Background Proteins and metabolites play crucial roles in various biological functions and are frequently interconnected through enzymatic or transport processes. Methods We present an integrated analysis of 4091 proteins and 630 metabolites in the Chronic Renal Insufficiency Cohort study (N=1708; average follow-up for kidney failure, 9.5 years, with 537 events). Proteins and metabolites were integrated using an unsupervised clustering method, and we assessed associations between clusters and CKD progression and kidney failure using Cox proportional hazards models. Analyses were adjusted for demographics and risk factors, including the eGFR and urine protein-creatinine ratio. Associations were identified in a discovery sample (random two thirds, n=1139) and then evaluated in a replication sample (one third, n=569). Results We identified 139 modules of correlated proteins and metabolites, which were represented by their principal components. Modules and principal component loadings were projected onto the replication sample, which demonstrated a consistent network structure. Two modules, representing a total of 236 proteins and 82 metabolites, were robustly associated with both CKD progression and kidney failure in both discovery and validation samples. Using gene set enrichment, several transmembrane-related terms were identified as overrepresented in these modules. Transmembrane-ephrin receptor activity displayed the largest odds (odds ratio=13.2, P value = 5.5x10(-5)). A module containing CRIM1 and NPNT expressed in podocytes demonstrated particularly strong associations with kidney failure (P value = 2.6x10(-5)). Conclusions This study demonstrates that integration of the proteome and metabolome can identify functions of pathophysiologic importance in kidney disease.

Per- and polyfluoroalkyl substances (PFAS) are a broad class of synthetic chemicals; some are present in most humans in developed countries. Some studies suggest that certain PFAS may have immunotoxic effects in humans, which could put individuals with high levels of exposure at increased risk for infectious diseases such as COVID-19. We conducted a case-control study to examine the association between COVID-19 diagnosis and PFAS serum concentrations among employees and retirees from two 3 M facilities, one of which historically generated perfluorooctanoic acid (PFOA), perfluorooctane sulfonic acid (PFOS), and perfluorohexane sulfonic acid (PFHxS). Participants completed enrollment and follow-up study visits in the Spring of 2021. Participants were categorized as cases if they reported a COVID-19 diagnosis or became sick with at least one symptom of COVID-19 when someone else in their household was diagnosed, otherwise they were categorized as a control. COVID-19 diagnosis was modeled in relation to concentration of serum PFAS measured at enrollment after adjusting for covariates. The analytic sample comprised 573 individuals, 111 cases (19.4%) and 462 controls (80.6%). In adjusted models, the odds ratio of COVID-19 was 0.94 per interquartile range (14.3 ng/mL) increase in PFOS (95% confidence interval 0.85, 1.04). Results for PFOA, PFHxS, and perfluorononanoic acid (PFNA) were similar. Other PFAS present at lower concentrations were examined as categorical variables (above the limit of quantification [LOQ], yes vs. no [referent category]), and also showed no positive associations. In our study, which used individual-level data and included people with high occupational exposure, the serum concentrations of all PFAS examined were not associated with an increased odds ratio for COVID-19. At this point, the epidemiologic data supporting no association of COVID-19 occurrence with PFAS exposure are stronger than those suggesting a positive association.

BACKGROUND Prior studies associating acute kidney injury (AKI) with more rapid subsequent loss of kidney function had methodological limitations, including inadequate control for differences between patients who had AKI and those who did not. OBJECTIVE To determine whether AKI is independently associated with subsequent kidney function trajectory among patients with chronic kidney disease (CKD). DESIGN Multicenter prospective cohort study. SETTING United States. PARTICIPANTS Patients with CKD (n = 3150). MEASUREMENTS Hospitalized AKI was defined by a 50% or greater increase in inpatient serum creatinine (SCr) level from nadir to peak. Kidney function trajectory was assessed using estimated glomerular filtration rate (eGFR) based on SCr level (eGFRcr) or cystatin C level (eGFRcys) measured at annual study visits. RESULTS During a median follow-up of 3.9 years, 433 participants had at least 1 AKI episode. Most episodes (92%) had stage 1 or 2 severity. There were decreases in eGFRcr (-2.30 [95% CI, -3.70 to -0.86] mL/min/1.73 m2) and eGFRcys (-3.61 [CI, -6.39 to -0.82] mL/min/1.73 m2) after AKI. However, in fully adjusted models, the decreases were attenuated to -0.38 (CI, -1.35 to 0.59) mL/min/1.73 m2 for eGFRcr and -0.15 (CI, -2.16 to 1.86) mL/min/1.73 m2 for eGFRcys, and the CI bounds included the possibility of no effect. Estimates of changes in eGFR slope after AKI determined by either SCr level (0.04 [CI, -0.30 to 0.38] mL/min/1.73 m2 per year) or cystatin C level (-0.56 [CI, -1.28 to 0.17] mL/min/1.73 m2 per year) also had CI bounds that included the possibility of no effect. LIMITATIONS Few cases of severe AKI, no adjudication of AKI cause, and lack of information about nephrotoxic exposures after hospital discharge. CONCLUSION After pre-AKI eGFR, proteinuria, and other covariables were accounted for, the association between mild to moderate AKI and worsening subsequent kidney function in patients with CKD was small. PRIMARY FUNDING SOURCE National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health.

