Supplementary Material for: Metabolomics of Chronic Kidney Disease Progression: A Case-Control Analysis in the Chronic Renal Insufficiency Cohort Study

<b><i>Background:</i></b> Whereas several longitudinal metabolomics studies have been conducted in individuals with normal estimated glomerular filtration rate (eGFR) at baseline, disease progression among individuals with established chronic kidney disease (CKD) has not been rigorously examined. <b><i>Methods:</i></b> We performed a nested case-control study of rapid CKD progression in the Chronic Renal Insufficiency Cohort Study, profiling baseline plasma from 200 individuals each with eGFR slope <-3 ml/min/1.73 m²/year (cases) or between -1 and +1 ml/min/1.73 m²/year (controls), matched on baseline eGFR and proteinuria. To directly assess how the kidney modulates circulating metabolites, we profiled plasma from the aorta and renal vein of 25 hospital-based individuals. <b><i>Results:</i></b> At baseline, cases and controls had a mean eGFR of 41.7 ± 13.3 and 45.0 ± 14.5 ml/min/1.73 m², respectively. Ten plasma metabolites were nominally associated with CKD progression in logistic regression models adjusted for age, sex, race/ethnicity, hypertension, systolic and diastolic blood pressure, diabetes, eGFR and proteinuria; no metabolite achieved the Bonferroni-adjusted significance threshold (p < 0.0003). In a cross-sectional analysis, all 6 of the metabolites that were higher in cases than controls were significantly associated with eGFR at baseline. By contrast, threonine, methionine and arginine were lower in cases than in controls and had no association with baseline eGFR. Furthermore, in the hospital-based cohort that underwent renal arteriovenous sampling, these 3 metabolites were net released from the kidney. Combining these metabolites into a panel of markers further strengthened their association with CKD progression. <b><i>Conclusion:</i></b> Our results motivate interest in arginine, methionine and threonine as potential indicators of renal metabolic function and markers of renal prognosis

Supplementary Material for: Serum Bicarbonate and Structural and Functional Cardiac Abnormalities in Chronic Kidney Disease - A Report from the Chronic Renal Insufficiency Cohort Study

<b><i>Background:</i></b> Heart failure (HF) is a frequent occurrence in chronic kidney disease (CKD) patients and predicts poor survival. Serum bicarbonate is associated with increased rates of HF in CKD; however, the mechanisms leading to this association are incompletely understood. This study aims to assess whether serum bicarbonate is independently associated with structural and functional cardiac abnormalities in CKD. <b><i>Methods:</i></b> The association between serum bicarbonate and left ventricular (LV) hypertrophy (LVH), LV mass indexed to height^2.7, LV geometry, ejection fraction (EF) and diastolic dysfunction was assessed in 3,483 participants without NYHA class III/IV HF, enrolled in the Chronic Renal Insufficiency Cohort study. <b><i>Results:</i></b> The mean estimated glomerular filtration rate was 42.5 ± 17 ml/min/1.73 m². The overall prevalence of LVH was 51.2%, with 57.8, 50.9 and 47.7% for bicarbonate categories <22, 22-26 and >26 mmol/l, respectively. Participants with low bicarbonate were more likely to have LVH and abnormal LV geometry (OR 1.32; 95% CI 1.07-1.64, and OR 1.57; 95% CI 1.14-2.16, respectively). However, the association was not statistically significant after adjustment for demographics, traditional cardiovascular risk factors, medications and kidney function (OR 1.07; 95% CI 0.66-1.72, and OR 1.27; 95% CI 0.64-2.51, respectively). No association was found between bicarbonate and systolic or diastolic dysfunction. During follow-up, no significant changes in LV mass or EF were observed in any bicarbonate strata. <b><i>Conclusions:</i></b> In a large CKD study, serum bicarbonate was associated with LV mass and concentric LVH; however, this association was attenuated after adjustment for clinical factors suggesting that the observed cardiac effects are mediated through yet unknown mechanisms