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RATIONALE & OBJECTIVE: The utility of conventional upper reference limits (URL) for N-terminal pro brain natriuretic peptide (NT-proBNP) and high-sensitivity cardiac troponin T (hsTnT) in chronic kidney disease (CKD) remains debated. We analyzed the distribution of hsTnT and NT-proBNP in people with CKD in ambulatory settings to examine the diagnostic value of conventional URL in this population. STUDY DESIGN: Observational study. SETTING & PARTICIPANTS: We studied participants of the Chronic Renal Insufficiency Cohort with CKD and no self-reported history of cardiovascular disease (CVD). EXPOSURE: Estimated glomerular filtration rate (eGFR). OUTCOMES: NT-proBNP and hsTnT at baseline. ANALYTICAL APPROACH:. We described the proportion of participants above the conventional URL for NT-proBNP (125 pg/ml) and hsTnT (14 ng/L) overall, and by eGFR. We then estimated 99(th) percentile URL for NT-proBNP and hsTnT. Using quantile regression of the 99(th) percentile, we modeled the association of eGFR with NT-proBNP and hsTnT. RESULTS: Among 2,312 CKD participants, 40% and 43% had levels of NT-proBNP and hsTnT above conventional URL, respectively. In those with eGFR

Disordered iron and mineral homeostasis are interrelated complications of chronic kidney disease that may influence cardiovascular and kidney outcomes. In a prospective analysis of 3747 participants in the Chronic Renal Insufficiency Cohort Study, we investigated risks of mortality, heart failure, end-stage kidney disease (ESKD), and atherosclerotic cardiovascular disease according to iron status, and tested for mediation by C-terminal fibroblast growth factor 23 (FGF23), hemoglobin and parathyroid hormone. Study participants were agnostically categorized based on quartiles of transferrin saturation and ferritin as: “Iron Replete” (27.1% of participants; referent group for all outcomes analyses), “Iron Deficiency” (11.1%), “Functional Iron Deficiency” (7.6%), “Mixed Iron Deficiency” (iron indices between the Iron Deficiency and Functional Iron Deficiency groups; 6.3%), “High Iron” (9.2%), or “Non-Classified” (the remaining 38.8% of participants). In multivariable-adjusted Cox models, Iron Deficiency independently associated with mortality (hazard ratio 1.28, 95% confidence interval 1.04–1.58) and heart failure (1.34, 1.05–1.72). Mixed Iron Deficiency associated with mortality (1.61, 1.27–2.04) and ESKD (1.33, 1.02–1.73). High Iron associated with mortality (1.54, 1.24–1.91), heart failure (1.58, 1.21–2.05), and ESKD (1.41, 1.13–1.77). Functional Iron Deficiency did not significantly associate with any outcome, and no iron group significantly associated with atherosclerotic cardiovascular disease. Among the candidate facilitators, FGF23 most significantly mediated the risks of mortality and heart failure conferred by Iron Deficiency. Thus, alterations in iron homeostasis associated with adverse cardiovascular and kidney outcomes in patients with chronic kidney disease.

Background Novel urine biomarkers may improve identification of children at greater risk of rapid kidney function decline, and elucidate the pathophysiology of CKD progression. Methods We investigated the relationship between urine biomarkers of kidney tubular health (EGF and α-1 microglobulin), tubular injury (kidney injury molecule-1; KIM-1), and inflammation (monocyte chemoattractant protein-1 [MCP-1] and YKL-40) and CKD progression. The prospective CKD in Children Study enrolled children aged 6 months to 16 years with an eGFR of 30-90ml/min per 1.73m2. Urine biomarkers were assayed a median of 5 months [IQR: 4-7] after study enrollment. We indexed the biomarker to urine creatinine by dividing the urine biomarker concentration by the urine creatinine concentration to account for the concentration of the urine. The primary outcome was CKD progression (a composite of a 50% decline in eGFR or kidney failure) during the follow-up period. Results Overall, 252 of 665 children (38%) reached the composite outcome over a median follow-up of 6.5 years. After adjustment for covariates, children with urine EGF concentrations in the lowest quartile were at a seven-fold higher risk of CKD progression versus those with concentrations in the highest quartile (fully adjusted hazard ratio [aHR], 7.1; 95% confidence interval [95% CI], 3.9 to 20.0). Children with urine KIM-1, MCP-1, and α-1 microglobulin concentrations in the highest quartile were also at significantly higher risk of CKD progression versus those with biomarker concentrations in the lowest quartile. Addition of the five biomarkers to a clinical model increased the discrimination and reclassification for CKD progression. Conclusions After multivariable adjustment, a lower urine EGF concentration and higher urine KIM-1, MCP-1, and α-1 microglobulin concentrations were each associated with CKD progression in children.

Introduction Management of chronic kidney disease (CKD) entails high medical complexity and often results in high hospitalization burden. There are limited data on the associations of longitudinal hospital utilization patterns with adverse clinical outcomes in individuals with CKD. Methods We derived cumulative all-cause hospitalization trajectory groups using latent class trajectory analysis in 3012 participants of the Chronic Renal Insufficiency Cohort (CRIC) Study who were alive and did not reach end-stage kidney disease (ESKD) within 4 years of study entry. Cox proportional hazards models tested the associations between hospitalization trajectory groups and risks of ESKD and death prior to the onset of ESKD (ESKD-censored death). Results Within 4 years of study entry, there were 5658 hospitalizations among 3012 participants. We identified 3 distinct subgroups of individuals with CKD based on cumulative all-cause hospitalization trajectories over 4 years: low-utilizer (n = 1066), intermediate-utilizer (n = 1802), and high-utilizer (n = 144). High-utilizers represented a patient population of lower socioeconomic status who had a greater prevalence of comorbid conditions and lower kidney function compared with intermediate- and low-utilizers. After the 4-year ascertainment period to form the trajectory subgroups, there were 544 ESKD events and 437 ESKD-censored deaths during a median follow-up time of 5.1 years. Compared with low-utilizers, intermediate-utilizers and high-utilizers were at 1.49-fold (95% confidence interval [CI] 1.22–1.84) and 1.75-fold (95% CI 1.20–2.56) higher risk of ESKD in adjusted analyses, respectively. Compared with low-utilizers, intermediate-utilizers and high-utilizers were at 1.48-fold (95% CI 1.17–1.87) and 2.58-fold (95% CI 1.74–3.83) higher risk of ESKD-censored death in adjusted analyses, respectively. Conclusions Trajectories of cumulative all-cause hospitalization identify subgroups of individuals with CKD who are at high risk of ESKD and death., Graphical abstract

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 (>232 pg/mL over 2 years) 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 (>3.37 ng/mL over 2 years) had significantly greater risk of incident HF (HR, 1.89 [95% CI, 1.13-3.16]), whereas those in the bottom quartile (≤−3.78 ng/mL over 2 years) 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.

RATIONALE & OBJECTIVE: Current dietary guidelines recommend that chronic kidney disease (CKD) patients restrict individual nutrients, such as sodium, potassium, phosphorus and protein. This approach can be difficult for patients to implement and ignores important nutrient interactions. Dietary patterns are an alternative method to intervene on diet. Our objective was to define the associations of four healthy dietary patterns with risk of CKD progression and all-cause mortality among people with CKD. STUDY DESIGN: Prospective cohort study. SETTING & PARTICIPANTS: 2,403 participants aged 21–74 years with an estimated glomerular filtration rate (eGFR) of 20–70 mL/min/1.73 m(2) and dietary data in the Chronic Renal Insufficiency Cohort (CRIC) study. EXPOSURES: Healthy Eating Index-2015 (HEI-2015), Alternative Healthy Eating Index-2010 (AHEI-2010), alternate Mediterranean diet (aMed), and Dietary Approaches to Stop Hypertension (DASH) diet scores were calculated from food frequency questionnaires. OUTCOMES: 1) CKD progression defined as ≥50% eGFR decline, kidney transplantation, or dialysis and 2) all-cause mortality. ANALYTICAL APPROACH: Cox proportional hazards regression models adjusted for demographic, lifestyle, and clinical covariates to estimate hazard ratios (HR) and 95% confidence intervals (CI). RESULTS: There were 855 cases of CKD progression and 773 deaths over a maximum of 14 years. Compared with participants with the lowest adherence, the most highly adherent tertile of AHEI-2010, aMed, and DASH had lower adjusted risk of CKD progression with the strongest results for aMed (HR: 0.75, 95% CI: 0.62–0.90). Compared with participants with the lowest adherence, the highest adherence tertiles for all scores had lower adjusted risk of all-cause mortality for each index (24–31% lower risk). LIMITATIONS: Self-reported dietary intake. CONCLUSIONS: Greater adherence to several healthy dietary patterns is associated with a lower risk of CKD progression and all-cause mortality among people with CKD. Guidance to adopt healthy dietary patterns can be considered as a strategy for managing CKD. INDEX WORDS: dietary patterns, nutrition, kidney disease, renal, mortality