Key Points Depressive symptoms are largely stable over time among individuals with mild-to-moderate CKD Low educational attainment, cigarette smoking, and poor quality of life are associated with persistent depressive symptoms Persistent depressive symptoms are associated with nonlinear and rapid decline in kidney function Background Although depression is highly prevalent among individuals with CKD, little is known about the course of depressive symptoms over time. We characterized trajectories of depressive symptoms and CKD progression and evaluated the association between depressive symptoms trajectory and CKD progression. Methods Two thousand three hundred sixty-one individuals with mild-to-moderate CKD enrolled in the Chronic Renal Insufficiency Cohort Study were analyzed. The Beck Depression Inventory (BDI) was used to assess depressive symptoms at baseline and biennially. Higher BDI scores indicate worse depressive symptoms. eGFR was calculated using the 2021 CKD-EPI equation. Group-based trajectory models were used to determine trajectories of BDI score and eGFR change over time. Multinomial logistic regression was used to examine factors associated with BDI trajectories and to evaluate the association of BDI trajectories with eGFR change. Results Over 8 years of follow-up, three patterns of depressive symptoms were identified: persistently low BDI score (57.7%), persistently moderate BDI score (33.1%), and persistently high BDI score (9.2%). Three eGFR trajectory groups were identified: nonlinear, rapid eGFR decline (21.5%); linear, expected eGFR decline (54.8%); and stable eGFR (23.7%). Predictors of persistently moderate and high BDI trajectories included low educational attainment, smoking, and poor quality of life. Compared with those with a persistently low BDI score, the odds for nonlinear, rapid eGFR decline were higher for those with persistently moderate BDI scores (odds ratio [OR], 1.45; 95% confidence interval [CI], 1.04 to 2.03) and persistently high BDI scores (OR, 1.90; 95% CI, 1.02 to 3.56). No association between moderate BDI score and linear, expected eGFR decline was observed. Conclusions Depressive symptoms remained largely stable among individuals with mild-to-moderate CKD, and persistently moderate and high BDI scores were associated with nonlinear, rapid eGFR decline. Future work is needed to better understand the interplay between depression and CKD progression.

BACKGROUND: Inadequate bone mineral density (BMD) is associated with an increased risk of fractures. Supplemen-tation of vitamin D is used to increase serum levels of 25-hydroxyvitamin D (25(OH)D). The purpose of this study was to determine if supplementation with vitamin D3 is associated with greater retention of BMD. METHODS: Seventeen NCAA Division I athletes participating in outdoor sports were recruited. Participants with base-line 25(OH)D below 30 ng/mL were supplemented with 50,000 IU of vitamin D3 once weekly for 12-weeks. Serum 25(OH)D was measured by liquid chromatography/tandem mass spectrometry following an intravenous blood draw. BMD was measured at baseline and postintervention using dual-energy X-ray absorptiometry. RESULTS: Mean age was 21.1 (SD=1.0; range 18.7-22.5), and mean BMD was 1.37 (SD=0.14; range 1.189-1.695). In this sample, seven participants (41%) were supplemented with Vitamin D3. After adjustment for covariates, supple-mentation in vitamin D deficient athletes was associated with a significantly smaller change in BMD, as compared to no supplementation in non-deficient athletes (0=0.09, 95% CI: 0.018, 0.16). CONCLUSIONS: Both groups showed a decrease in BMD over the 12-week period, however, the non-supplement group had a significantly greater loss in BMD than their supplemented counterparts. Supplementing with vitamin D3 may help student-athletes retain bone density during periods of intense training. (Cite this article as: Parr JJ, Porter AK. Serum vitamin D influence on bone mineral density in collegiate athletes. Gazz Med Ital -Arch Sci Med 2023;182:680-5. DOI: 10.23736/S0393-3660.23.05027-1)

