Immune cell mediated fibrosis after kidney transplantation: mechanisms and emerging immunomodulatory therapies

Renal allograft fibrosis is a common histological endpoint after multiple injuries, rather than an independent disease entity. Despite modern immunosuppression, recurrent alloimmune injury, ischemia reperfusion injury, infection, donor and recipient related factors, and drug toxicity can converge on interstitial fibrosis and tubular atrophy. This review examines how innate and adaptive immune responses contribute to the transition from early graft injury to chronic remodeling, with particular emphasis on cellular plasticity and intercellular communication. Human single cell and spatial studies show that immune, tubular epithelial, endothelial, and stromal cells form heterogeneous, stage dependent networks rather than fixed pathogenic populations. We prioritize evidence from human kidney allografts while clearly identifying mechanisms inferred from experimental models. Established immunosuppression remains essential for preventing immune mediated graft injury, whereas regulatory T cell therapies, macrophage state modulation, cytokine blockade, and CD38 directed therapy remain investigational. None has been proven to reverse established allograft fibrosis. Future diagnosis and treatment should integrate Banff histology, donor specific antibodies, donor derived cell free DNA, urinary chemokines, and biopsy-based transcriptomics. Clinical trials should determine whether targeted immunomodulation can slow the progression of allograft fibrosis and preserve long-term graft function and survival.