Effects of single and dual RAAS blockade therapy on progressive kidney disease transition to CKD in rats

Ischemic reperfusion (I/R) is the primary cause of acute kidney injury (AKI) in hospitalized patients. Although AKI resolution occurs in few days, it predisposes kidneys to progressive renal injury. Previously, administration of rennin-angiotensin-aldosterone system (RAAS) blocker spironolactone in acute phase was reported to attenuate various manifestations of chronic kidney disease (CKD) in rats. The present study investigates the effects of RAAS blockade during progressive kidney disease (30 days onwards) on CKD outcomes in rodent model of I/R injury. CKD was induced by clamping both renal pedicles for 45 min followed by 90 days of reperfusion in rats. Single and dual RAAS blocker therapy was initiated at 30 days post-I/R injury and continued until the end of the study period. Evaluation of proteinuria and creatinine levels was done every 30 days in various study groups. Assessment of CKD was done by analyzing renal tissue oxidative stress, inflammatory biomarker levels, and histological changes after 90 days of I/R injury. After 90 days, I/R rat kidneys displayed hypertrophy, reduced body weight, increased oxidative stress, elevated inflammatory biomarker levels, and histological abnormalities such as glomerulosclerosis, mesangial expansion, and tubulointerstitial fibrosis. Treatment with losartan or spironolactone alone significantly reduced various CKD-associated features. Remarkably, combined treatment with dual RAAS blocker in low dose or high dose exhibited highest beneficial effects on various parameters in CKD model, with low-dose combination showing fewer side effects. Therefore, we propose that combined low-dose RAAS blockade therapy might serve as a better therapeutic approach for retarding progressive kidney disease transition to CKD.