Chronic Renal Insufficiency Cohort Study Research Articles

A Thorough Literature Review of the Potential Benefits and Drawbacks of Long-Term Aspirin Use for the Primary Prevention of Cardiovascular Disease.

This article examines the role of aspirin in the primary prevention of cardiovascular disease. It highlights findings from major studies such as ASPREE (ASPirin in Reducing Events in the Elderly), ARRIVE (Aspirin to Reduce Risk of Initial Vascular Events), and ASPREE-XT (ASPirin in Reducing Events in the Elderly - eXTension) , among others. The review focuses on aspirin's role in primary prevention for specific populations including older adults, diabetics, hypertension patients, rheumatoid arthritis patients, kidney transplant recipients, and those with specific lipoprotein(a) genotypes, among other groups. We review these studies, noting aspirin's role in reducing events such as myocardial infarctions and its potential for increasing bleeding risks. The review also considers the implications for patients with kidney disease, referencing the Chronic Renal Insufficiency Cohort (CRIC) study and the International Polycap Study-3 (TIPS-3) trial. Additionally, it addresses the shifting paradigms in guidelines from the US Preventive Services Task Force and other entities, underscoring the importance of individualized aspirin use by balancing benefits against bleeding risks. The article further explores the concept of platelet reactivity, discusses strategies for improving adherence to aspirin therapy, and identifies existing research gaps, such as the phenomenon of aspirin resistance. It concludes by suggesting potential areas for future investigation to enhance understanding and application of aspirin in cardiovascular disease prevention.

#1559 Using nephrology clinic data to emulate cohorts: a comparison between an electronic health records service and Chronic Renal Insufficiency Cohort

Abstract Background and Aims The amount of data contributed to evidence-synthesis is inequitably distributed among various countries in a way that most of the data is emerged from developed and/or upper middle and high income countries. One efficient and low-cost solution can be the implementation of scattered electronic health records (EHR) sources in those countries into emulated cohort studies. We aim to compare the characteristics of a custom-built nephrology clinic electronic health records (CBNC-EHR) service that is in practice for more than 13 years with Chronic Renal Insufficiency Cohort (CRIC) study which has approximately the same span and enrollment to find out about the feasibility, strengths, and challenges of the proposition. Method We compared measured variables of baseline characteristics and follow-up strategy of CRIC study with the data provided by CBNC-EHR to estimate if the care-centered database is capable of emulating a cohort study. Results Among variables of socioeconomic information at CRIC study, CBNC-EHR provides 33% at full, 33% are “partially available or easily accessible” (PAEA), and 33% are not available. 71% of variables of medical history are fully available for all patients, while only 14% are PAEA, and 14% are not available. For kidney function measures, CBNC-EHR provides 55% of variables completely, while the remaining 45% are PAEA. Obviously, no blood or urine sample were collected during ambulatory care, and no questionnaire on different aspects of health were used to gather supplementary data, contrary to CRIC study. Compared to follow-up strategy of CRIC study, which indicated Annual visits and laboratory tests and 6-month telephone follow-ups, CBNC-EHR yields data only upon personally-decided attention of patients for follow-up care, which varies widely from one patient to another. Nevertheless, the majority of patients have at least one office visit in a year, accompanied by relevant laboratory tests. CBNC-EHR provides a complete list of risk factors and comorbidities of each patient, which makes it suitable for subgrouping, as was designed in CRIC study regard the diabetes status of patients. CBNC-EHR currently has data of 6481 individuals with renal failure, compared to 3000 enrollment goal of CRIC study. However, much higher rates of dropout (estimated to be approximately 20%) and utilization of inclusion and exclusion criteria will contribute to the actual available cases to emulate a cohort study. Conclusion Implementing a care-centered database into emulation of a cohort study, is challenging and complicated. Lack of consistency, high dropout rates, imperfect baseline and complementary information, and need for extensive data cleaning are all difficulties. However, contribution to equitability of data share in evidence-synthesis, extremely lower cost of conduction, and less heterogeneity are strengths of this procedure which can have a remarkable effect on transforming medical data from less-developed countries (which understandably prioritize healthcare to research due to scarcity of resources) to effective research studies. In this paper, we compared a renowned nephrology cohort with a private nephrology clinic EHR in a developing country and showed virtual availability of data to emulate a cohort study based on the care-centered database.

