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Chronic kidney disease (CKD) is a major global public health problem with significant gaps in research, care, and policy. In order to mitigate the risks and adverse effects of CKD, the International Society of Nephrology has created a cohesive set of activities to improve the global outcomes of people living with CKD. Improving monitoring of renal disease progression can be done by screening and monitoring albuminuria and estimated glomerular filtration rate in primary care. Consensus on how many times and how often albuminuria and estimated glomerular filtration rate are measured should be defined. Meaningful changes in both renal biomarkers should be determined in order to ascertain what is clinically relevant. Increasing social awareness of CKD and partnering with the technological community may be ways to engage patients. Furthermore, improving the prediction of cardiovascular events in patients with CKD can be achieved by including the renal risk markers albuminuria and estimated glomerular filtration rate in cardiovascular risk algorithms and by encouraging uptake of assessing cardiovascular risk by general practitioners and nephrologists. Finally, examining ways to further validate and implement novel biomarkers for CKD will help mitigate the global problem of CKD. The more frequent use of renal biopsy will facilitate further knowledge into the underlying etiologies of CKD and help put new biomarkers into biological context. Real-world assessments of these biomarkers in existing cohorts is important, as well as obtaining regulatory approval to use these biomarkers in clinical practice. Collaborations among academia, physician and patient groups, industry, payer organizations, and regulatory authorities will help improve the global outcomes of people living with CKD. Copyright (C) 2017, International Society of Nephrology. Published by Elsevier Inc. All rights reserved.

Item does not contain fulltext BACKGROUND: Change in albuminuria as a surrogate endpoint for progression of chronic kidney disease is strongly supported by biological plausibility, but empirical evidence to support its validity in epidemiological studies is lacking. We aimed to assess the consistency of the association between change in albuminuria and risk of end-stage kidney disease in a large individual participant-level meta-analysis of observational studies. METHODS: In this meta-analysis, we collected individual-level data from eligible cohorts in the Chronic Kidney Disease Prognosis Consortium (CKD-PC) with data on serum creatinine and change in albuminuria and more than 50 events on outcomes of interest. Cohort data were eligible if participants were aged 18 years or older, they had a repeated measure of albuminuria during an elapsed period of 8 months to 4 years, subsequent end-stage kidney disease or mortality follow-up data, and the cohort was active during this consortium phase. We extracted participant-level data and quantified percentage change in albuminuria, measured as change in urine albumin-to-creatinine ratio (ACR) or urine protein-to-creatinine ratio (PCR), during baseline periods of 1, 2, and 3 years. Our primary outcome of interest was development of end-stage kidney disease after a baseline period of 2 years. We defined an end-stage kidney disease event as initiation of kidney replacement therapy. We quantified associations of percentage change in albuminuria with subsequent end-stage kidney disease using Cox regression in each cohort, followed by random-effects meta-analysis. We further adjusted for regression dilution to account for imprecision in the estimation of albuminuria at the participant level. We did multiple subgroup analyses, and also repeated our analyses using participant-level data from 14 clinical trials, including nine clinical trials not in CKD-PC. FINDINGS: Between July, 2015, and June, 2018, we transferred and analysed data from 28 cohorts in the CKD-PC, which included 693 816 individuals (557 583 [80%] with diabetes). Data for 675 904 individuals and 7461 end-stage kidney disease events were available for our primary outcome analysis. Change in ACR was consistently associated with subsequent risk of end-stage kidney disease. The adjusted hazard ratio (HR) for end-stage kidney disease after a 30% decrease in ACR during a baseline period of 2 years was 0.83 (95% CI 0.74-0.94), decreasing to 0.78 (0.66-0.92) after further adjustment for regression dilution. Adjusted HRs were fairly consistent across cohorts and subgroups (ie, estimated glomerular filtration rate, diabetes, and sex), but the association was somewhat stronger among participants with higher baseline ACR than among those with lower baseline ACR (pinteraction

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 to 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 seven US clinical centers. SETTING & PARTICIPANTS: Participants (N=3379) had up to 12.3 years of follow-up; 47% had diabetes. PREDICTORS: Thirty 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 (KRT). 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, the mean (SD) eGFR slope was −1.4 (3.3) and −2.7 (4.7) mL/min/1.73m(2)/year. Among participants with diabetes, multivariable-adjusted hazard of the composite outcome was approximately twofold or greater with higher levels of the inflammatory chemokine CXCL12, the cardiac marker N-terminal pro-B-type natriuretic peptide (NTproBNP) and the kidney injury marker urine neutrophil gelatinase-associated lipocalin (NGAL). Among those without diabetes, low serum bicarbonate as well as higher high-sensitivity troponin T, NTproBNP and urine NGAL 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 urine NGAL exceeded that of systolic blood pressure ≥140 mmHg, a well-established risk factor for CKD progression. This warrants further investigation into the potential mechanisms these markers indicate and opportunities to use them to improve risk stratification. CLINICALTRIALS.GOV IDENTIFIER: NCT00304148

Background Non-Hispanic blacks and Hispanics with end-stage renal disease have a lower risk for death than non-Hispanic whites, but data for racial/ethnic variation in cardiovascular outcomes for non–dialysis-dependent chronic kidney disease are limited. Study Design Prospective cohort. Setting & Participants 3,785 adults with entry estimated glomerular filtration rates of 20 to 70mL/min/1.73m 2 enrolled in the CRIC (Chronic Renal Insufficiency Cohort) Study. Predictors Race/ethnicity (non-Hispanic white, non-Hispanic black, and Hispanic). Outcomes Cardiovascular outcomes (atherosclerotic events [myocardial infarction, stroke, or peripheral arterial disease] and heart failure) and a composite of each cardiovascular outcome or all-cause death. Measurements Multivariable Cox proportional hazards. Results During a median follow-up of 6.6 years, we observed 506 atherosclerotic events, 551 heart failure events, and 692 deaths. In regression analyses, there were no significant differences in atherosclerotic events among the 3 racial/ethnic groups. In analyses stratified by clinical site, non-Hispanic blacks had a higher risk for heart failure events (HR, 1.59; 95% CI, 1.29-1.95), which became nonsignificant after adjustment for demographic factors and baseline kidney function. In contrast, Hispanics had similar risk for heart failure events as non-Hispanic whites. In analyses stratified by clinical site, compared with non-Hispanic whites, non-Hispanic blacks were at similar risk for atherosclerotic events or death. However, after further adjustment for cardiovascular risk factors, medications, and mineral metabolism markers, non-Hispanic blacks had 17% lower risk for the outcome (HR, 0.83; 95% CI, 0.69-0.99) than non-Hispanic whites, whereas there was no significant association with Hispanic ethnicity. Limitations Hispanics were largely recruited from a single center, and the study was underpowered to evaluate the association between Hispanic ethnicity and mortality. Conclusions There were no significant racial/ethnic differences in adjusted risk for atherosclerotic or heart failure outcomes. Future research is needed to better explain the reduced risk for atherosclerotic events or death in non-Hispanic blacks compared with non-Hispanic whites.

Peripheral artery disease (PAD) is highly prevalent and associated with significant morbidity and mortality, but sex-based differences are incompletely understood. We sought to define the associations between PAD and physical outcome measures and to determine if these associations differed by sex in the Chronic Renal Insufficiency Cohort.Among 3,543 participants, we assessed the cross-sectional relationship between PAD severity defined by ankle-brachial index; and (1) physical activity (metabolic equivalent [MET]-hr/wk), (2) walking pace (slow versus medium and/or fast), and (3) physical function (12-item Short Form Health Survey [SF-12]) at baseline.In a multivariable linear regression model, PAD severity was not associated with physical activity defined by total MET-hr per wk in men or women (P = 0.432). However, PAD severity was significantly associated with walking activity (P = 0.037), although this relationship did not differ by sex (P = 0.130). Similarly, PAD severity was significantly associated with walking pace (P 0.001), although this relationship did not differ by sex (P = 0.086). In contrast, there was an independent association between PAD severity and SF-12 (P = 0.018), with a significant interaction by sex (P 0.001).These data suggest that tools used to evaluate the functional consequences of PAD should focus on walking activity and walking pace, as well as physical function, where sex-specific associations should be accounted for.

