Serum metabolomic alterations associated with proteinuria in CKD

Background and objectives Data are scarce on blood metabolite associations with proteinuria, a strong risk factor for adverse kidney outcomes. We sought to investigate associations of proteinuria with serum metabolites identified using untargeted profiling in populations with CKD. Design, setting, participants, & measurements Using stored serum samples from the African American Study of Kidney Disease and Hypertension (AASK; n=962) and the Modification of Diet in Renal Disease (MDRD) study (n=620), two rigorously conducted clinical trialswith per-protocol measures of 24-hour proteinuria and GFR, we evaluated cross-sectional associations between urine protein-to-creatinine ratio and 637 known, nondrug metabolites, adjusting for key clinical covariables. Metabolites significantly associated with proteinuria were tested for associations with CKD progression. Results In the AASK and the MDRD study, respectively, the median urine protein-to-creatinine ratio was 80 (interquartile range [IQR], 28-359) and 188 (IQR, 54-894)mg/g,mean agewas 56 and 52 years, 39%and 38%were women, 100%and 7%were black, andmedianmeasuredGFRwas 48 (IQR, 35-57) and 28 (IQR, 18-39)ml/min per 1.73m². Linear regression identified 66 serummetabolites associatedwith proteinuria in one or both studies after Bonferroni correction (P<7.8×10^-5), 58 of which were statistically significant in a meta-analysis (P<7.8×10^-4). Themetaboliteswith the lowest P values (P<10^-27)were 4-hydroxychlorthalonil and 1,5-anhydroglucitol; all six quantified metabolites in the phosphatidylethanolamine pathway were also significant. Of the 58 metabolites associated with proteinuria, four were associated with ESKD in both the AASK and the MDRD study. ConclusionsWeidentified 58 serummetaboliteswith cross-sectional associationswith proteinuria, some ofwhich were also associated with CKD progression.