Search

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.

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 AND OBJECTIVES: Patients with CKD are at high risk for cardiovascular disease, ESKD, and mortality. Vascular calcification is one pathway through which cardiovascular disease risks are increased. We hypothesized that a novel measure of serum calcification propensity is associated with cardiovascular disease events, ESKD, and all-cause mortality among patients with CKD stages 2–4. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Among 3404 participants from the prospective, longitudinal Chronic Renal Insufficiency Cohort Study, we quantified calcification propensity as the transformation time (T(50)) from primary to secondary calciprotein particles, with lower T(50) corresponding to higher calcification propensity. We used multivariable-adjusted Cox proportional hazards regression models to assess the associations of T(50) with risks of adjudicated atherosclerotic cardiovascular disease events (myocardial infarction, stroke, and peripheral artery disease), adjudicated heart failure, ESKD, and mortality. RESULTS: The mean T(50) was 313 (SD 79) minutes. Over an average 7.1 (SD 3.1) years of follow-up, we observed 571 atherosclerotic cardiovascular disease events, 633 heart failure events, 887 ESKD events, and 924 deaths. With adjustment for traditional cardiovascular disease risk factors, lower T(50) was significantly associated with higher risk of atherosclerotic cardiovascular disease (hazard ratio [HR] per SD lower T(50), 1.14; 95% confidence interval [95% CI], 1.05 to 1.25), ESKD within 3 years from baseline (HR per SD lower T(50), 1.68; 95% CI, 1.52 to 1.86), and all-cause mortality (HR per SD lower T(50), 1.16; 95% CI, 1.09 to 1.24), but not heart failure (HR per SD lower T(50), 1.06; 95% CI, 0.97 to 1.15). After adjustment for eGFR and 24-hour urinary protein, T(50) was not associated with risks of atherosclerotic cardiovascular disease, ESKD, and mortality. CONCLUSIONS: Among patients with CKD stages 2–4, higher serum calcification propensity is associated with atherosclerotic cardiovascular disease events, ESKD, and all-cause mortality, but this association was not independent of kidney function. PODCAST: This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2019_10_28_CJN04710419.mp3

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

Background and objectives Serum β-trace protein (BTP) and β-2 microglobulin (B2M) are associated with risk of ESRD and death in the general population and in populations at high risk for these outcomes (GP/HR) and those with CKD, but results differ among studies. Design, setting, participants, & measurements We performed an individual patient-level meta-analysis including three GP/HR studies (n=17,903 participants) and three CKD studies (n=5415). We compared associations, risk prediction, and improvement in reclassification of eGFR using BTP (eGFRBTP) and B2M (eGFRB2M) alone and the average (eGFRavg) of eGFRBTP, eGFRB2M, creatinine (eGFRcr), and cystatin C (eGFRcys), to eGFRcr, eGFRcys, and their combination (eGFRcr-cys) for ESRD (2075 events) and death (7275 events). Results Mean (SD) follow up times for ESRD and mortality for GP/HR and CKD studies were 13 (4), 6.2 (3.2), 14 (5), and 7.5 (3.9) years, respectively. Compared with eGFRcr, eGFRBTP and eGFRB2M improved risk associations and modestly improved prediction for ESRD and death even after adjustment for established risk factors. eGFRavg provided the most consistent improvement in associations and prediction across both outcomes and populations. Assessment of heterogeneity did not yield clinically relevant differences. For ESRD, addition of albuminuria substantially attenuated the improvement in risk prediction and risk classification with novel filtration markers. For mortality, addition of albuminuria did not affect the improvement in risk prediction with the use of novel markers, but lessened improvement in risk classification, especially for the CKD cohort. Conclusions These markers do not provide substantial additional prognostic information to eGFRcr and albuminuria, but may be appropriate in circumstances where eGFRcr is not accurate or albuminuria is not available. Educational efforts to increase measurement of albuminuria in clinical practice may be more cost-effective than measurement of BTP and B2M for improving prognostic information.