Background Serum β-trace protein (BTP) and β 2 -microglobulin (B2M) are independently associated with end-stage renal disease (ESRD) and mortality in the general population and high-risk groups with diabetes or advanced chronic kidney disease (CKD). Less is known about their associations with outcomes and predictive ability in adults with moderate CKD. Study Design Prospective cohort study. Setting & Participants 3,613 adults from the CRIC (Chronic Renal Insufficiency Cohort) Study (45% women; mean age, 57.9 years; 41.0% non-Hispanic black; 51.9% with diabetes). Predictors BTP and B2M levels with a reciprocal transformation to reflect their associations with filtration, creatinine-based estimated glomerular filtration rate (eGFR cr ), measured GFR, and a 4-marker composite score combining BTP, B2M, creatinine, and cystatin C levels. Predictors were standardized as z scores for comparisons across filtration markers. Outcomes ESRD, all-cause mortality, and new-onset cardiovascular disease. Results During a 6-year median follow-up, 755 (21%) participants developed ESRD, 653 died, and 292 developed new-onset cardiovascular disease. BTP, B2M, and the 4-marker composite score were independent predictors of ESRD and all-cause mortality, and B2M and the 4-marker composite score of cardiovascular events, after multivariable adjustment. These associations were stronger than those observed for eGFR cr ( P vs eGFR cr ≤0.02). The 4-marker composite score led to improvements in C statistic and 2.5-year risk reclassification beyond eGFR cr for all outcomes. Limitations Filtration markers measured at one time point; measured GFR available in subset of cohort. Conclusions BTP and B2M levels may contribute additional risk information beyond eGFR cr , and the use of multiple markers may improve risk prediction beyond this well-established marker of kidney function among persons with moderate CKD.

Background Cognitive impairment is common among patients with chronic kidney disease (CKD); however, its prognostic significance is unclear. We assessed the independent association between cognitive impairment and CKD progression in adults with mild to moderate CKD. Study Design Prospective cohort. Setting & Participants Adults with CKD participating in the CRIC (Chronic Renal Insufficiency Cohort) Study. Mean age of the sample was 57.7±11.0 years and mean estimated glomerular filtration rate (eGFR) was 45.0±16.9mL/min/1.73m 2 . Predictor Cognitive function was assessed with the Modified Mini-Mental State Examination at study entry. A subset of participants 55 years and older underwent 5 additional cognitive tests assessing different domains. Cognitive impairment was defined as a score > 1 SD below the mean score on each test. Covariates included demographics, kidney function, comorbid conditions, and medications. Outcomes Incident end-stage renal disease (ESRD) and incident ESRD or 50% decline in baseline eGFR. Results In 3,883 CRIC participants, 524 (13.5%) had cognitive impairment at baseline. During a median 6.1 years of follow-up, 813 developed ESRD and 1,062 developed ESRD or a ≥50% reduction in eGFR. There was no significant association between cognitive impairment and risk for ESRD (HR, 1.07; 95% CI, 0.87-1.30) or the composite of ESRD or 50% reduction in eGFR (HR, 1.06; 95% CI, 0.89-1.27). Similarly, there was no association between cognitive impairment and the joint outcome of death, ESRD, or 50% reduction in eGFR (HR, 1.06; 95% CI, 0.91-1.23). Among CRIC participants who underwent additional cognitive testing, we found no consistent association between impairment in specific cognitive domains and risk for CKD progression in adjusted analyses. Limitations Unmeasured potential confounders, single measure of cognition for younger participants. Conclusions Among adults with CKD, cognitive impairment is not associated with excess risk for CKD progression after accounting for traditional risk factors.

CKD is a global public health problem with significant mortality and morbidity.We examined the multivariable association of plasma levels of IL-1, IL-1 receptor antagonist, IL-6, TNF-α, TGF-β, high-sensitivity C-reactive protein, fibrinogen, and serum albumin with progression of CKD in 3430 Chronic Renal Insufficiency Cohort study participants.Over a median follow-up time of 6.3 years, 899 participants reached the composite end point of ≥50% decline in eGFR from baseline or onset of ESRD. Elevated plasma levels of fibrinogen, IL-6, and TNF-α and lower serum albumin were associated with a greater decline in eGFR over time. After adjusting for demographics, BP, laboratory variables, medication use, and baseline eGFR, hazard ratios for the composite outcome were greater for the patients in the highest quartile of fibrinogen (hazard ratio, 2.05; 95% confidence interval, 1.64 to 2.55; P0.001), IL-6 (hazard ratio, 1.44; 95% confidence interval, 1.17 to 1.77; P0.01), and TNF-α (hazard ratio, 1.94; 95% confidence interval, 1.52 to 2.47; P0.001) compared with those in the respective lowest quartiles. The hazard ratio was 3.48 (95% confidence interval, 2.88 to 4.21; P0.001) for patients in the lowest serum albumin quartile relative to those in the highest quartile. When also adjusted for albuminuria, the associations of fibrinogen (hazard ratio, 1.49; 95% confidence interval, 1.20 to 1.86; P0.001), serum albumin (hazard ratio, 1.52; 95% confidence interval, 1.24 to 1.87; P0.001), and TNF-α (hazard ratio, 1.42; 95% confidence interval, 1.11 to 1.81; P0.001) with outcome were attenuated but remained significant.Elevated plasma levels of fibrinogen and TNF-α and decreased serum albumin are associated with rapid loss of kidney function in patients with CKD.

Studies using vitamin D-binding protein (DBP) concentrations to estimate free and bioavailable vitamin D have increased dramatically in recent years. Combinations of two single-nucleotide polymorphisms (SNPs) produce three major DBP isoforms (Gc1f, Gc1s, and Gc2). A recent study showed that DBP concentrations quantified by liquid chromatography-tandem mass spectrometry (LC-MS/MS) did not differ by race, whereas a widely used monoclonal enzyme-linked immunosorbent assay (ELISA) quantified DBP differentially by isoform, yielding significantly lower DBP concentrations in black versus white individuals. We compared measurements of serum DBP using a monoclonal ELISA, a polyclonal ELISA, and LC-MS/MS in 125 participants in the Chronic Renal Insufficiency Cohort (CRIC). Serum free and bioavailable 25OHD were calculated based on DBP concentrations from these three assays in homozygous participants, and race differences were compared. We confirmed that the monoclonal ELISA quantifies DBP differentially by isoform and showed that the polyclonal ELISA is not subject to this bias. Whereas ≤9% of the variability in DBP concentrations quantified using either LC-MS/MS or the polyclonal ELISA was explained by genotype, 85% of the variability in the monoclonal ELISA-based measures was explained by genotype. DBP concentrations measured by the monoclonal ELISA were disproportionately lower than LC-MS/MS-based results for Gc1f homozygotes (median difference -67%; interquartile range [IQR] -71%, -64%), 95% of whom were black. In contrast, the polyclonal ELISA yielded consistently and similarly higher measurements of DBP than LC-MS/MS, irrespective of genotype, with a median percent difference of +50% (IQR +33%, +65%). Contrary to findings using the monoclonal ELISA, DBP concentrations did not differ by race, and free and bioavailable 25OHD were significantly lower in black versus white participants based on both the polyclonal ELISA and LC-MS/MS, consistent with their lower total 25OHD. Future studies of DBP and free or bioavailable vitamin D metabolites should employ DBP assays that are not biased by DBP genotype. © 2016 American Society for Bone and Mineral Research.

Background: Heart failure (HF) is a frequent occurrence in chronic kidney disease (CKD) patients and predicts poor survival. Serum bicarbonate is associated with increased rates of HF in CKD; however, the mechanisms leading to this association are incompletely understood. This study aims to assess whether serum bicarbonate is independently associated with structural and functional cardiac abnormalities in CKD. Methods: The association between serum bicarbonate and left ventricular (LV) hypertrophy (LVH), LV mass indexed to height2.7, LV geometry, ejection fraction (EF) and diastolic dysfunction was assessed in 3,483 participants without NYHA class III/IV HF, enrolled in the Chronic Renal Insufficiency Cohort study. Results: The mean estimated glomerular filtration rate was 42.5 ± 17 ml/min/1.73 m2. The overall prevalence of LVH was 51.2%, with 57.8, 50.9 and 47.7% for bicarbonate categories 26 mmol/l, respectively. Participants with low bicarbonate were more likely to have LVH and abnormal LV geometry (OR 1.32; 95% CI 1.07-1.64, and OR 1.57; 95% CI 1.14-2.16, respectively). However, the association was not statistically significant after adjustment for demographics, traditional cardiovascular risk factors, medications and kidney function (OR 1.07; 95% CI 0.66-1.72, and OR 1.27; 95% CI 0.64-2.51, respectively). No association was found between bicarbonate and systolic or diastolic dysfunction. During follow-up, no significant changes in LV mass or EF were observed in any bicarbonate strata. Conclusions: In a large CKD study, serum bicarbonate was associated with LV mass and concentric LVH; however, this association was attenuated after adjustment for clinical factors suggesting that the observed cardiac effects are mediated through yet unknown mechanisms.