RATIONALE & OBJECTIVE:Frailty is common in individuals with chronic kidney disease (CKD) and increases the risk of adverse outcomes in adults with kidney failure requiring dialysis. However, this relationship has not been thoroughly evaluated among those with non-dialysis-dependent CKD. STUDY DESIGN:Prospective cohort study. SETTING & PARTICIPANTS:2,539 adults in the Chronic Renal Insufficiency Cohort Study. EXPOSURE:Frailty status assessed using 5 criteria: slow gait speed, muscle weakness, low physical activity, exhaustion, and unintentional weight loss. OUTCOME:Atherosclerotic events, incident heart failure, all-cause death, and cardiovascular death. ANALYTICAL APPROACH:Cause-specific hazards models. RESULTS:At study entry, the participants' mean age was 62 years, 46% were female, the mean estimated glomerular filtration rate was 45.4mL/min/1.73m2, and the median urine protein was 0.2mg/day. Frailty status was as follows: 12% frail, 51% prefrail, and 37% nonfrail. Over a median follow-up of 11.4 years, there were 393 atherosclerotic events, 413 heart failure events, 497 deaths, and 132 cardiovascular deaths. In multivariable regression analyses, compared with nonfrailty, both frailty and prefrailty status were each associated with higher risk of an atherosclerotic event (HR, 2.03 [95% CI, 1.41-2.91] and 1.77 [95% CI, 1.35-2.31], respectively) and incident heart failure (HR, 2.22 [95% CI, 1.59-3.10] and 1.39 [95% CI, 1.07-1.82], respectively), as well as higher risk of all-cause death (HR, 2.52 [95% CI, 1.84-3.45] and 1.76 [95% CI, 1.37-2.24], respectively) and cardiovascular death (HR, 3.01 [95% CI, 1.62-5.62] and 1.78 [95% 1.06-2.99], respectively). LIMITATIONS:Self-report of aspects of the frailty assessment and comorbidities, which may have led to bias in some estimates. CONCLUSIONS:In adults with CKD, frailty status was associated with higher risk of cardiovascular events and mortality. Future studies are needed to evaluate the impact of interventions to reduce frailty on cardiovascular outcomes in this population. PLAIN-LANGUAGE SUMMARY:Frailty is common in individuals with chronic kidney disease (CKD) and increases the risk of adverse outcomes. We sought to evaluate the association of frailty status with cardiovascular events and death in adults with CKD. Frailty was assessed according to the 5 phenotypic criteria detailed by Fried and colleagues. Among 2,539 participants in the CRIC Study, we found that 12% were frail, 51% were prefrail, and 37% were nonfrail. Frailty status was associated with an increased risk of atherosclerotic events, incident heart failure, and death.

Purpose: The work environment for an athletic trainer (AT) working in a secondary school is typified by heavy workloads and job-related stress. Occupational stress can have negative effects on productivity, absenteeism, employee turnover, and quality of life. Research suggests that personal and situational factors can influence the coping process adopted by an individual. The approach-avoidance framework suggests that people cope with a stressor by either attempting to reduce it or removing oneself from that stressor. Previous research on other healthcare professionals suggested that use of avoidance coping was correlated with higher levels of job stress and those who perceived greater social support possessed lower work-related stress. However, the relationship between coping strategies and perceived social support has not been examined in ATs. The purpose of this study was to examine the relationship among coping strategies, perceived social support, and workload in secondary school ATs. Method: This was a cross-sectional study completed via an online survey. Three hundred, ninety-two (392) secondary school athletic trainers (35.7 ± 11.1 years old) from all NATA districts responded to the survey. Outcomes included the Brief COPE, Multidimensional Scale of Perceived Social Support, and average hours worked. Results: The average workload reported was 44.10 ± 12.96 hours a week over the school year (i.e., fall and spring). The regression model showed that avoidant coping (B=0.34, 95% CI=0.12, 0.56, p=.005) was directly associated with the average number of hours worked (adjusted R2=.07). Approach coping (B=-0.28, 95% CI=-0.43, -0.12, p=.007) was indirectly associated with the average numbers of hours worked. However, perceived social support did not display a significant association with any variable of interest. Conclusions: Our findings suggest that a relationship between average workload and coping strategies adopted by secondary school ATs may exist. Increased workloads were related to increases in avoidance coping strategies. Further research in this area is needed to determine how coping strategies affect patient care.