#373 Risk factors for progressive cardiorenal syndrome in patients with chronic kidney disease: the CRIC study

Abstract Background and Aims Cardiorenal syndrome (CRS) is associated with poor outcomes. However, risk factors for progressive CRS are not well studied in patients with chronic kidney disease (CKD). We studied the incidence and risk factors for progressive CRS in a cohort of CKD patients. Method 3 557 participants with CKD in the Chronic Renal Insufficiency Cohort (CRIC) Study were included in this analysis after excluding those with heart failure (HF) at baseline visits. The mean follow-up time was 10.5 years. Progressive CRS was defined as development of both HF and renal failure (RF) (dialysis or transplant) within 12 months of each other. Cox proportional hazards models were used to examine the association of risk factors with progressive CRS. In a sensitivity analysis, risk factors for CRS type 2 (HF preceded RF during entire follow up) and CRS type 4 (RF preceded HF) were analyzed. Results The average baseline age was 59 years for those with progressive CRS and 57 years for those without. The age-adjusted incidence of progressive CRS was 4.5/1000 person-years and was 5.0/1000 person-years in Men and 5.9 in Black. The multivariable-adjusted hazard ratios (HRs) with corresponding 95% confidence intervals (CIs) for traditional risk factors are as follow: less than high school education (1.82, 1.2-2.73), history of cardiovascular disease (CVD) (1.48, 1.03-2.12), lower educational attainment (per 1 standard deviation [SD]) in eGFR (1.83, 1.40-2.39), and higher (per 1 SD) albumin-to-creatinine ratio (ACR) (2.26, 1.78-2.86). The multivariable-adjusted HRs with corresponding 95% CIs for a one-standard deviation increase in novel risk factors are as follows: hemoglobin (0.82, 0.68-0.99), hemoglobin A1C (1.31, 1.14-1.52), log alkaline phosphatase (1.18, 1.00-1.38), and log brain natriuretic peptide (1.32, 1.10-1.57), adjusting for age, sex, race, clinic sites, and all significant traditional risk factors (education, CVD, eGFR, and ACR). In sensitivity analysis, the risk factor associated with both CRS type 2 and 4 were kidney dysfunction, albuminuria, and mineral bone disorder (higher alkaline phosphatase and FGF23), inflammation (TNF-α), and fibrotic factor (GDF-15), while diabetes, CVD, systolic blood pressure, waist circumference, anemia, HbA1c, and volume overload were more strongly associated with CRS type 2 compared to CRS type 4. Conclusion This study indicates that education level, history of CVD, kidney dysfunction, albuminuria, mineral bone disorder, diabetes control, anemia, volume overload, inflammation, and fibrotic factors are associated with progressive CRS. Many of these risk factors are modifiable. Further studies are warranted to assess the benefits of specific interventions to improve CRS outcomes.

#2201 Assessment of long-term cardiovascular comorbidities in patients with anti-neutrophil cytoplasmic antibody-associated vasculitis

Abstract Background and Aims ANCA associated vasculitis (AAV) is closely correlated to elevated cardiovascular disease (CVD) rates, positioning it a one of the leading causes of death among these patients. The impact of AAV on the risk of CVD has not been described in large prospective cohorts with a long-term follow up. The aim of our study was to evaluate the occurrence of cardiovascular events, encompassing major adverse cardiovascular events (MACE), to delineate associated risk factors, and to draw comparisons with other cohorts of patients diagnosed with CKD. Method We included 848 patients with a diagnosis of AAV who participated in 7 EUVAS RCTs (NORAM, CYCAZAREM, CYCLOPS, MEPEX, IMPROVE, RITUXVAS, and MYCYC), recruited from 74 centers in 17 European countries. The three-point MACE outcome was defined as acute myocardial infarction (AMI), stroke, or death from cardiovascular event. We used multivariate logistic regression analysis to assess the risk factors of MACE. Patients from our cohort were compared to the patients from the Chronic Renal Insufficiency Cohort (CRIC), which is a multicenter, prospective observational cohort study of participants with CKD. Results During the median follow up of 8 years (range 0-24.5, IQR: 2.9-13.6), 100 (11.8%) patients developed diabetes, 98 (13.4%) coronary heart disease (CHD), 90 (12.1%) hypertension, 70 (9.6%) deep vein thrombosis (DVT), 43 patients (5.9%) had a stroke and 28 (3.8%) an AMI. The number of MACE during FU was 144 (17%). MACE was more frequent among patients older than 65 years (n = 62 (43.1%); p-value: 0.013). CVD was the primary cause of death in 43 patients (14%). During the first 5 years after randomization, there was a significant increase in the number of cardiovascular events compared to the period 6 years- end of follow up (CHD: n = 55 vs n = 23, p ≤ 0.001; DVT: n = 55 vs n = 29; p < 0.001; stroke: n = 35 vs n = 24, p-value < 0.001). The prognostic factors for MACE in our cohort were hemodialysis dependency during RCT, age, male sex, previous history of CHD and stroke, and occurrence of diabetes during follow up. Within the subset of patients who underwent kidney biopsy, those in the crescentic class (n = 16) followed by the mixed class (n = 15) exhibited a significant higher incidence of MACE (p = 0.02). When compared to the cohort of patients with CKD from the CRIC study, the risk for CHD was higher (13.4% (95% CI: 11.16-16.11) vs 5.4% (95% CI 4.5-6.5); respectively; RR: 2.49 (95% CI 1.91-3.24); p-value<0.01). Additionally, there was a higher risk for stroke (5.6% (95% CI 4.2-7.4) vs 2.8% (95% CI 2.2- 3.7); RR 1.97 (95% CI: 1.33- 2.91) p-value: 0.0006). Conclusion Patients with AAV had an increased risk of stroke and CHD compared to patients with CKD from other etiologies. During the first years after diagnosis, there is an increased risk for CVD occurrence. The prognostic factors for MACE in our cohort were hemodialysis dependency, age, male sex, previous story of CHD and stroke, and diabetes during follow up. Patients with AAV should be considered at high cardiovascular risk; therefore, the therapeutic approach should include the management of traditional cardiovascular risk factors and lifestyle modification. Efforts should be made to meet strict therapeutic targets and to implement early CVD detection programs.

