Epithelial cell states associated with kidney and allograft injury

The kidney epithelium, with its intricate arrangement of highly specialized cell types, constitutes the functional core of the organ. Loss of kidney epithelium is linked to the loss of functional nephrons and a subsequent decline in kidney function. In kidney transplantation, epithelial injury signatures observed during post-transplantation surveillance are strong predictors of adverse kidney allograft outcomes. However, epithelial injury is currently neither monitored clinically nor addressed therapeutically after kidney transplantation. Several factors can contribute to allograft epithelial injury, including allograft rejection, drug toxicity, recurrent infections and postrenal obstruction. The injury mechanisms that underlie allograft injury overlap partially with those associated with acute kidney injury (AKI) and chronic kidney disease (CKD) in the native kidney. Studies using advanced transcriptomic analyses of single cells from kidney or urine have identified a role for kidney injury-induced epithelial cell states in exacerbating and sustaining damage in AKI and CKD. These epithelial cell states and their associated expression signatures are also observed in transplanted kidney allografts, suggesting that the identification and characterization of transcriptomic epithelial cell states in kidney allografts may have potential clinical implications for diagnosis and therapy. This Review describes parallels in the injury mechanisms that underlie acute kidney injury, chronic kidney disease and allograft injury, and explains how our understanding of the molecular changes that occur in epithelia in the context of kidney disease may contribute to the therapeutic targeting of specific epithelial cell phenotypes for the treatment of transplantation complications. Transcriptomic studies using single-cell sequencing and spatial transcriptomics have identified epithelial cell populations associated with acute kidney injury (AKI) and chronic kidney disease (CKD) in mouse and human kidneys.These injured epithelial cell populations are especially predominant in the proximal tubules but extend to other cell types, particularly in human AKI and CKD.AKI- and CKD-associated epithelial cell populations show a marked downregulation of marker genes associated with the healthy kidney epithelium and can show a pro-inflammatory and pro-fibrotic gene expression profile.Some injured epithelial cell populations can persist for a period of time after AKI and in CKD, attracting and activating fibroblasts and leukocytes, and thereby potentially promoting further kidney damage.Epithelial injury is an under-appreciated major risk factor of allograft survival after episodes of rejection in kidney transplants.Molecular signatures of injured epithelial cell populations in kidney transplants after post-transplantation complications are highly reminiscent of those seen in AKI and CKD, and offer potential new avenues for monitoring and therapy.