#2247 Trandolapril attenuates renal fibrosis in rats with a dual-injury model of kidney disease progression

Abstract Background and Aims Chronic kidney disease (CKD) is a progressive and currently irreversible disease affecting almost 10% of the global population. Its burden on patients and healthcare systems becomes increasingly significant every year. The lack of preventive and therapeutic strategies is evidenced by the rising mortality and underlying risk to suffer kidney failure and cardiovascular disease. This study aimed to evaluate the renoprotective effects of the angiotensin-converting enzyme (ACE) inhibitor trandolapril in a rat model of CKD progression. Method We developed a transition model from acute kidney injury (AKI) to CKD, where the acute phase of the disease is induced through the administration of a nephrotoxic single dose of cisplatin (5 mg/kg). Following recovery of kidney function, a subsequent kidney injury induced through unilateral renal ischemia-reperfusion surgery initiated the transition to CKD. During this transition, impaired renal repair mechanisms facilitate the development of a pronounced fibrotic and inflammatory response within the kidney. Treatment with 0.7 mg/kg trandolapril in drinking water is administered for 3 months during the aforementioned transition phase to evaluate whether it is effective in preventing the development of interstitial fibrosis and focal inflammation infiltrates. Results We observed a distinct fibrogenic pattern in the kidney, where individual nephron failure and death lead to scarring of isolated regions of tissue, surrounded by interstitial fibrosis, tubular atrophy, and accumulation of inflammatory cells. The administration of trandolapril was effective in reducing the accumulation of extracellular matrix as a consequence of the fibrotic process. This was assessed and quantified through collagen specific histology stains and immunohistochemistry staining for fibrosis and inflammation markers. The mechanism through which trandolapril prevents AKI to CKD transition is not yet elucidated. However, we did not observe a decline in blood pressure in the treatment groups, possible due to the dose employed being lower than the therapeutic range for hypertensive patients. Although the treatment did improve the kidney morphology, we did not observe significant changes in kidney function in the treatment group, evidenced through biochemical analyses used in daily clinical practice. Conclusion Our study provides evidence that trandolapril can mitigate the development of renal fibrosis in a rat model transitioning from AKI to CKD. This beneficial effect, observed despite the absence of hemodynamic and kidney function changes, highlights the potential of ACE inhibitors to prevent long-term structural damage and may have important implications for the management of patients at risk for CKD progression after AKI episodes. This research was funded by grants from Instituto de Salud Carlos III (ISCIII), Ministerio de Ciencia e Innovación (PI21/01226 and PI21/00548 co-funded by the European Union; and RICORS2040, RD21/0005/0004, co-funded by the European Union – NextGenerationEU, Mecanismo para la Recuperación y la Resiliencia (MRR)) funds.