Five-Year Cumulative Cardiovascular Health and Clinical Events in Patients With Chronic Kidney Disease: The CRIC Study.

Higher cardiovascular health (CVH) score is associated with lower risks of cardiovascular disease (CVD) and mortality in the general population. However, it is unclear whether cumulative CVH is associated with CVD, end-stage kidney disease (ESKD), and death in patients with chronic kidney disease. Among individuals from the prospective CRIC (Chronic Renal Insufficiency Cohort) Study, we used the percentage of the maximum possible CVH score attained from baseline to the year 5 visit to calculate cumulative CVH score. Multivariable-adjusted Cox proportional hazards regression was used to investigate the associations of cumulative CVH with risks of adjudicated CVD (myocardial infarction, stroke, and heart failure), ESKD, and all-cause mortality. A total of 3939 participants (mean age, 57.7 years; 54.9% men) were included. The mean (SD) cumulative CVH score attained during 5 years was 55.5% (12.3%). Over a subsequent median 10.2-year follow-up, 597 participants developed CVD, 656 had ESKD, and 1324 died. A higher cumulative CVH score was significantly associated with lower risks of CVD, ESKD, and mortality, independent of the CVH score at year 5. Multivariable-adjusted hazard ratios and 95% CIs per 10% higher cumulative CVH score during 5 years were 0.81 (0.69-0.95) for CVD, 0.82 (0.70-0.97) for ESKD, and 0.80 (0.72-0.89) for mortality. Among patients with chronic kidney disease stages 2 to 4, a better CVH status maintained throughout 5 years is associated with lower risks of CVD, ESKD, and all-cause mortality. The findings support the need for interventions to maintain ideal CVH status for prevention of adverse outcomes in the population with chronic kidney disease.

A Bayesian Joint Model of Longitudinal Kidney Disease Progression, Recurrent Cardiovascular Events, and Terminal Event in Patients with Chronic Kidney Disease

AbstractNearly 15% (37 million) of adults in the United States (US) have chronic kidney disease (CKD). The longitudinal decline of kidney function is intricately related to the development of cardiovascular disease (CVD) and eventual “terminal” event (kidney failure and mortality) in patients with CKD. Understanding the mechanism and risk factors underlying the three key outcome processes, (1) CKD progression, (2) CVD, and (3) subsequent terminal event in the CKD patient population remains incomplete. Thus, in this work, we develop a novel trivariate joint model to study the risk factors associated with the interdependent outcomes of kidney function (as measured by longitudinal estimated glomerular filtration rate), recurrent cardiovascular events, and the terminal event. Efficient estimation and inference is proposed within a Bayesian framework using Markov Chain Monte Carlo and Bayesian P-splines for hazard functions. The proposed Bayesian framework is directly generalizable beyond trivariate outcome processes to accommodate other potential modeling of complex multi-disease processes. The method is applied to study the aforementioned trivariate processes using data from the Chronic Renal Insufficiency Cohort Study, an ongoing prospective cohort study, established by the National Institute of Diabetes and Digestive and Kidney Diseases to address the rising epidemic of CKD in the US.

Characterization of CKD illness representation profiles using patient-level factors.

Illness perceptions are the unique perspective individuals have on their illness, based on their context and experiences, and are associated with patient outcomes including coping and adherence. The purpose of this study was to explore characteristics that may be driving membership in illness perceptions cluster groups for adults with chronic kidney disease (CKD). This study was conducted within the multicenter longitudinal Chronic Renal Insufficiency Cohort (CRIC) Study. Cross-sectional data were collected and combined with CRIC data. Illness perceptions were measured using the Revised Illness Perception Questionnaire. Clustering analysis was conducted in R, and bivariate analysis including linear regression was performed in STATA 16. The sample (n = 197) had a mean age of 68, was 52% women, 53% non-White, and mean estimated glomerular filtration rate (eGFR) 56 ml/min/1.73 m2. Three cluster groups were identified, labeled as "Disengaged" (n = 20), "Well-Resourced" (n = 108), and "Distressed" (n = 69). The "Disengaged" group was characterized by low CKD knowledge, many recent hospitalization days, and the lowest perceived CKD burden. The "Well-Resourced" group was characterized by the highest levels of education, CKD knowledge, optimism, and medication adherence. The "Distressed" group was characterized by the highest levels of depression scores, comorbidity burden, CKD burden, CKD symptoms, and lowest optimism. Group membership significantly predicted the number of hospitalization days in adjusted analyses. Illness perceptions groups are associated with number of hospitalization days but are independent of many patient characteristics. Illness perceptions data could be used to tailor care for specific patients at risk for poor health outcomes.

