biomarkers may be associated with loss of kidney function through shared mechanisms involving cardiac and kidney injury. We evaluated the associations of cardiac and stress biomarkers [N-terminal pro-B-type natriuretic peptide (NT-proBNP), high-sensitivity troponin T (hsTnT), growth differentiation factor 15 (GDF-15), soluble ST-2 (sST-2)] with progression of chronic kidney disease (CKD). METHODS: We included 3664 participants with CKD from the Chronic Renal Insufficiency Cohort study. All biomarkers were measured at entry. The primary outcome was CKD progression, defined as progression to end-stage renal disease (ESRD) or 50% decline in estimated glomerular filtration rate (eGFR). Cox models tested the association of each biomarker with CKD progression, adjusting for demographics, site, diabetes, cardiovascular disease, eGFR, urine proteinuria, blood pressure, body mass index, cholesterol, medication use, and mineral metabolism. RESULTS: There were 1221 participants who had CKD progression over a median (interquartile range) follow-up of 5.8 (2.4-8.6) years. GDF-15, but not sST2, was significantly associated with an increased risk of CKD progression [hazard ratios (HRs) are per SD increase in log-transformed biomarker]: GDF-15 (HR, 1.50; 95% CI, 1.35-1.67) and sST2 (HR, 1.07; 95% CI, 0.99-1.14). NT-proBNP and hsTnT were also associated with increased risk of CKD progression, but weaker than GDF-15: NT-proBNP (HR, 1.24; 95% CI, 1.13-1.36) and hsTnT (HR, 1.11; 95% CI, 1.01-1.22). CONCLUSIONS: Increases in GDF-15, NT-proBNP, and hsTnT are associated with greater risk for CKD progression. These biomarkers may inform mechanisms underlying kidney injury.

Incident Type 2 Diabetes Among Individuals With CKD: Findings From the Chronic Renal Insufficiency Cohort (CRIC) Study.

RATIONALE & OBJECTIVE: Few studies have examined incident type 2 diabetes mellitus (T2DM) in chronic kidney disease (CKD). Our objective was to examine rates of and risk factors for T2DM in CKD, using several alternative measures of glycemic control. STUDY DESIGN: Prospective cohort study. SETTING & PARTICIPANTS: 1,713 participants with reduced glomerular filtration rates and without diabetes at baseline, enrolled in the Chronic Renal Insufficiency Cohort (CRIC) Study. PREDICTORS: Measures of kidney function and damage, fasting blood glucose, hemoglobin A1c (HbA1c), HOMA-IR (homeostatic model assessment of insulin resistance), demographics, family history of diabetes mellitus (DM), smoking status, medication use, systolic blood pressure, triglyceride level, high-density lipoprotein cholesterol level, body mass index, and physical activity. OUTCOME: Incident T2DM (defined as fasting blood glucose ≥ 126mg/dL or prescription of insulin or oral hypoglycemic agents). ANALYTICAL APPROACH: Concordance between fasting blood glucose and HbA1c levels was assessed using κ. Cause-specific hazards modeling, treating death and end-stage kidney disease as competing events, was used to predict incident T2DM. RESULTS: Overall T2DM incidence rate was 17.81 cases/1,000 person-years. Concordance between fasting blood glucose and HbA1c levels was low (κ for categorical versions of fasting blood glucose and HbA1c = 13%). Unadjusted associations of measures of kidney function and damage with incident T2DM were nonsignificant (P ≥ 0.4). In multivariable models, T2DM was significantly associated with fasting blood glucose level (P = 0.002) and family history of DM (P = 0.03). The adjusted association of HOMA-IR with T2DM was comparable to that of fasting blood glucose level; the association of HbA1c level was nonsignificant (P ≥ 0.1). Harrell's C for the models ranged from 0.62 to 0.68. LIMITATIONS: Limited number of outcome events; predictors limited to measures taken at baseline. CONCLUSIONS: The T2DM incidence rate among individuals with CKD is markedly higher than in the general population, supporting the need for greater vigilance in this population. Measures of glycemic control and family history of DM were independently associated with incident T2DM.

Single Measurements of Carboxy-Terminal Fibroblast Growth Factor 23 and Clinical Risk Prediction of Adverse Outcomes in CKD.