Patients with chronic kidney disease (CKD) experience significantly greater morbidity than the general population. The hospitalization rate for patients with CKD is significantly higher than the general population. The extent to which neighborhood-level socioeconomic status (SES) is associated with hospitalization has been less explored, both in the general population and among those with CKD.We evaluated the relationship between neighborhood SES and hospitalizations for adults with CKD participating in the Chronic Renal Insufficiency Cohort Study. Neighborhood SES quartiles were created utilizing a validated neighborhood-level SES summary measure expressed as z-scores for 6 census-derived variables. The relationship between neighborhood SES and hospitalizations was examined using Poisson regression models after adjusting for demographic characteristics, individual SES, lifestyle, and clinical factors while taking into account clustering within clinical centers and census block groups.Among 3291 participants with neighborhood SES data, mean age was 58 years, 55% were male, 41% non-Hispanic white, 49% had diabetes, and mean estimated glomerular filtration rate (eGFR) was 44 ml/min/1.73 m. In the fully adjusted model, compared to individuals in the highest SES neighborhood quartile, individuals in the lowest SES neighborhood quartile had higher risk for all-cause hospitalization (rate ratio [RR], 1.28, 95% CI, 1.09-1.51) and non-cardiovascular hospitalization (RR 1.30, 95% CI, 1.10-1.55). The association with cardiovascular hospitalization was in the same direction but not statistically significant (RR 1.21, 95% CI, 0.97-1.52).Neighborhood SES is associated with risk for hospitalization in individuals with CKD even after adjusting for individual SES, lifestyle, and clinical factors.

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.

Motivation Functional enrichment testing methods can reduce data comprising hundreds of altered biomolecules to smaller sets of altered biological ‘concepts’ that help generate testable hypotheses. This study leveraged differential network enrichment analysis methodology to identify and validate lipid subnetworks that potentially differentiate chronic kidney disease (CKD) by severity or progression. Results We built a partial correlation interaction network, identified highly connected network components, applied network-based gene-set analysis to identify differentially enriched subnetworks, and compared the subnetworks in patients with early-stage versus late-stage CKD. We identified two subnetworks ‘triacylglycerols’ and ‘cardiolipins-phosphatidylethanolamines (CL-PE)’ characterized by lower connectivity, and a higher abundance of longer polyunsaturated triacylglycerols in patients with severe CKD (stage ≥4) from the Clinical Phenotyping Resource and Biobank Core. These finding were replicated in an independent cohort, the Chronic Renal Insufficiency Cohort. Using an innovative method for elucidating biological alterations in lipid networks, we demonstrated alterations in triacylglycerols and cardiolipins-phosphatidylethanolamines that precede the clinical outcome of end-stage kidney disease by several years. Availability and implementation A complete list of NetGSA results in HTML format can be found at http://metscape.ncibi.org/netgsa/12345-022118/cric_cprobe/022118/results_cric_cprobe/main.html. The DNEA is freely available at https://github.com/wiggie/DNEA. Java wrapper leveraging the cytoscape.js framework is available at http://js.cytoscape.org. Supplementary information Supplementary data are available at Bioinformatics online.

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.

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.

BACKGROUND AND OBJECTIVES: Nontargeted metabolomics can measure thousands of low-molecular-weight biochemicals, but important gaps limit its utility for biomarker discovery in CKD. These include the need to characterize technical and intraperson analyte variation, to pool data across platforms, and to outline analyte relationships with eGFR. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Plasma samples from 49 individuals with CKD (eGFR1000 analytes with low technical CVs, and agreement for overlapping metabolites across two leading platforms is excellent. Many metabolites demonstrate substantial intraperson variation and correlation with eGFR.

RATIONALE & OBJECTIVE: Higher urine net acid excretion (NAE) is associated with slower chronic kidney disease (CKD) progression, particularly in patients with diabetes mellitus. To better understand potential mechanisms and assess modifiable components, we evaluated independent predictors of NAE in the CRIC (Chronic Renal Insufficiency Cohort) Study. STUDY DESIGN: Cross-sectional SETTING & PARTICIPANTS: A randomly selected subcohort of adults with CKD, enrolled in the CRIC Study, with measurements of NAE. PREDICTORS: A comprehensive set of variables across pre-specified domains including demographics, comorbidities, medications, laboratory values, diet, physical activity, and body composition OUTCOME: 24h urine NAE ANALYTICAL APPROACH: NAE was defined as the sum of urine ammonium and calculated titratable acidity in a subset of CRIC participants. A total of 22 individuals were excluded for urine pH

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.

Background: The arteriovenous fistula (AVF) is the preferred vascular access for hemodialysis. However, approximately half of AVFs fail to mature. The use of angiotensin converting enzyme inhibitors (ACE-Is), angiotensin receptor blockers (ARBs), and calcium channel blockers (CCBs) exerts favorable endothelial effects and may promote AVF maturation. We tested associations of ACE-I and ARBs, CCBs, beta-blockers, and diuretics with the maturation of newly created AVFs. Methods: We evaluated 602 participants from the Hemodialysis Fistula Maturation Study, a multi-center, prospective cohort study of AVF maturation. We ascertained the use of each medication class within 45 days of AVF creation surgery. We defined maturation outcomes by clinical use within 9 months of surgery or 4 weeks of initiating hemodialysis. Results: Unassisted AVF maturation failure without intervention occurred in 54.0% of participants, and overall AVF maturation failure (with or without intervention) occurred in 30.1%. After covariate adjustment, CCB use was associated with a 25% lower risk of overall AVF maturation failure (95% CI 3%–41% lower) but a non-significant 10% lower risk of unassisted maturation failure (95% CI 23% lower to 5% higher). ACE-I/ARB, beta-blocker, and diuretic use was not significantly associated with AVF maturation outcomes. None of the antihypertensive medication classes were associated with changes in AVF diameter or blood flow over 6 weeks following surgery. Conclusions: CCB use may be associated with a lower risk of overall AVF maturation failure. Further studies are needed to determine whether CCBs might play a causal role in improving AVF maturation outcomes.

BackgroundThe clinical relevance of arachidonic acid (AA) metabolites in chronic kidney disease (CKD) progression is poorly understood. We aimed to compare the concentrations of 85 enzymatic pathway products of AA metabolism in patients with CKD who progressed to end-stage kidney disease (ESKD) versus patients who did not in a subcohort of Chronic Renal Insufficiency Cohort (CRIC) and to estimate the risk of CKD progression and major cardiovascular events by levels of AA metabolites and their link to enzymatic metabolic pathways.MethodsA total 123 patients in the CRIC study who progressed to ESKD were frequency matched with 177 nonprogressors and serum eicosanoids were quantified by mass spectrometry. We applied serum collected at patients’ Year 1 visit and outcome of progression to ESKD was ascertained over the next 10 years. We used logistic regression models for risk estimation.ResultsBaseline 15-hydroxyeicosatetraenoate (HETE) and 20-HETE levels were significantly elevated in progressors (false discovery rate Q ≤ 0.026). The median 20-HETE level was 7.6 pmol/mL [interquartile range (IQR) 4.2–14.5] in progressors and 5.4 pmol/mL (IQR 2.8–9.4) in nonprogressors (P ConclusionsWe found higher odds of CKD progression associated with higher 20-HETE, LOX and CYP450 metabolic pathways. These alterations precede CKD progression and may serve as targets for interventions aimed at halting progression.

Background: The chronic kidney disease (CKD) epidemic continues to grow, and cardiovascular disease (CVD) is the leading cause of death. To modify CVD risk, CKD patients are asked to engage in health promoting behaviors. However, older patients with CKD likely face challenges to engage in healthy behaviors due to social and health factors. This study examined the relationship of social and health factors to health promoting behaviors among younger and older CKD patients and the association of these behaviors with CVD events, death, and CKD progression. Methods: Data from the Chronic Renal Insufficiency Cohort (CRIC) Study were analyzed using latent class analysis (LCA) to identify health promoting behavior clusters, stratified by 20 and ≤25kg/m 2 vs. other, healthy diet vs. not, physical activity ≥150min/week vs. not, blood pressure ≤140/90mmHg vs. greater, never/past smoker vs. current, and Results: All social and health factors significantly differed between age groups. Three clusters with varying levels of engagement in health promoting behaviors were identified separately among Conclusion: This study demonstrated three clusters of health promoting behaviors that distinguish risk for CVD and other outcomes among older and younger CKD patients. These clusters could identify high-risk groups and be targeted for aggressive management. Clusters with less health promoting behaviors were associated with self-efficacy and depressive symptoms, which could serve as potential targets for intervention.