Cardiovascular disease (CVD) is a major complication in individuals with chronic kidney disease (CKD). In Japan, the incidence of CVD among persons with CKD is lower than that in the United States. Although various classes of antihypertensive agents are prescribed to prevent CVD, the proportion varies between the United States and Japan. Until now, few studies have compared clinical practices and CVD prevalence among patients with CKD in the United States vs. Japan. In this study, we performed a cross-sectional comparison of the prevalence of CVD and the prescription of β-blockers at study entry to the Chronic Kidney Disease Japan Cohort (CKD-JAC) Study and the Chronic Renal Insufficiency Cohort (CRIC) Study. The mean patient age was 58.2 and 60.3 years, the mean estimated glomerular filtration rate (eGFR) was 42.8 and 28.9 (mL/min/1.73 m(2)), and the median urinary albumin:creatinine ratio was 51.9 and 485.9 (mg/g) among 3939 participants in the CRIC Study and 2966 participants in the CKD-JAC Study, respectively. The prevalence of any CVD according to a self-report (CRIC Study) was 33%, while that according to a medical chart review (CKD-JAC Study) was 24%. These findings were consistent across eGFR levels. Prescriptions for β-blockers differed between the CRIC and CKD-JAC Studies (49% and 20%, respectively). The odds ratios for the association of any history of CVD and β-blocker prescription were 3.0 [2.6–3.5] in the CRIC Study and 2.0 [1.6–2.5] in the CKD-JAC Study (P

Background Studies in the general population suggest that atrial fibrillation (AF) is an independent risk factor for decline in cognitive function, but this relationship has not been examined in adults with chronic kidney disease (CKD). We investigated the association between incident AF and changes in cognitive function over time in this population. Methods and Results We studied a subgroup of 3254 adults participating in the Chronic Renal Insufficiency Cohort Study. Incident AF was ascertained by 12-lead electrocardiogram (ECG) obtained at a study visit and/or identification of a hospitalization with AF during follow-up. Cognitive function was assessed biennially using the Modified Mini-Mental State Exam. Linear mixed effects regression was used to evaluate the association between incident AF and longitudinal change in cognitive function. Compared with individuals without incident AF (n = 3158), those with incident AF (n = 96) were older, had a higher prevalence of cardiovascular disease and hypertension, and lower estimated glomerular filtration rate. After median follow-up of 6.8 years, we observed no significant multivariable association between incident AF and change in cognitive function test score. Conclusion In this cohort of adults with CKD, incident AF was not associated with a decline in cognitive function.

Background Patients with chronic kidney disease (CKD) face risks of not only end-stage kidney disease (ESKD), cardiovascular disease (CVD) and death, but also decline in kidney function, quality of life (QOL) and mental and physical well-being. This study describes the multidimensional trajectories of CKD using clinical events, kidney function and patient-reported outcome measures (PROMs). We hypothesized that more advanced CKD stages would associate with more rapid decline in each outcome. Methods Among 3939 participants enrolled in the Chronic Renal Insufficiency Cohort (CRIC) Study, we evaluated multidimensional disease trajectories by G- and A-stages of enrollment estimated glomerular filtration rate (eGFR) and albuminuria, respectively. These trajectories included clinical events (ESKD, CVD, heart failure and death), eGFR decline and PROMs [kidney disease QOL (KDQOL) burden, effects and symptoms questionnaires, as well as the 12-item short form mental and physical component summaries]. We also evaluated a group-based multitrajectory model to group participants on the basis of longitudinal PROMs and compared group assignments by enrollment G- and A-stage. Results The mean participant age was 58 years, 45% were women, mean baseline eGFR was 44 mL/min/1.73 m2 and median urine albumin:creatinine ratio was 52 mg/g. The incidence of all clinical events was greater and eGFR decline was faster with more advanced G- and A-stages. While baseline KDQOL and physical component measures were lower with more advanced G- and A-stage of CKD, changes in PROMs were inconsistently related to the baseline CKD stage. Groups formed on PROM trajectories were fairly distinct from existing CKD staging (observed agreement 60.6%) and were associated with the risk of ESKD, CVD, heart failure and death. Conclusions More advanced baseline CKD stage was associated with a higher risk of clinical events and faster eGFR decline, and was only weakly related to changes in patient-reported metrics over time.

Introduction Cardiovascular disease (CVD) is the leading cause of mortality among individuals with chronic kidney disease (CKD). Cardiac biomarkers of myocardial distention, injury, and inflammation may signal unique pathways underlying CVD in CKD. In this analysis, we studied the association of baseline levels and changes in 4 traditional and novel cardiac biomarkers with risk of all-cause, CV, and non-CV mortality in a large cohort of patients with CKD. Methods Among 3664 adults with CKD enrolled in the Chronic Renal Insufficiency Cohort Study, we conducted a cohort study to examine the associations of baseline levels of N-terminal pro-B-type natriuretic peptide (NT-proBNP), cardiac high-sensitivity troponin T (hsTnT), growth differentiation factor−15 (GDF-15), and soluble ST-2 (sST-2) with risks of all-cause and cardiovascular (CV) mortality. Among a subcohort of 842 participants, we further examined the associations between change in biomarker levels over 2 years with risk of all-cause mortality. We used Cox proportional hazards regression models and adjusted for demographics, kidney function measures, cardiovascular risk factors, and medication use. Results After adjustment, elevated baseline levels of each cardiac biomarker were associated with increased risk of all-cause mortality: NT-proBNP (hazard ratio [HR] = 1.92, 95% confidence interval [CI] = 1.73−2.12); hsTnT (HR = 1.62, 95% CI = 1.48, 1.78]); GDF-15 (HR = 1.61, 95% CI = 1.46−1.78]); and sST-2 (HR = 1.26, CI = 1.16−1.37). Higher baseline levels of all 4 cardiac biomarkers were also associated with increased risk of CV. Declines in NT-proBNP (adjusted HR = 0.55, 95% CI = 0.36−0.86) and sST2 (HR = 0.55, 95% CI = 0.36−0.86]) over 2 years were associated with lower risk of all-cause mortality. Conclusion In a large cohort of CKD participants, elevations of NT-proBNP, hsTnT, GDF-15, and sST-2 were independently associated with greater risks of all-cause and CV mortality., Graphical abstract

Rationale & Objective Studies using a single measurement of fibroblast growth factor 23 (FGF-23) suggest that elevated FGF-23 levels are associated with increased risk for requirement for kidney replacement therapy (KRT) in patients with chronic kidney disease. However, the data do not account for changes in FGF-23 levels as kidney disease progresses. Study Design Case-cohort study. Setting & Participants To evaluate the association between serial FGF-23 levels and risk for requiring KRT, our primary analysis included 1,597 individuals in the Chronic Renal Insufficiency Cohort Study who had up to 5 annual measurements of carboxy-terminal FGF-23. There were 1,135 randomly selected individuals, of whom 266 initiated KRT, and 462 individuals who initiated KRT outside the random subcohort. Exposure Serial FGF-23 measurements and FGF-23 trajectory group membership. Outcomes Incident KRT. Analytical Approach To handle time-dependent confounding, our primary analysis of time-updated FGF-23 levels used time-varying inverse probability weighting in a discrete time failure model. To compare our results with prior data, we used baseline and time-updated FGF-23 values in weighted Cox regression models. To examine the association of FGF-23 trajectory subgroups with risk for incident KRT, we used weighted Cox models with FGF-23 trajectory groups derived from group-based trajectory modeling as the exposure. Results In our primary analysis, the HR for the KRT outcome per 1 SD increase in the mean of natural log–transformed (ln)FGF-23 in the past was 1.94 (95% CI, 1.51-2.49). In weighted Cox models using baseline and time-updated values, elevated FGF-23 level was associated with increased risk for incident KRT (HRs per 1 SD ln[FGF-23] of 1.18 [95% CI, 1.02-1.37] for baseline and 1.66 [95% CI, 1.49-1.86] for time-updated). Membership in the slowly and rapidly increasing FGF-23 trajectory groups was associated with ∼3- and ∼21-fold higher risk for incident KRT compared to membership in the stable FGF-23 trajectory group. Limitations Residual confounding and lack of intact FGF-23 values. Conclusions Increasing FGF-23 levels are independently associated with increased risk for incident KRT.

The worldwide burden of kidney disease is rising, but public awareness remains limited, underscoring the need for more effective communication by stakeholders in the kidney health community. Despite this need for clarity, the nomenclature for describing kidney function and disease lacks uniformity. In June 2019, Kidney Disease: Improving Global Outcomes (KDIGO) convened a Consensus Conference with the goal of standardizing and refining the nomenclature used in the English language to describe kidney function and disease, and of developing a glossary that could be used in scientific publications. Guiding principles of the conference were that the revised nomenclature should be patient-centered, precise, and consistent with nomenclature used in the KDIGO guidelines. Conference attendees reached general consensus on the following recommendations: (i) to use "kidney" rather than "renal" or "nephro-" when referring to kidney disease and kidney function; (ii) to use "kidney failure" with appropriate descriptions of presence or absence of symptoms, signs, and treatment, rather than "end-stage kidney disease"; (iii) to use the KDIGO definition and classification of acute kidney diseases and disorders (AKD) and acute kidney injury (AKI), rather than alternative descriptions, to define and classify severity of AKD and AKI; (iv) to use the KDIGO definition and classification of chronic kidney disease (CKD) rather than alternative descriptions to define and classify severity of CKD; and (v) to use specific kidney measures, such as albuminuria or decreased glomerular filtration rate (GFR), rather than "abnormal" or "reduced" kidney function to describe alterations in kidney structure and function. A proposed 5-part glossary contains specific items for which there was general agreement. Conference attendees acknowledged limitations of the recommendations and glossary, but they considered standardization of scientific nomenclature to be essential for improving communication.

