Diclofenac induced-acute kidney injury is linked with oxidative stress and pro-inflammatory changes in Sprague Dawley rats
AbstractObjectives: Diclofenac induces oxidative stress in the body and became the main cause of nephrotoxicity and acute kidney injury (AKI). The traditional markers of AKI are blood urea and serum creatinine which are regarded as low sensitive and low specific in detection the early renal damage. Therefore, the aim of present study was to evaluate oxidative stress and pro-inflammatory biomarkers in diclofenac induced- AKI in rats. Methods: Twenty Sprague Dawley Male rat were used and randomly divided in to 2 groups. Group1 (n=10): Rats treated with distilled water plus normal saline for 12 days. Group2 (n=10) : Rats treated with distilled water plus diclofenac 15mg/kg for 12 days. Rat body weight, body mass index and estimated glomerular filtration rate (eGFR) were evaluated in both groups. Blood urea, serum creatinine, serum malondialdehyde (MDA), superoxide dismutase (SOD), glutathione reductase (GSH), Neutrophil Gelatinase Associated Lipocalin (NGAL) , kidney injury molecules (KIM-1) and Cystatin-c were estimated. Results: Diclofenac 15mg/kg led to significant AKI through elevation of blood urea and serum creatinine with significant reduction of eGFR. KIM-1 serum level was significantly elevated with high sensitivity and specificity compared to the other tested biomarkers. Conclusion: KIM-1 serum level is more sensitive and specific with high accuracy compared to the other renal biomarkers in diclofenac induced- AKI. Estimation of KIM-1 serum levels should be regarded as a cornerstone for early detection of AKI in high risk patients.
2. Inoue T, Anai S, Onishi S, Miyake M, Tanaka N, Hirayama A, et al.Inhibition of COX-2 expression by topical diclofenac enhanced radiation sensitivity via enhancement of TRAIL in human prostate adenocarcinoma xenograft model. BMC Urol. 2013; 13:1.
3. Bickel M, Khaykin P, Stephan C, Schmidt K, Buettner M, Amann K, et al. Acute kidney injury caused by tenofovir disoproxil fumarate and diclofenac co-administration. HIV Med. 2013; 14(10):633-8.
4. Yasmeen T, Qureshi GS, Perveen S. Adverse effects of diclofenac sodium on renal parenchyma of adult albino rats. J Pak Med Assoc. 2007; 57(7):349-51.
5. Yarlagadda SG, Perazella MA. Drug-induced crystal nephropathy: an update. Expert Opin Drug Saf. 2008;7(2):147-58.
6. Schrama YC, van Dam T, Fijnheer R, Hené RJ, de Groot P, Rabelink TJ. Cyclosporine is associated with endothelial dysfunction but not with platelet activation in renaltransplantation. Neth J Med. 2001; 59(1):6-15.
7. Pendergraft WF , Herlitz LC, Thornley-Brown D, Rosner M, Niles JL. Nephrotoxic effects of common and emerging drugs of abuse. Clin J Am Soc Nephrol. 2014;9(11):1996-2005.
8. Yu Y, Stubbe J, Ibrahim S, Song WL, Smyth EM, Funk CD, et al. Cyclooxygenase-2-dependent prostacyclin formation and blood pressure homeostasis: targeted exchange of cyclooxygenase isoforms in mice. Circ Res.2010; 106(2):337-45.
9. Hur J, Liu Z, Tong W, Laaksonen R, Bai JP.Drug-induced rhabdomyolysis: from systems pharmacology analysis to biochemical flux. Chem Res Toxicol. 2014; 27(3):421-32.
10. Abu Hamad R, Berman S, Hachmo Y, Stark M, Hasan F, Doenyas-Barak K, Efrati S. Response of Renal Podocytes to Excessive Hydrostatic Pressure: A Pathophysiologic Cascade in a Malignant Hypertension Model. Kidney Blood Press Res. 2017; 42(6):1104-1118.
11. Issa N, Kukla A, Ibrahim HN. Calcineurin inhibitor nephrotoxicity: a review and perspective of the evidence. Am J Nephrol. 2013; 37(6):602-12.
12. Gómez-Oliván LM, Galar-Martínez M, García-Medina S, Valdés-Alanís A, Islas-Flores H, Neri-Cruz N. Genotoxic response and oxidative stress induced by diclofenac, ibuprofen and naproxen in Daphnia magna. Drug Chem Toxicol. 2014; 37(4):391-9.
