STATINS INDUCED NEPHROTOXICITY: A DOSE DEPENDENT STUDY IN ALBINO RATS
Keywords:
Atorvastatin, Nephrotoxicity, Oxidative stressAbstract
Objective: The objective of the study was to evaluate the dose dependent effects of atorvastatin on rat kidneys.
Methods: The selected doses of atorvastatin were administered orally for 17 days to rats. The statin induced nephrotoxicity was accessed by carrying out renal function tests and is by renal histopathology analysis. Measurements of antioxidant enzymes were also carried out to check whether atorvastatin at the selected dose level interfere with any of the antioxidant system. Atorvastatin at three doses 5mg/kg, 10mg/kg and 20mg/kg was tested.
Results: Higher doses of atorvastatin exhibits considerable degree of renal toxicity in rats, while the low doses do not interfere with renal functions in rats. Atorvastatin at all the tested dose levels not interfere with cellular anti-oxidant mechanisms.
Conclusions: Atorvastatin at 20mg/kg exhibit significant toxicity on rat kidneys. Atorvastatin at the selected dose level does not interfere with any of the antioxidant mechanisms. It indicated that atorvastatin not cause oxidative stress induced renal damage and rhabdomyolysis may be the reason for renal damage induced by atorvastatin at the high dose level.
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V Tandom, G Bano, V Khachuria, A Parihar, S Guptha. Pleotropic effects of statins. IJP 2005;37:77-85.
Adalbert Schiller. Statin therapy in chronic kidney diseases. TMJ 2007;11:1-5.
Vasilios G Athyros, Konstantinos Tziomalos, Asteros Karagiannis, Dimitri P Mikhailidis. Statins and cardiovascular events in patients with end-stage renal disease on hemodialysis. The AURORA results suggest the need for earlier intervention. Curr Vasc Pharmacol 2009;7:264-6.
Myles Joyce, Cathal Kelly, Des Winter, Gang Chen, Austin Leahy, David Bouchier-Hayes. Pravastatin, A 3-Hydroxy-3-Methylglutaryl Coenzyme A reductase inhibitor, attenuates renal injury in an experimental model of ischemia-reperfusion. JSR 2001;101:79–84.
Daniel J Antoine, Abhishek Srivastava, Munir Pirmohamed, B Kevin Park. Statins inhibit aminoglycoside accumulation and cytotoxicity to renal proximal tubule cells. Biochem Pharm 2010;79:647–54.
Emin Ozbek, Mustafa Cekmen, Yusuf Ozlem Ilbey, Abdulmuttalip, Simsek Emre, Can Polat, et al. Atorvastatin prevents gentamicin-induced renal damage in rats through the inhibition of p38-mapk and nf-kb pathways. Renal Failure 2009;31:382–92.
Roal van Zyl-Smit, Jean C Firth1, Maureen Duffield, A David Marais. Renal tubular toxicity of HMG-CoA reductase inhibitors. Nephrol. Dial. Trans plant 2000;419:3176–9.
Davis Nancy A, Olson Kristen M, Lukaszek Victoria, A Inman Sharon. Simvastatin attenuates renal ischemia/reperfusion injury in rats administered cyclosporine. Am J Med Sci 2003;326:117-21.
Kelvin J A Davies. Oxidative stress, antioxidant defenses, and damage removal, repair, and replacement systems. IUBMB 2000;50:279–89.
Roberto Cangemi, Lorenzo Loffredo, Roberto Carnevale, Ludovica Perri, Maria Patrizia Patrizi, Valerio Sanguigni, et al. Early decrease of oxidative stress by atorvastatin in hypercholesterolaemic patients: effect on circulating vitamin E. Eur. Heart J 2008;29:54-62.
Judith Haendeler, Jorg Hoffmann, Andreas M. Zeiher, Stefanie Dimmeler,. Antioxidant effects of statins via S-nitrosylation and activation of thioredoxin in endothelial cells a novel vasculoprotective function of statins. Circulation 2010;3:134-40.
Peter Stenvinkel, Ernesto RodrÃguez-Ayala, Ziad A Massy, Abdul Rashid Qureshi, Peter Barany, Bengt Fellström. Statin treatment and diabetes affect myeloperoxidase activity in maintenance hemodialysis patients. CJASN 2006;1:281-7.