Background After accounting for known risk factors for CKD progression in children, clinical outcomes among children with CKD still vary substantially. Biomarkers of tubular injury (such as KIM-1), repair (such as YKL-40), or inflammation (such as MCP-1, suPAR, TNF receptor-1 [TNFR-1], and TNFR-2) may identify children with CKD at risk for GFR decline. Methods We investigated whether plasma KIM-1, YKL-40, MCP-1, suPAR, TNFR-1, and TNFR-2 are associated with GFR decline in children with CKD and in subgroups defined by glomerular versus nonglomerular cause of CKD. We studied participants of the prospective CKiD Cohort Study which enrolled children with an eGFR of 30-90 ml/min per 1.73 m2 and then assessed eGFR annually. Biomarkers were measured in plasma collected 5 months after study enrollment. The primary endpoint was CKD progression, defined as a composite of a 50% decline in eGFR or incident ESKD. Results Of the 651 children evaluated (median age 11 years; median baseline eGFR of 53 ml/min per 1.73 m2), 195 (30%) had a glomerular cause of CKD. Over a median follow-up of 5.7 years, 223 children (34%) experienced CKD progression to the composite endpoint. After multivariable adjustment, children with a plasma KIM-1, TNFR-1, or TNFR-2 concentration in the highest quartile were at significantly higher risk of CKD progression compared with children with a concentration for the respective biomarker in the lowest quartile (a 4-fold higher risk for KIM-1 and TNFR-1 and a 2-fold higher risk for TNFR-2). Plasma MCP-1, suPAR, and YKL-40 were not independently associated with progression. When stratified by glomerular versus nonglomerular etiology of CKD, effect estimates did not differ significantly. Conclusions Higher plasma KIM-1, TNFR-1, and TNFR-2 are independently associated with CKD progression in children.

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

Rationale & Objectives Few studies have investigated racial disparities in survival among dialysis patients in a manner that considers risk factors and mortality during the phase of kidney disease before maintenance dialysis. Our objective was to explore racial variations in survival among dialysis patients and relate them to racial differences in comorbid conditions and rates of death in the setting of kidney disease not yet requiring dialysis therapy. Study Design Retrospective cohort study. Settings & Participants 3,288 black and white participants in the Chronic Renal Insufficiency Cohort (CRIC), none of whom were receiving dialysis at enrollment. Exposure Race. Outcome Mortality. Analytic Approach Cox proportional hazards regression was used to examine the association between race and mortality starting at: (1) time of dialysis initiation and (2) entry into the CRIC. Results During 7.1 years of median follow-up, 678 CRIC participants started dialysis. Starting from the time of dialysis initiation, blacks had lower risk for death (unadjusted HR, 0.67; 95% CI, 0.51-0.87) compared with whites. Starting from baseline CRIC enrollment, the strength of the association between some risk factors and dialysis was notably stronger for whites than blacks. For example, the HR for dialysis onset in the presence (vs absence) of heart failure at CRIC enrollment was 1.30 (95% CI, 1.01-1.68) for blacks versus 2.78 (95% CI, 1.90-4.50) for whites, suggesting differential severity of these risk factors by race. When we included deaths occurring both before and after dialysis, risk for death was higher among blacks (vs whites) starting from CRIC enrollment (HR, 1.41; 95% CI, 1.22-1.64), but this finding was attenuated in adjusted models (HR, 1.08; 95% CI, 0.91-1.28). Limitations Residual confounding. Conclusions The apparent survival advantage among blacks over whites treated with dialysis may be attributed to selected transition of a subset of whites with more severe comorbid conditions onto dialysis.

Rationale & Objective The pathogenesis of disordered mineral metabolism in chronic kidney disease (CKD) is largely informed by cross-sectional studies of humans and longitudinal animal studies. We sought to characterize the longitudinal evolution of disordered mineral metabolism during the course of CKD. Study Design Retrospective analysis nested in a cohort study. Setting & Participants Participants in the Chronic Renal Insufficiency Cohort (CRIC) Study who had up to 5 serial annual measurements of estimated glomerular filtration rate, fibroblast growth factor 23 (FGF-23), parathyroid hormone (PTH), serum phosphate, and serum calcium and who subsequently reached end-stage kidney disease (ESKD) during follow-up (n = 847). Exposure Years before ESKD. Outcomes Serial FGF-23, PTH, serum phosphate, and serum calcium levels. Analytical Approach To assess longitudinal dynamics of disordered mineral metabolism in human CKD, we used "ESKD-anchored longitudinal analyses" to express time as years before ESKD, enabling assessments of mineral metabolites spanning 8 years of CKD progression before ESKD. Results Mean FGF-23 levels increased markedly as time before ESKD decreased, while PTH and phosphate levels increased modestly and calcium levels declined minimally. Compared with other mineral metabolites, FGF-23 levels demonstrated the highest rate of change (velocity: first derivative of the function of concentration over time) and magnitude of acceleration (second derivative). These changes became evident approximately 5 years before ESKD and persisted without deceleration through ESKD onset. Rates of changes in PTH and phosphate levels increased modestly and without marked acceleration around the same time, with modest deceleration immediately before ESKD, when use of active vitamin D and phosphate binders increased. Limitations Individuals who entered the CRIC Study at early stages of CKD and who did not progress to ESKD were not studied. Conclusions Among patients with progressive CKD, FGF-23 levels begin to increase 5 years before ESKD and continue to rapidly accelerate until transition to ESKD.

Rationale and Objective: Glomerular filtration rate (GFR) estimation based on creatinine and cystatin C (eGFRcr-cys) is more accurate than estimated GFR (eGFR) based on creatinine or cystatin C alone (eGFRcr or eGFRcys, respectively), but the inclusion of creatinine in eGFRcr-cys requires specification of a person's race. beta 2-Microglobulin (B2M) and beta-trace protein (BTP) are alternative filtration markers that appear to be less influenced by race than creatinine is.Study Design: Study of diagnostic test accuracy.Setting and Participants: Development in a pooled population of 7 studies with 5,017 participants with and without chronic kidney disease. External validation in a pooled population of 7 other studies with 2,245 participants. Tests Compared: Panel eGFR using B2M and BTP in addition to cystatin C (3-marker panel) or creatinine and cystatin C (4-marker panel) with and without age and sex or race. Outcomes: GFRmeasured as the urinary clearance of iothalamate, plasmaclearanceof iohexol, orplasma clearance of [Cr-51]EDTA.Results: Mean measured GFRs were 58.1 and 83.2 mL/min/1.73 m(2), and the proportions of Black participants were 38.6% and 24.0%, in the development and validation populations, respectively. In development, addition of age and sex improved the performance of all equations compared with equations without age and sex, but addition of race did not further improve the performance. In validation, the 4-marker panels were more accurate than the 3-marker panels (P < 0.001). The 3-marker panel without race was more accurate than eGFRcys (percentage of estimates greater than 30% different from measured GFR [1-P30] of 15.6% vs 17.4%; P = 0.01), and the 4-marker panel without race was as accurate as eGFRcr-cys (1-P-30 of 8.6% vs 9.4%; P = 0.2). Results were generally consistent across subgroups.Limitations: No representation of participants with severe comorbid illness and from geographic areas outside of North America and Europe.Conclusions: The 4-marker panel eGFR is as accurate as eGFRcr-cys without requiring specification of race. A more accurate race-free eGFR could be an important advance.