The Chronic Renal Insufficiency Cohort (CRIC) Study is a United States multicenter, prospective study of racially and ethnically diverse patients with CKD. Although the original aims of the study were to identify novel predictors of CKD progression and to elucidate the risk and manifestations of cardiovascular disease among nearly 4000 individuals with CKD, the CRIC Study has evolved into a national resource for investigation of a broad spectrum of CKD-related topics. The study has produced >90 published scientific articles, promoted many young investigative careers in nephrology, and fostered international collaborations focused on understanding the global burden of CKD. The third phase of the CRIC Study will complete enrollment of 1500 additional study participants in 2015 and is designed to answer questions regarding morbidity and mortality in mild-to-moderate CKD and to assess the burden of CKD in older persons. This review highlights some of the salient findings of the CRIC Study in the areas of race and ethnicity, CKD progression, CKD and cognition, and cardiovascular disease outcomes; it also outlines the ongoing and forthcoming opportunities for the global nephrology community to enhance its understanding of CKD and related complications through the study.

Disorders of mineral metabolism are more common in African Americans with CKD than in European Americans with CKD. Previous studies have focused on the differences in mineral metabolism by self-reported race, making it difficult to delineate the importance of environmental compared with biologic factors.In a cross-sectional analysis of 3013 participants of the Chronic Renal Insufficiency Cohort study with complete data, we compared markers of mineral metabolism (phosphorus, calcium, alkaline phosphatase, parathyroid hormone, fibroblast growth factor 23, and urine calcium and phosphorus excretion) in European Americans versus African Americans and separately, across quartiles of genetic African ancestry in African Americans (n=1490).Compared with European Americans, African Americans had higher blood concentrations of phosphorus, alkaline phosphatase, fibroblast growth factor 23, and parathyroid hormone, lower 24-hour urinary excretion of calcium and phosphorus, and lower urinary fractional excretion of calcium and phosphorus at baseline (P0.001 for all). Among African Americans, a higher percentage of African ancestry was associated with lower 24-hour urinary excretion of phosphorus (Ptrend0.01) in unadjusted analyses. In linear regression models adjusted for socio-demographic characteristics, kidney function, serum phosphorus, and dietary phosphorus intake, higher percentage of African ancestry was significantly associated with lower 24-hour urinary phosphorus excretion (each 10% higher African ancestry was associated with 39.6 mg lower 24-hour urinary phosphorus, P0.001) and fractional excretion of phosphorus (each 10% higher African ancestry was associated with an absolute 1.1% lower fractional excretion of phosphorus, P=0.01).A higher percentage of African ancestry was independently associated with lower 24-hour urinary phosphorus excretion and lower fractional excretion of phosphorus among African Americans with CKD. These findings suggest that genetic variability might contribute to racial differences in urinary phosphorus excretion in CKD.

Significant advances are needed to improve the diagnosis, prognosis, and management of persons with CKD. Discovery of new biomarkers and improvements in currently available biomarkers for CKD hold great promise to achieve these necessary advances. Interest in identification and evaluation of biomarkers for CKD has increased substantially over the past decade. In 2009, the National Institute of Diabetes and Digestive and Kidney Diseases established the CKD Biomarkers Consortium (http://www.ckdbiomarkersconsortium.org/), a multidisciplinary, collaborative study group located at over a dozen academic medical centers. The main objective of the consortium was to evaluate new biomarkers for purposes related to CKD in established prospective cohorts, including those enriched for CKD. During the first 5 years of the consortium, many insights into collaborative biomarker research were gained that may be useful to other investigators involved in biomarkers research. These lessons learned are outlined in this Special Feature and include a wide range of issues related to biospecimen collection, storage, and retrieval, and the internal and external quality assessment of laboratories that performed the assays. The authors propose that investigations involving biomarker discovery and validation are greatly enhanced by establishing and following explicit quality control metrics, including the use of blind replicate and proficiency samples, by carefully considering the conditions under which specimens are collected, handled, and stored, and by conducting pilot and feasibility studies when there are concerns about the condition of the specimens or the accuracy or reproducibility of the assays.