Association of Integrated Proteomic and Metabolomic Modules with Risk of Kidney Disease Progression.

Proteins and metabolites play crucial roles in various biological functions and are frequently interconnected through enzymatic or transport processes. We present an integrated analysis of 4,091 proteins and 630 metabolites in the Chronic Renal Insufficiency Cohort Study (N=1,708; average follow-up for kidney failure [KF], 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 estimated glomerular filtration rate (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). We identified 139 modules of correlated proteins and metabolites, which were represented by their principal components (PC). Modules and PC 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 over-represented in these modules. Transmembrane-ephrin receptor activity displayed the largest odds (OR = 13.2, P-value = 5.5×10 -5 ). A module containing CRIM1 and NPNT expressed in podocytes demonstrated particularly strong associations with kidney failure (P-value = 2.6×10 -5 ). This study demonstrates that integration of the proteome and metabolome can identify functions of pathophysiologic importance in kidney disease.

227 Depressive Symptoms and Incident Peripheral Arterial Disease among adults in the Chronic Renal Insufficiency Cohort (CRIC) Study

227 Depressive Symptoms and Incident Peripheral Arterial Disease among adults in the Chronic Renal Insufficiency Cohort (CRIC) Study

Klotho and Clinical Outcomes in CKD

Rationale & ObjectiveKlotho deficiency may affect clinical outcomes in chronic kidney disease (CKD) through fibroblast growth factor-23 (FGF23)-dependent and independent pathways. However, the association between circulating Klotho and clinical outcomes in CKD remains unresolved and was the focus of this study. Study DesignProspective observational study. Setting & Participants1088 participants of the Chronic Renal Insufficiency Cohort (CRIC) Study with estimated glomerular filtration rate (eGFR) 20-70 ml/min/1.73m2. ExposurePlasma Klotho level at the year-1 study visit. Outcomes5-year risks of all-cause mortality, heart failure hospitalization, atherosclerotic cardiovascular events, and a composite kidney endpoint comprised of a sustained 50% decline in eGFR, dialysis, kidney transplantation, or eGFR <15 ml/min/1.73 m2. Analytical ApproachWe divided Klotho into six groups to account for its non-normal distribution. We used Cox proportional hazards regression and subdistribution hazards models to compare survival and clinical outcomes, respectively, between Klotho groups. We sequentially adjusted for demographics, kidney function, cardiovascular risk factors, sample age, and FGF23. ResultsMean eGFR was 42 ml/min/1.73m2, and median Klotho was 0.31 ng/ml (interquartile range 0.10-3.27 ng/ml). When compared to the lowest Klotho group, survival (hazard ratio [HR] 0.77, 95% confidence interval [CI] 0.32-1.89), heart failure hospitalization (HR 1.10, 95% CI 0.38-3.17), atherosclerotic cardiovascular events (HR 1.19, 95% CI 0.57-2.52), and CKD progression (HR 1.05, 95% CI 0.58-1.91) did not differ in the high Klotho group. In contrast, FGF23 was significantly associated with mortality and heart failure hospitalization independent of Klotho levels. LimitationsDespite adjustments, we cannot exclude potential influence of residual confounding or sample storage on the results. A single measurement of plasma Klotho may not capture Klotho patterns over time. ConclusionsIn a large, diverse, well-characterized CKD cohort, Klotho was not associated with clinical outcomes, and Klotho deficiency did not confound the association of FGF23 with mortality or heart failure hospitalization.

Association of Albuminuria With Chronic Kidney Disease Progression in Persons With Chronic Kidney Disease and Normoalbuminuria : A Cohort Study.