RATIONALE & OBJECTIVE: An elevated fibroblast growth factor 23 (FGF-23) level is independently associated with adverse outcomes in populations with chronic kidney disease, but it is unknown whether FGF-23 testing can improve clinical risk prediction in individuals. STUDY DESIGN: Prospective cohort study. SETTING & PARTICIPANTS: Participants in the Chronic Renal Insufficiency Cohort (CRIC) Study (n = 3,789). EXPOSURE: Baseline carboxy-terminal FGF-23 (cFGF-23) level. OUTCOMES: All-cause and cardiovascular (CV) mortality, incident end-stage renal disease (ESRD), heart failure (HF) admission, and atherosclerotic events at 3, 5, and 8 years. ANALYTICAL APPROACH: We assessed changes in model performance by change in area under the receiver operating characteristic curve (ΔAUC), integrated discrimination improvement (IDI), relative IDI, and net reclassification index (NRI) above standard clinical factors. We performed sensitivity analyses, including an additional model comparing the addition of phosphate rather than cFGF-23 level and repeating our analyses using an internal cross-validation cohort. RESULTS: Addition of a single baseline value of cFGF-23 to a base prediction model improved prediction of all-cause mortality (ΔAUC, 0.017 [95% CI, 0.001-0.033]; IDI, 0.021 [95% CI, 0.006-0.036]; relative IDI, 32.7% [95% CI, 8.5%-56.9%]), and HF admission (ΔAUC, 0.008 [95% CI, 0.0004-0.016]; IDI, 0.019 [95% CI, 0.004-0.034]; relative IDI, 10.0% [95% CI, 1.8%-18.3%]), but not CV mortality, ESRD, or atherosclerotic events at 3 years of follow-up. The NRI did not reach statistical significance for any of the 3-year outcomes. The incremental predictive utility of cFGF-23 level diminished in analyses of the 5- and 8-year outcomes. The cFGF-23 models outperformed the phosphate model for each outcome. LIMITATIONS: Power to detect increased CV mortality likely limited by low event rate. The NRI is not generalizable without accepted prespecified risk thresholds. CONCLUSIONS: Among individuals with CKD, single measurements of cFGF-23 improve prediction of risks for all-cause mortality and HF admission but not CV mortality, ESRD, or atherosclerotic events. Future studies should evaluate the predictive utility of repeated cFGF-23 testing.

Use of Measures of Inflammation and Kidney Function for Prediction of Atherosclerotic Vascular Disease Events and Death in Patients With CKD: Findings From the CRIC Study.

RATIONALE & OBJECTIVE: Traditional risk estimates for atherosclerotic vascular disease (ASVD) and death may not perform optimally in the setting of chronic kidney disease (CKD). We sought to determine whether the addition of measures of inflammation and kidney function to traditional estimation tools improves prediction of these events in a diverse cohort of patients with CKD. STUDY DESIGN: Observational cohort study. SETTING & PARTICIPANTS: 2,399 Chronic Renal Insufficiency Cohort (CRIC) Study participants without a history of cardiovascular disease at study entry. PREDICTORS: Baseline plasma levels of biomarkers of inflammation (interleukin 1ß [IL-1ß], IL-1 receptor antagonist, IL-6, tumor necrosis factor α [TNF-α], transforming growth factor ß, high-sensitivity C-reactive protein, fibrinogen, and serum albumin), measures of kidney function (estimated glomerular filtration rate [eGFR] and albuminuria), and the Pooled Cohort Equation probability (PCEP) estimate. OUTCOMES: Composite of ASVD events (incident myocardial infarction, peripheral arterial disease, and stroke) and death. ANALYTICAL APPROACH: Cox proportional hazard models adjusted for PCEP estimates, albuminuria, and eGFR. RESULTS: During a median follow-up of 7.3 years, 86, 61, 48, and 323 participants experienced myocardial infarction, peripheral arterial disease, stroke, or death, respectively. The 1-decile greater levels of IL-6 (adjusted HR [aHR], 1.12; 95% CI, 1.08-1.16; P<0.001), TNF-α (aHR, 1.09; 95% CI, 1.05-1.13; P<0.001), fibrinogen (aHR, 1.07; 95% CI, 1.03-1.11; P<0.001), and serum albumin (aHR, 0.96; 95% CI, 0.93-0.99; P<0.002) were independently associated with the composite ASVD-death outcome. A composite inflammation score (CIS) incorporating these 4 biomarkers was associated with a graded increase in risk for the composite outcome. The incidence of ASVD-death increased across the quintiles of risk derived from PCEP, kidney function, and CIS. The addition of eGFR, albuminuria, and CIS to PCEP improved (P=0.003) the area under the receiver operating characteristic curve for the composite outcome from 0.68 (95% CI, 0.66-0.71) to 0.73 (95% CI, 0.71-0.76). LIMITATIONS: Data for cardiovascular death were not available. CONCLUSIONS: Biomarkers of inflammation and measures of kidney function are independently associated with incident ASVD events and death in patients with CKD. Traditional cardiovascular risk estimates could be improved by adding markers of inflammation and measures of kidney function.

