Abstract
Coagulation system activation plays an important role in the pathophysiology of different diseases. In spite of massive research regarding cisplatin-induced nephrotoxicity, the role of coagulation cascade in such toxicity is still questionable. Here, we aim to investigate the role of activation of coagulation system in the initiation of cisplatin-induced acute renal tubular necrosis. Moreover, the role of the anticoagulant rivaroxaban against such toxicity was investigated. Briefly, animals were classified into seven groups, eight rats each. Group 1 served as normal control group, groups (2–7) received i.p. single doses of cisplatin (6 mg/kg b.w), groups (6–7) were treated with rivaroxaban (5 and 7 mg/kg b.w, p.o., respectively) 7 days before cisplatin injection and completed for 4 days. Animals in groups (2, 3, and 4) were sacrificed after 1, 2 and 3 days of cisplatin injection, respectively, while groups (1, 5, 6, and 7) were sacrificed after 4 days of cisplatin injection. Serum cystatin-c, urea, creatinine and γ-glutamyl transferase, urinary Lipocaline-2, and KIM-1 protein densities, as well as glomerular filtration rate (GFR) were assessed. Immunofluorescence examination of glomeruli fibrin and tissue factor (TF) was also performed coupled with a histopathological study. Cisplatin administration increased expression of fibrin and TF starting 24 h of cisplatin injection even before renal failure markers elevated. Leukocytosis, thrombocytopenia, and increased prothrombin time were also observed. Cisplatin also induced tubular damage evidenced by increased serum cystatin-c, urea, and creatinine with significant decrease in GFR and Gamma glutamyl transferase (GGT) activity. Rivaroxaban significantly decreased elevation of fibrin and TF with significant reduction in serum creatinine, BUN and cystatin-c levels. Rivaroxaban also significantly improved hematological markers and histological features as well. This study showed that activation of coagulation system plays an important role in the pathophysiology of cisplatin-induced acute renal tubular damage. Interference with coagulation cascade may be a promising nephroprotective strategy against chemical nephrotoxicity.
Highlights
Acute tubular necrosis (ATN) is one of acute renal failure (ARF) leading cause where it represents about 85% of all ARF cases (Mehta et al, 2004)
Acute Tubular necrosis may results from oxygen deficiency, septic or toxic kidney injury which caused by radio-contrast agents or antibacterial, antimycotic or cytotoxic drugs (Waikar et al, 2008)
All animal housing and handling were conducted in compliance with the Beni-Suef University guidelines and in accordance with the research protocols established by the Animal Care Committee of the National Research Center (Cairo, Egypt) which followed the recommendations of the National Institutes of Health Guide for Care and Use of Laboratory Animals (Publication No 85–23, revised 1985)
Summary
Acute tubular necrosis (ATN) is one of acute renal failure (ARF) leading cause where it represents about 85% of all ARF cases (Mehta et al, 2004). Drug induced kidney injury is recognized as a major factor in about 20% of cases and its incidence may be as high as 66% among older adults (Naughton, 2008; Barrantes and Horwedel, 2012). One of these drugs which play an important role in cancer chemotherapy is cisplatin (CP)
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