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BackgroundPatients with acute kidney injury (AKI) have higher risks of developing chronic kidney disease (CKD). The basis for the AKI-to-CKD transition remains poorly understood, but studies in animal models suggest a linkage between the inflammatory response to injury and subsequent nephron loss and interstitial fibrosis. The proximal tubule is the primary venue of injury and progression of disease during this process.MethodsMouse unilateral ischemia/reperfusion injury (U-IRI) model was used to study the kinetics of proximal injury marker expression during AKI-to-CKD transition. Immortalized MPT cells and primary cultured renal cells were used to study factor(s) that induce vascular cell adhesion protein-1 (VCAM-1) expression in proximal tubule cells.ResultsKidney injury molecule-1 (KIM-1) was rapidly upregulated on day 1 after injury and gradually reduced close to the baseline; whereas VCAM-1 was not upregulated on day 1 but markedly increased afterwards during AKI-to-CKD transition. The proximal tubular VCAM-1 expression is induced by proinflammatory cytokines including TNFα and IL-1β. Blockade of these signaling pathways by using NF-κB inhibitor or by using double null mutant Myd88 and Trif derived PCRC in vitro or decrease of immune cell recruitment using Ccr2 null mouse in vivo significantly suppressed VCAM-1 expression. Human single cell transcriptome analysis identified a distinct cluster of injured proximal tubules that highly expressed VCAM1 but not HAVCR1 (KIM1), and the population of these VCAM1-positive proximal tubule cells was associated with CKD progression and VCAM-1 levels were significantly higher in the patients with Stage 3 CKD as compared to the healthy references.ConclusionsProximal tubule cells upregulated KIM-1 and VCAM-1 in an orchestrated fashion after injury. Upregulation of VCAM-1 associated with chronic tubular injury and interstitial fibrosis and may mark the earliest molecular event during AKI-to-CKD transition.

Incomplete repair after acute kidney injury (AKI) is associated with progressive loss of tubular cell function and development of chronic kidney disease (CKD). Here, we compared mice subjected to either unilateral ischemia-reperfusion kidney injury with contralateral nephrectomy (IRI/CL-NX, in which tubule repair predominates) or unilateral IRI with contralateral kidney intact (U-IRI, in which fibrosis and atrophy predominates) to investigate the mechanism(s) underlying transition to CKD following AKI. The initial injury and early recruitment and activation of macrophages, dendritic cells (DCs), neutrophils, and T cells were similar through day 7 but markedly diverged afterwards between the two models. By day 14, kidneys subjected to U-IRI had greater numbers of macrophages with higher expression of Ccl2, Ccl7, Ccl8, Ccl12, and Cxcl16. These chemokines correlated with a second wave of Ccr1-positive neutrophils and Cxcr6-positive T cells, resulting in a proinflammatory milieu, accompanied by increased expression of tubular cell injury, oxidative stress and major histocompatibility complex genes. This second wave of immune dysfunction led to a distinct profile of tubule injury with morphologic kidney atrophy and a decreased proportion of differentiated tubule cells. Combined depletion of neutrophils and T cells beginning on day 5 after U-IRI was found to reduce tubular cell loss and the associated kidney atrophy. In kidney biopsy samples from patients with AKI, the number of interstitial T cells and neutrophils negatively correlated with 6-month recovery of GFR. Together, our findings demonstrate that macrophage persistence after AKI promotes a T cell- and neutrophil-mediated proinflammatory milieu that leads to progressive tubule damage.