Kidney Toxicity Studies in Mice (BALB/c) Recurrently infected with Plasmodium berghei and treated with either artemether plus lumefantrine (AL) or artesunate plus amodiaquine (AA)

Document Type : Original Articles

Authors

1 Pure and Applied Zoology Department, Federal University of Agriculture, Abeokuta

2 Department of Pure and Applied Zoology, College of Biosciences, Federal University of Agriculture, Abeokuta, Ogun State, Nigeria.

3 Department of Veterinary Pathology, College of Veterinary Medicine, Federal University of Agriculture, Abeokuta, Ogun State, Nigeria.

10.32592/ARI.2024.79.5.1075

Abstract

Individuals living in areas where malaria is prevalent are often exposed to the disease and subsequently treated. This frequent exposure to malaria and its treatment could put a strain on the kidneys, which are responsible for eliminating metabolites, possibly leading to oxidative stress, and potentially impairing their function. Hence, this study explored the potential consequences of repeated exposure to malaria parasites and treatment with artemether plus lumefantrine (AL) or artesunate plus amodiaquine (AA) on kidney oxidative stress and functional markers. Three groups of randomly assigned male mice were used: the control group was given distilled water, whereas the other two groups were infected with Plasmodium berghei and treated with either AL or AA for six consecutive periods. Examination of the study parameters was carried out on the blood and kidney tissues after the initial, third, and sixth exposure intervals. Concentration of malondialdehyde (MDA) in the kidneys was significantly higher in mice exposed to P. berghei and treated with either AL (p < 0.001) or AA (p < 0.01) after the first, third, and sixth exposures than in the control group. Activities of kidney glutathione peroxidase (GPx), superoxide dismutase (SOD), and catalase (CAT) increased considerably (p < 0.001) following the third and sixth exposures to P. berghei and AL or AA. Increases in MDA, GPx, SOD, and CAT levels did not follow a consistent upward trend. Moreover, no significant differences (p > 0.05) were observed in the levels of plasma sodium, potassium, chloride, and creatinine between the groups exposed to P. berghei and treated with AL or AA and the control group after the sixth exposure. Histological analysis showed evidence of glomerulus oedema in the kidney tissue of mice infected with P. berghei and treated with AL or AA for the first, third, and sixth exposure periods. Mice repeatedly exposed to malarial parasites and AL or AA therapeutic treatment showed higher kidney lipid peroxidation during consecutive exposures, with elevated levels of GPx, SOD, and CAT activity in the kidneys, potentially protecting against lipid peroxidation and preserving renal function. Nevertheless, the observed antioxidant activity proved to be inadequate in preventing glomerular oedema.