Rationale & Objective Elevated levels of deoxycholic acid (DCA) are associated with adverse outcomes and may contribute to vascular calcification in patients with chronic kidney disease (CKD). We tested the hypothesis that elevated levels of DCA were associated with increased risks of cardiovascular disease, CKD progression, and death in patients with CKD. Study Design Prospective observational cohort study. Setting & Participants We included 3,147 Chronic Renal Insufficiency Cohort study participants who had fasting DCA levels. The average age was 59 ± 11 years, 45.3% were women, 40.6% were African American, and the mean estimated glomerular filtration rate was 42.5 ± 16.0 mL/min/1.73 m2. Predictor Fasting DCA levels in Chronic Renal Insufficiency Cohort study participants. Outcomes Risks of atherosclerotic and heart failure events, end-stage kidney disease (ESKD), and all-cause mortality. Analytical Approach We used Tobit regression to identify predictors of DCA levels. We used Cox regression to examine the association between fasting DCA levels and clinical outcomes. Results The strongest predictors of elevated DCA levels in adjusted models were increased age and nonuse of statins. The associations between log-transformed DCA levels and clinical outcomes were nonlinear. After adjustment, DCA levels above the median were independently associated with higher risks of ESKD (HR, 2.67; 95% CI, 1.51-4.74) and all-cause mortality (HR, 2.13; 95% CI, 1.25-3.64). DCA levels above the median were not associated with atherosclerotic and heart failure events, and DCA levels below the median were not associated with clinical outcomes. Limitations We were unable to measure DCA longitudinally or in urinary or fecal samples, and we were unable to measure other bile acids. We also could not measure many factors that affect DCA levels. Conclusions In 3,147 participants with CKD stages 2-4, DCA levels above the median were independently associated with ESKD and all-cause mortality., Graphical abstract

BACKGROUND: The association between socioeconomic factors and development of peripheral artery disease (PAD) has not been as well characterized compared to other cardiovascular diseases (CVD). We sought to define how annual income, sex, race, and education level are associated with newly diagnosed PAD in a well-characterized, diverse set of adults with CKD. METHODS: The Chronic Renal Insufficiency Cohort Study (CRIC) is a multicenter, prospective cohort study designed to examine risk factors for progression of CKD and cardiovascular disease. Demographic and clinical data including ankle brachial index (ABI) and interventions were collected at baseline, as well as yearly during follow-up visits. Annual income was categorized as: < $25,000, $25,000–50,000, $50,000–100,000, or above $100,000. We excluded those with pre-existing PAD, defined as enrollment ABI of 1.4, or missing income data. Cox proportional hazards regression was used to estimate the risk for incident PAD during CRIC enrollment, defined as a drop in ABI to < 0.90 or a confirmed PAD intervention, including revascularization or amputation. RESULTS: A total of 3,313 patients met inclusion criteria, the mean age was 58.7 yrs, 56% were male, and 42% were Black. Over a median follow-up of 10.1 years, 639 participants (19%) were newly diagnosed with PAD. After adjusting for cardiovascular risk factors, all lower levels of annual household income were associated with increased incidence of PAD (income $100,000 (overall p-value=0.02). In the multivariable model, there was no association between education level and PAD incidence (p=0.80). Black race (HR 1.2, 95% CI 1.0–1.5, p=0.023) and female sex (HR 1.7, 95% CI 1.4–2.0, p

BACKGROUND: The inclusion of race in equations to estimate the glomerular filtration rate (GFR) has become controversial. Alternative equations that can be used to achieve similar accuracy without the use of race are needed. METHODS: In a large national study involving adults with chronic kidney disease, we conducted cross-sectional analyses of baseline data from 1248 participants for whom data, including the following, had been collected: race as reported by the participant, genetic ancestry markers, and the serum creatinine, serum cystatin C, and 24-hour urinary creatinine levels. RESULTS: Using current formulations of GFR estimating equations, we found that in participants who identified as Black, a model that omitted race resulted in more underestimation of the GFR (median difference between measured and estimated GFR, 3.99 ml per minute per 1.73 m(2) of body-surface area; 95% confidence interval [CI], 2.17 to 5.62) and lower accuracy (percent of estimated GFR within 10% of measured GFR [P(10)], 31%; 95% CI, 24 to 39) than models that included race (median difference, 1.11 ml per minute per 1.73 m(2); 95% CI, −0.29 to 2.54; P(10), 42%; 95% CI, 34 to 50). The incorporation of genetic ancestry data instead of race resulted in similar estimates of the GFR (median difference, 1.33 ml per minute per 1.73 m(2); 95% CI, −0.12 to 2.33; P(10), 42%; 95% CI, 34 to 50). The inclusion of non-GFR determinants of the serum creatinine level (e.g., body-composition metrics and urinary excretion of creatinine) that differed according to race reported by the participants and genetic ancestry did not eliminate the misclassification introduced by removing race (or ancestry) from serum creatinine–based GFR estimating equations. In contrast, the incorporation of race or ancestry was not necessary to achieve similarly statistically unbiased (median difference, 0.33 ml per minute per 1.73 m(2); 95% CI, −1.43 to 1.92) and accurate (P(10), 41%; 95% CI, 34 to 49) estimates in Black participants when GFR was estimated with the use of cystatin C. CONCLUSIONS: The use of the serum creatinine level to estimate the GFR without race (or genetic ancestry) introduced systematic misclassification that could not be eliminated even when numerous non-GFR determinants of the serum creatinine level were accounted for. The estimation of GFR with the use of cystatin C generated similar results while eliminating the negative consequences of the current race-based approaches. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases and others.)

Importance National initiatives have emphasized the use of autogenous arteriovenous fistulas (AVFs) for hemodialysis, but their purported benefits have been questioned. Objective To examine AVF usability, longer-term functional patency, and remedial procedures to facilitate maturation, manage complications, or maintain patency in the Hemodialysis Fistula Maturation (HFM) Study. Design, setting, and participants The HFM Study was a multicenter (n = 7) prospective National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases cohort study performed to identify factors associated with AVF maturation. A total of 602 participants were enrolled (dialysis, kidney failure: 380; predialysis, chronic kidney disease [CKD]: 222) with AVF maturation ascertained for 535 (kidney failure, 353; CKD, 182) participants. Interventions All clinical decisions regarding AVF management were deferred to the individual centers, but remedial interventions were discouraged within 6 weeks of creation. Main outcomes and measures In this case series analysis, the primary outcome was unassisted maturation. Functional patency, freedom from intervention, and participant survival were summarized using Kaplan-Meier analysis. Results Most participants evaluated (n = 535) were men (372 [69.5%]) and had diabetes (311 [58.1%]); mean (SD) age was 54.6 (13.6) years. Almost two-thirds of the AVFs created (342 of 535 [64%]) were in the upper arm. The AVF maturation rates for the kidney failure vs CKD participants were 29% vs 10% at 3 months, 67% vs 38% at 6 months, and 76% vs 58% at 12 months. Several participants with kidney failure (133 [37.7%]) and CKD (63 [34.6%]) underwent interventions to facilitate maturation or manage complications before maturation. The median time from access creation to maturation was 115 days (interquartile range [IQR], 86-171 days) but differed by initial indication (CKD, 170 days; IQR, 113-269 days; kidney failure, 105 days; IQR, 81-137 days). The functional patency for the AVFs that matured at 1 year was 87% (95% CI, 83.2%-90.2%) and at 2 years, 75% (95% CI, 69.7%-79.7%), and there was no significant difference for those receiving interventions before maturation. Almost half (188 [47.5%]) of the AVFs that matured had further intervention to maintain patency or treat complications. Conclusions and relevance The findings of this study suggest that AVF remains an accepted hemodialysis access option, although both its maturation and continued use require a moderate number of interventions to maintain patency and treat the associated complications.

BACKGROUND Vascular calcification contributes to cardiovascular disease (CVD) and mortality in individuals with chronic kidney disease (CKD). Vitamin K-dependent proteins function as calcification inhibitors in vascular tissue. OBJECTIVE We sought to determine the association of vitamin K status with mortality and CVD events in adults with CKD. DESIGN Plasma dephospho-uncarboxylated matrix gla protein ((dp)ucMGP), which increases when vitamin K status is low, and plasma phylloquinone (vitamin K1), which decreases when vitamin K status is low, were measured in 3066 Chronic Renal Insufficiency Cohort participants (median age = 61 years, 45% female, 41% non-Hispanic Black, median eGFR = 41 mL/min/1.73m2). The association of vitamin K status biomarkers with all-cause mortality and atherosclerotic-related CVD was determined using multivariable Cox proportional hazards regression. RESULTS There were 1122 deaths and 599 atherosclerotic CVD events over the median 12.8 follow-up years. All-cause mortality risk was 21-29% lower among participants with plasma (dp)ucMGP

BACKGROUND: Proteomic profiling may allow identification of plasma proteins that associate with subsequent changesin kidney function, elucidating biologic processes underlying the development and progression of CKD. METHODS: We quantified the association between 4877 plasma proteins and a composite outcome of ESKD or decline in eGFR by ≥50% among 9406 participants in the Atherosclerosis Risk in Communities (ARIC) Study (visit 3; mean age, 60 years) who were followed for a median of 14.4 years. We performed separate analyses for these proteins in a subset of 4378 participants (visit 5), who were followed at a later time point, for a median of 4.4 years. For validation, we evaluated proteins with significant associations (false discovery rate

Zelnick et al1 analyzed data from the Chronic Renal Insufficiency Cohort (CRIC) obtained from the National Institute of Diabetes and Digestive and Kidney Diseases central repository and reported that the Chronic Kidney Disease-Epidemiology (CKD-EPI) equation estimated glomerular filtration rates (eGFR) were higher than iothalamate clearance glomerular filtration rates (iGFR) among self-reported Black participants with iGFR less than 45 mL/min/1.73 m2. Using the CKD-EPI equation without a (Black vs non-Black) race coefficient appeared to attenuate the difference between eGFR and iGFR (eGFR − iGFR). The authors suggested that the latter approach should be used more widely in clinical practice. We believe that examining potential bias in eGFR values within subgroups defined by iGFR is problematic. An unbiased eGFR estimation aims to ensure that for the set of individuals who have the same eGFR value, the mean iGFR value is the same as the eGFR. The correlation between the difference between eGFR and iGFR (eGFR − iGFR) and iGFR is expected for an unbiased eGFR estimation.2 We offer an alternative view of the data here with different clinical implications.