This address was delivered by Harold I. Feldman, MD, MSCE, at the Annual Meeting of the American College of Epidemiology in New Orleans, Louisiana, on September 26, 2017. Dr. Feldman is George S. Pepper Professor of Public Health and Preventive Medicine, Professor of Epidemiology and Medicine, and Chair, Department of Biostatistics, Epidemiology, and Informatics at the Perelman School of Medicine at the University of Pennsylvania. He is recognized nationally and internationally for his expertise in kidney disease epidemiology. Dr. Feldman pioneered the integration of epidemiology and renal medicine with his first studies of dialyzer reuse and hemodialysis vascular access morbidity. He is internationally renowned in nephrology and clinical epidemiology and an architect of one of the largest and most successful epidemiological research programs in chronic kidney disease. For over 15 years, he has led NIH's Chronic Renal Insufficiency Cohort Study, placing him at the helm of the “Framingham Study of Renal Disease”. It has elucidated the chronic kidney disease–specific relationships of mineral dysmetabolism and cardiovascular complications; dietary sodium and heart failure; novel vascular stiffness metrics and renal disease progression; cardiovascular biomarkers and heart failure; and cognitive decline and renal dysfunction, among others. He has also led the nation's largest trials targeting hemodialysis vascular access morbidity, discovered the benefits of transplantation before dialysis dependence, elucidated racial disparities and the role of genetics in kidney failure, and shaped our understanding of the toxicity from unregulated reuse of medical devices. He is the past President of the American College of Epidemiology and directs one of the nation's largest clinical epidemiology and biostatistics programs. Dr. Feldman has an MD from Boston University and an MSCE from the University of Pennsylvania. He is an elected member of the American Society of Clinical Investigation, the Association of American Physicians, and the American Epidemiological Society.

RATIONALE & OBJECTIVE: Determining whether a change in estimated glomerular filtration rate (eGFR) or albuminuria is clinically significant requires knowledge of short-term within-person variability of the measurements, which few studies have addressed in the setting of chronic kidney disease. STUDY DESIGN: Cross-sectional study with multiple collections over less than 4 weeks. SETTING & PARTICIPANTS: Clinically stable outpatients with chronic kidney disease (N = 50; mean age, 56.8 years; median eGFR, 40 mL/min/1.73 m(2); median urinary albumin-creatinine ratio (UACR), 173 mg/g). EXPOSURE: Repeat measurements from serially collected samples across 3 study visits. OUTCOMES: Measurements of urine albumin concentration (UAC), UACR, and plasma creatinine, cystatin C, β(2)-microglobulin (B2M), and beta trace protein (BTP). ANALYTICAL APPROACH: We calculated within-person coefficients of variation (CV(w)) values and corresponding reference change positive and negative (RCV(pos) and RCV(neg)) values using log-transformed measurements. RESULTS: Median CV(w) (RCV(pos); RCV(neg)) values of filtration markers were 5.4% (+16%; –14%) for serum creatinine, 4.1% (+12%; –11%) for cystatin C, 7.4% (+23%; –18%) for BTP, and 5.6% (+17%; –14%) for B2M. Results for albuminuria were 33.2% (+145%; –59%) for first-morning UAC, 50.6% (+276%; –73%) for random spot UAC, 32.5% (+141%; –58%) for first-morning UACR, and 29.7% (124%; –55%) for random spot UACR. CV(w) values for filtration markers were comparable across the range of baseline eGFRs. CV(w) values for UAC and UACR were comparable across the range of baseline albuminuria values. LIMITATIONS: Small sample size limits the ability to detect differences in variability across markers. Participants were recruited and followed up in a clinical and not research setting, so some preanalytical factors could not be controlled. CONCLUSIONS: eGFR markers appear to have relatively low short-term within-person variability, whereas variability in albuminuria appears to be high, making it difficult to distinguish random variability from meaningful biologic changes.

Background In the context of an aging end-stage renal disease population with multiple comorbid conditions, transplantation professionals face challenges in evaluating the global health of patients awaiting kidney transplantation. Functional status might be useful for identifying which patients will derive a survival benefit from transplantation versus dialysis. Study Design Retrospective cohort study of wait-listed patients using data for functional status from a national dialysis provider linked to United Network for Organ Sharing registry data. Setting & Participants Adult kidney transplantation candidates added to the waiting list between 2000 and 2006. Predictor Physical Functioning scale of the Medical Outcomes Study 36-Item Short Form Health Survey, analyzed as a time-varying covariate. Outcomes Kidney transplantation; survival benefit of transplantation versus remaining wait-listed. Measurements We used multivariable Cox regression to assess the association between physical function with study outcomes. In survival benefit analyses, transplantation status was modeled as a time-varying covariate. Results The cohort comprised 19,242 kidney transplantation candidates (median age, 51 years; 36% black race) receiving maintenance dialysis. Candidates in the lowest baseline Physical Functioning score quartile were more likely to be inactivated (adjusted HR vs highest quartile, 1.30; 95% CI, 1.21-1.39) and less likely to undergo transplantation (adjusted HR vs highest quartile, 0.64; 95% CI, 0.61-0.68). After transplantation, worse Physical Functioning score was associated with shorter 3-year survival (84% vs 92% for the lowest vs highest function quartiles). However, compared to dialysis, transplantation was associated with a statistically significant survival benefit by 9 months for patients in every function quartile. Limitations Functional status is self-reported. Conclusions Even patients with low function appear to live longer with kidney transplantation versus dialysis. For wait-listed patients, global health measures such as functional status may be more useful in counseling patients about the probability of transplantation than in identifying who will derive a survival benefit from it.

Background and objectives Liver fatty acid binding protein (L-FABP), kidney injury molecule 1 (KIM-1), N -acetyl- β -d-glucosaminidase (NAG), and neutrophil gelatinase–associated lipocalin (NGAL) are urinary markers of tubular injury that may also be markers of chronic kidney damage. We evaluated the association of these markers with incident ESRD in a community-based sample from the Atherosclerosis Risk in Communities Study. Design, setting, participants, & measurements This was a matched case-control study of 135 patients with ESRD and 186 controls who were matched on sex, race, kidney function, and diabetes status at baseline (Atherosclerosis Risk in Communities Study visit 4, 1996–1998). Urinary KIM-1 indexed to creatinine (Cr), NAG/Cr, NGAL/Cr, and L-FABP/Cr were measured in stored spot urine samples from the baseline examination. Associations of KIM-1/Cr, NAG/Cr, and NGAL/Cr with patients with incident ESRD through 2008 were modeled continuously and categorically (quartiles) using conditional logistic regression. L-FABP/Cr was modeled only categorically because of a large number of measurements below the lower limit of detection for the assay (2.4 ng/ml). Results No significant associations were observed for NAG/Cr, NGAL/Cr, or L-FABP/Cr with ESRD. Those in the highest category for KIM-1/Cr had a higher risk of ESRD compared with those with undetectable biomarker levels (reference group) in unadjusted models (odds ratio, 2.24; 95% confidence interval, 1.97 to 4.69; P =0.03) or adjustment for age (odds ratio, 2.23; 95% confidence interval, 1.06 to 4.67; P =0.03). This association was attenuated with additional adjustment for baseline kidney function (odds ratio, 2.02; 95% confidence interval, 0.95 to 4.31; P =0.07 after additional adjustment for eGFR and natural log of the urinary albumin-to-creatinine ratio). No association between KIM-1/Cr and ESRD was found when KIM-1/Cr was analyzed as a continuous variable. Conclusions Elevated urinary KIM-1/Cr may be associated with a higher risk of incident ESRD, but it does not add to risk prediction after accounting for traditional markers of kidney function in this population.

Objective Among chronic hemodialysis patients, hyperphosphatemia is common and associated with mortality. Behavioral economics and complementary behavior-change theories may offer valuable approaches to achieving phosphorus (PO4) control. The aim was to determine feasibility of implementing financial incentives and structured coaching to improve PO4 in the hemodialysis setting. Design and Methods This pilot randomized controlled trial was conducted in 3 urban dialysis units for 10 weeks among 36 adults with elevated serum PO4 (median >5.5 mg/dL over 3 months). Interventions Twelve participants each were randomized to: (1) financial incentives for lowering PO4, (2) coaching about dietary and medication adherence, or (3) usual care. PO4 was measured during routine clinic operations. Each incentives arm participant received the equivalent of $1.50/day if the PO4 was ≤5.5 mg/dL or >5.5 mg/dL but decreased ≥0.5 mg/dL since the prior measurement. The coach was instructed to contact coaching arm participants at least 3 times per week. Main Outcome Measures The outcome measures included: (1) enrollment rate, (2) dropout rate, and (3) change in PO4 from beginning to end of 10-week intervention period. Results Of 66 eligible patients, 36 (55%) enrolled. Median age was 53 years, 83% were black race, and 78% were male. Median baseline PO4 was 6.0 (interquartile range 5.6, 7.5). Using stratified generalized estimation equation analyses, the monthly decline in PO4 was −0.32 mg/dL (95% CI −0.60, −0.04) in the incentives arm, −0.40 mg/dL (−0.60, −0.20) in the coaching arm, and −0.24 mg/dL (−0.60, 0.08) in the usual care arm. No patients dropped out. All intervention arm participants expressed interest in receiving similar support in the future. Conclusions This pilot trial demonstrated good feasibility in enrollment and implementation of novel behavioral health strategies to reduce PO4 in dialysis patients.

