Tubule-derived growth differentiation factor 15 limits renal transplant injury by reprogramming macrophage responses

Kidney transplantation remains the gold standard for end-stage renal disease, but ischemia-reperfusion injury and delayed graft function continue to hinder outcomes. Growth differentiation factor 15 (GDF15), a stress-responsive cytokine from the transforming growth factor-β superfamily, is upregulated in response to cellular injury and hypoxia. Although GDF15 has been studied in acute kidney injury and sepsis, its role in kidney transplantation remains unclear. In this study, we combined transcriptomic analysis of human kidney allografts with murine models to investigate GDF15's role in transplant injury. GDF15 was upregulated in renal tubular epithelial cells, particularly in delayed graft function, and its levels in urine correlated with serum creatinine levels, indicating a link to graft dysfunction. In syngeneic and allogeneic murine transplant models, GDF15 deficiency worsened tubular injury and inflammation, while recombinant GDF15 protected against injury and promoted an anti-inflammatory M2 macrophage phenotype. We also identified activating transcription factor 4 as a key regulator of GDF15 in renal stress, with its knockout reducing GDF15 expression and worsening transplant injury. Macrophage depletion confirmed that macrophage-mediated inflammation was a major factor in GDF15-deficient graft injury. In conclusion, GDF15 regulates kidney transplant injury by modulating macrophage polarization, making it a potential therapeutic target for improving transplant outcomes.