Contains fulltext : 215593.pdf (Publisher’s version ) (Closed access) Although blood pressure control is a major goal in chronic kidney disease, no worldwide overview of either its achievement or antihypertensive prescriptions is currently available. To evaluate this we compared crude prevalence of uncontrolled blood pressure among 17 cohort studies, including 34 602 individuals with estimated glomerular filtration rate under 60 ml/min/1.73 m(2) and treated hypertension across four continents, and estimated observed to expected prevalence ratios, adjusted for potential confounders. Crude prevalence of blood pressure of 140/90 mm Hg or more varied from 28% to 61% and of blood pressure of 130/80 or more from 54% to 84%. Adjusted prevalence ratios indicated poorer hypertension control than expected in cohorts from European countries, India, and Uruguay, and better control in patients from North American and high-income Asian countries. Four antihypertensive drug classes or more were prescribed to more than 30% of participants in North American and some European cohorts, but this practice was less common elsewhere. Renin angiotensin-aldosterone system inhibitors were the most common antihypertensive drugs, prescribed for 54% to 91% of cohort participants. Differences for other drug classes were much stronger, ranging from 11% to 79% for diuretics, 22% to 70% for beta-blockers, and 27% to 75% for calcium-channel blockers. The confounders studied explain only a part of the international variation in blood pressure control among individuals with chronic kidney disease. Thus, considerable heterogeneity in prescription patterns worldwide calls for further investigation into the impact of different approaches on patient outcomes.

Author(s): Hsu, Raymond K; Hsu, Chi-Yuan; McCulloch, Charles E; Yang, Jingrong; Anderson, Amanda H; Chen, Jing; Feldman, Harold I; He, Jiang; Liu, Kathleen D; Navaneethan, Sankar D; Porter, Anna C; Rahman, Mahboob; Tan, Thida C; Wilson, F Perry; Xie, Dawei; Zhang, Xiaoming; Go, Alan S; Chronic Renal Insufficiency Cohort (CRIC) Study Investigators | Abstract: Background:Observational studies relying on clinically obtained data have shown that acute kidney injury (AKI) is linked to accelerated chronic kidney disease (CKD) progression. However, prior reports lacked uniform collection of important confounders such as proteinuria and pre-AKI kidney function trajectory, and may be susceptible to ascertainment bias, as patients may be more likely to undergo kidney function testing after AKI. Methods:We studied 444 adults with CKD who participated in the prospective Chronic Renal Insufficiency Cohort (CRIC) Study and were concurrent members of a large integrated healthcare delivery system. We estimated glomerular filtration rate (eGFR) trajectories using serum creatinine measurements from (i) the CRIC research protocol (yearly) and (ii) routine clinical care. We used linear mixed effects models to evaluate the associations of AKI with acute absolute change in eGFR and post-AKI eGFR slope, and explored whether these varied by source of creatinine results. Models were adjusted for demographic characteristics, diabetes status and albuminuria. Results:During median follow-up of 8.5 years, mean rate of eGFR loss was -0.31 mL/min/1.73nm2/year overall, and 73 individuals experienced AKI (55% Stage 1). A significant interaction existed between AKI and source of serum creatinine for acute absolute change in eGFR level after discharge; in contrast, AKI was independently associated with a faster rate of eGFR decline (mean additional loss of -0.67 mL/min/1.73nm2/year), which was not impacted by source of serum creatinine. Conclusions:AKI is independently associated with subsequent steeper eGFR decline regardless of the serum creatinine source used, but the strength of association is smaller than observed in prior studies after taking into account key confounders such as pre-AKI eGFR slope and albuminuria.

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.

RATIONALE & OBJECTIVE: Traditional risk estimates for atherosclerotic vascular disease (ASVD) and death may not perform optimally in the setting of 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: 2399 Chronic Renal Insufficiency Cohort (CRIC) study participants without history of cardiovascular disease at study entry. PREDICTORS: Baseline plasma levels of biomarkers of inflammation (interleukin (IL)-1β, IL-1RA (IL-1 receptor antagonist), IL-6, tumor necrosis factor (TNF)-α, transforming growth factor β (TGFβ), high sensitivity C-Reactive protein (hs-CRP), 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 (MI), peripheral arterial disease (PAD), 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 MI, PAD, stroke, or death, respectively. 1-decile greater levels of IL-6 (adjusted Hazard Ratio [aHR], 1.12; 95% CI, 1.08-1.16; p

Background Insulin resistance contributes to the metabolic syndrome, which is associated with the development of kidney disease. However, it is unclear if insulin resistance independently contributes to an increased risk of chronic kidney disease (CKD) progression or CKD complications. Additionally, predisposing factors responsible for insulin resistance in the absence of diabetes in CKD are not well described. This study aimed to describe factors associated with insulin resistance and characterize the relationship of insulin resistance to CKD progression, cardiovascular events and death among a cohort of non-diabetics with CKD. Methods Data was utilized from Chronic Renal Insufficiency Cohort Study participants without diabetes (N = 1883). Linear regression was used to assess associations with insulin resistance, defined using the Homeostasis Model Assessment of Insulin Resistance (HOMA-IR). The relationship of HOMA-IR, fasting glucose, hemoglobin A1c (HbA1c), and C-peptide with CKD progression, cardiovascular events, and all-cause mortality was examined with Cox proportional hazards models. Results Novel positive associations with HOMA-IR included serum albumin, uric acid, and hemoglobin A1c. After adjustment, HOMA-IR was not associated with CKD progression, cardiovascular events, or all-cause mortality. There was a notable positive association of one standard deviation increase in HbA1c with the cardiovascular endpoint (HR 1.16, 95% CI: 1.00–1.34). Conclusion We describe potential determinants of HOMA-IR among a cohort of non-diabetics with mild-moderate CKD. HOMA-IR was not associated with renal or cardiovascular events, or all-cause mortality, which adds to the growing literature describing an inconsistent relationship of insulin resistance with CKD-related outcomes. Electronic supplementary material The online version of this article (10.1186/s12882-019-1220-6) contains supplementary material, which is available to authorized users.

The last two decades have witnessed an explosion in research focused on the development and assessment of novel biomarkers for improved prognosis of diseases. As a result, best practice standards guiding biomarker research have undergone extensive development. Currently, there is great interest in the promise of biomarkers to enhance research efforts and clinical practice in the setting of chronic kidney disease, acute kidney injury, and glomerular disease. However, some have questioned whether biomarkers currently add value to the clinical practice of nephrology. The current state of the art pertaining to statistical analyses regarding the use of such measures is critical. In December 2014, the National Institute of Diabetes and Digestive and Kidney Diseases convened a meeting, "Toward Building Better Biomarker Statistical Methodology," with the goals of summarizing the current best practice recommendations and articulating new directions for methodological research. This report summarizes its conclusions and describes areas that need attention. Suggestions are made regarding metrics that should be commonly reported. We outline the methodological issues related to traditional metrics and considerations in prognostic modeling, including discrimination and case mix, calibration, validation, and cost-benefit analysis. We highlight the approach to improved risk communication and the value of graphical displays. Finally, we address some "new frontiers" in prognostic biomarker research, including the competing risk framework, the use of longitudinal biomarkers, and analyses in distributed research networks.

RATIONALE & OBJECTIVE: Most circulating biomarkers of chronic kidney disease (CKD) progression focus on factors reflecting glomerular filtration. Few biomarkers capture non-glomerular pathways of kidney injury or damage, which may be particularly informative in populations at high risk for CKD progression such as individuals with diabetes. STUDY DESIGN: Cohort study. SETTING & PARTICIPANTS: 594 participants (mean age 70, 53% women) of the Reason for Geographic and Racial Differences in Stroke study who had diabetes and an estimated glomerular filtration rate (eGFR)

Introduction: In individuals with chronic kidney disease (CKD), healthy dietary patterns are inversely associated with CKD progression. Metabolomics, an approach which measures many small molecules in biofluids, can identify biomarkers of healthy dietary patterns and elucidate metabolic pathways underlying diet-disease associations. Hypothesis: We hypothesized that adherence to 4 healthy dietary patterns would be associated with a set of known metabolites in CKD patients. Methods: We examined associations between 634 plasma metabolites assessed using the Broad platform at year 1 and Healthy Eating Index (HEI)-2015, Alternative Healthy Eating Index (AHEI)-2010, the Dietary Approaches to Stop Hypertension (DASH) diet, and alternate Mediterranean diet (aMED), and their food components in 1,117 participants in the CRIC Study. Usual dietary intakes were assessed using a food frequency questionnaire at baseline and year 2. We conducted multivariable linear regression models to study associations between diet scores and individual plasma metabolites, adjusting for sociodemographic characteristics, health behaviors, and clinical factors. Results: After Bonferroni correction, we identified a total of 362 diet-metabolite associations (HEI=78; AHEI=127; DASH=97; aMED=60), and 101 metabolites were associated with more than 1 dietary pattern. The most common metabolite categories were triacylglycerols and diacylglycerols. Most lipids were negatively associated with healthy dietary patterns, except for cholesterols esters and triacylglycerols with ≥7 double bonds. Triacylglycerols with high number of double bonds were positively associated with healthy fat intake (e.g., higher monounsaturated and polyunsaturated fatty acid, omega-3 fatty acid, fish) within HEI, AHEI, and aMED ( Table ). Conclusions: We identified many metabolites associated with healthy dietary patterns, indicative of food consumption. If replicated, they may be considered biomarkers of healthy dietary patterns in CKD patients.

