Transcriptome-wide association study of cardiovascular outcomes in chronic kidney disease: The chronic renal insufficiency cohort.

Genome-wide association studies (GWAS) identified multiple loci for cardiovascular disease, but their relevance to individuals with chronic kidney disease (CKD), who are at higher risk of cardiovascular disease, is unknown. In this study, we performed GWAS analyses of coronary heart disease (CHD) or all-cause stroke in African (AFR) and European (EUR) American participants with CKD of the Chronic Renal Insufficiency Cohort (CRIC). Mixed- effect logistic regression models were race-stratified and adjusted for age, sex, site of recruitment, estimated glomerular filtration rate (eGFR), and principal components, followed by meta-analysis. We attempted replication in participants from two biobanks with biomarker or ICD-10 (International Classification of Diseases, 10th Revision) diagnostic codes for CKD. We assessed the association of single nucleotide variants (SNVs) at known CHD and stroke loci in CRIC and tested the genetic correlation among CRIC, a biobank-based cohort and published GWAS of cardiovascular disease. Among 3,588 CRIC participants, 1,203 had CHD and 535 had all-cause stroke. We identified six SNVs across three loci ( LINC02744 , AZIN1- AS1 , and ATP6V0A4 ) associated with all-cause stroke, and two intronic SNVs at the PPARG locus associated with CHD. However, SNV associations were not significant in replication studies. Published SNVs for CHD or stroke were not associated with cardiovascular outcomes in CRIC. When testing the genetic correlations between published GWAS and CRIC GWAS, they were significant for CHD (genetic correlations (rg) range of 0.39 to 0.51, p-value< 0.007). These findings suggest some differences in the genetic architecture of CHD and stroke among individuals with CKD compared to those from the general population, although large numbers of CKD participants are needed to assess if findings are related to participant selection and CKD severity, or non-traditional risk factors in people with CKD.

Relationship Between Baseline and Longitudinal Self-Reported Physical Function and Cardiorenal Outcomes in CKD: Findings From the CRIC 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.

Cardiovascular disease (CVD) is a major complication in individuals with chronic kidney disease (CKD). In Japan, the incidence of CVD among persons with CKD is lower than that in the United States. Although various classes of antihypertensive agents are prescribed to prevent CVD, the proportion varies between the United States and Japan. Until now, few studies have compared clinical practices and CVD prevalence among patients with CKD in the United States vs. Japan. In this study, we performed a cross-sectional comparison of the prevalence of CVD and the prescription of β-blockers at study entry to the Chronic Kidney Disease Japan Cohort (CKD-JAC) Study and the Chronic Renal Insufficiency Cohort (CRIC) Study. The mean patient age was 58.2 and 60.3 years, the mean estimated glomerular filtration rate (eGFR) was 42.8 and 28.9 (mL/min/1.73 m2), and the median urinary albumin:creatinine ratio was 51.9 and 485.9 (mg/g) among 3939 participants in the CRIC Study and 2966 participants in the CKD-JAC Study, respectively. The prevalence of any CVD according to a self-report (CRIC Study) was 33%, while that according to a medical chart review (CKD-JAC Study) was 24%. These findings were consistent across eGFR levels. Prescriptions for β-blockers differed between the CRIC and CKD-JAC Studies (49% and 20%, respectively). The odds ratios for the association of any history of CVD and β-blocker prescription were 3.0 [2.6-3.5] in the CRIC Study and 2.0 [1.6-2.5] in the CKD-JAC Study (P < 0.001 for the interaction). In conclusion, the prevalence of CVD and treatment with β-blockers were higher in the CRIC Study across eGFR levels.

