Failed Tubule Recovery, AKI-CKD Transition, and Kidney Disease Progression

Abstract

The transition of AKI to CKD has major clinical significance. As reviewed here, recent studies show that a subpopulation of dedifferentiated, proliferating tubules recovering from AKI undergo pathologic growth arrest, fail to redifferentiate, and become atrophic. These abnormal tubules exhibit persistent, unregulated, and progressively increasing profibrotic signaling along multiple pathways. Paracrine products derived therefrom perturb normal interactions between peritubular capillary endothelium and pericyte-like fibroblasts, leading to myofibroblast transformation, proliferation, and fibrosis as well as capillary disintegration and rarefaction. Although signals from injured endothelium and inflammatory/immune cells also contribute, tubule injury alone is sufficient to produce the interstitial pathology required for fibrosis. Localized hypoxia produced by microvascular pathology may also prevent tubule recovery. However, fibrosis is not intrinsically progressive, and microvascular pathology develops strictly around damaged tubules; thus, additional deterioration of kidney structure after the transition of AKI to CKD requires new acute injury or other mechanisms of progression. Indeed, experiments using an acute-on-chronic injury model suggest that additional loss of parenchyma caused by failed repair of AKI in kidneys with prior renal mass reduction triggers hemodynamically mediated processes that damage glomeruli to cause progression. Continued investigation of these pathologic mechanisms should reveal options for preventing renal disease progression after AKI.

Persistent activation of autophagy in kidney tubular cells promotes renal interstitial fibrosis during unilateral ureteral obstruction

“…1 The complex feedback interactions between tubular cells and interstitial cells make the separation of individual sources of cytokine production difficult; however, emerging evidence has suggested that the synthesis and secretion of these cytokines is initiated in persistently injured tubular cells and reinforced by themselves and other interstitial cells including macrophages and fibroblasts or myofibroblasts. 3,4 Regulation of FGF2 production by autophagy in proximal tubules during UUO is a very interesting finding in our study. Four well-documented profibrotic cytokines, including TGFB1, CTGF, PDGFB, and FGF2, were examined.…”

“…1 Among them, the tubular epithelium plays an active role in regulating renal interstitial fibrosis, especially in the context of the transition from acute kidney injury (AKI) to CKD. [2][3][4] Earlier studies show the appearance of focal fibrotic lesions around the atrophic, but not intact, proximal tubules after AKI. 5,6 Further studies indicate that these atrophic proximal tubules are poorly differentiated, with hyperactive, autoregulated TGFB signaling and enhanced production of profibrotic cytokines.…”

“…12 Therefore, diseased proximal tubules may be a driving force for interstitial fibrosis through autocrine signals on themselves and paracrine activities on neighboring cells. 3,4 Autophagy is a cellular process of bulk degradation of cytoplasmic components via the formation of autophagosomes followed by autolysosomes. 13 In addition to its bona fide function of catabolism, autophagy is a cellular response to stress and plays important roles in the pathogenesis of various diseases.…”

Paracrine Wnt1 Drives Interstitial Fibrosis without Inflammation by Tubulointerstitial Cross-Talk

“…49). This central role of tubular epithelial responses to acute injury provides a cellular model for understanding the very strong epidemiologic link between episodes of AKI and increased future risk of CKD and ESRD.…”

Das Leben nach dem akutem Nierenversagen

“…Entgegen früherer Annahmen ist die Niere nicht in jedem Fall in der Lage, nach einem ANV die Organfunktion ad Integrum wiederherzustellen. Die genaue Pathophysiologie des ANV und der nachfolgenden Regeneration ist bis heute nur teilweise bekannt [57]. Die Schädigung des Nierenrindenparenchyms betrifft vor allem die Funktion des Nephrons und führt unter anderem zu einem Verlust der Polarität und des charakteristischen Bürstensaums der proximalen Tubulusepithelien.…”