Serum glutathione and 4-hydroxynonenal profiles in relation to diabetic kidney disease severity and progression: a multicenter cross-sectional study and a longitudinal cohort

Background Diabetic kidney disease (DKD) is clinically heterogeneous. We assessed whether circulating glutathione (GSH) and 4-hydroxynonenal (4-HNE) were associated with DKD severity and subsequent progression. Methods We analyzed a multicenter cross-sectional cohort of 377 adults with DKD and a single-center ambidirectional cohort of 156 adults with early-stage DKD. Serum GSH and 4-HNE were measured using commercial assays. Progression was assessed using Kaplan-Meier methods and Cox models adjusted for baseline estimated glomerular filtration rate (eGFR) and urinary albumin-to-creatinine ratio (UACR). Exploratory within-cohort discrimination was evaluated using 24-month time-dependent receiver operating characteristic (ROC) curves and bootstrap assessment of calibration and incremental discrimination. Results GSH was lowest and 4-HNE highest in advanced-stage DKD (both P < 0.001 for association with ordered stage). During a mean time to event or censoring of 25.18 ± 11.43 months, 29 participants (18.6%) progressed. Low GSH (≤10.30 μmol/L; hazard ratio [HR], 3.19; 95% CI, 1.17–8.67) and high 4-HNE (>495.19 pg/mL; HR, 5.01; 95% CI, 2.03–12.35) were associated with progression, with directionally consistent continuous analyses. The combined biomarker score had a 24-month area under the curve (AUC) of 0.820. Adding both biomarkers to eGFR and UACR increased the optimism-corrected Harrell’s concordance index (C-index) from 0.689 to 0.821 (corrected increment, 0.133). Conclusions Lower GSH and higher 4-HNE were associated with progression in early-stage DKD. GSH varied nonmonotonically across severity categories, with the lowest GSH and highest 4-HNE in advanced-stage disease. Joint assessment improved discrimination within this cohort, suggesting that the two biomarkers provide complementary information for assessing progression risk in early-stage DKD.