Background Cardiometabolic disease is a major cause of morbidity and mortality in persons with chronic kidney disease (CKD). Fractalkine (CX3CL1) is a potential mediator of both atherosclerosis and metabolic disease. Studies of the relationship of CX3CL1 with risk of cardiovascular disease (CVD) events and metabolic traits are lacking, particularly in the high-risk setting of CKD. Study Design Cross-sectional and longitudinal observational analysis. Setting & Participants Adults with CKD from 7 US sites participating in the Chronic Renal Insufficiency Cohort (CRIC) Study. Predictor Quartiles of plasma CX3CL1 levels at baseline. Outcomes Baseline estimated glomerular filtration rate from a creatinine and cystatin C–based equation, prevalent and incident CVD, diabetes, metabolic syndrome and its criteria, homeostatic model assessment of insulin resistance, hemoglobin A 1c level, myocardial infarction, all-cause mortality, and the composite outcome of myocardial infarction/all-cause mortality. Results Among 3,687 participants, baseline CX3CL1 levels were associated positively with several CVD risk factors and metabolic traits, lower estimated glomerular filtration rate, and higher levels of inflammatory cytokines, as well as prevalent CVD (OR, 1.09; 95% CI, 1.01-1.19; P =0.03). Higher CX3CL1 level also was associated with prevalent diabetes (OR, 1.26; 95% CI, 1.16-1.38; P P =0.02) and the composite outcome (1.09; 95% CI, 1.00-1.19; P =0.04). Limitations Study design did not allow evaluation of changes over time, correlation with progression of phenotypes, or determination of causality of effect. Conclusions Circulating CX3CL1 level may contribute to both atherosclerotic CVD and diabetes in a CKD cohort. Further studies are required to establish mechanisms through which CX3CL1 affects the pathogenesis of atherosclerosis and diabetes.

Background In general populations, healthy lifestyle is associated with fewer adverse outcomes. We estimated the degree to which adherence to a healthy lifestyle decreases the risk of renal and cardiovascular events among adults with chronic kidney disease (CKD). Study Design Prospective cohort. Setting & Participants 3,006 adults enrolled in the Chronic Renal Insufficiency Cohort (CRIC) Study. Predictors 4 lifestyle factors (regular physical activity, body mass index [BMI] of 20- 2 , nonsmoking, and "healthy diet"), individually and in combination. Outcomes CKD progression (50% decrease in estimated glomerular filtration rate or end-stage renal disease), atherosclerotic events (myocardial infarction, stroke, or peripheral arterial disease), and all-cause mortality. Measurements Multivariable-adjusted Cox proportional hazards. Results During a median follow-up of 4 years, we observed 726 CKD progression events, 355 atherosclerotic events, and 437 deaths. BMI≥25kg/m 2 and nonsmoking were associated with reduced risk of CKD progression (HRs of 0.75 [95% CI, 0.58-0.97] and 0.61 [95% CI, 0.45-0.82] for BMIs of 25 to 2 , respectively, versus 20 to 2 ; HR for nonsmoking of 0.68 [95% CI, 0.55-0.84] compared to the current smoker reference group) and reduced risk of atherosclerotic events (HRs of 0.67 [95% CI, 0.46-0.96] for BMI of 25- 2 and 0.55 [95% CI, 0.40-0.75] vs current smoker). Factors associated with reduced all-cause mortality were regular physical activity (HR, 0.64 [95% CI, 0.52-0.79] vs inactive), BMI≥30kg/m 2 (HR, 0.64 [95% CI, 0.43-0.96] vs 20- 2 ), and nonsmoking (HR, 0.45 [95% CI, 0.34-0.60] vs current smoker). BMI 2 was associated with increased all-cause mortality risk (HR, 2.11 [95% CI, 1.13-3.93] vs 20- 2 ). Adherence to all 4 lifestyle factors was associated with a 68% lower risk of all-cause mortality compared to adherence to no lifestyle factors (HR, 0.32; 95% CI, 0.11-0.89). Limitations Lifestyle factors were measured only once. Conclusions Regular physical activity, nonsmoking, and BMI≥25kg/m 2 were associated with lower risk of adverse outcomes in this cohort of individuals with CKD.

Background Blood pressure (BP) is often inadequately controlled in patients with chronic kidney disease (CKD). Previous reports of the longitudinal association between achieved level of BP and end-stage renal disease (ESRD) have not incorporated time-updated BP with appropriate adjustment for known confounders.

Fibroblast growth factor-23 is a bone-derived hormone that increases urinary phosphate excretion and inhibits hydroxylation of 25-hydroxyvitamin D. Recent studies suggest that fibroblast growth factor-23 may be an early biomarker of CKD progression. However, its role in kidney function decline in the general population is unknown. We assessed the relationship between baseline (1990–1992) serum levels of intact fibroblast growth factor-23 and incident ESRD in 13,448 Atherosclerosis Risk in Communities study participants (56.1% women, 74.7% white) followed until December 31, 2010. At baseline, the mean age of participants was 56.9 years and the mean eGFR was 97 ml/min per 1.73 m2. During a median follow-up of 19 years, 267 participants (2.0%) developed ESRD. After adjustment for demographic characteristics, baseline eGFR, traditional CKD risk factors, and markers of mineral metabolism, the highest fibroblast growth factor-23 quintile (>54.6 pg/ml) compared with the lowest quintile (

BACKGROUND: Advanced chronic kidney disease (CKD) is associated with an elevated risk of cognitive impairment. However, it is not known if and how cognitive impairment is associated with planning and preparation for end stage renal disease. STUDY DESIGN: Retrospective observational study. SETTING & PARTICIPANTS: 630 adults participating in the CRIC (Chronic Renal Insufficiency Cohort) Study who had cognitive assessments in late stage CKD, defined as an estimated glomerular filtration rate (eGFR) ≤ 20 ml/min/1.73m(2), and subsequently initiated maintenance dialysis. PREDICTOR: Pre-dialysis cognitive impairment, defined as a score on the Modified Mini-Mental State Examination below previously-derived age-based threshold scores. Covariates included age, race/ethnicity, educational attainment, comorbid conditions, and health literacy. OUTCOMES: Peritoneal dialysis (PD) as first dialysis modality, pre-emptive permanent access placement, venous catheter avoidance at dialysis initiation, and pre-emptive wait-listing for kidney transplantation. MEASUREMENTS: Multivariable-adjusted logistic regression. RESULTS: Pre-dialysis cognitive impairment was present in 117 participants (19%). PD was the first dialysis modality among 16% of participants (n=100), 75% had pre-emptive access placed (n=473), 45% avoided using a venous catheter at dialysis initiation (n=279), and 20% were pre-emptively wait-listed (n=126). Pre-dialysis cognitive impairment was independently associated with an 78% lower odds of PD as the first dialysis modality (adjusted Odds Ratio [aOR], 0.22; 95% Confidence Interval [CI], 0.06–0.74; p=0.02) and a 42% lower odds of venous catheter avoidance at dialysis initiation (aOR, 0.58; 95% CI, 0.34–0.98; p=0.04). Pre-dialysis cognitive impairment was not independently associated with pre-emptive permanent access placement or wait-listing. LIMITATIONS: Potential unmeasured confounders; single measure of cognitive function. CONCLUSIONS: Pre-dialysis cognitive impairment is associated with a lower likelihood of PD as a first dialysis modality and of venous catheter avoidance at dialysis initiation. Future studies may consider addressing cognitive function when testing strategies to improve patient transitions to dialysis.

