Immune-mediated Tubule Atrophy Promotes Acute Kidney Injury to Chronic Kidney Disease Transition

Abstract

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.