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.

BACKGROUND: Adherence to healthy behaviors reduces risks of cardiovascular disease and death in the general population. However, among people with kidney disease, a group at higher risk for cardiovascular disease, such benefits have not been established. METHODS: We pooled data from three cohort studies with a total of 27,271 participants. Kidney function was categorized on the basis of eGFR (≥60, 45 to

Background and objectives Metabolomics facilitates the discovery of biomarkers and potential therapeutic targets for CKD progression. Design, setting, participants, & measurements We evaluated an untargeted metabolomics quantification of stored plasma samples from 645 Chronic Kidney Disease in Children (CKiD) participants. Metabolites were standardized and logarithmically transformed. Cox proportional hazards regression examined the association between 825 nondrug metabolites and progression to the composite outcome of KRT or 50% reduction of eGFR, adjusting for age, sex, race, body mass index, hypertension, glomerular versus nonglomerular diagnosis, proteinuria, and baseline eGFR. Stratified analyses were performed within subgroups of glomerular/nonglomerular diagnosis and baseline eGFR. Results Baseline characteristics were 391 (61%) male; median age 12 years; median eGFR 54 ml/min per 1.73 m2; 448 (69%) nonglomerular diagnosis. Over a median follow-up of 4.8 years, 209 (32%) participants developed the composite outcome. Unique association signals were identified in subgroups of baseline eGFR. Among participants with baseline eGFR ≥60 ml/min per 1.73 m2, two-fold higher levels of seven metabolites were significantly associated with higher hazards of KRT/halving of eGFR events: three involved in purine and pyrimidine metabolism (N6-carbamoylthreonyladenosine, hazard ratio, 16; 95% confidence interval, 4 to 60; 5,6-dihydrouridine, hazard ratio, 17; 95% confidence interval, 5 to 55; pseudouridine, hazard ratio, 39; 95% confidence interval, 8 to 200); two amino acids, C-glycosyltryptophan, hazard ratio, 24; 95% confidence interval 6 to 95 and lanthionine, hazard ratio, 3; 95% confidence interval, 2 to 5; the tricarboxylic acid cycle intermediate 2-methylcitrate/homocitrate, hazard ratio, 4; 95% confidence interval, 2 to 7; and gulonate, hazard ratio, 10; 95% confidence interval, 3 to 29. Among those with baseline eGFR Conclusions Untargeted plasma metabolomic profiling facilitated discovery of novel metabolite associations with CKD progression in children that were independent of established clinical predictors and highlight the role of select biologic pathways.

Rationale & Objectives Adiposity and physical fitness levels are major drivers of cardiometabolic risk, but these relationships have not been well-characterized in chronic kidney disease (CKD). We examined the associations of visceral adipose tissue (VAT), subcutaneous adipose tissue (SAT), intrahepatic fat, and physical function with inflammation, insulin resistance, and adipokine levels in patients with CKD. Study Design Prospective cohort study. Setting & Participants Participants with stages 3-5 CKD not receiving maintenance dialysis, followed up at one of 8 clinical sites in the Chronic Renal Insufficiency Cohort (CRIC) Study, and who underwent magnetic resonance imaging of the abdomen at an annual CRIC Study visit (n = 419). Predictors VAT volume, SAT volume, intrahepatic fat, body mass index, waist circumference, and time taken to complete the 400-m walk test (physical function). Outcomes Markers of inflammation (interleukin 1β [IL-1β], IL-6, tumor necrosis factor receptor 1 [TNFR1], and TNFR2), insulin resistance (homeostasis model assessment of insulin resistance), and adipokine levels (adiponectin, total and high molecular weight, resistin, and leptin). Analytical Approach Multivariable linear regression of VAT and SAT volume, intrahepatic fat, and physical function with individual markers (log-transformed values), adjusting for relevant covariates. Results Mean age of the study population was 64.3 years; 41% were women, and mean estimated glomerular filtration rate was 53.2 ± 14.6 (SD) mL/min/1.73 m2. More than 85% were overweight or obese, and 40% had diabetes. Higher VAT volume, SAT volume, and liver proton density fat fraction were associated with lower levels of total and high-molecular-weight adiponectin, higher levels of leptin and insulin resistance, and lower high-density lipoprotein cholesterol and higher serum triglyceride levels. A slower 400-m walk time was associated only with higher levels of leptin, total adiponectin, plasma IL-6, and TNFR1 and did not modify the associations between fat measures and cardiometabolic risk factors. Limitations Lack of longitudinal data and dietary details. Conclusions Various measures of adiposity are associated with cardiometabolic risk factors. Physical function was also associated with the cardiometabolic risk factors studied and does not modify associations between fat measures and cardiometabolic risk factors. Longitudinal studies of the relationship between body fat and aerobic fitness with cardiovascular and kidney disease progression are warranted.

Objective To determine whether electronic health record alerts for acute kidney injury would improve patient outcomes of mortality, dialysis, and progression of acute kidney injury. Design Double blinded, multicenter, parallel, randomized controlled trial. Setting Six hospitals (four teaching and two non-teaching) in the Yale New Haven Health System in Connecticut and Rhode Island, US, ranging from small community hospitals to large tertiary care centers. Participants 6030 adult inpatients with acute kidney injury, as defined by the Kidney Disease: Improving Global Outcomes (KDIGO) creatinine criteria. Interventions An electronic health record based “pop-up” alert for acute kidney injury with an associated acute kidney injury order set upon provider opening of the patient’s medical record. Main outcome measures A composite of progression of acute kidney injury, receipt of dialysis, or death within 14 days of randomization. Prespecified secondary outcomes included outcomes at each hospital and frequency of various care practices for acute kidney injury. Results 6030 patients were randomized over 22 months. The primary outcome occurred in 653 (21.3%) of 3059 patients with an alert and in 622 (20.9%) of 2971 patients receiving usual care (relative risk 1.02, 95% confidence interval 0.93 to 1.13, P=0.67). Analysis by each hospital showed worse outcomes in the two non-teaching hospitals (n=765, 13%), where alerts were associated with a higher risk of the primary outcome (relative risk 1.49, 95% confidence interval 1.12 to 1.98, P=0.006). More deaths occurred at these centers (15.6% in the alert group v 8.6% in the usual care group, P=0.003). Certain acute kidney injury care practices were increased in the alert group but did not appear to mediate these outcomes. Conclusions Alerts did not reduce the risk of our primary outcome among patients in hospital with acute kidney injury. The heterogeneity of effect across clinical centers should lead to a re-evaluation of existing alerting systems for acute kidney injury. Trial registration ClinicalTrials.gov NCT02753751 .