Albuminuria is a major risk factor for chronic kidney disease (CKD) progression, especially when categorized as moderate (30 to 300 mg/g) or severe (>300 mg/g). However, there are limited data on the prognostic value of albuminuria within the normoalbuminuric range (<30 mg/g) in persons with CKD. To estimate the increase in the cumulative incidence of CKD progression with greater baseline levels of albuminuria among persons with CKD who had normoalbuminuria (<30 mg/g). Multicenter prospective cohort study. 7 U.S. clinical centers. 1629 participants meeting criteria from the CRIC (Chronic Renal Insufficiency Cohort) study with CKD (estimated glomerular filtration rate [eGFR], 20 to 70 mL/min/1.73 m2) and urine albumin-creatinine ratio (UACR) less than 30 mg/g. Baseline spot urine albumin divided by spot urine creatinine to calculate UACR as the exposure variable. The 10-year adjusted cumulative incidences of CKD progression (composite of 50% eGFR decline or kidney failure [dialysis or kidney transplantation]) from confounder adjusted survival curves using the G-formula. Over a median follow-up of 9.8 years, 182 of 1629 participants experienced CKD progression. The 10-year adjusted cumulative incidences of CKD progression were 8.7% (95% CI, 5.9% to 11.6%), 11.5% (CI, 8.8% to 14.3%), and 19.5% (CI, 15.4% to 23.5%) for UACR levels of 0 to less than 5 mg/g, 5 to less than 15 mg/g, and 15 mg/g or more, respectively. Comparing persons with UACR 15 mg/g or more to those with UACR 5 to less than 15 mg/g and 0 to less than 5 mg/g, the absolute risk differences were 7.9% (CI, 3.0% to 12.7%) and 10.7% (CI, 5.8% to 15.6%), respectively. The 10-year adjusted cumulative incidence increased linearly based on baseline UACR levels. UACR was measured once. Persons with CKD and normoalbuminuria (<30 mg/g) had excess risk for CKD progression, which increased in a linear fashion with higher levels of albuminuria. None.

Abstract P414: Serum Potassium Trajectories Among Chronic Kidney Disease Patients: The Chronic Renal Insufficiency Cohort Study

Background: Patients with chronic kidney disease (CKD) are at an increased risk for blood electrolyte imbalances and compromised cardiac and renal regulatory functions. Our objective is to characterize serum potassium trajectories in patients with CKD. Methods: Data from the Chronic Renal Insufficiency Cohort Study were used to analyze 5,625 participants with CKD. Serum potassium measurements were collected annually. Hyperkalemia was defined as &gt;5.0 mmol/L, hypokalemia as &lt;3.5 mmol/L, and normokalemia as 3.5 - 5.0 mmol/L. Trajectory analysis using a semiparametric modeling strategy was conducted, incorporating hierarchical modeling and latent class models. Group-based trajectory models were used to fit longitudinal data and estimate probabilities for multiple trajectories. Models were tested using a censored normal model with various numbers of trajectory groups and functional forms (e.g., linear, quadratic, cubic). Maximum likelihood was used to estimate model parameters and model fit was assessed by comparing Bayesian Information Criterion. Posterior predicted probabilities for each individual were estimated for each trajectory group and participants were assigned the highest posterior predicted probability. Results: Participants were 56% male, 43% Black, and had a median age of 67.0 years. Overall mean serum potassium was 4.3 mmol/L over 12 annual visits with a median follow-up of 9 years. Based on model fit and statistical significance, five distinct trajectory groups were identified (Figure). Four trajectories (one hyperkalemia and three normokalemia) were stable over time. One trajectory started in the normokalemia range and increased into hyperkalemia. Conclusions: Five trajectories of serum potassium were identified among CKD patients. Characterizing serum potassium trajectories over time can help to understand who may be at increased risk for abnormal potassium and related complications and potentially inform the development of interventions to maintain normokalemia in patients with CKD.

Glycated Albumin and Adverse Clinical Outcomes in Patients With CKD: A Prospective Cohort Study

Rationale & ObjectiveHbA1c is widely used to estimate glycemia, yet it is less reliable in patients with chronic kidney disease (CKD). There is growing interest in the complementary use of glycated albumin (GA) to improve glycemic monitoring and risk stratification. However, whether GA associates with clinical outcomes in a non-dialysis dependent CKD population remains unknown. Study DesignProspective cohort study. Setting& Participants: 3110 participants with CKD from the Chronic Renal Insufficiency Cohort study. ExposureBaseline GA levels. OutcomesIncident end-stage kidney disease (ESKD), cardiovascular disease (CVD) events, and all-cause mortality. Analytical ApproachCox proportional hazards regression. ResultsParticipant characteristics included mean age 59.0 (SD 10.8) years; 1357 (43.6%) female; 1550 (49.8%) with diabetes. The median GA was 18.7 (interquartile range, 15.8-23.3)%. During an average 7.9-year follow-up, there were 980 ESKD events, 968 CVD events, and 1084 deaths. Higher GA levels were associated with greater risks of all outcomes, regardless of diabetes status: hazard ratios for ESKD, CVD, and death among participants with the highest quartile compared with quartile 2 (reference) were 1.42 (95%CI, 1.19-1.69), 1.67 (CI, 1.39-2.01), and 1.63 (CI, 1.37-1.94), respectively. The associations with CVD and death appeared J-shaped, with increased risk also seen at the lowest GA levels. Among patients with coexisting CKD and diabetes, the associations of GA with outcomes remained significant even after adjusting for HbA1c. For each outcome, we observed a significant increase in the fraction of new prognostic information when both GA and HbA1c were added to models. LimitationsLack of longitudinal GA measurements; HbA1c measurements were largely unavailable in participants without diabetes. ConclusionsAmong patients with CKD, GA levels were independently associated with risks of ESKD, CVD, and mortality, regardless of diabetes status. GA added prognostic value to HbA1c among patients with coexisting CKD and diabetes.