Albuminuria and Allograft Failure, Cardiovascular Disease Events, and All-Cause Death in Stable Kidney Transplant Recipients: A Cohort Analysis of the FAVORIT Trial.

RATIONALE & OBJECTIVE: Cardiovascular disease (CVD) is common and overall graft survival is suboptimal among kidney transplant recipients. Although albuminuria is a known risk factor for adverse outcomes among persons with native chronic kidney disease, the relationship of albuminuria with cardiovascular and kidney outcomes in transplant recipients is uncertain. STUDY DESIGN: Post hoc longitudinal cohort analysis of the Folic Acid for Vascular Outcomes Reduction in Transplantation (FAVORIT) Trial. SETTING & PARTICIPANTS: Stable kidney transplant recipients with elevated homocysteine levels from 30 sites in the United States, Canada, and Brazil. PREDICTOR: Urine albumin-creatinine ratio (ACR) at randomization. OUTCOMES: Allograft failure, CVD, and all-cause death. ANALYTICAL APPROACH: Multivariable Cox models adjusted for age; sex; race; randomized treatment allocation; country; systolic and diastolic blood pressure; history of CVD, diabetes, and hypertension; smoking; cholesterol; body mass index; estimated glomerular filtration rate (eGFR); donor type; transplant vintage; medications; and immunosuppression. RESULTS: Among 3,511 participants with complete data, median ACR was 24 (Q1-Q3, 9-98) mg/g, mean eGFR was 49±18 (standard deviation) mL/min/1.73m2, mean age was 52±9 years, and median graft vintage was 4.1 (Q1-Q3, 1.7-7.4) years. There were 1,017 (29%) with ACR < 10mg/g, 912 (26%) with ACR of 10 to 29mg/g, 1,134 (32%) with ACR of 30 to 299mg/g, and 448 (13%) with ACR ≥ 300mg/g. During approximately 4 years, 282 allograft failure events, 497 CVD events, and 407 deaths occurred. Event rates were higher at both lower eGFRs and higher ACR. ACR of 30 to 299 and ≥300mg/g relative to ACR < 10mg/g were independently associated with graft failure (HRs of 3.40 [95% CI, 2.19-5.30] and 9.96 [95% CI, 6.35-15.62], respectively), CVD events (HRs of 1.25 [95% CI, 0.96-1.61] and 1.55 [95% CI, 1.13-2.11], respectively), and all-cause death (HRs of 1.65 [95% CI, 1.23-2.21] and 2.07 [95% CI, 1.46-2.94], respectively). LIMITATIONS: No data for rejection; single ACR assessment. CONCLUSIONS: In a large population of stable kidney transplant recipients, elevated baseline ACR is independently associated with allograft failure, CVD, and death. Future studies are needed to evaluate whether reducing albuminuria improves these outcomes.

Mineral Metabolism Disturbances and Arteriovenous Fistula Maturation.

BACKGROUND: The arteriovenous fistula (AVF) is central to haemodialysis treatment, but up to half of surgically created AVF fail to mature. Chronic kidney disease often leads to mineral metabolism disturbances that may interfere with AVF maturation through adverse vascular effects. This study tested associations between mineral metabolism markers and vein histology at AVF creation and unassisted and overall clinical AVF maturation. METHODS: Concentrations of fibroblast growth factor 23, parathyroid hormone, calcium, phosphate, and vitamin D metabolites: 1,25(OH)2D, 24,25(OH)2D, 25(OH)D, and bioavailable 25(OH)D were measured in pre-operative serum samples from 562 of 602 participants in the Haemodialysis Fistula Maturation Study, a multicentre, prospective cohort study of patients undergoing surgical creation of an autologous upper extremity AVF. Unassisted and overall AVF maturation were ascertained for 540 and 527 participants, respectively, within nine months of surgery or four weeks of dialysis initiation. Study personnel obtained vein segments adjacent to the portion of the vein used for anastomosis, which were processed, embedded, and stained for measurement of neointimal hyperplasia, calcification, and collagen deposition in the medial wall. RESULTS: Participants in this substudy were 71% male, 43% black, and had a mean age of 55 years. Failure to achieve AVF maturation without assistance occurred in 288 (53%) participants for whom this outcome was determined. In demographic and further adjusted models, mineral metabolism markers were not significantly associated with vein histology characteristics, unassisted AVF maturation failure, or overall maturation failure, other than a biologically unexplained association of higher 24,25(OH)2D with overall failure. This exception aside, associations were non-significant for continuous and categorical analyses and relevant subgroups. CONCLUSIONS: Serum concentrations of measured mineral metabolites were not substantially associated with major histological characteristics of veins in patients undergoing AVF creation surgery, or with AVF maturation failure, suggesting that efforts to improve AVF maturation rates should increase attention to other processes such as vein mechanics, anatomy, and cellular metabolism among end stage renal disease patients.