Background People with chronic kidney disease (CKD) are at high risk for cognitive impairment and progressive cognitive decline. Retention of protein-bound organic solutes that are normally removed by tubular secretion is hypothesized to contribute to cognitive impairment in CKD. Methods We followed 2362 participants who were initially free of cognitive impairment and stroke in the prospective Chronic Renal Insufficiency Cohort (CRIC) Study. We estimated tubular secretory clearance by the 24-hour kidney clearances of eight endogenous solutes that are primarily eliminated by tubular secretion. CRIC study investigators assessed participants' cognitive function annually using the Modified Mini-Mental State (3MS) Examination. Cognitive decline was defined as a sustained decrease of more than five points in the 3MS score from baseline. Using Cox regression models adjusted for potential confounders, we analyzed associations between secretory solute clearances, serum solute concentrations, and cognitive decline. Results The median number of follow-up 3MS examinations was six per participant. There were 247 incident cognitive decline events over a median of 9.1 years of follow-up. Lower kidney clearances of five of the eight secretory solutes (cinnamoylglycine, isovalerylglycine, kynurenic acid, pyridoxic acid, and tiglylglycine) were associated with cognitive decline after adjustment for baseline eGFR, proteinuria, and other confounding variables. Effect sizes ranged from a 17% to a 34% higher risk of cognitive decline per 50% lower clearance. In contrast, serum concentrations of the solutes were not associated with cognitive decline. Conclusions Lower kidney clearances of secreted solutes are associated with incident global cognitive decline in a prospective study of CKD, independent of eGFR. Further work is needed to determine the domains of cognition most affected by decreased secretory clearance and the mechanisms of these associations.

Introduction: Recent studies have suggested a higher incidence of cardiovascular disease (CVD) among patients with chronic kidney disease (CKD) in the USA than in Japan. Hyperphosphatemia, a possible risk for CVD, may explain this difference; however, international differences in phosphate parameters in CKD have not been well elaborated. Methods: By using the baseline data from the USA and the Japanese nation-wide, multicenter, CKD cohort studies; the Chronic Renal Insufficiency Cohort Study (CRIC, N = 3,870) and the Chronic Kidney Disease-Japan Cohort Study (CKD-JAC, N = 2,632), we harmonized the measures and compared clinical parameters regarding phosphate metabolism or serum phosphate, fibroblast growth factor-23 (FGF23), and parathyroid hormone (PTH), in the cross-sectional model. Results: Multivariable linear regression analyses revealed that serum phosphate levels were significantly higher in CRIC across all levels of estimated glomerular filtration rate (eGFR) with the greatest difference being observed at lower levels of eGFR. Serum FGF23 and 25-hydroxy vitamin D (25OHD) levels were higher in CRIC, while PTH levels were higher in CKD-JAC at all levels of eGFR. Adjustments for demographics, 25OHD, medications, dietary intake or urinary excretion of phosphate, PTH, and FGF23 did not eliminate the difference in serum phosphate levels between the cohorts (0.43, 0.46, 0.54, 0.64, and 0.78 mg/dL higher in CRIC within eGFR strata of >50, 41–50, 31–40, 21–30, and ≤20 mL/min/1.73 m2, respectively). These findings were consistent when only Asian CRIC participants (N = 105) were included in the analysis. Conclusion: Serum phosphate levels in CRIC were significantly higher than those of CKD-JAC across all stages of CKD, which may shed light on the international variations in phosphate parameters and thus in cardiovascular risk among CKD patients. The key mechanisms for the substantial differences in phosphate parameters need to be elucidated.

