Comparative study of Valsartan and Leucovorin alone or in combination for renal protection in methotrexate-induced acute kidney injury in rats
DOI:
https://doi.org/10.12923/cipms-2026-0009Słowa kluczowe:
methotrexate, oxidative stress, Valsartan, acute kidney injury, renoprotection, LeucovorinAbstrakt
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.
Bibliografia
1. Kutbi D, Almalki RS. Valsartan mitigates the progression of methotrexate induced acute kidney injury in rats via attenuation of renal inflammation and oxidative stress. J Inflamm Res. 2024;17:2233-43. https://doi.org/10.2147/JIR.S456610
2. Kremer JM, Alarcón GS, Lightfoot RW Jr, Willkens RF, Furst DE, Williams HJ, et al. Methotrexate for rheumatoid arthritis. Arthritis Rheum. 1994;37(3):316 28. https://doi.org/10.1002/art.1780370304
3. Shea B, Swinden MV, Ghogomu ET, Ortiz Z, Katchamart W, Rader T, et al. Folic acid and folinic acid for reducing side effects in patients receiving methotrexate for rheumatoid arthritis. Cochrane Database Syst Rev. 2013; 2013(5):CD000951. https://doi.org/10.1002/14651858.CD000951.pub2
4. Tomsa AM, Alexa AL, Junie ML, Rachisan AL, Ciumarnean L. Oxidative stress as a potential target in acute kidney injury. PeerJ. 2019;7:e8046. https://doi.org/10.7717/peerj.8046
5. Kalender B, Öztürk M, Tunçdemir M, Uysal Ö, Dağıstanlı FK, Yeğenağa I, et al. Renoprotective effects of valsartan and enalapril in STZ induced diabetes in rats. Acta Histochem. 2002;104(2):123-30. https://doi.org/10.1078/0065-1281-00643
6. Flombaum CD, Liu D, Yan SQ, Chan A, Mathew S, Meyers PA, et al. Management of patients with acute methotrexate nephrotoxicity with high dose leucovorin. Pharmacotherapy. 2018;38(7):714-24.
7. Wang W, Qiu L, Howard A, Solis N, Li C, Wang X, et al. Protective effects of aliskiren and valsartan in mice with diabetic nephropathy. J Renin Angiotensin Aldosterone Syst. 2014;15(4):384-395. https://doi.org/10.1177/1470320313507123
8. Gu C, Zhou G, Noble NA, Border WA, Cheung AK, Huang Y. Targeting reduction of proteinuria in glomerulonephritis: maximizing the antifibrotic effect of valsartan by protecting podocytes. J Renin Angiotensin Aldosterone Syst. 2014;15(2):177 89. https://doi.org/10.1177/1470320312466127
9. Jiang R, Mei S, Zhao Z. Leucovorin (folinic acid) rescue for high-dose methotrexate: a review. J Clin Pharm Ther. 2022;47(9):1452-60. https://doi.org/10.1111/jcpt.13739
10. Sobral AF, Cunha A, Silva V, Gil-Martins E, Silva R, Barbosa DJ. Unveiling the therapeutic potential of folate dependent one carbon metabolism in cancer and neurodegeneration. Int J Mol Sci. 2024;25(17):9339. https://doi.org/10.3390/ijms25179339.
11. Widemann BC, Adamson PC. Understanding and managing methotrexate nephrotoxicity. Oncologist. 2006;11(6):694-703. https://doi.org/10.1634/theoncologist.11-6-694
12. Howard SC, McCormick J, Pui CH, Buddington RK, Harvey RD. Preventing and managing toxicities of high-dose methotrexate. Oncologist. 2016;21(12):1471 82. https://doi.org/10.1634/theoncologist.2015-0164
13. Uz E, Sahin G, Uz B, Acar A, Isik B, Beydemir S, et al. The protective effect of erdosteine on methotrexate-induced renal oxidative stress. Hum Exp Toxicol. 2009;28(6):353-8
14. Bleyer WA. The clinical pharmacology of methotrexate: new applications of an old drug. Cancer. 1978;41(1):36 51. https://doi.org/10.1002/1097-0142(197801)41:1<36::AID-CNCR2820410108 >3.0.CO;2-I
15. Mezzano SA, Aros C, Droguett A, Burgos ME, Ardiles L, Flores C, et al. Renin angiotensin system activation and interstitial inflammation in human diabetic nephropathy. Kidney Int Suppl. 2003;(86):S64-S70.
16. Benter IF, Yousif MH, Anim JT, Dhaunsi GS, Chappell MC. Valsartan improves oxidative stress and endothelial function
in a rat model of hypertension. Am J Nephrol. 2005;25(5):453-62.
17. Khan SA, Priyamvada S, Khan S, Khan MW, Farooq N, Yusufi AN. Valsartan ameliorates cisplatin induced nephrotoxicity via antioxidant mechanisms. J Renal Inj Prev. 2016;5(1):29-33.
18. Allegra CJ, Drake JC, Jolivet J, Chabner BA. Folinic acid rescue in methotrexate therapy: biochemical and pharmacologic rationale. J Clin Oncol. 1985;3(10):1347-59
19. Shapira MY, Brenner B, Ben Bassat I. Leucovorin protection in methotrexate therapy: mechanism and clinical relevance. Leuk Lymphoma. 2001;41(3-4):273-82
20. Hauser IA, Krüger B, Gauer S, Becker JU, Hohenstein B, Theilig F, et al. Combination therapies in nephroprotection: facts and perspectives. Nephrol Dial Transplant. 2005;20(4):861-71
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Prawa autorskie (c) 2026 Jayshree Dawane , Sonali Suryawanshi, Harshita Jain, Priti Dhande, Sandhya Shukla (Autor)
Utwór dostępny jest na licencji Creative Commons Uznanie autorstwa – Użycie niekomercyjne – Bez utworów zależnych 4.0 Międzynarodowe.
