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

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posted on 08.07.2021, 13:35 by Farsad Afshinnia, Thekkelnaycke M. Rajendiran, Chenchen He, Jaeman Byun, Daniel Montemayor, Manjula Darshi, Jana Tumova, Jiwan Kim, Christine P Limonte, Rachel G. Miller, Tina Costacou, Trevor J. Orchard, Tarunveer S. Ahluwalia, Peter Rossing, Janet K Snell-Bergeon, Ian H. de Boer, Loki Natarajan, George Michailidis, Kumar Sharma, Subramaniam Pennathur
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.

Funding

Supported by the JDRF Network Grant (KS), NIH grants K08DK106523, R03DK121941, R01DK034818, P30DK089503, P30DK081943, P30DK020572 and 1R01DK110541-01A1 and JDRF Center for Excellence (5-COE-2019-861-S-B).

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