Urinary Active IL-18 in Type 2 Diabetes: Association with Kidney Risk Factors but Not Predictive of Future eGFR Decline

Background: IL-18 is a potent proinflammatory cytokine implicated in kidney disease, including diabetic kidney disease (DKD). Synthesized as an inactive precursor, IL-18 is cleaved by caspase-1 within the inflammasome to become biologically active. We have established a system to specifically detect the biologically active form of IL-18 (aIL-18). Methods: We analyzed patients with type 2 diabetes mellitus enrolled in our biobank cohort (protocol ID: 20241023-2). Urinary aIL-18 concentrations were measured using a specific ELISA employing monoclonal antibody 9-10.2, which recognizes the neoepitope of aIL-18. Kidney-related risk factors and changes in estimated glomerular filtration rate (eGFR) were assessed over a 3-year period. Results: A total of 81 patients (mean age 66.4 years, 58% male, mean HbA1c 9.0%) were included. The mean urinary aIL-18 concentration was 40.6 pg/mL. The average annual eGFR decline was −5.4 mL/min/1.73 m2/year. Annual eGFR decline correlated significantly with HbA1c, urinary albumin-to-creatinine ratio (ACR), and protein/creatinine ratio, but not with urinary aIL-18 levels. Among 51 patients with rapid eGFR decline (≤−3.0 mL/min/1.73 m2/year), 28 exhibited normoalbuminuria. Nine of the 28 normoalbuminuric patients had urinary aIL-18 concentrations ≥20 pg/mL, and one had ≥60 pg/mL. Among 30 patients with slower eGFR decline (>−3.0 mL/min/1.73 m2/year), 17 had normoalbuminuria; of these, 4 had urinary aIL-18 ≥20 pg/mL. Urinary aIL-18 levels were significantly associated with ACR and the C-peptide index. Conclusion: Although urinary aIL-18 levels were associated with established kidney risk factors, they did not predict future eGFR decline over a 3-year follow-up period.