Background Adults with chronic kidney disease (CKD) are hospitalized more frequently than those without CKD, but the magnitude of this excess morbidity and the factors associated with hospitalizations are not well known. Methods and findings Data from 3,939 participants enrolled in the Chronic Renal Insufficiency Cohort (CRIC) Study between 2003 and 2008 at 7 clinical centers in the United States were used to estimate primary causes of hospitalizations, hospitalization rates, and baseline participant factors associated with all-cause, cardiovascular, and non-cardiovascular hospitalizations during a median follow up of 9.6 years. Multivariable-adjusted Poisson regression was used to identify factors associated with hospitalization rates, including demographics, blood pressure, estimated glomerular filtration rate (eGFR), and proteinuria. Hospitalization rates in CRIC were compared with rates in the Nationwide Inpatient Sample (NIS) from 2012. Of the 3,939 CRIC participants, 45.1% were female, and 41.9% identified as non-Hispanic black, with a mean age of 57.7 years, and the mean eGFR is 44.9 ml/min/1.73m2. CRIC participants had an unadjusted overall hospitalization rate of 35.0 per 100 person-years (PY) [95% CI: 34.3 to 35.6] and 11.1 per 100 PY [95% CI: 10.8 to 11.5] for cardiovascular-related causes. All-cause, non-cardiovascular, and cardiovascular hospitalizations were associated with older age (≥65 versus 45 to 64 years), more proteinuria (≥150 to 65 years. Limitations of the study include possible misclassification by diagnostic codes, residual confounding, and potential bias from healthy volunteer effect due to its observational nature. Conclusions In this study, we observed that adults with CKD had a higher hospitalization rate than the general population that is hospitalized, and even moderate reductions in kidney function were associated with elevated rates of hospitalization. Causes of hospitalization were predominantly related to cardiovascular disease, but other causes contributed, particularly, genitourinary, digestive, and endocrine, nutritional, and metabolic illnesses. High levels of proteinuria were observed to have the largest association with hospitalizations across a wide range of kidney function levels., Hsiang-Yu Chen and colleagues report the factors associated with hospitalization in patients with Chronic Kidney Disease., Author summary Why was this study done? Chronic kidney disease (CKD) (or non-dialysis-dependent kidney disease) is increasingly common globally, and individuals with CKD have a high risk of health complications, including hospitalizations. Many of the hospitalizations experienced by those with CKD are thought to be due to cardiovascular disease, but little else is known about the other causes for hospitalization or why people with kidney disease are at higher risk of hospitalizations. Learning more about causes of hospitalization and risk factors for hospitalizations can guide outpatient management. Research to date on hospitalizations in kidney disease has mainly focused on those with dialysis-dependent kidney disease. What did the researchers do and find? We looked at hospitalization data from adults with CKD who were followed for nearly 10 years. We classified hospitalizations by the primary discharge code and found that non-cardiovascular causes, such as genitourinary-, digestive-, and endocrine-related causes, comprised the majority of hospitalizations and that the largest single contributor to hospitalizations was due to cardiovascular reasons. We modeled the risk of hospitalizations with patient characteristics, such as age and sex, and clinical factors, such as level of kidney function, blood pressure, and proteinuria, and found that high levels of proteinuria were found to have a high risk of hospitalization regardless of kidney function level, and the risk of hospitalizations occurred even at moderate levels of kidney function. We also compared the hospitalization data from individuals with known CKD to a sample of the general hospitalized population in the United States and found that adults with CKD have higher hospitalization rates than this general sample. What do these findings mean? These findings highlight the need for developing better approaches to identifying patients at risk for severe complications of CKD and to guiding outpatient management strategies to improve outcomes in CKD. The findings may be particularly relevant to health care providers in general medicine since the increased risk of hospitalization occurred with even moderate reductions in kidney function, which do not typically correspond to being under the care of a kidney disease expert. Our study’s findings might not be applicable to other CKD populations since the study enrolled volunteers, who might be healthier than other populations.

Background The secretion of organic solutes by the proximal tubules is an essential intrinsic kidney function. The degree to which secretory solute clearance corresponds with the glomerular filtration rate (GFR) and potential metabolic implications of net secretory clearance are largely unknown. Methods We evaluated 1240 participants with chronic kidney disease (CKD) from the multicenter Chronic Renal Insufficiency Cohort (CRIC) Study. We used targeted mass-spectrometry to quantify candidate secretory solutes in paired 24-h urine and plasma samples. CRIC study personnel measured GFR using 125I-iothalamate clearance (iGFR). We used correlation and linear regression to determine cross-sectional associations of secretory clearances with iGFR and common metabolic complications of CKD. Results Correlations between iGFR and secretory solute clearances ranged from ρ = +0.30 for hippurate to ρ = +0.58 for kynurenic acid. Lower net clearances of most secretory solutes were associated with higher serum concentrations of parathyroid hormone (PTH), triglycerides and uric acid. Each 50% lower kynurenic acid clearance was associated with a 21% higher serum PTH concentration [95% confidence interval (CI) 15–26%] and a 10% higher serum triglyceride concentration (95% CI 5–16%) after adjustment for iGFR, albuminuria and other potential confounders. Secretory solute clearances were not associated with statistically or clinically meaningful differences in serum calcium, phosphate, hemoglobin or bicarbonate concentrations. Conclusions Tubular secretory clearances are modestly correlated with measured GFR among adult patients with CKD. Lower net secretory clearances are associated with selected metabolic complications independent of GFR and albuminuria, suggesting potential clinical and biological relevance.

The Chronic Renal Insufficiency Cohort (CRIC) Study is an ongoing, multicenter, longitudinal study of nearly 5500 adults with CKD in the United States. Over the past 10 years, the CRIC Study has made significant contributions to the understanding of factors associated with CKD progression. This review summarizes findings from longitudinal studies evaluating risk factors associated with CKD progression in the CRIC Study, grouped into the following six thematic categories: (1) sociodemographic and economic (sex, race/ethnicity, and nephrology care); (2) behavioral (healthy lifestyle, diet, and sleep); (3) genetic (apoL1, genome-wide association study, and renin-angiotensin-aldosterone system pathway genes); (4) cardiovascular (atrial fibrillation, hypertension, and vascular stiffness); (5) metabolic (fibroblast growth factor 23 and urinary oxalate); and (6) novel factors (AKI and biomarkers of kidney injury). Additionally, we highlight areas where future research is needed, and opportunities for interdisciplinary collaboration.

Background: Increasing evidence has demonstrated that AQP4-IgG can cause damage to kidney in AQP4 antibody-positive neuromyelitis optica spectrum disorder (NMOSD) patients. However, renal impairment in AQP4 antibody-positive NMOSD patients have not been conducted thus far. This study aimed to test and evaluate the changes of estimated glomerular filtration rates (eGFR) in NMOSD patients.Methods: We performed a cross-sectional study that recruited 93 NMOSD patients, 56 multiple sclerosis (MS) patients and 100 age- and sex-matched healthy controls (HCs), at the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China during November 2012 and November 2017. eGFR, including eGFRCr, eGFRCysC and eGFRCr-CysC were conducted for all study individuals.Results: NMOSD patients has mildly, but statistically lower eGFRCysC value at both the acute and stable phases than MS patients and HCs, respectively. (NMOSD vs. MS: adjusted model: p=0.034 at the acute phase, pvs. HCs: adjusted model: p=0.001 at the acute phase, pCysC between MS patients and HCs at both the acute and stable phases. In addition, for NMOSD patients with low-dose glucocorticoid therapy, eGFRCysC2 was more likely to occur at the stable phase, compared to the acute phase (OR =4.68, 95% CI 1.19 to 18.34).Conclusions: Mildly impaired renal function might occur in patients with AQP4 antibody-positive NMOSD compared to MS.

Rationale & Objective Evaluating repeated measures of estimated glomerular filtration rate (eGFR) and urinary protein-creatinine ratio (UPCR) over time may enhance our ability to understand the association between changes in kidney parameters and cardiovascular disease risk. Study Design Prospective cohort study. Setting & Participants Annual visit data from 2,438 participants in the Chronic Renal Insufficiency Cohort (CRIC). Exposures Average and slope of eGFR and UPCR in time-updated, 1-year exposure windows. Outcomes Incident heart failure, atherosclerotic cardiovascular disease events, death, and a composite of incident heart failure, atherosclerotic cardiovascular disease events, and death. Analytical Approach A landmark analysis, a dynamic approach to survival modeling that leverages longitudinal, iterative profiles of laboratory and clinical information to assess the time-updated 3-year risk of adverse cardiovascular outcomes. Results Adjusting for baseline and time-updated covariates, every standard deviation lower mean eGFR (19 mL/min/1.73 m2) and declining slope of eGFR (8 mL/min/1.73 m2 per year) were independently associated with higher risks of heart failure (hazard ratios [HRs] of 1.82 [95% CI, 1.39-2.44] and 1.28 [95% CI, 1.12-1.45], respectively) and the composite outcome (HRs of 1.32 [95% CI, 1.11-1.54] and 1.11 [95% CI, 1.03-1.20], respectively). Every standard deviation higher mean UPCR (136 mg/g) and increasing UPCR (240 mg/g per year) were also independently associated with higher risks of heart failure (HRs of 1.58 [95% CI, 1.28-1.97] and 1.20 [95% CI, 1.10-1.29], respectively) and the composite outcome (HRs of 1.33 [95% CI, 1.17-1.50] and 1.12 [95% CI, 1.06-1.18], respectively). Limitations Limited generalizability of annual eGFR and UPCR assessments; several biomarkers for cardiovascular disease risk were not available annually. Conclusions Using the landmark approach to account for time-updated patterns of kidney function, average and slope of eGFR and proteinuria were independently associated with 3-year cardiovascular risk. Short-term changes in kidney function provide information about cardiovascular risk incremental to level of kidney function, representing possible opportunities for more effective management of patients with chronic kidney disease.

Kidney failure is an important outcome for patients, clinicians, researchers, healthcare systems, payers, and regulators. However, no harmonized international consensus definitions of kidney failure and key surrogates of progression to kidney failure exist specifically for clinical trials. The International Society of Nephrology convened an international multi-stakeholder meeting to develop consensus on this topic. A core group, experienced in design, conduct, and outcome adjudication of clinical trials, developed a database of 64 randomized trials and the 163 included definitions relevant to kidney failure. Using an iterative process, a set of proposed consensus definitions were developed and subsequently vetted by the larger multi-stakeholder group of 83 participants representing 18 different countries. The consensus of the meeting participants was that clinical trial kidney failure outcomes should be comprised of a composite that includes receipt of a kidney transplant, initiation of maintenance dialysis, and death from kidney failure; it may also include outcomes based solely on laboratory measurements of glomerular filtration rate: a sustained low glomerular filtration rate and a sustained percent decline in glomerular filtration rate. Discussion included important considerations, such as (i) recognition of existing nomenclature for kidney failure; (ii) applicability across resource settings; (iii) ease of understanding for all stakeholders; and (iv) avoidance of inappropriate complexity so that the definitions can be used across ranges of populations and trial methodologies. The final definitions reflect the consensus for use in clinical trials.