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  1. Maiga FO, Wele M, Toure SM, Keita M, Tangara CO, Refeld RR, et al. Artemisinin-based combination therapy for uncomplicated Plasmodium falciparum malaria in Mali: a systematic review and meta-analysis. Malaria Journal. 2021;20(1): 356.
  2. Audu D, Petagine L, Idowu OA, Patel VB, Idowu AB. Biomarkers of the Toxic Effects of Chemotherapeutic Agents: A Focus on Antimalarials. 2023; 1–27.
  3. Wiwanitkit V. Antimalarial drug and renal toxicity. Journal of Nephropharmacology. 2015;5(1): 11–12.
  4. Geraldo Bezerra da Silva J, Pinto JR, Barros EJG, Farias GMN, Daher EDF. Kidney involvement in malaria: an update. Revista do Instituto de Medicina Tropical de São Paulo. 2017;59.
  5. Gomes ARQ, Cunha N, Varela ELP, Brígido HPC, Vale VV, Dolabela MF, et al. Oxidative Stress in Malaria: Potential Benefits of Antioxidant Therapy. International Journal of Molecular Sciences. 2022;23(11): 5949.
  6. Audu D, Patel VB, Idowu OA, Mshelbwala FM, Idowu AB. Baseline and recurrent exposure to the standard dose of artemisinin-based combination therapies (ACTs) induces oxidative stress and liver damage in mice (BALB/c). Egyptian Liver Journal. 2023;13(1): 53.
  7. Ndiaye JLA, Faye B, Gueye A, Tine R, Ndiaye D, Tchania C, et al. Repeated treatment of recurrent uncomplicated Plasmodium falciparum malaria in Senegal with fixed-dose artesunate plus amodiaquine versus fixed-dose artemether plus lumefantrine: a randomized, open-label trial. Malaria Journal. 2011;10(1): 237.
  8. Sagara I, Fofana B, Gaudart J, Sidibe B, Togo A, Toure S, et al. Repeated Artemisinin-Based Combination Therapies in a Malaria Hyperendemic Area of Mali: Efficacy, Safety, and Public Health Impact. The American Journal of Tropical Medicine and Hygiene. 2012;87(1): 50–56.
  9. Audu D, Ajoke O, Vinood B, Mshelbwala F. The effects of repeated therapeutic administration of artesunate-amodiaquine and artemether-lumefantrine on haematological markers in healthy mice. Biology, Medicine, & Natural Product Chemistry. 2023;12(1): 233–240.
  10. Beuge J, Aust S. The thiobarbituric acid assay. 1978.
  11. Rotruck JT, Pope AL, Ganther HE, Swanson AB, Hafeman DG, Hoekstra WG. Selenium: Biochemical role as a component of glatathione peroxidase. Science. 1973;179(4073): 588–590.
  12. Marklund S, Marklund G. Involvement of the Superoxide Anion Radical in the Autoxidation of Pyrogallol and a Convenient Assay for Superoxide Dismutase. European Journal of Biochemistry. 1974;47(3): 469–474.
  13. Shangari N, O’Brien PJ. Catalase activity assays. Current protocols in toxicology. editorial board, Mahin D. 2006;Chapter 7.
  14. Murray RL. Creatinine. Clinical Chemistry. The CV Mosby Co. St Louis, Toronto, Princeton. 1984.
  15. Trinder P. Quantitative determination of serum sodium by colometric method. Analyst. 1951;76: 596–598.
  16. Terry AE, Sesin PG. Qualitative determination of serum potassium by colorimetric method. American Journal of Clinical Pathology. 1958;29: 86–88.
  17. Burtis CA, Ashwood ER, Bruns DE. Tietz Textbook of Clinical Chemistry. 1999.
  18. Sharma L, Kaur J, Rishi P, Shukla G. Plasmodium berghei: influence of infection on the oxidant and antioxidants levels in pregnant BALB/c mice. Experimental Parasitology. 2012;131(2): 215–222.
  19. Mueangson O, Mahittikorn A, Anabire NG, Mala W, Kotepui M. Increased Blood Concentrations of Malondialdehyde in Plasmodium Infection: A Systematic Review and Meta-Analysis. Antioxidants. 2023;12(8): 1502.
  20. Idowu ET, Alimba CG, Olowu EA, Otubanjo AO. Artemether-Lumefantrine treatment combined with albendazole and ivermectin induced genotoxicity and hepatotoxicity through oxidative stress in Wistar rats. Egyptian Journal of Basic and Applied Sciences. 2015;2(2): 110–119.
  21. Bergin P, Leggett A, Cardwell CR, Woodside JV, Thakkinstian A, Maxwell AP, et al. The effects of vitamin E supplementation on malondialdehyde as a biomarker of oxidative stress in haemodialysis patients: a systematic review and meta-analysis. BMC Nephrology. 2021;22(1): 126.
  22. Hong Y, Hu Y, Sun Y an, Shi J quan, Xu J. High-fat diet caused renal damage in ApoE mice via the activation of RAGE-mediated inflammation. Toxicology Research. 2021;10(6): 1171–1176.
  23. Hong YA, Park CW. Catalytic Antioxidants in the Kidney. Antioxidants. 2021;10(1): 130.
  24. Ndako JA, Olisa JA, Ozoadibe OY, Dojumo VT, Fajobi VO, Akinwumi JA. Evaluation of the association between malaria infection and electrolyte variation in patients: Use of Pearson correlation analytical technique. Informatics in Medicine Unlocked. 2020;21: 100437.
  25. Bobkova I, Chebotareva N, Kozlovskaya L, Shilov E. Edema in Renal Diseases Current View on Pathogenesis. Nephrology Point of Care. 2016;2(1): pocj.5000204.