Cardiovascular Events after New-Onset Atrial Fibrillation in Adults with CKD: Results from the Chronic Renal Insufficiency Cohort (CRIC) Study.

BACKGROUND: Atrial fibrillation (AF), the most common sustained arrhythmia in CKD, is associated with poor clinical outcomes in both patients without CKD and patients with dialysis-treated ESRD. However, less is known about AF-associated outcomes in patients with CKD who do not require dialysis. METHODS: To prospectively examine the association of new-onset AF with subsequent risks of cardiovascular disease events and death among adults with CKD, we studied participants enrolled in the Chronic Renal Insufficiency Cohort Study who did not have AF at baseline. Outcomes included heart failure, myocardial infarction, stroke, and death occurring after diagnosis of AF. We used Cox regression models and marginal structural models to examine the association of incident AF with subsequent risk of cardiovascular disease events and death, adjusting for patient characteristics, laboratory values, and medication use. RESULTS: Among 3080 participants, 323 (10.5%) developed incident AF during a mean 6.1 years of follow-up. Compared with participants who did not develop AF, those who did had higher adjusted rates of heart failure (hazard ratio [HR], 5.17; 95% confidence interval [95% CI], 3.89 to 6.87), myocardial infarction (HR, 3.64; 95% CI, 2.50 to 5.31), stroke (HR, 2.66; 95% CI, 1.50 to 4.74), and death (HR, 3.30; 95% CI, 2.65 to 4.12). These associations remained robust with additional adjustment for biomarkers of inflammation, cardiac stress, and mineral metabolism; left ventricular mass; ejection fraction; and left atrial diameter. CONCLUSIONS: Incident AF is independently associated with two- to five-fold increased rates of developing subsequent heart failure, myocardial infarction, stroke, or death in adults with CKD. These findings have important implications for cardiovascular risk reduction.

Prediction of Arteriovenous Fistula Clinical Maturation from Postoperative Ultrasound Measurements: Findings from the Hemodialysis Fistula Maturation Study.

BACKGROUND: The utility of early postoperative ultrasound measurements in predicting arteriovenous fistula (AVF) clinical maturation is uncertain. METHODS: We investigated the relationships of ultrasound parameters with AVF clinical maturation in newly created AVF, measured at 1 day and 2 and 6 weeks, in 602 participants of a multicenter, observational cohort study. A backward elimination algorithm identified ultrasound measurements that independently predicted unassisted and overall AVF maturation. Candidate variables included AVF blood flow, diameter, and depth, upper arm arterial diameter, presence of stenosis, presence of accessory veins, seven case-mix factors (age, sex, black race, AVF location, diabetes, dialysis status, and body mass index), and clinical center. We evaluated the accuracy of the resulting models for clinical prediction. RESULTS: At each ultrasound measurement time, AVF blood flow, diameter, and depth each predicted in a statistically significant manner both unassisted and overall clinical maturation. Moreover, neither the remaining ultrasound parameters nor case-mix factors were associated with clinical AVF maturation after accounting for blood flow, diameter, and depth, although maturation probabilities differed among clinical centers before and after accounting for these parameters. The crossvalidated area under the receiver operating characteristic curve for models constructed using these three ultrasound parameters was 0.69, 0.74, and 0.79 at 1 day and 2 and 6 weeks, respectively, for unassisted AVF clinical maturation and 0.69, 0.71, and 0.76, respectively, for overall AVF maturation. CONCLUSIONS: AVF blood flow, diameter, and depth moderately predicted unassisted and overall AVF clinical maturation. The other factors considered did not further improve AVF maturation prediction.

Longitudinal FGF23 Trajectories and Mortality in Patients with CKD.