13. Al-Kuraishy HM, Al-Gareeb AI, Al-Maiahy TJ. Concept and connotation of oxidative stress in preeclampsia. J Lab Physicians. 2018;10(3):276-282.
14. Al-Kuraishy HM, Al-Gareeb AI.Eustress and Malondialdehyde (MDA): Role of Panax Ginseng: Randomized Placebo Controlled Study. Iran J Psychiatry. 2017;12(3):194-200.
15. Al-Kuraishy HM, Al-Gareeb AI.Potential Effects of Pomegranate on Lipid Peroxidation and Pro-inflammatory Changes in Daunorubicin-induced Cardiotoxicity in Rats.
16. Santos-Alves E, Marques-Aleixo I, Coxito P, Balça MM, Rizo-Roca D, Rocha-Rodrigues S, et al. Exercise mitigates diclofenac-induced liver mitochondrial dysfunction. Eur J Clin Invest. 2014;44(7):668-77.
17. Barcelos RP, Bresciani G, Cuevas MJ, Martínez-Flórez S, Soares FAA, González-Gallego J. Diclofenac pretreatment modulates exercise-induced inflammation in skeletal muscle of rats through the TLR4/NF-κB pathway. Appl PhysiolNutrMetab. 2017; 42(7):757-764.
18. Li Y, Deng H, Ju L, Zhang X, Zhang Z, Yang Z, et al.Screening and validation for plasma biomarkers of nephrotoxicity based on metabolomics in male rats. Toxicol Res (Camb). 2015; 5(1):259-267.
19. Hosohata K, Yoshioka D, Tanaka A, Ando H, Fujimura A. Early urinary biomarkers for renal tubular damage in spontaneously hypertensive rats on a high salt intake. Hypertens Res. 2016;39(1):19-26.
20. Bazzi C, Rizza V, Olivieri G, Casellato D, D'Amico G. Tubular reabsorption of high, middle and low molecular weight proteins according to the tubulo-interstitial damage marker N-acetyl-β-D-glucosaminidase in glomerulonephritis. J Nephrol. 2015;28(5):541-8.
21. Park CH, Yokozawa T, Noh JS. Oligonol. A low-molecular-weight polyphenol derived from lychee fruit, attenuates diabetes-induced renal damage through the advanced glycation end product-related pathway in db/db mice. J Nutr. 2014;144(8):1150-7.
22. Liu SJ, Zhai YP, Yu YP, Liu HN, Li F, Song P, et al.Significance of low molecular weight urinary protein for assessment of early renal damage in patients with multiple myeloma. Zhongguo Shi Yan Xue Ye Xue Za Zhi. 2013; 21(2):410-4.
23. Zhang J, Zeng H, Wang N, Tian X, Dou W, Shi P. Beneficial effects of creatine phosphate sodium for the treatment of Henoch-Schönlein purpura in patients with early renal damage detected using urinary kidney injury molecule-1 levels. Eur J Pediatr. 2016; 175(1):49-55.
24. Collier JB, Schnellmann RG. Extracellular Signal-Regulated Kinase 1/2 Regulates Mouse Kidney Injury Molecule-1 Expression Physiologically and Following Ischemic and Septic Renal Injury. J Pharmacol Exp Ther. 2017;363(3):419-427.
25. Gauer S, Urbschat A, Gretz N, Hoffmann SC, Kränzlin B, Geiger H, et al. Kidney Injury Molecule-1 Is Specifically Expressed in Cystically-Transformed Proximal Tubules of the PKD/Mhm (cy/+) Rat Model of Polycystic Kidney Disease. Int J Mol Sci. 2016;17(6). pii: E802.
26. Kunutsor SK, Flores-Guerrero JL, Kieneker LM, Nilsen T, Hidden C, Sundrehagen E, et al. Plasma neutrophil gelatinase-associated lipocalin and risk of cardiovascular disease: Findings from the PREVEND prospective cohort study. Clin Chim Acta. 2018; 486:66-75.
27. Eren Z, Günal MY, Arı E, Çoban J, Çakalağaoğlu F, Çağlayan B, et al. Pleiotropic and Renoprotective Effects of Erythropoietin Beta on Experimental Diabetic Nephropathy Model. Nephron. 2016;132(4):292-300.