Risk factors for hip and vertebral fractures in chronic kidney disease: the CRIC study.

Fracture risk is high in chronic kidney disease (CKD) and underlying pathophysiology and risk factors may differ from the general population. In a cohort study of 3939 participants in the chronic renal insufficiency cohort (CRIC), we used Cox regression to test associations of putative risk factors with the composite of first hip or vertebral fracture assessed using hospital discharge codes. Mean age was 58years, 45% were female, 42% were Black, and 13% were Hispanic. There were 82 hip and 24 vertebral fractures over a mean (SD) 11.1 (4.8) years (2.4 events per 1000 person-years [95% CI: 2.0, 2.9]). Measured at baseline, diabetes, lower body mass index (BMI), steroid use, proteinuria, and elevated parathyroid hormone (PTH) were each associated with fracture risk after adjusting for covariates. Lower time-updated estimated glomerular filtration rate (eGFR) was associated with fractures (HR 1.20 per 10mL/min/1.73m2 lower eGFR; 95% CI: 1.04, 1.38) as were lower time-updated serum calcium and bicarbonate concentrations. Among time-updated categories of kidney function, hazard ratios (95% CI) for incident fracture were 4.53 (1.77, 11.60) for kidney failure treated with dialysis and 2.48 (0.86, 7.14) for post-kidney transplantation, compared with eGFR ≥60. Proton pump inhibitor use, dietary calcium intake, measures of vitamin D status, serum phosphate, urine calcium and phosphate, and plasma fibroblast growth factor-23 were not associated with fracture risk. In conclusion, lower eGFR in CKD is associated with higher fracture risk, which was highest in kidney failure. Diabetes, lower BMI, steroid use, proteinuria, higher serum concentrations of PTH, and lower calcium and bicarbonate concentrations were associated with fractures and may be modifiable risk factors.

Metabolites Associated With Uremic Symptoms in Patients With CKD: Findings From the Chronic Renal Insufficiency Cohort (CRIC) Study

Rationale & ObjectiveThe toxins contributing to uremic symptoms in patients with CKD are unknown. We sought to apply complementary statistical modeling approaches to data from untargeted plasma metabolomic profiling to identify solutes associated with uremic symptoms in patients with CKD. Study DesignCross-sectional. Setting & Participants1,761 Chronic Renal Insufficiency Cohort (CRIC) participants with CKD not on dialysis. PredictorsMeasurement of 448 known plasma metabolites. OutcomesThe uremic symptoms fatigue, anorexia, pruritus, nausea, paresthesia, and pain were assessed by single items on the Kidney Disease Quality of Life-36 (KDQOL) instrument. Analytical ApproachMultivariable adjusted linear regression, Lasso linear regression, and random forest models were used to identify metabolites associated with symptom severity. After adjustment for multiple comparisons, metabolites selected in at least two of the three modeling approaches were deemed “overall” significant. ResultsParticipant mean eGFR was 43 mL/min/1.73 m2, with 44% self-identifying as female and 41% Non-Hispanic Black. The prevalence of uremic symptoms ranged from 22 – 55%. We identified 17 metabolites for which a higher level was associated with greater severity of at least one uremic symptom, and 9 metabolites inversely associated with uremic symptom severity. Many of these metabolites demonstrated at least a moderate correlation with eGFR (Pearson’s r ≥ 0.5), and some were also associated with risk of developing kidney failure or death in multivariable adjusted Cox regression models. LimitationsLack of a second independent cohort for external validation of our findings. ConclusionsMetabolomic profiling was used to identify multiple solutes associated with uremic symptoms in adults with CKD, but future validation and mechanistic studies are needed.

Adherence to Plant-Based Diets and Risk of CKD Progression and All-Cause Mortality: Findings From the Chronic Renal Insufficiency Cohort (CRIC) Study