BACKGROUND: To slow chronic kidney disease (CKD) progression and its complications, patients need to engage in self-management behaviors. The objective of this study was to classify CKD self-management behaviors into phenotypes, and assess the association of these phenotypes with clinical outcomes. STUDY DESIGN: Prospective cohort study SETTING & PARTICIPANTS: Adults with mild to moderate CKD enrolled in the Chronic Renal Insufficiency Cohort (CRIC) Study. The 3,939 participants in the CRIC Study recruited between 2003 and 2008 served as the derivation cohort and the 1,560 participants recruited between 2013 and 2015 served as the validation cohort. PREDICTORS: CKD self-management behavior phenotypes OUTCOMES: CKD progression, atherosclerotic events, heart failure events, death from any cause MEASUREMENTS: Latent class analysis stratified by diabetes was used to identify CKD self-management phenotypes based on measures of: body mass index, diet, physical activity, blood pressure, smoking status, and hemoglobin A1c (if diabetic); Cox Proportional Hazards models. RESULTS: Three identified phenotypes varied according to the extent implementation of recommended CKD self-management behaviors: Phenotype I characterized study participants with the most recommended behaviors; Phenotype II, participants with a mixture of recommended and not recommended behaviors; and Phenotype III, participants with minimal recommended behaviors. In multivariable-adjusted models for those with and without diabetes, Phenotype III was strongly associated with CKD progression (HRs of 1.82 and 1.49), death (HRs of 1.95 and 4.14), and atherosclerotic events (HRs of 2.54 and 1.90) (each p-value

Rationale & Objective Abnormal cardiac structure and function are common in chronic kidney disease (CKD) and end-stage renal disease (ESRD) and linked with mortality and heart failure. We examined changes in echocardiographic measures during the transition from CKD to ESRD and their associations with post-ESRD mortality. Study Design Prospective study. Setting & Participants We studied 417 participants with CKD in the Chronic Renal Insufficiency Cohort (CRIC) who had research echocardiograms during CKD and ESRD. Predictor We measured change in left ventricular mass index, left ventricular ejection fraction (LVEF), diastolic relaxation (normal, mildly abnormal, and moderately/severely abnormal), left ventricular end-systolic (LVESV), end-diastolic (LVEDV) volume, and left atrial volume from CKD to ESRD. Outcomes All-cause mortality after dialysis therapy initiation. Analytical Approach Cox proportional hazard models were used to test the association of change in each echocardiographic measure with postdialysis mortality. Results Over a mean of 2.9 years between pre- and postdialysis echocardiograms, there was worsening of mean LVEF (52.5% to 48.6%; P Limitations Some missing or technically inadequate echocardiograms. Conclusions In a longitudinal study of patients with CKD who subsequently initiated dialysis therapy, LVEF and LVESV worsened and were significantly associated with greater risk for postdialysis mortality. There may be opportunities for intervention during this transition period to improve outcomes.

Intimal hyperplasia and stenosis are often cited as causes of arteriovenous fistula maturation failure, but definitive evidence is lacking. We examined the associations among preexisting venous intimal hyperplasia, fistula venous stenosis after creation, and clinical maturation failure. The Hemodialysis Fistula Maturation Study prospectively observed 602 men and women through arteriovenous fistula creation surgery and their postoperative course. A segment of the vein used to create the fistula was collected intraoperatively for histomorphometric examination. On ultrasounds performed 1 day and 2 and 6 weeks after fistula creation, we assessed fistula venous stenosis using pre-specified criteria on the basis of ratios of luminal diameters and peak blood flow velocities at certain locations along the vessel. We determined fistula clinical maturation using criteria for usability during dialysis. Preexisting venous intimal hyperplasia, expressed per 10% increase in a hyperplasia index (range of 0%-100%), modestly associated with lower fistula blood flow rate (relative change, -2.5%; 95% confidence interval [95% CI], -4.6% to -0.4%; P=0.02) at 6 weeks but did not significantly associate with stenosis (odds ratio [OR], 1.07; 95% CI, 1.00 to 1.16; P=0.07) at 6 weeks or failure to mature clinically without procedural assistance (OR, 1.07; 95% CI, 0.99 to 1.15; P=0.07). Fistula venous stenosis at 6 weeks associated with maturation failure (OR, 1.98; 95% CI, 1.25 to 3.12; P=0.004) after controlling for case mix factors, dialysis status, and fistula location. These findings suggest that postoperative fistula venous stenosis associates with fistula maturation failure. Preoperative venous hyperplasia may associate with maturation failure but if so, only modestly.

Background Half of surgically created arteriovenous fistulas (AVFs) require additional intervention to effectively support hemodialysis. Postoperative care and complications may affect clinical maturation. Study Design Hemodialysis Fistula Maturation (HFM) Study, a 7-center prospective cohort study. Setting & Participants 491 patients with single-stage AVFs who had neither thrombosis nor AVF intervention before a 6-week postoperative ultrasonographic examination and who required maintenance hemodialysis. Predictors Postoperative care processes and complications. Outcomes Attempted cannulation, successful cannulation, and unassisted and overall clinical maturation as defined by the HFM Study criteria. Results AVF cannulation was attempted in 443 of 491 (90.2%) participants and was eventually successful in 430 of these 443 (97.1%) participants. 263 of these 430 (61.2%) reached unassisted and 118 (27.4%) reached assisted AVF maturation (overall maturation, 381/430 [88.6%]). Attempted cannulation was less likely in patients of surgeons with policies for routine 2-week versus later-than-2-week first postoperative visits (OR, 0.21; 95% CI, 0.06-0.70), routine second postoperative follow-up visits (OR, 0.39; 95% CI, 0.15-0.97), and a routine clinical postoperative ultrasound (OR, 0.28; 95% CI, 0.14-0.55). Attempted cannulation was also less likely among patients undergoing procedures to assist maturation (OR, 0.51; 95% CI, 0.27-0.98). Unassisted maturation was more likely for patients treated in facilities with access coordinators (OR, 1.91; 95% CI, 1.17-3.12), but less likely after precannulation nonstudy ultrasounds (OR per ultrasound, 0.42 [95% CI, 0.26-0.68]) and initial unsuccessful cannulation attempts (OR per each additional attempt, 0.90 [95% CI, 0.83-0.98]). Overall maturation was less likely with infiltration before successful cannulation (OR, 0.44; 95% CI, 0.22-0.89). Among participants receiving maintenance hemodialysis before AVF surgery, unassisted and overall maturation were less likely with longer intervals from surgery to initial cannulation (ORs for each additional month of 0.81 [95% CI, 0.76-0.88] and 0.93 [95% CI, 0.89-0.98], respectively) and from initial to successful cannulation (ORs for each additional week of 0.87 [95% CI, 0.81-0.94] and 0.88 [95% CI, 0.83-0.94], respectively). Limitations Surgeons' management policies were assessed only by questionnaire at study onset. Most participants received upper-arm AVFs, planned 2-stage AVFs were excluded, and maturation time windows were imposed. Some care processes may have been missed and the observational design limits causal attribution. Conclusions Multiple processes of care and complications are associated with AVF maturation outcomes.

Introduction: Chronic kidney disease (CKD) is associated with dyslipidemia (particularly elevated triglycerides [TG] and reduced HDL-cholesterol [HDL-C]) and increased risk of atherosclerotic cardiovascular disease (CVD). However, the association between lipoprotein measures and CVD events in CKD is not well defined. Hypothesis: We hypothesize that high TG and low HDL-C are associated with increased risk for CVD (myocardial infarction [MI] and ischemic stroke) in CKD. Methods: The Chronic Renal Insufficiency Cohort (CRIC) is a prospective study of adults with CKD. We compared tertiles of TG, total cholesterol (TC), VLDL-cholesterol (VLDL-C), LDL-cholesterol (LDL-C), HDL-C, apolipoprotein B (apoB), and apolipoprotein A-I (apoA-I) with risk for MI and ischemic stroke using Fine and Gray methods with death as a competing risk. The lowest tertile was used as the reference category except for HDL-C and apoA-I, in which the highest tertile was used. In secondary analyses, we excluded participants with previous MI or stroke. Results: Among 3811 participants (55% men, 42% Caucasian) with mean age 57.7±11.0 years, 351 had an MI, 132 had an ischemic stroke, and 963 died over a median follow-up of 7.9 years. After adjusting for potential confounders, the hazard ratio (HR, 95% CI) for CVD was 1.04 (0.80-1.34) for high LDL-C, 1.31 (1.01-1.69) for high TG, 1.33 (1.04-1.70) for high VLDL-C, 1.30 (1.01-1.68) for high apoB, 1.65 (1.25-2.17) for low HDL-C, and 1.31 (1.01-1.70) for low apoA-I. In secondary analyses of 2751 participants with no CVD history, high TG (HR 1.46, 1.02-2.10), high VLDL-C (HR 1.56, 1.08-2.25), low HDL-C (HR 2.11, 1.40-3.16) and low apoA-I (HR 2.28, 1.54-3.37) were significantly associated with incident CVD. Conclusions: While high LDL-C is associated with increased CVD risk in the general population, we found no such association in CKD. Instead, high TG, high VLDL-C, low HDL-C and low apoA-I levels show strong associations with increased CVD risk and incident CVD events in CKD.

