Molecular Mechanisms of the Acute Kidney Injury to Chronic Kidney Disease Transition: An Updated View

Abstract

Increasing evidence has demonstrated the bidirectional link between acute kidney injury (AKI) and chronic kidney disease (CKD) such that, in the clinical setting, the new concept of a unified syndrome has been proposed. The pathophysiological reasons, along with the cellular and molecular mechanisms, behind the ability of a single, acute, apparently self-limiting event to drive chronic kidney disease progression are yet to be explained. This acute injury could promote progression to chronic disease through different pathways involving the endothelium, the inflammatory response and the development of fibrosis. The interplay among endothelial cells, macrophages and other immune cells, pericytes and fibroblasts often converge in the tubular epithelial cells that play a central role. Recent evidence has strengthened this concept by demonstrating that injured tubules respond to acute tubular necrosis through two main mechanisms: The polyploidization of tubular cells and the proliferation of a small population of self-renewing renal progenitors. This alternative pathophysiological interpretation could better characterize functional recovery after AKI.

Keywords: acute kidney injury; chronic kidney disease; polyploidization; renal progenitors.

Figure 1

The interplay between endothelial dysfunction, interstitial inflammation, fibrosis and tubular epithelial injury concur to explain the acute kidney injury-to-chronic kidney disease (AKI-to-CKD) transition.

Figure 2

A new pathophysiological interpretation of tubular response to AKI leading towards CKD: The proliferation of renal progenitors and polyploidization of tubular cells. (A) Schematic localization of renal progenitors scattered along the S1–S2 segment, the S3 segment, and thick ascending limb (TAL) in the nephron. (Figure modified from Lazzeri et al., Trends Mol Med, 2019); (B) Top: In the uninjured proximal tubule S1–S2 segment, tubular epithelial cells enhance their working capacity by entering the cell cycle to increase their DNA content without division, resulting in polyploid tubular cells (i.e., polyploidization). Bottom: In the necrotic proximal tubule S3 segment, renal progenitors proliferate and complete cell division to drive regeneration, while the remnant tubular epithelial cells undergo polyploidization rather than mitosis. ATN: Acute tubular necrosis.