Studies have shown that generally healthy individuals who consume diets rich in plant foods have a lower risk of incident chronic kidney disease (CKD) and cardiovascular disease. This study investigated the prospective associations of plant-based diets with the risk of CKD progression and all-cause mortality in individuals with CKD. Prospective cohort study. 2,539 participants with CKD recruited between 2003-2008 into the Chronic Renal Insufficiency Cohort (CRIC) Study. Responses on the Diet History Questionnaire were used to calculate scores for the overall plant-based diet index, healthy plant-based diet index, and unhealthy plant-based diet index. (1) CKD progression defined as≥50% estimated glomerular filtration rate decline from baseline or kidney replacement therapy (dialysis, transplant) and (2) all-cause mortality. Cox proportional hazards models to compute hazard ratios and 95% confidence intervals adjusting for lifestyle, socioeconomic, and clinical covariates. There were 977 CKD progression events and 836 deaths during a median follow-up period of 7 and 12 years, respectively. Participants with the highest versus lowest adherence to overall plant-based diets and healthy plant-based diets had 26% (HR, 0.74 [95% CI, 0.62-0.88], P trend<0.001) and 21% (HR, 0.79 [95% CI, 0.66-0.95], P trend=0.03) lower risks of all-cause mortality, respectively. Each 10-point higher score of unhealthy plant-based diets was modestly associated with a higher risk of CKD progression (HR, 1.14 [95% CI, 1.03-1.25) and all-cause mortality (HR, 1.11 [95% CI, 1.00-1.23). Self-reported diet may be subject to measurement error. Adherence to an overall plant-based diet and a healthy plant-based diet is associated with a reduced risk of all-cause mortality among individuals with CKD. An unhealthy plant-based was associated with an elevated risk of CKD progression and all-cause mortality. Plant-based diets are healthful dietary patterns that have been linked to a lower risk of chronic diseases. However, the impact of plant-based diets on clinical outcomes in patients with chronic kidney disease (CKD) is not well established. In 2,539 individuals with CKD, we examined the associations of adherence to 3 different types of plant-based diets with the risks of CKD progression and all-cause mortality. We found that following an overall plant-based diet and a healthy plant-based diet was associated with a lower risk of all-cause mortality. By contrast, following an unhealthy plant-based diet was associated with a higher risk of CKD progression and all-cause mortality. These results suggest that the quality of plant-based diets may be important for CKD management.

FGF-23, Left Ventricular Hypertrophy, and Mortality in Patients With CKD: A Revisit With Mediation Analysis

BackgroundIn patients with chronic kidney disease (CKD), fibroblast growth factor (FGF)-23 is suspected to cause death or cardiovascular disease by inducing left ventricular hypertrophy (LVH). ObjectivesThis study aims to quantify the mediational effect of LVH in the hypothetical causal pathway from FGF-23 to long-term adverse outcomes. MethodsFrom 3,939 adults with CKD stages 2 to 4 enrolled in the CRIC (Chronic Renal Insufficiency Cohort) study, 2,368 participants with available data of FGF-23, left ventricular mass index at 1 year, and covariates were included. We employed linear and Cox proportional hazards regression models to investigate the association between FGF-23 and LVH, all-cause mortality, atrial fibrillation (AF), or congestive heart failure (CHF). Mediation analysis was used within a counterfactual framework to decompose the effect of FGF-23 into natural direct and indirect effects. ResultsAmong 2,368 participants (mean age: 57.7 years, 1,252 males, median FGF-23 level: 138.8 RU/mL), left ventricular mass index was positively correlated with FGF-23. During a median of 12.0, 11.1, and 11.1 years, FGF-23 was associated with all-cause mortality (HR: 1.62, 95% CI: 1.24-2.12), AF (HR: 1.58, 95% CI: 1.12-2.24), and CHF (HR: 1.32, 95% CI: 0.95-1.84) when the highest quartile was compared to the lowest quartile. LVH mediated 7.4%, 11.2%, and 21.9% of the effect of FGF-23 on all-cause mortality, AF, and CHF, respectively. ConclusionsIn CKD patients, FGF-23 had a minor effect on the development of long-term adverse outcomes through LVH. Other potential mediators and the validity of negative effect of FGF-23 should be explored.

Abstract 15660: Mitral Regurgitation in Patients With Chronic Kidney Disease: Results From the Chronic Renal Insufficiency Cohort Study

Background: Mitral regurgitation (MR) is more common in patients with chronic kidney disease (CKD) compared to the general population, However, longitudinal associations of MR and adverse outcomes in CKD, such as mortality and heart failure (HF), have not been well studied yet. Hypothesis/Aim: We aim to investigate the prevalence of MR and its association with mortality, incidence of HF, and atrial fibrillation (AF) in patients with CKD. Methods: We studied patients with CKD who had an echocardiography exam (2008-2013) in the Chronic Renal Insufficiency Cohort (CRIC) study. Independent t-tests and Chi-square tests were used to compare clinical and echocardiographic characteristics in patients with vs. without MR. The degree of MR was quantified using effective regurgitant orifice area (EROA) from apical-four chamber view and further categorized as trace, mild and moderate/severe. Kaplan-Meier (KM) Curves and Cox hazard models were used to estimate the association of MR degree and EROA with mortality, incidence of HF and AF. Results: Among a total of 2951 patients with CKD, 2167 (73.4%) patients had MR (EROA, 0.14±0.19 cm 2 ) with degrees of trace, mild, and moderate /severe MR comprising 54.3%, 12.5%, and 6.6%, respectively. Patients with MR were more likely to be female (47.39 vs. 42.73%), non-White race (51.8 vs. 46.8%), and have worse B-type Natriuretic Peptide (NTproBNP; 524.86 vs. 271.66 pg/ml) and left ventricular ejection fraction (53.7 vs. 55.8%) compared to those without MR. When stratified by estimated glomerular filtration rate (eGFR; 60-45, 45-30, &lt;30 ml/min/1.73 m 2 ), the group in the lowest eGFR category (n=703) had the highest prevalence of moderate/severe MR (9.2%, p &lt;0.05). KM Curves showed patients with CKD and moderate/sever MR had higher incidence of HF and AF than those with CKD and absent, trace, or mild MR ( p &lt;0.01). EROA was associated with the incidence of AF (hazard ratio [HR] = 1.08, p &lt;0.01) and HF (HR=1.06, p &lt;0.01), independent of age, sex, race, traditional cardiovascular risk factors, urine albumin-to-creatinine ratio, eGFR and NTproBNP, but not mortality. Conclusion: In patients with CKD, MR is independently associated with HF and AF, highlighting the importance of MR-specific interventions to improve cardiovascular outcomes.