Candidate Gene Association Study of Coronary Artery Calcification in Chronic Kidney Disease: Findings From the CRIC Study (Chronic Renal Insufficiency Cohort)

Risks of Adverse Events in Advanced CKD: The Chronic Renal Insufficiency Cohort (CRIC) Study

Chronic kidney disease (CKD) has raised to a global health concern with huge economic burden and detrimental consequences for health. Among the risk factors, diabetes is a leading cause for CKD and renal failure. Multiple studies such as familial aggregation studies have provided evidence for a genetic component to the kidney disease. Heritability estimates of eGFRcrea are reported between 0.41 and 0.75 in individuals with the major CKD risk factors, hypertension and diabetes. However, precise genetic loci predicting CKD with or without diabetes are unknown. Here, we test the hypothesis that genetic polymorphisms are distinct between CKD patients with and without diabetes. We performed a genome-wide association studies using data from the Chronic Renal Insufficiency Cohort (CRIC) study to identify genetic various related to diabetes among CKD patients. CRIC Study is a United States multicenter, prospective study of racially and ethnically diverse patients with CKD. Clean genotype data from 970,342 genotyped or imputed single-nucleotide polymorphisms (SNPs) were available for 3,541 patients (1,953 males and 1,588 females) in CRIC study. Logistic regressions were carried out comparing distribution of SNPs among CKD patients with or without diabetes controlling for confounding factors of gender and race. Among all 3,541 CKD patients in CRIC, 1,724 CKD patients had Diabetes at baseline (Mean of Glycosylated hemoglobin =7.7%). We found that three genes, including KCNMB4 (rs767397, encoding calcium-activated potassium channel, subfamily M subunit beta 4), FOXA1 (rs911822, encoding a forkhead transcription factor) and SIMC1 (rs16831314, encoding SUMO-interacting motif containing protein 1), were putative risk genes for diabetes among CKD patients (P-value&lt;5х10 -6 ). These results are the first demonstrating that distinct genetic polymorphisms present in CKD patients with diabetes, indicating that these genes may be used to assess the risk of CKD with diabetes and that proteins encoded by these genes may contribute to diabetic nephropathy.

Isolated Diastolic Hypertension and Kidney and Cardiovascular Outcomes in CKD: The Chronic Renal Insufficiency Cohort (CRIC) Study

Ten-Year Risk-Prediction Equations for Incident Heart Failure Hospitalizations in Chronic Kidney Disease: Findings from the Chronic Renal Insufficiency Cohort Study and the Multi-Ethnic Study of Atherosclerosis

Relationship between macular and retinal diseases with prevalent atrial fibrillation — An analysis of the Australian Heart Eye Study

Genome-wide association studies revealed an association between a locus at 10q11, downstream from CXCL12, and myocardial infarction (MI). However, the relationship among plasma CXCL12, cardiovascular disease (CVD) risk factors, incident MI, and death is unknown. We analysed study-entry plasma CXCL12 levels in 3687 participants of the Chronic Renal Insufficiency Cohort (CRIC) Study, a prospective study of cardiovascular and kidney outcomes in chronic kidney disease (CKD) patients. Mean follow-up was 6 years for incident MI or death. Plasma CXCL12 levels were positively associated with several cardiovascular risk factors (age, hypertension, diabetes, hypercholesterolaemia), lower estimated glomerular filtration rate (eGFR), and higher inflammatory cytokine levels (P < 0.05). In fully adjusted models, higher study-entry CXCL12 was associated with increased odds of prevalent CVD (OR 1.23; 95% confidence interval 1.14, 1.33, P < 0.001) for one standard deviation (SD) increase in CXCL12. Similarly, one SD higher CXCL12 increased the hazard of incident MI (1.26; 1.09,1.45, P < 0.001), death (1.20; 1.09,1.33, P < 0.001), and combined MI/death (1.23; 1.13-1.34, P < 0.001) adjusting for demographic factors, known CVD risk factors, and inflammatory markers and remained significant for MI (1.19; 1.03,1.39, P = 0.01) and the combined MI/death (1.13; 1.03,1.24, P = 0.01) after further controlling for eGFR and urinary albumin:creatinine ratio. In CKD, higher plasma CXCL12 was associated with CVD risk factors and prevalent CVD as well as the hazard of incident MI and death. Further studies are required to establish if plasma CXCL12 reflect causal actions at the vessel wall and is a tool for genomic and therapeutic trials.