28. Knight EL , Verhave JC, Spiegelman D, Hillege HL, de Zeeuw D, Curhan GC, et al .Factors influencing serum cystatin C levels other than renal function and the impact on renal function measurement. Kidney Int. 2004; 65(4):1416-21.
29. Wei L, Ye X, Pei X, Wu J, Zhao W. Reference intervals for serum cystatin C and factors influencing cystatin C levels other than renalfunction in the elderly. PLoS One.2014; 9(1):e86066.
30. Zhou X, Ma B, Lin Z, Qu Z, Huo Y, Wang J, et al. Evaluation of the usefulness of novel biomarkers for drug-induced acute kidney injury in beagle dogs. Toxicol Appl Pharmacol. 2014; 280(1):30-5.
31. Singh AP, Junemann A, Muthuraman A, Jaggi AS, Singh N, Grover K, et al. Animal models of acute renal failure. Pharmacol Rep.2012; 64(1):31-44.
32. Gacka E, Życzkowski M, Bogacki R, Paradysz A, Hyla-Klekot L. The Usefulness of Determining Neutrophil Gelatinase Associated Lipocalin Concentration Excreted in the Urine in the Evaluation of Cyclosporine A Nephrotoxicity in Children with Nephrotic Syndrome. Dis Markers. 2016; 6872149.
33. Alabi QK, Akomolafe RO, Adefisayo MA, Olukiran OS, Nafiu AO, Fasanya MK, Oladele A. Kolaviron. Attenuates diclofenac-induced nephrotoxicity in male Wistar rats. Appl Physiol Nutr Metab. 2018;43(9):956-968.
34. Tomohiro Mizuno , Kazuma Ito , Yasuhiro Miyagawa , Kazuhiro Ishikawa , Yasuhiro Suzuki , Masashi Mizuno , et al. Short-term Administration of Diclofenac Sodium Affects Renal Function After Laparoscopic Radical Nephrectomy in Elderly Patients. Jpn J Clin Oncol. 2012; 42(11)1073– 1078
35. Hung SC , Kuo KL , Peng CH , Wu CH , Wang YC , Tarng DC . Association of fluid retention with anemia and clinical outcomes among patients with chronic kidney disease. J Am Heart Assoc. 2015; 5;4(1):e001480.
36. Hickey EJ, Raje RR, Reid VE, Gross SM, Ray SD. Diclofenac induced in vivo nephrotoxicity may involve oxidative stress-mediated massive genomic DNA fragmentation and apoptotic cell death. Free Radic Biol Med. 2001;31(2):139-52.
37. Bunel V, Tournay Y, Baudoux T, De Prez E, Marchand M, et al. Early detection of acute cisplatin nephrotoxicity: interest of urinary monitoring of proximal tubular biomarkers. Clin Kidney J. 2017; 10(5):639-647.
38. Harrill AH, Lin H, Tobacyk J, Seely JC. Mouse population-based evaluation of urinary protein and miRNA biomarker performance associated with cisplatin renal injury. Exp Biol Med (Maywood). 2018; 243(3):237-247.
39. Lan Z, Bi KS, Chen XH. Ligustrazine attenuates elevated levels of indoxyl sulfate, kidney injury molecule-1 and clusterin in rats exposed to cadmium. Food Chem Toxicol. 2014; 63:62-8.
40. Vaidya VS, Ozer JS, Dieterle F, Collings FB, Ramirez V, Troth S, et al. Kidney injury molecule-1 outperforms traditional biomarkers of kidney injury in preclinical biomarker qualification studies. Nat Biotechnol. 2010; 28(5):478-85.
41. Qi-Hui Luo , Meng-Lu , Chen Zheng-Li , Chen Chao , Huang An-Chun Cheng et al .Evaluation of KIM-1 and NGAL as Early Indicators for Assessment of Gentamycin- Induced Nephrotoxicity In Vivo and In Vitro. Kidney Blood Press Res 2016; 41:911-918.
42. Dönmez O, Korkmaz HA, Yıldız N, Ediz B. Comparison of serum cystatin C and creatinine levels in determining glomerular filtration rate in children with stage I to III chronic renal disease. Ren Fail. 2015; 37(5):784-90.
43. Harman G, Akbari A, Hiremath S, White CA, Ramsay T, Kokolo MB, Craig J, t al. Accuracy of cystatin C-based estimates of glomerular filtration rate in kidney transplant recipients: a systematic review. Nephrol Dial Transplant.. 2013; 28(3):741-57.