Nephrotoxicity Risk of Cyclophosphamide in Lupus Model
DOI:
https://doi.org/10.30872/j.trop.pharm.chem.v5i3.205Keywords:
cyclophosphamide, nephrotoxic, lupus treatment, IL-6, lupus miceAbstract
Cyclophosphamide is one of the standard therapies for lupus, especially lupus nephritis based on its immunosuppressive effect. However, cyclophosphamide is also known as a nephrotoxic agent. Therefore, this research was aimed to measure the effect of cyclophosphamide at the dose that comparable to the human dose of 1 mg/kg BW on the kidney of lupus mice induced by means of 2,6,10,14-tetramethylpentadecane (TMPD). In this research, the IL-6 as a pro-inflammatory cytokine was tested by using flow cytometry method. In addition, the structural damage of the kidney tissues was assessed by means of Moroni’s kidney organ scoring method for lupus. The result showed that cyclophosphamide reduced the IL-6 significantly with the value of 36.72±22.79% for the TMPD-treated group; 32.59±9.97% for the cyclophosphamide group; and 30.25±4.48% for the naïve group. Moreover, the damages of the kidney tissues on the cyclophosphamide group were more severe than the TMPD-treated group. In conclusion, despite its anti-inflammatory effect which is useful for lupus, cyclophosphamide has a severe nephrotoxic effect which harms the patient. The effects may be a cause of the long interval use of cyclophosphamide. It can be a consideration for the further research and the next revision of the guideline for lupus nephritis treatment.
References
Schiffer L, Sinha J, Wang X, Gonsdorff G Von, Schiffer M, Michael P, et al. 2003. Short Term Administration of Costimulatory Blockade and Cyclophosphamide Induces Remission of Systemic Lupus Erythematosus Nephritis in NZB/W F 1 Mice by a Mechanism Downstream of Renal Immune Complex Deposition. J Immunol, 41: 489–497.
[2] Mok CC, Yap DYH, Navarra S V., Liu ZH, Zhao MH, Lu L, et al. 2013. Overview of lupus nephritis management guidelines and perspective from Asia. Int J Rheum Dis 16(6): 625–36.
[3] Kulkarni O, Eulberg D, Selve N, Zöllner S, Allam R, Pawar RD, et al. 2009. Anti-CCl2 Spiegelmer permits 75% dose reduction of cyclophosphamide to control diffuse proliferative lupus nephritis and pneumonitis in MRL-Fas(lpr) mice. J Pharmacol Exp Ther 328(2):371–7.
[4] Bomback AS, Appel GB, 2010. Updates on the treatment of lupus nephritis. J Am Soc Nephrol. 21(12):2028–35.
[5] Takada K, Illei GG, Boumpas DT., 2001. Cyclophosphamide for the treatment of systemic lupus erythematosus. Lupus, 10(3):154–61.
[6] Ayhanci A, Günes S, Sahinturk V, Appak S, Uyar R, Cengiz M, et al. 2010. Seleno L-methionine acts on cyclophosphamide-induced kidney toxicity. Biol Trace Elem Res 136(2):171–9.
[7] Rehman MU, Tahir M, Ali F, Qamar W, Lateef A, Khan R, et al. 2012. Cyclophosphamide-induced nephrotoxicity, genotoxicity, and damage in kidney genomic DNA of Swiss albino mice: The protective effect of Ellagic acid. Mol Cell Biochem, 365(1–2):119–27.
[8] Bender AT, Pereira A, Fu K, Samy E, Wu Y, Liu-Bujalski L, et al. 2016. Btk inhibition treats TLR7/IFN driven murine lupus. Clin Immunol, 164:65–77.
[9] Lin Y, Yan Y, Zhang H, Chen Y, He Y, Wang S, et al. 2016. Salvianolic acid A alleviates renal injury in systemic lupus erythematosus induced by pristane in BALB/c mice. Acta Pharm Sin B 2016;0–7.
[10] Calvani N, Satoh M, Croker BP, Reeves WH, Richards HB,2003. Nephritogenic autoantibodies but absence of nephritis in Il-12p35-deficient mice with pristane-induced lupus. Kidney Int; 64(3):897–905.
