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An Integrated View of Molecular Changes, Histopathology and Outcomes in Kidney Transplants

Data‐driven approaches to deteriorating kidney transplants, incorporating histologic, molecular and HLA antibody findings, have created a new understanding of transplant pathology and why transplants fail. Transplant dysfunction is best understood in terms of three elements: diseases, the active injury–repair response and the cumulative burden of injury. Progression to failure is mainly attributable to antibody‐mediated rejection, nonadherence and glomerular disease. Antibody‐mediated rejection usually develops late due to de novo HLA antibodies, particularly anti‐class II, and is often C4d negative. Pure treated T cell‐mediated rejection does not predispose to graft loss because it responds well, even with endothelialitis, but it may indicate nonadherence. The cumulative burden of injury results in atrophy‐fibrosis (nephron loss), arterial fibrous intimal thickening and arteriolar hyalinosis, but these are not progressive without ongoing disease/injury, and do not explain progression. Calcineurin inhibitor toxicity has been overestimated because burden‐of‐injury lesions invite this default diagnosis when diseases such as antibody‐mediated rejection are missed. Disease/injury triggers a stereotyped active injury–repair response, including de‐differentiation, cell cycling and apoptosis. The active injury–repair response is the strongest correlate of organ function and future progression to failure, but should always prompt a search for the initiating injury or disease.