BACKGROUND Chronic kidney disease (CKD) is associated with increased risk of cardiovascular disease (CVD) and it is especially common among Blacks. Left ventricular hypertrophy (LVH) is an important subclinical marker of CVD, but there are limited data on racial variation in left ventricular structure and function among persons with CKD. METHODS In a cross-sectional analysis of the Chronic Renal Insufficiency Cohort Study, we compared the prevalence of different types of left ventricular remodeling (concentric hypertrophy, eccentric hypertrophy, and concentric remodeling) by race/ethnicity. We used multinomial logistic regression to test whether race/ethnicity associated with different types of left ventricular remodeling independently of potential confounding factors. RESULTS We identified 1,164 non-Hispanic Black and 1,155 non-Hispanic White participants who completed Year 1 visits with echocardiograms that had sufficient data to categorize left ventricular geometry type. Compared to non-Hispanic Whites, non-Hispanic Blacks had higher mean left ventricular mass index (54.7 ± 14.6 vs. 47.4 ± 12.2 g/m2.7; P < 0.0001) and prevalence of concentric LVH (45.8% vs. 24.9%). In addition to higher systolic blood pressure and treatment with >3 antihypertensive medications, Black race/ethnicity was independently associated with higher odds of concentric LVH compared to White race/ethnicity (odds ratio: 2.73; 95% confidence interval: 2.02, 3.69). CONCLUSION In a large, diverse cohort with CKD, we found significant differences in left ventricular mass and hypertrophic morphology between non-Hispanic Blacks and Whites. Future studies will evaluate whether higher prevalence of LVH contribute to racial/ethnic disparities in cardiovascular outcomes among CKD patients.

Background: Acute kidney injury is common in hospitalized patients, increases morbidity and mortality, and is under-recognized. To improve provider recognition, we previously developed an electronic alert system for acute kidney injury. To test the hypothesis that this electronic acute kidney injury alert could improve patient outcome, we designed a randomized controlled trial to test the effectiveness of this alert in hospitalized patients. The study design presented several methodologic, ethical, and statistical challenges. Purpose: To highlight the challenges faced and the solutions employed in the design and implementation of a clinical trial to determine whether the provision of an early electronic alert for acute kidney injury would improve outcomes in hospitalized patients. Challenges included how to randomize the delivery of the alert system and the ethical framework for waiving informed consent. Other methodologic challenges included the selection and statistical evaluation of our study outcome, a ranked-composite of a continuous covariate (creatinine) and two dichotomous outcomes (dialysis and death), and the use of the medical record as a source of trial data. Methods: We have designed a randomized trial to assess the effectiveness of an electronic alert system for acute kidney injury. With broad inclusion criteria, and a waiver of informed consent, we enroll and randomize virtually every patient with acute kidney injury in our hospital. Results: As of 31 March 2014, we have enrolled 2373 patients of 2400 targeted. Pre-alert data demonstrated a strong association between severity of acute kidney injury and inpatient mortality with a range of 6.4% in those with mild, stage 1 acute kidney injury, to 29% among those with stage 3 acute kidney injury (p < 0.001). We judged that informed consent would undermine the scientific validity of the study and present harms that are out of proportion to the very low risk intervention. Conclusion: Our study demonstrates the feasibility of designing an ethical randomized controlled trial of an early electronic alert for acute kidney injury without obtaining informed consent from individual participants. Our study outcome may serve as a model for other studies of acute kidney injury, insofar as our paradigm accounts for the effect that early death and dialysis have on assessment of acute kidney injury severity as defined by maximum achieved serum creatinine.

Propensity scores are widely used to control for confounding when estimating the effect of a binary treatment in observational studies. They have been generalized to ordinal and continuous treatments in the recent literature. Following the definition of propensity function and its parameterizations (called the propensity parameter in this paper) proposed by Imai and van Dyk, we explore sufficient conditions for selecting propensity parameters to control for confounding for continuous treatments in the context of regression-based adjustment in linear models. Typically, investigators make parametric assumptions about the form of the dose-response function for a continuous treatment. Such assumptions often allow the analyst to use only a subset of the propensity parameters to control confounding. When the treatment is the only predictor in the structural, that is, causal model, it is sufficient to adjust only for the propensity parameters that characterize the expectation of the treatment variable or its functional form. When the structural model includes selected baseline covariates other than the treatment variable, those baseline covariates, in addition to the propensity parameters, must also be adjusted in the model. We demonstrate these points with an example estimating the dose-response relationship for the effect of erythropoietin on hematocrit level in patients with end-stage renal disease.

Retinal abnormalities may be associated with changes in the renal vasculature. This study assessed the association between retinopathy and progression of kidney disease in participants of the Chronic Renal Insufficiency Cohort (CRIC) study.This was a prospective study in which patients with CKD enrolled in CRIC had nonmydriatic fundus photographs of both eyes. All CRIC participants in six clinical sites in which fundus cameras were deployed were offered participation. Photographs were reviewed at a reading center. The presence and severity of retinopathy and vessel calibers were assessed using standard protocols by graders masked to clinical information. The associations of retinal features with changes in eGFR and the need for RRT (ESRD) were assessed.Retinal images and renal progression outcomes were obtained from 1852 of the 2605 participants (71.1%) approached. During follow-up (median 2.3 years), 152 participants (8.2%) developed ESRD. Presence and severity of retinopathy at baseline were strongly associated with the risk of subsequent progression to ESRD and reductions in eGFR in unadjusted analyses. For example, participants with retinopathy were 4.4 times (95% confidence interval [95% CI], 3.12 to 6.31) more likely to develop ESRD than those without retinopathy (P0.001). However, this association was not statistically significant after adjustment for initial eGFR and 24-hour proteinuria. Venular and arteriolar diameter calibers were not associated with ESRD or eGFR decline. The results showed a nonlinear relationship between mean ratio of arteriole/vein calibers and the risk of progression to ESRD; participants within the fourth arteriole/vein ratio quartile were 3.11 times (95% CI, 1.51 to 6.40) more likely to develop ESRD than those in the first quartile (P0.001).The presence and severity of retinopathy were not associated with ESRD and decline in eGFR after taking into account established risk factors.

This study examined rates and determinants of vitamin D supplementation among Chronic Renal Insufficiency Cohort (CRIC) participants and determined the association between dose and 25-hydroxyvitamin D (25(OH)D) level. The 2010 Institute of Medicine Report noted a significant increase in vitamin D supplementation in the general population, but use in chronic kidney disease (CKD) is unknown.CRIC is a multicenter prospective observational cohort study of 3,939 participants with a median baseline age of 60 and an estimated glomerular filtration rate (eGFR) of 42.1 mL/minute per 1.73 m2. Of the cohort, 54.9% was male, 42.1% were Black, and 48.4% were diabetic. Multivariable logistic generalized estimating equations were used to examine determinants of supplementation use assessed annually between 2003 and 2011. Cross-sectional linear regression models, based on a subset of 1,155 participants, assessed associations between supplement dose and 25(OH)D level, measured by high-performance liquid chromatography coupled with tandem mass spectrometry.The proportion of participants reporting supplement use increased (P.0001), from 10% at baseline to 44% at 7-year follow-up visits. This was largely due to initiation of products containing only ergocalciferol or cholecalciferol. The odds of supplementation were greater in older, female, non-Black, married participants with greater education and lower body mass index. Among participants taking supplementation, dose was positively associated with 25(OH)D level, adjusted for race, season, diabetes, dietary intake, eGFR, and proteinuria. Only 3.8% of non-Black and 16.5% of Black participants taking a supplement were deficient (20 ng/mL), whereas 22.7% of non-Black and 62.4% of black participants not reporting supplement use were deficient.Vitamin D supplementation rates rose significantly among CRIC participants over 7 years of follow-up and were associated with greater serum 25(OH)D levels. Studies of vitamin D levels on clinical outcomes in CKD and future vitamin D interventional studies should consider these changes in supplementation practices.

