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Review
. 2024 Jul;20(7):447-459.
doi: 10.1038/s41581-024-00834-0. Epub 2024 Apr 17.

Epithelial cell states associated with kidney and allograft injury

Christian Hinze  1 , Svjetlana Lovric  1 , Philip F Halloran  2   3 , Jonathan Barasch  4 , Kai M Schmidt-Ott  5
Affiliations
Review

Epithelial cell states associated with kidney and allograft injury

Christian Hinze et al. Nat Rev Nephrol. 2024 Jul.

Abstract

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.

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Figures

Fig. 1
Fig. 1. Induction of cell states in the kidney tubule following AKI.
The schematic illustrates a general model of the involvement of tubular epithelial cell states in AKI. This includes the emergence of distinct AKI-induced epithelial cell states, labeled by different colors. An unknown population of injured dedifferentiated epithelial cells undergoes cell cycling and replaces neighboring cells that have been lost. While some injured epithelial cells are able to regenerate and restore normal kidney epithelium through adaptive repair, a subset of dedifferentiated epithelial cells may persist in an aberrant cell state, contributing to chronic injury through a pro-inflammatory secretory phenotype. This further attracts immune cells and potentially causes harm to adjacent healthy kidney epithelium. It is important to note that this figure represents a single time point after AKI, where multiple AKI-induced cell states coexist. It should be noted that the presence and abundance of these cell states may vary between individuals and within any individual depending on the time point after AKI. It is of note that these mechanisms not restricted to the PT.
Fig. 2
Fig. 2. Conserved epithelial injury responses in PT, TAL and DCT cells in human AKI.
We observed that AKI in the context of severe systemic inflammation induces the emergence of four distinct injured cell states in PT, TAL and DCT associated with oxidative stress, hypoxia, inflammation/translation and EMT. AKI patient heterogeneity can be partly explained by an individual composition of these injured epithelial cell states.
Fig. 3.
Fig. 3.. Signaling pathways between injured and healthy epithelial cells, immune cells and stromal cells potentially propagating fibrosis.
Recent single cell studies have highlighted the spatial proximity of injured epithelial cells, leukocytes, and stromal cells within fibrotic microenvironments. The signaling interactions between these cell types are believed to contribute to persistent inflammation. The pathways, depicted in the figure, are a selection of potential interactions reported in recent human single cell sequencing studies.
Fig. 4.
Fig. 4.
Potential mechanisms of epithelial injury after kidney transplantation
Fig. 5
Fig. 5. Potential models for epithelial injury after TCMR or ABMR.
Epithelial injury occurs in, both, TCMR and ABMR. As epithelial injury is the most important predictor of allograft survival after ABMR or TCMR, this might suggest a model of persistence of maladaptive injured epithelial cells propagating further kidney allograft damage. Importantly, whether maladaptive or injured epithelial cell states persisting after ABMR or TCMR are identical or distinct remains unknown.
Fig. 6
Fig. 6. Potential applications using injured epithelial cells and epithelial cell signaling after kidney transplantation.
A. Epithelial cell information can be obtained from kidney tissue from biopsies or kidney cells shed into the urine. Having, both, tissue and urine single cell data can help in associating kidney tissue injury signatures with the corresponding cell population in the urine. The so-identified injured cell populations in patient urine can be non-invasively measured over time using either single cell sequencing or other faster and more cost-effective techniques such as FACS or measuring RNA or protein levels of specific targets derived from single cell sequencing data. B. Applications of data from injured epithelial cell states as mentioned in the text including allograft monitoring (decaying/delayed graft function), unbiased disease classification and novel therapies.
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