Elevated fibroblast growth factor 23 (FGF23) levels, measured at a single time, are strongly associated with increased risk of mortality in patients with CKD. There are minimal data on serial FGF23 measurements in CKD. In a prospective case-cohort study of the Chronic Renal Insufficiency Cohort, we measured FGF23 at two to five annual time points (mean 4.0±1.2) in a randomly selected subcohort of 1135 participants, of whom 203 died, and all remaining 390 participants who died through mid-2013. Higher FGF23 was independently associated with increased risk of death in multivariable-adjusted analyses of time-varying FGF23 (hazard ratio per 1-SD increase in ln-transformed FGF23, 1.84; 95% CI, 1.67 to 2.03). Median FGF23 was stable over 5 years of follow-up, but its gradually right-skewed distribution suggested a subpopulation with markedly elevated FGF23. Trajectory analysis revealed three distinct trajectories: stable FGF23 in the majority of participants (slope of lnFGF23 per year =0.03, 95% CI, 0.02 to 0.04, n=724) and smaller subpopulations with slowly (slope=0.14, 95% CI, 0.12 to 0.16, n=486) or rapidly (slope=0.46, 95% CI, 0.38 to 0.54, n=99) rising levels. Compared with stable FGF23, participants with slowly rising FGF23 trajectories were at 4.49-fold higher risk of death (95% CI, 3.17 to 6.35) and individuals with rapidly rising FGF23 trajectories were at 15.23-fold higher risk of death (95% CI, 8.24 to 28.14) in fully adjusted analyses. Trajectory analyses that used four or three annual FGF23 measurements yielded qualitatively similar results. In conclusion, FGF23 levels are stable over time in the majority of patients with CKD, but serial measurements identify subpopulations with rising levels and exceptionally high risk of death.

A Behavioral Weight Loss Program and Nonurinary Incontinence Lower Urinary Tract Symptoms in Overweight and Obese Women with Urinary Incontinence: A Secondary Data Analysis of PRIDE.

PURPOSE: We sought to determine whether a behavioral weight reduction intervention would improve nonurinary incontinence lower urinary tract storage symptoms at 6 months, including urinary frequency, nocturia and urgency, compared to a structured education program serving as the control group among overweight and obese women with urinary incontinence. MATERIALS AND METHODS: PRIDE (Program to Reduce Incontinence by Diet and Exercise) was a randomized clinical trial performed in 338 overweight or obese women with urinary incontinence. Participants were randomized, including 226 to 6-month behavioral weight loss intervention and 112 to the control group. All participants received a self-help behavioral treatment booklet to improve bladder control. On this secondary data analysis we examined changes in nonurinary incontinence lower urinary tract storage symptoms from baseline to 6 months and the impact of treatment allocation (intervention vs control), weight loss and physical activity. RESULTS: Nonurinary incontinence lower urinary tract storage symptoms were common at baseline, varying from 48% to 62%. In the 2 groups combined women experienced significant improvement in nocturia, urgency and International Prostate Symptom Score at 6 months (all p <0.001). However, lower urinary tract storage symptom outcomes at 6 months did not differ between the intervention and control groups. Similarly no difference was observed in the amount of weight lost (5% or greater vs less than 5%) or physical activity (1,500 kcal or greater expenditure per week compared to less than 1,500 kcal). CONCLUSIONS: Lower urinary tract storage symptoms were common among overweight and obese women with urinary incontinence. The prevalence decreased significantly after 6 months independent of treatment group assignment, amount of weight lost or physical activity. These improvements may have been due to self-help behavioral educational materials, trial participation or repeat assessment of symptoms.

Correlates of Health Care Seeking Activities in Patients with Urological Chronic Pelvic Pain Syndromes: Findings from the MAPP Cohort.