Introduction: Metabolomics could offer novel prognostic biomarkers and elucidate mechanisms of diabetic kidney disease (DKD) progression. Via metabolomic analysis of urine samples from 995 CRIC participants with diabetes and state-of-the-art statistical modeling, we aimed to identify metabolites prognostic to DKD progression. Methods: Urine samples (N = 995) were assayed for relative metabolite abundance by untargeted flow-injection mass spectrometry, and stringent statistical criteria were used to eliminate noisy compounds, resulting in 698 annotated metabolite ions. Utilizing the 698 metabolites’ ion abundance along with clinical data (demographics, blood pressure, HbA1c, eGFR, and albuminuria), we developed univariate and multivariate models for the eGFR slope using penalized (lasso) and random forest models. Final models were tested on time-to-ESKD (end-stage kidney disease) via cross-validated C-statistics. We also conducted pathway enrichment analysis and a targeted analysis of a subset of metabolites. Results: Six eGFR slope models selected 9–30 variables. In the adjusted ESKD model with highest C-statistic, valine (or betaine) and 3-(4-methyl-3-pentenyl)thiophene were associated (p < 0.05) with 44% and 65% higher hazard of ESKD per doubling of metabolite abundance, respectively. Also, 13 (of 15) prognostic amino acids, including valine and betaine, were confirmed in the targeted analysis. Enrichment analysis revealed pathways implicated in kidney and cardiometabolic disease. Conclusions: Using the diverse CRIC sample, a high-throughput untargeted assay, followed by targeted analysis, and rigorous statistical analysis to reduce false discovery, we identified several novel metabolites implicated in DKD progression. If replicated in independent cohorts, our findings could inform risk stratification and treatment strategies for patients with DKD.

RATIONALE & OBJECTIVE:Social support in older adults with chronic kidney disease (CKD) is a potentially modifiable factor that may affect important clinical outcomes such as health-related quality of life, cognitive function, and frailty. However, limited data about the effects of social support in older patients with non-dialysis-dependent CKD exist. Our objective was to evaluate the association of social support with health-related quality of life, cognitive function, and frailty in older adults with CKD. STUDY DESIGN:Cross-sectional analysis of a prospective cohort study. SETTING & POPULATION:1,851 participants older than 65 years with CKD enrolled in the Chronic Renal Insufficiency Cohort (CRIC) Study. EXPOSURE:Social support (Lubben Social Network Scale [LSNS]). OUTCOMESS:Health-related quality of life (Kidney Disease Quality of Life-36), cognitive function (Modified Mini-Mental State Examination, Trail Making Test A & B, and Buschke Selective Reminder Tests), and frailty (modified Fried frailty criteria). ANALYTIC APPROACH:Multivariable, linear, and logistic regression to determine the association between social support and health-related quality of life, cognitive function, and frailty. RESULTS:Low social support, defined as LSNS score < 12, was present in 22% of participants. On multivariable analysis, higher social support was associated with higher health-related quality of life (β coefficient per 1-SD increase in LSNS score; burden subscale, 2.57 (95% CI, 1.57-3.56); effects subscale, 2.21 (95% CI, 1.52-2.9); symptoms subscale, 1.64 (95% CI, 0.88-2.41); mental health composite subscale, 1.91 (95% CI, 1.40-2.43); and physical health composite score, 0.64 (95% CI, 0.03-1.24)). Higher social support was associated with better cognitive function (β coefficient per 1-SD increase in LSNS score; Modified Mini-Mental State Examination, 0.81 (95% CI, 0.44 to 1.19); Trail Making Test A & B, -2.53 (95% CI, -4.29 to -0.76) and -6.53 (95% CI, -10.07 to -2.99), respectively; Buschke Selective Reminder Test 1, 2, and 3, 0.19 (95% CI, 0.07 to 0.30); 1.59 (95% CI, 0.96 to 2.22); and 0.40 (95% CI, 0.23 to 0.56), respectively. Higher social support was associated with higher likelihood of being nonfrail (OR, 1.77; 95% CI per 1-SD higher LSNS score, 1.24-2.53). LIMITATIONS:Conclusions about causality cannot be drawn from an observational cross-sectional study. CONCLUSIONS:In older patients with CKD, higher social support was associated with higher health-related quality of life and cognitive function and less frailty.

