Chronic Allograft Injury

Abstract

With the incremental improvements in long-term kidney transplant survival, there is renewed focus on what causes failure of the transplanted allograft. Over the past decade, our understanding of the injuries that lead to loss of graft function over time has evolved. Chronic allograft injury includes both immune-mediated and nonimmune-mediated injuries, which may involve the organ donor, the recipient, or both. The targets of injury include the kidney tubular epithelium, the endothelium, and the glomerulus. As a response to injury, there are the expected tissue remodeling and repair processes. However, if inflammation persists, which is not uncommon in the transplant setting, the resulting maladaptive response is matrix deposition and/or fibrosis. This ultimately leads to declining graft function and, finally, failure. With our advancing knowledge of the multiple etiologies and mechanisms, enhanced by more recent cohort studies in humans, there is an opportunity to identify those at greater risk to initiate new strategies to ameliorate the process. Although the most recent studies focus on immune-mediated injuries, there is a critical need to identify both markers of injury and mechanisms of injury. In this review, we highlight the findings of recent studies, highlight the potential therapeutic targets, and identify the continued unmet need for understanding the mechanisms of late graft failure.

Keywords: allografts; chronic allograft failure; kidney transplantation series; renal fibrosis; renal injury; transplantation.

Figure 1.

Schema of the potential sites of injury associated with late allograft failure. There may be “fixed” injury as a consequence of the donation and transplant process (“pretransplant injury”). Three target sites of injury within the kidney are shown, with defined histologic characteristics. The entities that contribute to these sites directly (solid arrows) are shown aligned to their injury at that site. There may also be “crosstalk” of disease processes between compartments (hashed arrows) as well as cumulative injury from multiple entities directly (solid arrows) or indirectly (hashed arrows). ATN, acute tubular necrosis; CNI, calcineurin inhibitor; UTI, urinary tract infection.