Previous studies in chronic disease states have demonstrated an association between lower urinary creatinine excretion (UCr) and increased mortality, a finding presumed to reflect the effect of low muscle mass on clinical outcomes. Little is known about the relationship between UCr and other measures of body composition in terms of the ability to predict outcomes of interest.Using data from the Chronic Renal Insufficiency Cohort (CRIC), the relationship between UCr, fat free mass (FFM) as estimated by bioelectrical impedance analysis, and (in a subpopulation) whole-body dual-energy x-ray absorptiometry assessment of appendicular lean mass were characterized. The associations of UCr and FFM with mortality and ESRD were compared using Cox proportional hazards models.A total of 3604 CRIC participants (91% of the full CRIC cohort) with both a baseline UCr and FFM measurement were included; of these, 232 had contemporaneous dual-energy x-ray absorptiometry measurements. Participants were recruited between July 2003 and March 2007. UCr and FFM were modestly correlated (rho=0.50; P0.001), while FFM and appendicular lean mass were highly correlated (rho=0.91; P0.001). Higher urinary urea nitrogen, black race, younger age, and lower serum cystatin C level were all significantly associated with higher UCr. Over a median (interquartile range) of 4.2 (3.1-5.0) years of follow-up, 336 (9.3%) participants died and 510 (14.2%) reached ESRD. Lower UCr was associated with death and ESRD even after adjustment for FFM (adjusted hazard ratio for death per 1 SD higher level of UCr, 0.63 [95% confidence interval, 0.56 to 0.72]; adjusted hazard ratio for ESRD per 1 SD higher level of UCr, 0.70 [95% confidence interval, 0.63 to 0.75]).Among a cohort of individuals with CKD, lower UCr is associated with death and ESRD independent of FFM as assessed by bioelectrical impedance analysis.

Background and objectives: The objective of this study was to describe the prevalence of ocular fundus pathology in the Chronic Renal Insufficiency Cohort (CRIC) study, a multicenter, longitudinal study of individuals with varying stages of chronic kidney disease (CKD). Design, setting, participants, & measurements: In this cross-sectional study, 45° digital photos of the disc and macula in both eyes were obtained by nonophthalmologic personnel using a nonmydriatic Canon CR-DGI fundus camera in 1936 individuals who participated in the CRIC study. Photographs were assessed in a masked manner by graders and a retinal specialist at a central photograph reading center. The purpose of this review was to inform participants quickly of conditions that warranted a complete eye examination by an ophthalmologist. Results: Among the 1936 participants who were photographed, 1904 (98%) had assessable photographs in at least one eye. Eye pathologies that required a follow-up examination by an ophthalmologist were identified in 864 (45%) of these 1904 participants. These eye pathologies included, among others, retinopathy (diabetic and/or hypertensive), a finding that was observed in 482 (25%) of these 1904 participants. Three percent (65 participants) of the 1904 participants had serious eye conditions that required urgent follow-up and treatment. Lower estimated GFR and cardiovascular disease were associated with greater eye pathology. Estimated GFR

Background and objectives: The prevalence of chronic kidney disease (CKD) has increased over the past two decades. The sensitivity of serum creatinine (sCr) to identify CKD is low. As a result, many healthcare centers report estimated GFR (eGFR) with routine blood work. The aim of this study was to determine the cost-effectiveness of automatic eGFR reporting compared with reporting sCr alone. Design, setting, participants, & measurements: A Markov model was designed to evaluate the cost-effectiveness of reporting eGFR compared with reporting sCr alone in a hypothetical cohort of 60-yr-old individuals undergoing annual blood chemistry testing over 18 yr. Paths and path probabilities were identical between the two arms, except for the sensitivity and specificity of eGFR and sCr to detect CKD. Results: eGFR reporting was dominant with a cost/effectiveness ratio of $16,751/quality-adjusted life year (QALY) versus $16,779/QALY for sCr reporting. Monte Carlo microsimulations in a hypothetical cohort of 10,000 patients demonstrated that over 18 yr, an average of 13 fewer deaths, 29 fewer ESRD events, and 11,348 more false positive CKD (FP-CKD) cases occurred with eGFR reporting. A sensitivity analysis revealed that decreasing the FP-CKD quality of life by > 2% rendered sCr reporting more cost-effective than eGFR reporting. If FP-CKD reduced quality of life by 5%, the incremental cost-effectiveness ratio for sCr reporting versus eGFR reporting would be $4367/QALY. Conclusion: A decision analysis suggests that reporting eGFR may be beneficial, but this limited benefit was reversed with virtually any reduction in quality of life caused by incorrect diagnosis of CKD.