PURPOSE: We examined health care seeking activities during a 12-month period in a cohort of men and women with urological chronic pelvic pain syndromes. MATERIALS AND METHODS: A total of 191 men and 233 women with urological chronic pelvic pain syndrome were followed with biweekly, Internet based questionnaires about symptoms and health care seeking activities, including 1) health care provider contacts, 2) office visits, 3) emergency room/urgent care visits, 4) medication changes and 5) medical procedures. Multivariable modeling was used to determine the association of demographic and clinical variables with health care seeking. Super users were defined as individuals who reported health care seeking activity at least 11 times during the 23 biweekly assessments. RESULTS: Health care seeking activities included a mean of 2.4 office contacts, 2.5 office visits, 1.9 medication changes, 0.9 medical procedures and 0.3 emergency room/urgent care visits. A total of 31 health care seeking super users accounted for 26% of health care seeking activities. Worse baseline pain severity and female gender were associated with a higher rate of all health care seeking activities except emergency room/urgent care visits. A nonurological chronic pain condition was associated with more provider contacts, office visits and medical procedures. Greater baseline depression symptoms were associated with more provider contacts, office visits and medication changes. Other examined variables, including patient age, symptom duration, catastrophizing, anxiety, urinary symptom severity and symptom variability, had a minimal association with health care seeking. CONCLUSIONS: Health care seeking activities were strongly influenced by the severity of pain in patients with urological chronic pelvic pain syndromes but not by urinary symptom severity. Women and patients with nonurological overlapping pain conditions were more likely to be seen and treated for symptoms.

Mental Health, Sleep and Physical Function in Treatment Seeking Women with Urinary Incontinence.

PURPOSE: We examined how mental health measures, sleep and physical function are associated with the presence and type of urinary incontinence and severity in women seeking treatment for lower urinary tract symptoms. MATERIALS AND METHODS: This baseline cross-sectional analysis was performed in treatment seeking women with lower urinary tract symptoms. All participants completed the LUTS (Lower Urinary Tract Symptoms) Tool (Pfizer, New York, New York), which was used to classify women based on urinary incontinence symptoms and measure severity. The PROMIS (Patient-Reported Outcomes Measurement Information System) questionnaire for depression, anxiety, sleep disturbance and physical function, the PSS (Perceived Stress Scale) and the IPAQ-SF (International Physical Activity Questionnaire Short Form) were administered. Multivariable regression modeling was done to assess associations with urinary symptom presence, type and severity. RESULTS: We studied 510 women with a mean ± SD age of 56 ± 14 years. Of the women 82% were Caucasian, 47% were obese and 14% reported diabetes. Urinary incontinence was reported by 420 women (82.4%), including stress urinary incontinence in 70, urgency urinary incontinence in 85, mixed urinary incontinence in 240 and other urinary incontinence in 25. On adjusted analyses there was no difference in any mental health, sleep or physical function measure based on the presence vs the absence of urinary incontinence. Among women with urinary incontinence PROMIS anxiety and sleep disturbance scores were higher in those with mixed urinary incontinence than stress urinary incontinence. Increasing urinary incontinence severity was associated with higher PROMIS depression and anxiety scores, and higher PSS scores. However, higher urinary incontinence severity was not associated with a difference in sleep or physical function. CONCLUSIONS: Among treatment seeking women with lower urinary tract symptoms, increasing urinary incontinence severity rather than the presence or type of urinary incontinence was associated with increased depression, anxiety and stress.

Baseline Lower Urinary Tract Symptoms in Patients Enrolled in LURN: A Prospective, Observational Cohort Study.

PURPOSE: We described and compared the frequency and type of lower urinary tract symptoms reported by men and women at the time that they were recruited from urology and urogynecology clinics into the Symptoms of Lower Urinary Tract Dysfunction Research Network multicenter, prospective, observational cohort study. MATERIALS AND METHODS: At 6 research sites treatment seeking men and women were enrolled who reported any lower urinary tract symptoms at a frequency more than rarely during the last month on the LUTS (Lower Urinary Tract Symptoms) Tool. At baseline the study participants underwent a standardized clinical evaluation and completed validated questionnaires. Urological tests were performed, including pelvic/rectal examination, post-void residual urine measurement and urinalysis. RESULTS: A total of 545 women and 519 men were enrolled in the study. Mean ± SD age was 58.8 ± 14.1 years. At baseline nocturia, frequency and a sensation of incomplete emptying were similar in men and women but men experienced more voiding symptoms (90% vs 85%, p = 0.007) and women reported more urgency (85% vs 66%, p <0.001). Women also reported more of any type of urinary incontinence than men (82% vs 51% p <0.001), which was mixed incontinence in 57%. Only 1% of men reported stress incontinence but they had other urinary incontinence, including post-void dribbling in 44% and urgency incontinence in 46%. Older participants had higher odds of reporting symptoms of nocturia and urgency. CONCLUSIONS: In this large, treatment seeking cohort of men and women lower urinary tract symptoms varied widely by gender and age. Men reported more voiding symptoms and nonstress or urgency urinary incontinence while women reported more incontinence overall and urgency. Older participants had greater odds of urgency and nocturia.