Rationale & Objective Among individuals with chronic kidney disease (CKD), poor self-reported health is associated with adverse outcomes including hospitalization and death. We sought to examine the association between health-related quality-of-life (HRQoL) and depressive symptoms in advanced CKD and subsequent access to the kidney transplant waiting list. Study Design Prospective cohort study. Setting & Population 1,676 Chronic Renal Insufficiency Cohort (CRIC) study participants with estimated glomerular filtration rates ≤ 30 mL/min/1.73 m2 at study entry or during follow-up. Exposures HRQoL ascertained by 5 scales of the Kidney Disease Quality of Life-36 Survey (Physical Component Summary [PCS], Mental Component Summary, Symptoms, Burdens, and Effects), with higher scores indicating better HRQoL, and depressive symptoms ascertained using the Beck Depression Inventory. Outcomes Time to kidney transplant wait-listing and time to pre-emptive wait-listing. Analytic Approach Time-to-event analysis using Cox proportional hazards regression. Results During a median follow-up of 5.1 years, 652 (39%) participants were wait-listed, of whom 304 were preemptively wait-listed. Adjusted for demographics, comorbid conditions, estimated glomerular filtration rate slope, and cognitive function, participants with the highest scores on the Burden and Effects scales, respectively, had lower rates of wait-listing than those with the lowest scores on the Burden (wait-listing adjusted hazard ratio [aHR], 0.70; 95% CI, 0.57-0.85; P, Visual abstract

Background Chronic kidney disease (CKD) is an increasing epidemic globally that is associated with adverse health outcomes including end stage kidney disease (ESKD), cardiovascular disease (CVD), and death. American Indians (AIs) have a higher prevalence of CKD than most other racial/ethnic groups, due in part to a high prevalence of type 2 diabetes. Other genetic and environmental factors not yet identified may also contribute to the disproportionate burden of CKD in AIs. Method We will establish 3 clinical centers to recruit AIs from the Southwest United States (US) to expand the Chronic Renal Insufficiency Cohort (CRIC) study. We will follow the current CRIC protocol for kidney and cardiovascular measures and outcomes, which include ambulatory monitoring of kidney function and the use of mobile health technologies for CVD sub-phenotyping, and compare the outcomes in AIs with those in other racial/ethnic groups in CRIC. Discussion AI-CRIC will identify the role of various risk factors for rapid loss of kidney function among AIs of the Southwest US. In addition, to better understand the natural history of CKD and CVD in this high-risk population, we will identify unique risk factors for CKD and CVD progression in AIs. We will also compare event rates and risk factors for kidney and cardiovascular events in AIs with the other populations represented in CRIC.

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

Background 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.

OBJECTIVES: Current dietary guidelines recommend that chronic kidney disease (CKD) patients reduce intake of individual nutrients, such as sodium, potassium, phosphorus, and protein. This approach can be difficult for patients to implement and ignores important nutrient interactions. Our objective was to define the association of healthy dietary patterns with risk of CKD progression and all-cause mortality among people with CKD. METHODS: We analyzed data from 2403 participants aged 21–74 years with an estimated glomerular filtration rate (eGFR) of 20–70 mL/min/1.73 m(2) and dietary data in the Chronic Renal Insufficiency Cohort (CRIC) study. Healthy Eating Index-2015 (HEI-2015), Alternative Healthy Eating Index-2010 (AHEI-2010), alternate Mediterranean diet (aMed), and Dietary Approaches to Stop Hypertension (DASH) diet scores were calculated using data collected from food frequency questionnaires. We analyzed the association between these dietary patterns and two main outcomes: 1) CKD progression defined as ≥50% eGFR decline, kidney transplantation, or dialysis, and 2) all-cause mortality. Cox proportional hazards regression models adjusted for demographic, lifestyle, and clinical covariates were used to estimate hazard ratios (HR) and 95% confidence intervals (CI). RESULTS: There were 855 cases of CKD progression and 773 deaths over a maximum of 14 years. Compared with participants with the lowest adherence, the most highly adherent tertile of AHEI-2010, aMed, and DASH had lower adjusted risk of CKD progression with the strongest association for aMed (HR: 0.75, 95% CI: 0.62–0.90). Nuts and legumes were independently associated with lower risk of CKD progression. Compared with participants with the lowest adherence, the highest adherence tertiles for all four scores had a 24–31% lower adjusted risk of all-cause mortality. CONCLUSIONS: Greater adherence to a healthy dietary pattern is associated with a lower risk of CKD progression and all-cause mortality among people with CKD. Guidance to adopt healthy dietary patterns should be incorporated into guidelines for individuals with CKD. FUNDING SOURCES: NIH (NHLBI, NIDDK).

Rationale & Objective Biomarkers that provide reliable evidence of future diabetic kidney disease (DKD) are needed to improve disease management. In a cross-sectional study, we previously identified 13 urine metabolites that had levels reduced in DKD compared with healthy controls. We evaluated associations of these 13 metabolites with future DKD progression. Study Design Prospective cohort. Setting & Participants 1,001 Chronic Renal Insufficiency Cohort (CRIC) participants with diabetes with estimated glomerular filtration rates (eGFRs) between 20 and 70mL/min/1.73m2 were followed up prospectively for a median of 8 (range, 2-10) years. Predictors 13 urine metabolites, age, race, sex, smoked more than 100 cigarettes in lifetime, body mass index, hemoglobin A1c level, blood pressure, urinary albumin, and eGFR. Outcomes Annual eGFR slope and time to incident kidney failure with replacement therapy (KFRT; ie, initiation of dialysis or receipt of transplant). Analytical Approach Several clinical metabolite models were developed for eGFR slope as the outcome using stepwise selection and penalized regression, and further tested on the time-to-KFRT outcome. A best cross-validated (final) prognostic model was selected based on high prediction accuracy for eGFR slope and high concordance statistic for incident KFRT. Results During follow-up, mean eGFR slope was−1.83±1.92 (SD) mL/min/1.73m2 per year; 359 (36%) participants experienced KFRT. Median time to KFRT was 7.45 years from the time of entry to the CRIC Study. In our final model, after adjusting for clinical variables, levels of metabolites 3-hydroxyisobutyrate (3-HIBA) and 3-methylcrotonyglycine had a significant negative association with eGFR slope, whereas citric and aconitic acid were positively associated. Further, 3-HIBA and aconitic acid levels were associated with higher and lower risk for KFRT, respectively (HRs of 2.34 [95% CI, 1.51-3.62] and 0.70 [95% CI, 0.51-0.95]). Limitations Subgroups for whom metabolite signatures may not be optimal, nontargeted metabolomics by flow-injection analysis, and 2-stage modeling approaches. Conclusions Urine metabolites may offer insights into DKD progression. If replicated in future studies, aconitic acid and 3-HIBA could identify individuals with diabetes at high risk for GFR decline, potentially leading to improved clinical care and targeted therapies.

Background: Acute kidney injury (AKI) represents an abrupt decline in kidney function occurring over hours or days. While hospital-acquired AKI has been extensively studied, data on community-acquired AKI are scarce. The aim of this study was to examine the incidence and causes of AKI among patients presenting to the emergency department (ED). Methods: This was a prospective case-control study in which serum creatinine (SCr) of all individuals admitted to the ED of Landspitali-The National University Hospital were examined for the presence of AKI. We present data from January 1 until March 3, 2020 and May 19 until September 21, 2020. The study was paused between these periods due to the COVID-19 epidemic. All patients who met the KDIGO criteria for AKI were invited to participate. Randomly selected control cases (1:2) were paired according to age, sex and time of ED admission. Participants answered questions about their medical history and use of medications, including over-the-counter (OTC) drugs. Medical records were reviewed with regard to medical history. Logistic regression was used to identify factors associating with AKI. Results: A total of 372 persons with AKI were identified, 315 (85%) of whom participated in the study. The mean (±SD) age of AKI cases and controls was 66.6±16.1 years and 66.3±16.2 years, respectively;46% of cases and controls were female. AKI cases were significantly more likely than controls to have used non-steroidal antiinflammatory drugs (NSAIDs) (31.1% vs 22.2%, p=0,003) in the week preceding the ED visit, particularly OTC NSAIDs (24.7% vs 16.2%, p=0.001). In the logistic regression analysis, AKI was associated with vomiting (OR 2.40 95%CI 1.74-3.35), diarrhea (OR 1.35, 95%CI 1.00-1.84), diabetes (OR 1.66, 95%CI 1,17-2,35) and NSAID use (OR 1.60, 95%CI 1.18-2.23), but a statistically significant relationship was not observed for use of ACE inhibitors/angiotensin receptor blockers or diuretics, or a history of hypertension, vascular disease or chronic kidney disease. Conclusions: These results suggest that volume depletion and the use of NSAIDs play a major role in the development of AKI in the community setting. Frequent use of OTC NSAIDs is a concern and should be addressed in light of serious adverse effects.