Abstract 16652: Cardiovascular Outcomes of Renin-Angiotensin System Inhibition Amongst Non-Proteinuric Chronic Kidney Disease Patients in the Chronic Renal Insufficiency Cohort

Introduction: Chronic kidney disease is a leading cause of CVD morbidity and mortality. The majority of CKD patients do not have proteinuria. Current therapies, including renin-angiotensin system (RAS) blockers, are only known to be beneficial in proteinuric CKD. Our goal was to evaluate the association of RAS blockade with long-term CVD outcomes and survival among those with non-proteinuric CKD. Methods: The cohort included subjects in the prospective Chronic Renal Insufficiency Cohort Study without proteinuria at study entry. Non-proteinuric CKD was defined as urine protein &lt;0.5g/day. We excluded subjects with heart failure or not on hypertension treatment. We used Cox proportional hazards regression to evaluate the association of RAS blockade vs. other antihypertensive therapy with CVD outcomes and death. The primary outcome was a composite of physician-adjudicated CVD events, including MI, stroke, heart failure hospitalization and death. Baseline covariates were adjusted through inverse probability of treatment weighting including: age, sex, race, education, smoking, BMI, diabetes, blood pressure, eGFR, and statin use. Results: A total of 2,825 of subjects met inclusion criteria. There were 2,068 subjects using vs 757 not using (73% vs 27%) RAS blockade at entry. Users had a similar age (61 vs 62 years) and eGFR (50 vs 51ml/min/1.73m 2 ) to non-users. Users were more likely to be male (66% vs 46%), to have diabetes (59% vs 30%), and to be on a statin (61% vs 50%). No significant association was found between RAS blockade and CVD events (adjusted HR 0.90, 95% CI 0.76-1.07) or mortality (adjusted HR 0.84, 95% CI 0.68-1.04) compared to other antihypertensive therapy. Conclusions: Among adults with non-proteinuric CKD, baseline use of RAS blockade was not associated with a lower risk of long-term events or mortality. Further studies are needed to determine if RAS blockade may play a role in high-risk patients with non-proteinuric CKD.

Abstract 12444: Pulse Pressure and Cardiovascular and Renal Outcomes by Age in the Chronic Renal Insufficiency Cohort

Pulse pressure (PP) is associated with cardiovascular events and the progression of chronic kidney disease (CKD) to end stage kidney disease (ESKD). While PP is known to widen with age, it is less clear what other clinical factors affect PP and whether the risks associated with wide PP are the same across all ages. We used Cox proportional hazards models to investigate the association of PP with development of 1) atherosclerotic cardiovascular disease (ASCVD) events (congestive heart failure hospitalization, myocardial infarction, stroke and peripheral artery disease) or death and 2) 50% reduction in estimated glomerular filtration rate (eGFR) or ESKD in the Chronic Renal Insufficiency Cohort (CRIC) Study. In sensitivity analyses, we evaluated the association of time-updated PP with these outcomes, accounting for potential time-updated confounders using inverse probability of treatment weighting. We evaluated for effect modification by age (divided into tertiles), apparent treatment-resistant hypertension (HTN), baseline diabetes mellitus (DM) status, baseline CKD stage and baseline cardiovascular disease (CVD). Among 5,621 participants with CKD followed for ~5.4 years, mean PP was 57±19 mmHg, 1,396 (25%) had an ASCVD event, 1,186 (21%) died and 1,783 (32%) participants experienced the composite renal outcome. Every 10 mm Hg wider PP was associated with 6% higher risk of an ASCVD event or death (time-updated adjusted hazard ratio [HR]=1.06, 95% CI 1.04, 1.08) and 17% higher risk of the composite renal outcome (time-updated adjusted HR=1.17, 95% CI 1.16, 1.18). Wider PP was associated with a higher risk of ASCVD events or death among participants in the lowest age tertile (21-61 years; Figure 1A ), but a higher risk of the composite renal outcome in the oldest age tertile (71-79 years; Figure 1B ), suggesting PP may be associated with different pathophysiology across ages.