Introduction: Patients with chronic kidney disease (CKD) are at high risk for cardiovascular disease (CVD) events and vascular calcification is one pathway by which risk is increased. Hypothesis: We assessed the hypothesis that a novel measure of serum calcification propensity is associated with CVD events among patients with CKD stages 2-4. Methods: Among 3397 participants from the prospective longitudinal Chronic Renal Insufficiency Cohort (CRIC) Study, calcification propensity was quantified at baseline as the transformation time (T 50 ) from primary to secondary calciprotein particles, with lower T 50 corresponding to higher calcification propensity. CVD events are reported every six months and confirmed by medical record adjudication. Multivariable-adjusted Cox proportional hazards regression models, stratified by study site, were used to assess the associations of T 50 with risks of atherosclerotic CVD events (myocardial infarction, stroke, and peripheral artery disease) and congestive heart failure (CHF) events. Results: Over an average 7.1-year follow-up, we observed 571 atherosclerotic CVD events (312 myocardial infarction, 120 stroke, and 139 peripheral artery disease events) and 633 CHF events. The mean (standard deviation) T 50 was 313.4 (79.1) minutes. After adjustment for traditional CVD risk factors, lower T 50 was significantly associated with higher risk of atherosclerotic CVD, but not with risk of CHF. The addition of T 50 modestly improved atherosclerotic CVD event discrimination beyond ACC/AHA atherosclerotic CVD risk score variables (c-statistic 0.713 vs. 0.710; p&lt;0.001). Adjustment for kidney function attenuated the association between T 50 and CVD events (Table). Conclusions: Among patients with CKD stages 2-4, higher serum calcification propensity is significantly associated with atherosclerotic CVD events, but not with CHF events. Future studies should evaluate whether T 50 and its determinants represent novel therapeutic targets.

Introduction: Current prognostic models for chronic kidney disease (CKD) are complex and were designed to predict a single outcome. We aimed to develop and validate a simple and parsimonious prognostic model to predict cardio-kidney events and mortality. Methods: Patients from the CRIC Study (n = 3,718) were randomly divided into derivation (n = 2,478) and validation (n = 1,240) cohorts. Twenty-nine candidate variables were preselected. Multivariable Cox regression models were developed using stepwise selection for various cardio-kidney endpoints, namely, (i) the primary composite outcome of 50% decline in estimated glomerular filtration rate (eGFR) from baseline, end-stage renal disease, or cardiovascular (CV) mortality; (ii) hospitalization for heart failure (HHF) or CV mortality; (iii) 3-point major CV endpoints (3P-MACE); (iv) all-cause death. Results: During a median follow-up of 9 years, the primary outcome occurred in 977 patients of the derivation cohort and 501 patients of the validation cohort. Log-transformed N-terminal pro-B-type natriuretic peptide (NT-proBNP), log-transformed high-sensitive cardiac troponin T (hs-cTnT), log-transformed albuminuria, and eGFR were the dominant predictors. The primary outcome risk score discriminated well (c-statistic = 0.83) with a proportion of events of 11.4% in the lowest tertile of risk and 91.5% in the highest tertile at 10 years. The risk model presented good discrimination for HHF or CV mortality, 3P-MACE, and all-cause death (c-statistics = 0.80, 0.75, and 0.75, respectively). The 4-variable risk model achieved similar c-statistics for all tested outcomes in the validation cohort. The discrimination of the 4-variable risk model was mostly superior to that of published models. Conclusion: The combination of NT-proBNP, hs-cTnT, albuminuria, and eGFR in a single 4-variable model provides a unique individual prognostic assessment of multiple cardio-kidney outcomes in CKD.

Dietary Fiber Intake and Clinical Outcomes in Chronic Kidney Disease: A Report From the Chronic Renal Insufficiency Cohort Study

Klotho and Clinical Outcomes in CKD: Findings From the Chronic Renal Insufficiency Cohort (CRIC) Study