Circulating Free Fatty Acid and Phospholipid Signature Predicts Early Rapid Kidney Function Decline in Patients With Type 1 Diabetes

Objectives: Patients with type 1 diabetes (T1D) exhibit modest lipid abnormalities as measured by traditional metrics. This study aimed to identify lipidomic predictors of rapid decline of kidney function in T1D.

Research Design and Methods: In a Case-Control study, 817 T1D patients from 3 large cohorts were randomly split into training and validation subsets. Case was defined as >3 mL/min/1.73 m²/year decline in estimated glomerular filtration rate (eGFR) while Control was defined as <1 mL/min/1.73 m²/year decline over a minimum 4-year follow up. Lipids were quantified in baseline serum samples using a targeted mass spectrometry lipidomic platform.

Results: At individual lipids, free fatty-acid (FFA)20:2 was directly, and phosphatidylcholine (PC)16:0/22:6 was inversely and independently associated with rapid eGFR decline. When examined by lipid class, rapid eGFR decline was characterized by higher abundance of unsaturated FFAs, phosphatidylethanolamine (PE)-Ps and PCs with an unsaturated acyl chain at the sn1 carbon, and by lower abundance of saturated FFAs, longer triacylglycerols, and PCs, PEs, PE-Ps, and PE-Os with an unsaturated acyl chain at the sn1 carbon at eGFR ≥90 mL/min. A multi-lipid panel consisting of unsaturated FFAs and saturated PE-Ps predicted rapid eGFR decline better than individual lipids (C-statistic, 0.71) and improved C-statistic of clinical model from 0.816 to 0.841 (p=0.039). Observations were confirmed in the validation subset.

Conclusion: Distinct from previously reported predictors of GFR decline in type 2 diabetes, these findings suggest differential incorporation of FFAs at sn1 carbon of the phospholipids’ glycerol backbone as independent predictor of rapid GFR decline in T1D.