Severe Renal Mass Reduction Impairs Recovery and Promotes Fibrosis after AKI

Abstract

Preexisting CKD may affect the severity of and/or recovery from AKI. We assessed the impact of prior graded normotensive renal mass reduction on ischemia-reperfusion-induced AKI. Rats underwent 40 minutes of ischemia 2 weeks after right uninephrectomy and surgical excision of both poles of the left kidney (75% reduction of renal mass), right uninephrectomy (50% reduction of renal mass), or sham reduction of renal mass. The severity of AKI was comparable among groups, which was reflected by similarly increased serum creatinine (S Cr ; approximately 4.5 mg/dl) at 2 days, tubule necrosis at 3 days, and vimentinexpressing regenerating tubules at 7 days postischemia-reperfusion. However, S Cr remained elevated compared with preischemia-reperfusion values, and more tubules failed to differentiate during late recovery 4 weeks after ischemia-reperfusion in rats with 75% renal mass reduction relative to other groups. Tubules that failed to differentiate continued to produce vimentin, exhibited vicarious proliferative signaling, and expressed less vascular endothelial growth factor but more profibrotic peptides. The disproportionate failure of regenerating tubules to redifferentiate in rats with 75% renal mass reduction associated with more severe capillary rarefaction and greater tubulointerstitial fibrosis. Furthermore, initially normotensive rats with 75% renal mass reduction developed hypertension and proteinuria, 2-4 weeks postischemia-reperfusion. In summary, severe (.50%) renal mass reduction disproportionately compromised tubule repair, diminished capillary density, and promoted fibrosis with hypertension after ischemia-reperfusion-induced AKI in rats, suggesting that accelerated declines of renal function may occur after AKI in patients with preexisting CKD. 25: 149625: -150725: , 201425: . doi: 10.1681 Clinical studies suggest that AKI worsens preexisting CKD and accelerates progression to end stage because of residual structural and functional deficits. 1-7 CKD, per se, may increase the risk and severity of AKI and the likelihood of incomplete recovery from AKI. 8 Thus, AKI and CKD reinforce each other to increase nephron loss and tubulointerstitial fibrosis (TIF). 9 Nevertheless, causal relationships for both aspects of the AKI-CKD nexus 10 (AKI resulting in CKD/ESRD and CKD, per se, predisposing to AKI) have been questioned. 11,12 These concerns were recently reviewed. 13 AKI-CKD relationships have also been questioned on the grounds that mechanisms for AKI-CKD interactions are ill-defined and controversial. [14][15][16] We addressed these uncertainties by investigating the impact of normotensive renal mass reduction (RMR; 0%, 50%, and 75%) of 2-weeks duration on AKI induced by ischemia-reperfusion (I/R) in rats. We addressed three questions. (1) Does prior RMR increase AKI severity? (2) Does prior RMR impair recovery from AKI? (3) Does prior RMR predispose to the development of more severe TIF during J Am Soc Nephrol

Elevated BP after AKI

“…The likelihood that our results are caused by residual confounding is reduced by the multiple experimental studies showing plausible pathophysiologic pathways connecting AKI to subsequent parenchymal renal damage and elevated BP. 4,5,8,9,[33][34][35][36] To enhance internal validity, we did implement several design decisions as detailed above, recognizing that they may affect generalizability. We excluded patients who had prevalent hypertension at baseline.…”

αKlotho Mitigates Progression of AKI to CKD through Activation of Autophagy

“…Mice that underwent bilateral ischemia-reperfusion injury (Bi-IRI) or unilateral nephrectomy plus contralateral ischemiareperfusion injury (Npx-IRI) were fed normal rodent chow and followed for 20 weeks after this single episode of AKI. Because more severe AKI is associated with worse long-term outcome, including higher mortality and incidence of CKD, 3,4,45 we used the Bi-IRI model to vary the duration of ischemia to titrate the severity of AKI. Forty minutes of ischemia or longer led to no survival beyond 10 days ( Figure 1A).…”

Hypoxia: The Force that Drives Chronic Kidney Disease

“…This chronic hypoxia then induces a slew of pathological processes in tubular epithelial cells including apoptosis, the prevention of redifferentiation after regeneration and conversion to myofibrolasts. [256][257][258][259][260] Hypoxia also induces monocytes to express the β2 integrin family of adhesion molecules and kidney cells to express vascular cell adhesion molecule 1 and intracellular adhesion molecule 1 as well as the monocyte chemo-attractants C-C motif ligand 2 and C-X3-C motif ligand 1.…”