RATIONALE & OBJECTIVE:The clearance of protein-bound solutes by the proximal tubules is an innate kidney mechanism for removing putative uremic toxins that could exert cardiovascular toxicity in humans. However, potential associations between impaired kidney clearances of secretory solutes and cardiovascular events among patients with chronic kidney disease (CKD) remains uncertain.STUDY DESIGN:A multicenter, prospective, cohort study.SETTING & PARTICIPANTS:We evaluated 3,407 participants from the Chronic Renal Insufficiency Cohort (CRIC) study.EXPOSURES:Baseline kidney clearances of 8 secretory solutes. We measured concentrations of secretory solutes in plasma and paired 24-hour urine specimens using liquid chromatography-tandem mass spectrometry (LC-MS/MS).OUTCOMES:Incident heart failure, myocardial infarction, and stroke events.ANALYTICAL APPROACH:We used Cox regression to evaluate associations of baseline secretory solute clearances with incident study outcomes adjusting for estimated GFR (eGFR) and other confounders.RESULTS:Participants had a mean age of 56 years; 45% were women; 41% were Black; and the median estimated glomerular filtration rate (eGFR) was 43 mL/min/1.73 m2. Lower 24-hour kidney clearance of secretory solutes were associated with incident heart failure and myocardial infarction but not incident stroke over long-term follow-up after controlling for demographics and traditional risk factors. However, these associations were attenuated and not statistically significant after adjustment for eGFR.LIMITATIONS:Exclusion of patients with severely reduced eGFR at baseline; measurement variability in secretory solutes clearances.CONCLUSIONS:In a national cohort study of CKD, no clinically or statistically relevant associations were observed between the kidney clearances of endogenous secretory solutes and incident heart failure, myocardial infarction, or stroke after adjustment for eGFR. These findings suggest that tubular secretory clearance provides little additional information about the development of cardiovascular disease events beyond glomerular measures of GFR and albuminuria among patients with mild-to-moderate CKD.

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 < 0.001) and Effects scales (wait-listing aHR, 0.74; 95% CI, 0.59-0.92; P = 0.007). Participants with fewer depressive symptoms (ie, Beck Depression Inventory score < 14) had lower wait-listing rates than those with more depressive symptoms (aHR, 0.81; 95% CI, 0.66-0.99; P = 0.04). Participants with lower Burden and Effects scale scores and those with higher Symptoms and PCS scores had higher pre-emptive wait-listing rates (aHR in highest tertile of PCS relative to lowest tertile, 1.58; 95% CI, 1.12-2.23; P = 0.01). LIMITATIONS:Unmeasured confounders. CONCLUSIONS:Self-reported health in late-stage CKD may influence the timing of kidney transplantation.

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

Background: Physical activity is a modifiable behavior with cumulative health benefits across the lifespan. Most studies of adult exercise patterns have been cross-sectional and limited to non-US populations. Describing longitudinal changes in exercise from mid- to late-life can provide insight into targeted exercise recommendations for middle-aged and older adults. Objective: In the biracial ARIC Study (n=15792), we report trends in the type and duration of exercise among adults aged 45-64 years who were followed for over 20 years. We further examined exercise patterns in a subset of adults who reported engaging in exercise at each ARIC visit (n=1254). Methods: Individuals self-reported type and duration of up to 4 exercises participated in the past year at four visits. Participant’s total minutes/week of exercise was estimated as a composite of the 4 exercises. Type of exercise was categorized as defined in Table 1. Participants were identified as having engaged in <30 minutes or ≥30 minutes/week for each exercise category. Results: Overall, 9,866 adults (female n=5,288; Black n=1,874) reported engaging in exercise at baseline (Table 1). Adults who reported exercise participation at all visits (n=1254; female n=658; Black n=163) had, on average, increased and then decreased their exercise duration from visits 1 to 6. Consistently active adults participated in exercises for a longer duration over time, while among the whole cohort, duration decreased. Walking was the most frequently reported exercise overall for the whole and consistently active cohort. The number of consistently active adults who walked for at least 30 minutes/week increased from 704 to 790 at visits 1 and 6, respectively Conclusion: Exercise patterns differed for adults reporting participation in exercise at a minimum at visit 1 compared to consistently active adults. Further exploration of predictors (i.e. retirement or health status) of exercise change should be examined to guide recommendations that aim to optimize energy expenditure in adulthood.