Comparative study of Valsartan and Leucovorin alone or in combination for renal protection in methotrexate-induced acute kidney injury in rats

Methotrexate (MTX) is a widely used chemotherapeutic and immunosuppressive agent that may induce acute kidney injury (AKI), posing a major clinical challenge. This study investigated the renoprotective effects of Valsartan, Leucovorin and their combination in mitigating methotrexate (MTX)-induced renal damage in Wistar rats. The aim was to evaluate these effects in a rat model of MTX-induced acute kidney injury (AKI). After approval by the Institutional Animal Ethics Committee (IAEC), forty male Wistar rats were divided into five groups: control (saline), MTX (single intraperitoneal injection of 20 mg/kg), Valsartan (10 mg/kg/day), leucovorin (10 mg/kg/day), and combination (Valsartan plus leucovorin). Drug treatment was initiated one day before MTX administration and continued orally for five days. Renal function was assessed by measuring serum creatinine and blood urea nitrogen (BUN). Tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6) were evaluated as inflammatory markers, while malondialdehyde (MDA) and glutathione (GSH) were assessed as oxidative stress markers. Histopathological examination of renal tissue was also performed. Data were analyzed using GraphPad Prism version 6. The MTX group showed significant renal dysfunction (p < 0.001) and increased inflammatory and oxidative stress markers. Both Valsartan and leucovorin produced partial renoprotective effects, with Valsartan significantly reducing oxidative stress (p < 0.001) and leucovorin markedly decreasing inflammatory markers (p < 0.001). The combination therapy demonstrated the most pronounced renoprotective effect (p < 0.001), as evidenced by improved renal function and reduced oxidative damage and inflammation. Histopathological analysis revealed decreased tubular necrosis and inflammatory infiltration in the combination group. Valsartan and leucovorin exerted individual renoprotective effects; however, their combined administration provided highly significant protection against MTX-induced AKI. These findings suggest that combination therapy may represent a promising strategy for preventing renal injury in patients undergoing MTX treatment.