Delayed spironolactone administration prevents the transition from acute kidney injury to chronic kidney disease through improving renal inflammation

Abstract

Background: Acute kidney injury (AKI) is not as harmless as previously thought since it may lead to chronic kidney disease (CKD). Because most of the time ischemic AKI occurs unexpectedly, it is difficult to prevent its occurrence and there are no specific therapeutic approaches to prevent the AKI to CKD transition. We aimed to determine whether mineralocorticoid receptor blockade (MRB) in the first days after ischemia/reperfusion (IR) can prevent progression to CKD.

Methods: Four groups of male Wistar rats were included: sham and three groups of bilateral renal ischemia for 45 min, one without treatment and the other two receiving spironolactone for 5 or 10 days, starting 24 h after IR. The rats were studied at 10 days or 5 months after ischemia induction.

Results: After 5 months of follow-up, the untreated group exhibited clear evidence of AKI to CKD progression, such as proteinuria, reduced renal blood flow, tubulointerstitial fibrosis, glomerulosclerosis and glomerular hypertrophy. All these alterations were prevented by both spironolactone treatments initiated 24 h after IR, the 10-day treatment being more effective. Within the early mechanisms of the MRB protective effect are the reduction of inflammation and increased endothelin-B-receptor expression and endothelial nitric oxide synthase activation in the first 10 days after IR.

Conclusions: We propose that MRB, administered 24 h after the ischemic injury that leads to AKI, reduces inflammation and promotes efficient tissue repair that avoids the AKI to CKD transition. These data highlight a therapeutic window to preclude CKD development after AKI.

Keywords: mineralocorticoid receptor blockade; postischemic injury; renal fibrosis.