Sven Wassmann, Ulrich Laufs, Kirsten Müller, Christian Konkol, Katja Ahlbory, Anselm T. Bäumer, et al. Cellular antioxidant effects of atorvastatin in vitro and in vivo. Arterioscler Thromb Vasc Biol 2010;5:195-9.
Wenhao Cui1, Kuniharu Matsuno1, Kazumi Iwata1, Masakazu Ibi1, Masato Katsuyama1,Tomoko Kakeh, et al. NADPH oxidase isoforms and anti-hypertensive effects of atorvastatin demonstrated in two animal models. J Pharmacol Soc 2009;111:260–8.
Hua Hong, Jin-Sheng Zeng, David L. Kreulen, David Kaufman, Alex F. Atorvastatin protects against cerebral infarction via inhibition of NADPH oxidase-derived superoxide in ischemic stroke. APS 2006;6:456-60.
Marta Tomas, Mariano Sent, Ferran Garcıa-Faria, Juan Vila, Alex Torrents, Maribel Covas, et al. Effect of simvastatin therapy on paraoxonase activity and related lipoproteins in familial hypercholesterolemic patients. Arterioscler Thromb Vasc Biol 2010;3:467-78.
Najah RH, Mohammad A, Ammar R. Effect of atorvastatin on oxidative stress parameters and lipid profile in type 2 diabetic patients. IMJ 2009;8:43-8.
Jane Armitage. The safety of statins in clinical practice. Lancet 2007;370:1781–90.
Faikah gueler, Song rong, Joon-keun Park, Anette Fiebeler, Jan menne, Marlies elger, Dominik N Mueller, et al. Postischemic acute renal failure is reduced by short-term statin treatment in a rat model. J Am Soc Nephro 2002;13:2288–98.
Zorica Nesic, Zoran Todorovic, Radan Stojanovic, Gordana Basta-Jovanovic, Sanja Radojevic-Škodric, et al. Single-dose intravenous simvastatin treatment attenuates renal injury in an experimental model of ischemia-reperfusion in the rat. J Pharmacol Sci 2006;102:413–7.
Alejandro R Chade, Xiangyang Zhu, Oren P Mushin, Claudio Napoli. Simvastatin promotes angiogenesis and prevents microvascular remodeling in chronic renal ischemia. FASEB 2006;20:1015-22.
Ipek Midi, Ozgur Bilgin, Pınar Kahraman Koytak, Tulin Tanrıdag. Myopathy due to concominant use of statin and gemfibrosil in a patient with chronic renal failure: case report. Turkey Marmara Med J 2004;17:129-32.
Roger walker. Clinical pharmacy and therapeutics. edinberg churchil publishers: 2009;3rd Edition; 2009. p. 33-4.
Inman Sharon R, Davis Nancy A, Mazzone Maria E, Olson Kristen M, Lukaszek Victoria A, Yoder Kristy. N.Simvastatin and L-arginine preserve renal function after ischemia/reperfusion injury. Am J Med Sci 2005;329:13-7.
Rajitha Panonnummal, Joyamma Varkey, Dinoop D R. Are statins nephroprotective? A dose dependent study in albino rats. Int J Pharm Sci 2013;5:182-90.
DJ Kornbrust, JS MacDonald, CP Peter, DM Duchai, RJ Stubbs, AW Alberts. Toxicity of the HMG-coenzyme A reductase inhibitor, lovastatin, to rabbits. J Pharmacol Expe Ther 1989;248:498-05.
Behzad Najafian, Donald B. Franklin, Agnes B. Fogo. Acute renal failure and myalgia in a transplant patient. J Am Soci Nephrol 2007;18:2870–74.
Lewin JJ, JM Nappi, MH Taylor. Rhabdomyolysis with concurrent atorvastatin and diltiazem. Ann Pharmacother 2010;36:1546-9.
Maltz HC, Balog DL, Cheigh JS. Rhabdomyolysis associated with concomitant use of atorvastatin and cyclosporine. Ann Pharmacother 1999;33:1176-9.
Jimmy Jose, Kavitha Saravu, Barkur Anathakrishna Shastry. Atorvastatin-induced early-onset rhabdomyolysis in a patient with nephrotic syndrome. Am J Health Syst Pharm 2008;64(7):726-9.
Daniele Vallisa, M Raffaella Berte`, Iuseppe Civardi, Luigi Cavanna. Fatal rhabdomyolysis associated with simvastatin in a renal transplant patient. Am J M 2000;108:351-3.