Growth differentiation factor-15 in diabetic kidney disease: From pathophysiological mechanisms to clinical applications
TL;DR
Clinically, circulating and urinary GDF15 levels correlate with disease severity and independently predict renal function decline, suggesting utility in both early diagnosis and prognostic stratification and its potential role as a pharmacodynamic marker responsive to interventions such as metformin and SGLT2 inhibitors is supported.
Abstract
Background: Diabetic kidney disease (DKD) remains a major cause of end-stage renal disease worldwide, yet current clinical biomarkers such as albuminuria and estimated glomerular filtration rate lack sufficient sensitivity to detect early renal injury or predict individual disease trajectories. Growth differentiation factor 15 (GDF15), a stress-inducible cytokine belonging to the transforming growth factor-b superfamily, has emerged as a promising molecular link between metabolic stress, inflammation, mitochondrial dysfunction, and renal injury in diabetes. This review systematically synthesizes current experimental and clinical evidence on the role of GDF15 in DKD, with emphasis on its mechanistic involvement in renal pathophysiology and its translational potential as a biomarker and therapeutic target. Evidence from preclinical models and human studies indicates that GDF15 is upregulated in diabetic kidneys, particularly in tubular epithelial cells, in response to hyperglycemia-induced oxidative stress and mitochondrial dysfunction. Mechanistically, GDF15 modulates key pathogenic pathways in DKD, including NF-kB–mediated inflammation, NLRP3 inflammasome activation, macrophage polarization, TGF-b/Smad-driven fibrogenesis, and autophagy regulation through PI3K/Akt and AMPK signaling. Clinically, circulating and urinary GDF15 levels correlate with disease severity and independently predict renal function decline, suggesting utility in both early diagnosis and prognostic stratification. In addition, emerging evidence supports its potential role as a pharmacodynamic marker responsive to interventions such as metformin and SGLT2 inhibitors. However, its context-dependent biological effects, lack of assay standardization, and confounding elevation in systemic diseases remain key challenges. Overall, GDF15 represents a central stress-integrating mediator in DKD pathogenesis and a promising candidate for precision nephrology, warranting further validation in longitudinal multi-omics and interventional studies.