[11] Aparicio-Soto M, Sánchez-Hidalgo M, Cárdeno A, González-Benjumea A, Fernández-Bolaños JG, Alarcón-de-la-Lastra C. Dietary hydroxytyrosol and hydroxytyrosyl acetate supplementation prevent pristane-induced systemic lupus erythematous in mice. J Funct Foods, 29:84–92.
[12] Perini P, Calabrese M, Rinaldi L, Gallo P. 2008. Cyclophosphamide-based combination therapies for autoimmunity. Neurol Sci, 29(2):233–4.
[13] Tackey E, Lipsky PE, Illei GG. 2004. Rationale for interleukin-6 blockade in systemic lupus erythematosus, Lupus, 13(5):339–43.
[14] Jones S a, Richards PJ, Scheller J, Rose-John S, 2005. IL-6 transsignaling: the in vivo consequences. J Interferon Cytokine Res, 25(5):241–53.
[15] Zickert A, Amoudruz P, Sundström Y, Rönnelid J, Malmström V, Gunnarsson I., 2015. IL-17 and IL-23 in lupus nephritis - association to histopathology and response to treatment. BMC Immunol, 16 (7).
[16] Zhu W, Xu J, Jiang C, Wang B, Geng M, Wu X, et al. Pristane induces autophagy in macrophages, promoting a STAT1-IRF1-TLR3 pathway and arthritis. Clin Immunol 2017;175:56–68.
[17] dos Santos M, Poletti PT, Milhoransa P, Monticielo OA, Veronese FV., 2016. Unraveling the podocyte injury in lupus nephritis: Clinical and experimental approaches. Semin Arthritis Rheum 2016;1–10.
[18] Bonanni A, Vaglio A, Bruschi M, Sinico RA, Cavagna L, Moroni G, et al. 2015.Multi-antibody composition in lupus nephritis: Isotype and antigen specificity make the difference. Autoimmun Rev 14(8):692–702.
[19] Manson JJ, Mills K, Jury E, Mason L, D’Cruz DP, Ni L, et al. 2014. Pathogenic autoantibodies from patients with lupus nephritis cause reduced tyrosine phosphorylation of podocyte proteins, including tubulin. Lupus Sci Med,1(1):200-13.
[20] Arazi A, Neumann AU. 2013. The role of positive feedback loops involving anti-dsDNA and anti-anti-dsDNA antibodies in autoimmune glomerulonephritis. J Theor Biol , 319:8–22.
[21] Guo L, Liu W, Lu T, Guo W, Gao J, Luo Q, et al. 2015.Decrease of functional activated T and B cells and treatment of glomerulonephitis in lupus-prone mice using a natural flavonoid astilbin. PLoS One, 10(4):1–15.
[22] Summers SA, Hoi A, Steinmetz OM, O’Sullivan KM, Ooi JD, Odobasic D, et al. 2010. TLR9 and TLR4 are required for the development of autoimmunity and lupus nephritis in pristane nephropathy. J Autoimmun, 35(4):291–8.
[23] Moroni G, Depetri F, Ponticelli C. 2016. Lupus nephritis: When and how often to biopsy and what does it mean? J Autoimmun, 74:27–40.
[24] Sun D, Krishnan A, Su J, Lawrence R, Zaman K, Fernandes G. 2004. Regulation of immune function by calorie restriction and cyclophosphamide treatment in lupus-prone NZB/NZW F1 mice. Cell Immunol. 228(1):54–65.
[25] Le DT, Jaffee EM. 2012. Regulatory T-cell modulation using cyclophosphamide in vaccine approaches: A current perspective. Cancer Res., 72(14):3439–44.
[26] Ghiringhelli F, Larmonier N, Schmitt E, Parcellier A, Cathelin D, Garrido C, et al. 2004. CD4+CD25+ regulatory T cells suppress tumor immunity but are sensitive to cyclophosphamide which allows immunotherapy of established tumors to be curative. Eur J Immunol, 34(2):336–44.
[27] Mok CC, Yap DYH, Navarra SV, Liu ZH, Zhao MH, Lu L et al., 2014. Overview of Lupus Nephritis management guidelines and persperctive from Asia. Nephrology, 19:11-20.
[28] Hahn BH, McMahon MA, Wilkinson A, Wallace WD, Daikh DI, Fitzgerald JD, et al. 2012. American College of Rheumatology guidelines for screening, treatment, and management of lupus nephritis. Arthritis Care Res, 64(6):797–808.
