Human Data First: New Biological Premises for Arteriovenous Fistula Research.

Achieving a mature arteriovenous fistula (AVF) for hemodialysis remains a significant challenge, even for the most experienced vascular surgeons. Despite decades of research, ≈40% of new AVFs require salvage interventions or can never be used for dialysis. All clinical trials aimed at improving early AVF maturation have failed. This underscores the limitations of the existing biological model, which continues to frame stenosis through a reductionist lens centered on intimal hyperplasia, despite emerging evidence that this explanation is insufficient. This review seeks to redefine the biological framework of early AVF failure by adopting a human-centered perspective. In contrast to the prevailing paradigm, primarily built upon experimental data, our model is centered on human observational research and clinical trials. We then incorporate experimental data to provide mechanistic insights and contextualize or contrast the differences between human and animal biology. We unravel the biology of AVF maturation through 2 tightly connected phases: the acute biomechanical response, encompassing immediate structural and hemodynamic changes after AVF creation, and the subsequent vascular healing and remodeling processes that determine the long-term adaptation of the vein to supraphysiological circulation. By integrating these phases into a cohesive framework, this review advances a more comprehensive model of early AVF maturation failure, highlights therapeutic opportunities, and underscores that meaningful innovation in AVF biology remains both necessary and achievable.