FIGURE 17.

Schematic diagram representing the relationships between sources of injury and response to injury in kidney transplant biopsies based on injury analyses in MMDx.¹⁴³ Interplay between sources of injury, pre-existing limitations such as aging, and response to injury by the nephron. There are 2 routes to irreversible nephron shutdown, namely, direct epithelial injury and glomerulus injury with secondary nephron failure. Epithelial injury should trigger the response-to-wounding, which involves epithelium, matrix, and microcirculation, and evokes innate immunity. Failure to mount a response to wounding and adopting a “PC3”-related response (eg, PARD3) with minimal inflammation leads to failure to recover. Many sources of injury (separate from and including rejection) interact with the nephron epithelium, producing AKI. In this instance, the epithelium can be repaired and the organ can recover, or progress to nephron failure. Alternatively, aging and/or AMR can contribute to glomerular disease and AMR can additionally affect the microcirculation, affecting the glomerulus and again causing nephron shutdown, which eventually leads to CKD. If this occurs, a loss of nephrons and end-stage renal disease may occur. Different sources of injury may interact to cause many forms of injury, and injury itself predicts the graft survival while the rejection status does not. Thus, defining the heterogeneity within biopsy injury is an important part of clinical management. AKI, acute kidney injury; AMR, antibody-mediated rejection; CKD, chronic kidney disease; MMDx, Molecular Microscope Diagnostics System; TCMR, T cell–mediated rejection.