Increased tumor necrosis factor-receptor superfamily plasma levels are associated with early renal or retinal involvement in intermediate hyperglycemia.

Background: Diabetes and its associated microvascular complications, such as nephropathy and retinopathy, significantly impact global health. These complications often begin in the prediabetic stage, emphasizing the importance of early detection and intervention. Inflammatory pathways are key contributors to these conditions, and recent research has identified members of the tumor necrosis factor (TNF) receptor superfamily as potential biomarkers. However, their association with renal and retinal dysfunction in individuals with intermediate hyperglycemia (IH) remains underexplored. The Early Prevention of Diabetes Complications (ePREDICE) trial provides a valuable cohort to investigate these associations and improve risk assessment strategies.

Aim: To identify inflammatory biomarkers associated with early renal and retinal dysfunction in individuals with IH. Specifically, we evaluate the diagnostic and prognostic potential of TNF receptor superfamily members [TNF receptor 1 (TNF-R1), TNF receptor 2 (TNF-R2)], T-cell immunoglobulin and mucin domain 3 (TIM-3)/HAVCR2, galectin-3, and interleukin-6 (IL-6) in detecting kidney dysfunction and retinopathy in this high-risk population. By understanding their roles, we seek to enhance early screening methods and inform personalized intervention strategies.

Methods: A cross-sectional analysis of 967 individuals with IH from the ePREDICE trial was conducted. Participants underwent comprehensive anthropometric and biochemical assessments. Key inflammatory biomarkers, including TNF-R1, TNF-R2, TIM-3/HAVCR2, galectin-3, and IL-6, were quantified using immunoassays. Renal function was assessed using estimated glomerular filtration rate (eGFR) and albuminuria, while retinopathy was evaluated through fundoscopic examination. Statistical analyses included adjusted mean comparisons, correlation studies, and receiver operating characteristic curve analysis to assess biomarker diagnostic accuracy.

Results: TNF-R1, TNF-R2, and TIM-3/HAVCR2 were significantly associated with reduced filtration function (eGFR < 60 mL/minute/1.73 m²) and albuminuria, with area under the curve (AUC) values between 0.815 and 0.845. TIM-3/HAVCR2 emerged as the strongest predictor of retinopathy (AUC = 0.737). Strong correlations (r > 0.75) were observed among TNF-R1, TNF-R2, and TIM-3/HAVCR2, suggesting a coordinated role in inflammatory pathways.

Conclusion: Our findings highlight the potential of TNF receptor superfamily members as biomarkers for early-stage renal and retinal complications in individuals with IH. Their integration into clinical screening protocols could facilitate earlier detection, improving patient stratification and personalized management strategies. Further longitudinal studies are necessary to validate their predictive value and potential for guiding therapeutic interventions in IH and early diabetes management.