VCAM-1 mediates proximal tubule-immune cell crosstalk in failed tubule recovery during AKI-to-CKD transition.

Studies in animal models suggest a linkage between inflammatory response to injury and subsequent nephron loss during acute kidney injury (AKI) to chronic kidney disease (CKD) transition. Failure of normal repair during CKD transition correlates with de novo expression of vascular cell adhesion protein-1 (VCAM-1) by a subset of injured proximal tubule cells. This study identifies the role of VCAM-1 expression in promoting the failed repair state. Single-cell transcriptome analysis of patients with AKI and CKD, and whole kidney RNA and protein analyses of mouse models of CKD, confirmed a marked increase of VCAM-1 expression in the proximal tubules of injured kidneys. In immortalized mouse proximal tubular (MPT) cells and primary cultured renal cells (PCRCs), VCAM-1 expression was induced by proinflammatory cytokines including TNFα and IL-1ß. Analyses of bulk RNA sequencing of TNFα-treated PCRCs or pseudo-bulk RNA sequencing of biopsies from the Kidney Precision Medicine Project (KPMP) datasets indicated activation of NF-κB and an enrichment of inflammatory response and cell adhesion pathways in VCAM-1-positive cells. Pharmacologic inhibition of NF-κB signaling or genetic deletion of myeloid differentiation factor 88 (Myd88) and TIR-domain-containing adapter-inducing interferon-ß (Trif) suppressed TNFα- and IL-1ß-induced VCAM-1 expression in vitro. TNFα stimulation or overexpression of VCAM-1 significantly increased splenocyte adhesion to the MPT monolayer in culture. These results demonstrate that persistence of proinflammatory cytokines after AKI can induce NF-κB-dependent VCAM-1 expression by proximal tubule cells, mediating increased immune cell adhesion to the tubule and thus promoting further tubule injury and greater risk of progression from AKI to CKD.

Longitudinal biomarkers and kidney disease progression after acute kidney injury.

BACKGROUNDLongitudinal investigations of murine acute kidney injury (AKI) suggest that injury and inflammation may persist long after the initial insult. However, the evolution of these processes and their prognostic values are unknown in patients with AKI.METHODSIn a prospective cohort of 656 participants hospitalized with AKI, we measured 7 urine and 2 plasma biomarkers of kidney injury, inflammation, and tubular health at multiple time points from the diagnosis to 12 months after AKI. We used linear mixed-effect models to estimate biomarker changes over time, and we used Cox proportional hazard regressions to determine their associations with a composite outcome of chronic kidney disease (CKD) incidence and progression. We compared the gene expression kinetics of biomarkers in murine models of repair and atrophy after ischemic reperfusion injury (IRI).RESULTSAfter 4.3 years, 106 and 52 participants developed incident CKD and CKD progression, respectively. Each SD increase in the change of urine KIM-1, MCP-1, and plasma TNFR1 from baseline to 12 months was associated with 2- to 3-fold increased risk for CKD, while the increase in urine uromodulin was associated with 40% reduced risk for CKD. The trajectories of these biological processes were associated with progression to kidney atrophy in mice after IRI.CONCLUSIONSustained tissue injury and inflammation, and slower restoration of tubular health, are associated with higher risk of kidney disease progression. Further investigation into these ongoing biological processes may help researchers understand and prevent the AKI-to-CKD transition.FUNDINGNIH and NIDDK (grants U01DK082223, U01DK082185, U01DK082192, U01DK082183, R01DK098233, R01DK101507, R01DK114014, K23DK100468, R03DK111881, K01DK120783, and R01DK093771).