Background and objectives: Evidence exists that variability in hemoglobin may be an independent risk factor for mortality among hemodialysis patients. These observations were based on a 1996 cohort, a time when anemia management differed greatly from present. Design, settings, participants and measurements: A retrospective cohort study of patients incident to Fresenius Medical Care units between 2004 and 2005 (n = 6644). Hemoglobin variability (Hgb-Var) was defined for each subject as the residual SD of a linear regression model of time on hemoglobin. Results: The mean (SD) of Hgb-Var was 1.13 (0.55) g/dl. In the primary analysis, each g/dl increase of Hgb-Var was associated with an adjusted hazard ratio (95% confidence interval) for all-cause mortality of 1.11 (0.92 to 1.33). No significant interaction with Hgb-Var and mortality was found on the basis of age (P = 0.22), arterial disease (P = 0.45), Hgb slope (P = 0.68), or mean Hgb (P = 0.78). When Hgb-Var was defined by a regression model that included a quadratic term for time (enabling descriptions of curvilinear hemoglobin trajectories), model fit was greatly improved (P for difference

Success, like beauty, is difficult to define, but one knows it when one sees it. A reasonable definition is the achievement of satisfaction and happiness in one's profession, which then defers the definition to that of happiness and satisfaction. These will be dependent on the extent and directions of one's passion, the pursuit of which promotes satisfying productivity. Physicians who choose to conduct their careers in an academic setting have a multitude of career models to pursue, representing varied mixes of effort devoted to clinical care, research, teaching, and administration. Not uncommonly, the particular blend of activities may evolve over time and there may be transition from one institution to another. Despite these variations, the mid-career faculty member of North American medical schools share many common experiences and challenges. Despite their track record of success within academic medical centers, mid-career faculty may also experience frustration or loss of direction. There are many reasons that this may occur. For example, the academic “honeymoon” is over, whereby forgiveness for the errors of inexperience or naivete are long gone. Filling a niche within the institution brings stability, but may also engender the perception by the mid-career faculty member of being taken for granted. This may, in fact, be a misperception. In contrast to junior colleagues, the successful mid-career faculty member may no longer receive direct mentoring or institutional resources and may misinterpret this as abandonment. Contrary to this sentiment, supervisors of mid-career faculty members may see this evolution of institutional support as a discrete indication of success and the opportunity to redirect resources to those at an earlier stage in their careers. It is with these observations that we offer insights into maintaining and advancing a successful academic medical career. These challenges are part of a developmental process that unfolds in response both …

Background and objectives: Observational studies have demonstrated that short- and long-term mortality is increased in patients who develop contrast-induced nephropathy (CIN). The more clinically relevant questions, and the objectives of this review, are whether CIN is causally related to mortality, and to what extent could mortality in patients undergoing contrast procedures be reduced by preventing CIN. Design, setting, participants, & measurements: A literature review was conducted, focusing on observational studies that assessed factors associated with mortality in patients with CIN. Results: The deaths of some patients with CIN are complicated by factors that cannot be directly related to CIN, such as liver disease, sepsis, respiratory failure, bleeding, etc. However, it is plausible that CIN contributes to cardiovascular causes of death in patients with CIN. Conclusions: At the very least, CIN is a marker for increased mortality. More carefully designed prospective studies are needed to fully elucidate the relationship between CIN and death. In the absence of data disproving a causal relationship between CIN and death in all subgroups, reducing its incidence should remain a goal in clinical practice as well as a target for future research.