Objective The race-specific association of inflammation with adiposity and muscle mass in subjects with chronic kidney disease (CKD) was examined. Methods Plasma concentration of interleukin (IL)−1β, IL-1 receptor antagonist (IL-1RA), IL-6, IL-10, tumor necrosis factor (TNF)-α, TGF-β, high-sensitivity C-reactive protein (hs-CRP), fibrinogen, and serum albumin was measured in 3,939 Chronic Renal Insufficiency Cohort study participants. Bioelectric impedance analysis was used to determine body fat mass (BFM) and fat-free mass (FFM). Results Plasma levels of hs-CRP, fibrinogen, IL-1RA, IL-6, and TNF-α increased and serum albumin decreased across the quartiles of body mass index. In multivariable analysis, BFM and FFM were positively associated with hs-CRP, fibrinogen, IL-1β, IL-1RA, and IL-6. One standard deviation (SD) increase in BFM and FFM was associated with 0.36 (95% confidence interval [CI] = 0.33, 0.39) and 0.26 (95% CI = 0.22, 0.30) SD increase in log-transformed hs-CRP, respectively (P

An elevated level of fibroblast growth factor-23 (FGF-23) is the earliest abnormality of mineral metabolism in CKD. High FGF-23 levels promote left ventricular hypertrophy but not coronary artery calcification. We used survival analysis to determine whether elevated FGF-23 is associated with greater risk of adjudicated congestive heart failure (CHF) and atherosclerotic events (myocardial infarction, stroke, and peripheral vascular disease) in a prospective cohort of 3860 participants with CKD stages 2-4 (baseline estimated GFR [eGFR], 44±15 ml/min per 1.73 m(2)). During a median follow-up of 3.7 years, 360 participants were hospitalized for CHF (27 events/1000 person-years) and 287 had an atherosclerotic event (22 events/1000 person-years). After adjustment for demographic characteristics, kidney function, traditional cardiovascular risk factors, and medications, higher FGF-23 was independently associated with graded risk of CHF (hazard ratio [HR], 1.45 per doubling [95% confidence interval (CI), 1.28 to 1.65]; HR for highest versus lowest quartile, 2.98 [95% CI, 1.97 to 4.52]) and atherosclerotic events (HR per doubling, 1.24 [95% CI, 1.09 to 1.40]; HR for highest versus lowest quartile, 1.76 [95% CI, 1.20 to 2.59]). Elevated FGF-23 was associated more strongly with CHF than with atherosclerotic events (P=0.02), and uniformly was associated with greater risk of CHF events across subgroups stratified by eGFR, proteinuria, prior heart disease, diabetes, BP control, anemia, sodium intake, income, fat-free mass, left ventricular mass index, and ejection fraction. Thus, higher FGF-23 is independently associated with greater risk of cardiovascular events, particularly CHF, in patients with CKD stages 2-4.

Background Various indicators of progression of chronic kidney disease (CKD) have been used as outcomes in clinical research studies. The effect of using varying measures on the association of risk factors with CKD progression has not been well characterized. Study Design Prospective cohort study. Setting & Participants The Chronic Renal Insufficiency Cohort (CRIC) Study (N=3,939) enrolled men and women with mild to moderate CKD, 48% of whom had diabetes and 42% were self-reported black race. Predictors Age, race, sex, diabetes, baseline estimated glomerular filtration rate (eGFR), proteinuria, and other established CKD risk factors. Outcomes Death, end-stage renal disease (ESRD), and eGFR events, including: (1) eGFR halving, (2) eGFR 2 , (3) eGFR halving and 2 , (4) eGFR decrease of 20mL/min/1.73m 2 , (5) eGFR halving or decrease of 20mL/min/1.73m 2 , and (6) eGFR decrease of 25% and change in CKD stage. Results Mean entry eGFR was 44.9mL/min/1.73m 2 . Annual rates of death, ESRD, and eGFR halving were 2.5%, 4.0%, and 6.1%, respectively, during an average follow-up of 5.4 years. Associations between risk factors and ESRD and eGFR events were similar across different definitions. However, these associations were substantially different from those with death. HRs for ESRD, eGFR halving, and death in the highest compared to the lowest proteinuria category were 11.83 (95% CI, 8.40-16.65), 11.19 (95% CI, 8.53-14.68), and 1.47 (95% CI, 1.10-1.96), respectively. Limitations Participants may not be representative of the entire CKD population. Conclusions Using ESRD or eGFR events, but not death, in the definition of kidney disease outcomes is appropriate in follow-up studies to identify risk factors for CKD progression.

Background A large proportion of newly created arteriovenous fistulas cannot be used for dialysis because they fail to mature adequately to support the hemodialysis blood circuit. The Hemodialysis Fistula Maturation (HFM) Study was designed to elucidate clinical and biological factors associated with fistula maturation outcomes. Study Design Multicenter prospective cohort study. Setting & Participants Approximately 600 patients undergoing creation of a new hemodialysis fistula will be enrolled at 7 centers in the United States and followed up for as long as 4 years. Predictors Clinical, anatomical, biological, and process-of-care attributes identified pre-, intra-, or postoperatively. Outcomes The primary outcome is unassisted clinical maturation, defined as successful use of the fistula for dialysis for 4 weeks without maturation-enhancing procedures. Secondary outcomes include assisted clinical maturation, ultrasound-based anatomical maturation, fistula procedures, fistula abandonment, and central venous catheter use. Measurements Preoperative ultrasound arterial and venous mapping, flow-mediated and nitroglycerin-mediated brachial artery dilation, arterial pulse wave velocity, and venous distensibility; intraoperative vein tissue collection for histopathologic and molecular analyses; postoperative ultrasounds at 1 day, 2 weeks, 6 weeks, and prior to fistula intervention and initial cannulation. Results Assuming complete data, no covariate adjustment, and unassisted clinical maturation of 50%, there will be 80% power to detect ORs of 1.83 and 1.61 for dichotomous predictor variables with exposure prevalences of 20% and 50%, respectively. Limitations Exclusion of 2-stage transposition fistulas limits generalizability. The requirement for study visits may result in a cohort that is healthier than the overall population of patients undergoing fistula creation. Conclusions The HFM Study will be of sufficient size and scope to: (1) evaluate a broad range of mechanistic hypotheses, (2) identify clinical practices associated with maturation outcomes, (3) assess the predictive utility of early indicators of fistula outcome, and (4) establish targets for novel therapeutic interventions to improve fistula maturation.

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

Oxalate is a potentially toxic terminal metabolite that is eliminated primarily by the kidneys. Oxalate nephropathy is a well-known complication of rare genetic disorders and enteric hyperoxaluria, but oxalate has not been investigated as a potential contributor to more common forms of chronic kidney disease (CKD).To assess whether urinary oxalate excretion is a risk factor for more rapid progression of CKD toward kidney failure.This prospective cohort study assessed 3123 participants with stages 2 to 4 CKD who enrolled in the Chronic Renal Insufficiency Cohort study from June 1, 2003, to September 30, 2008. Data analysis was performed from October 24, 2017, to June 17, 2018.Twenty-four-hour urinary oxalate excretion.A 50% decline in estimated glomerular filtration rate (eGFR) and end-stage renal disease (ESRD).This study included 3123 participants (mean [SD] age, 59.1 [10.6] years; 1414 [45.3%] female; 1423 [45.6%] white). Mean (SD) eGFR at the time of 24-hour urine collection was 42.9 (16.8) mL/min/1.73 m2. Median urinary excretion of oxalate was 18.6 mg/24 hours (interquartile range [IQR], 12.9-25.7 mg/24 hours) and was correlated inversely with eGFR (r = -0.13, P .001) and positively with 24-hour proteinuria (r = 0.22, P .001). During 22 318 person-years of follow-up, 752 individuals reached ESRD, and 940 individuals reached the composite end point of ESRD or 50% decline in eGFR (CKD progression). Higher oxalate excretion was independently associated with greater risks of both CKD progression and ESRD: compared with quintile 1 (oxalate excretion,11.5 mg/24 hours) those in quintile 5 (oxalate excretion, ≥27.8 mg/24 hours) had a 33% higher risk of CKD progression (hazard ratio [HR], 1.33; 95% CI, 1.04-1.70) and a 45% higher risk of ESRD (HR, 1.45; 95% CI, 1.09-1.93). The association between oxalate excretion and CKD progression and ESRD was nonlinear and exhibited a threshold effect at quintiles 3 to 5 vs quintiles 1 and 2. Higher vs lower oxalate excretion (at the 40th percentile) was associated with a 32% higher risk of CKD progression (HR, 1.32; 95% CI, 1.13-1.53) and 37% higher risk of ESRD (HR, 1.37; 95% CI, 1.15-1.63). Results were similar when treating death as a competing event.Higher 24-hour urinary oxalate excretion may be a risk factor for CKD progression and ESRD in individuals with CKD stages 2 to 4.