Recent advances in acute kidney injury and its consequences and impact on chronic kidney disease

Abstract

Purpose of review: Acute kidney injury (AKI) remains a major unmet medical need and associates with high morbidity, mortality, and healthcare costs. Among survivors, long-term outcomes of AKI can include development of chronic kidney disease (CKD) or progression of preexisting CKD. In this review, we focus on ongoing efforts by the AKI community to understand the human AKI to CKD continuum, with an emphasis on the cellular stress responses that underlie AKI and the maladaptive responses that persist in the acute-to-chronic phase. The emphasis is on work that has been published in the past year in this rapidly expanding field.

Recent findings: Recent studies in preclinical models highlight the importance of mitochondrial dysfunction, cell death, and inflammation on the underlying pathogenesis of AKI. These pathogenic mechanisms can resolve with adaptive kidney repair but persist in maladaptive repair that leads to progressive chronic disease. The complexity and interconnections of these pathways involve cross-talk between the tubular epithelium, endothelium, and interstitial compartments.

Summary: Approaches which lessen or counteract these cellular responses represent novel strategies to prevent AKI and stop or slow down the progression to CKD.

Figure 1

Recent advances in the acute kidney injury to chronic kidney disease continuum address the complex interactions among epithelial, interstitial and vascular compartments. In response to renal injury, mitochondrial fragmentation and loss [26] are linked to activation of cell death pathways, including apoptosis and necroptosis. There is endothelial dysfunction and damage to the glycocalyx [68] which can lead to rarefaction, a long-term consequence. Cytokines and chemokines, containing the newly described members of the IL-1 superfamily, IL-33 and IL-36 [–61], exacerbate the pro-inflammatory milieu created by injured and dying cells as well as infiltrating immune cells. Adaptive responses lead to kidney repair. Dedifferentiation and proliferation of injured epithelial cells due to activation of gene programs and intracellular signaling pathways, such as YAP/TAZ signaling [71], promote kidney recovery. Mitochondrial biogenesis mediated by PGC-1alpha restores energy metabolism by driving the biosynthesis of NAD [30**, 32, 34**, 35**]. Restoration of the glycocalyx promotes vascular homeostasis [68]. With severe and repeated insults, the reparative process becomes maladaptive. Wnt9a accelerates senescence of tubular epithelial cells, which release cytokines and chemokines, such as TGF-β1, to promote fibrosis [62*]. Cyclin G1 and TASCC regulate G2-M arrest of kidney epithelial cells and fibrotic maladaptive repair [63**]. Components of the endothelial secretome released from damaged vascular cells also are pro-fibrogenic, activating fibroblasts to form myofibroblasts [66, 67*], as does YAP/TAZ signaling in Gli1+ fibroblasts [72]. Moreover, inflammation drives fibrosis. IL-1β activates kidney stromal cells to proliferate and deposit fibrotic matrix through a mechanism that involves stabilization of the oncoprotein MYC [23**]. The complex cross-talk between cellular compartments requires further study.