Capillary rarefaction is more closely associated with CKD progression after cisplatin, rhabdomyolysis, and ischemia-reperfusion-induced AKI than renal fibrosis

Abstract

Acute kidney injury (AKI) is a strong independent predictor of mortality and often results in incomplete recovery of renal function, leading to progressive chronic kidney disease (CKD). Many clinical trials have been conducted on the basis of promising preclinical data, but no therapeutic interventions have been shown to improve long-term outcomes after AKI. This is partly due to the failure of preclinical studies to accurately model clinically relevant injury and long-term outcomes on CKD progression. Here, we evaluated the long-term effects of AKI on CKD progression in three animal models reflecting diverse etiologies of AKI: repeat-dose cisplatin, rhabdomyolysis, and ischemia-reperfusion injury. Using transdermal measurement of glomerular filtration rate as a clinically relevant measure of kidney function and quantification of peritubular capillary density to measure capillary rarefaction, we showed that repeat-dose cisplatin caused capillary rarefaction and decreased renal function in mice without a significant increase in interstitial fibrosis, whereas rhabdomyolysis-induced AKI led to severe interstitial fibrosis, but renal function and peritubular capillary density were preserved. Furthermore, long-term experiments in mice with unilateral ischemia-reperfusion injury showed that restoration of renal function 12 wk after a contralateral nephrectomy was associated with increasing fibrosis, but a reversal of capillary rarefaction was seen at 4 wk. These data demonstrate that clear dissociation between kidney function and fibrosis in these models of AKI to CKD progression and suggest that peritubular capillary rarefaction is more strongly associated with CKD progression than renal fibrosis.

HIF in Nephrotoxicity during Cisplatin Chemotherapy: Regulation, Function and Therapeutic Potential

“…Under this circumstance, CKD progression is associated with impaired tubular regeneration, endothelial dysfunction and prolonged hypoxia, persistent inflammation, interstitial fibrosis, epigenetic alteration, activated renin-angiotensin-aldosterone-system (RAAS), mitochondrial dysfunction, and cellular senescence [ 141 , 142 , 143 , 144 ]. Some of these changes have been reported in cisplatin-induced CKD [ 9 , 135 , 145 , 146 , 147 , 148 ].…”

“…Chronic hypoxia is considered as a common pathological condition in CKD [ 10 , 163 ]. Though studies have revealed that multiple pathophysiological mechanisms are related to cisplatin-induced AKI to CKD progression [ 9 , 135 , 145 , 146 , 147 , 148 ], the investigation focusing on the role of HIF in this field is lacking. Nevertheless, HIF is a potential player in this process because of its essential role in hypoxia and its interactions with multiple pathophysiological procedures involved in the progression of CKD ( Figure 2 ).…”

Clinical and experimental approaches for imaging of acute kidney injury

“…Previous studies reported the use of these nanoparticles for BV assessment in both rat and mouse models, as well as their application to patients with CKD [64][65][66]. In this context, a recent experimental study has shown that capillary rarefaction is more closely associated with AKI-to-CKD progression than renal fibrosis [67]. This imaging technique may be effectively used for assessing AKI-to-CKD progression and for tracking and monitoring the distribution of specific cells (e.g., mesenchymal stem cells) in the AKI setting [68].…”

Septic acute kidney injury: a review of basic research

“…The renal capillary network was often destroyed during non-septic AKI [33], and angiogenesis was indispensable for efficient tubular recovery [34,35]. In septic AKI, microcirculation failure, rather than histological capillary destruction, caused changes in the oxygen supply to the tubules.…”