ReviewAnimal models of acute renal failure
Introduction
Acute renal failure (ARF) is characterized by a rapid, potentially reversible, decline in renal function including rapid fall in glomerular filtration rate (GFR) and retention of nitrogenous waste products over a period of hours or days. The mortality rate of patients with ARF has remained 25–70% despite the use of various pharmacologic agents. Therefore, it continues to be a frequent threatening complication following trauma, complex surgical procedures, and in patients hospitalized in intensive care units [73]. ARF increases the risk of death in patients after thoracoabdominal aortic surgery, bone marrow transplantation, amphotericin B therapy, in patients with liver cirrhosis and in cardiac surgery [30]. The various factors that predispose to ARF are hemodynamic instability, major vascular surgery, hypovolemia, atherosclerosis, diuretic therapy, preoperative starvation, congestive cardiac failure, peritonitis, ileus obstruction, biliary surgery, jaundice, diabetes mellitus, hypoxia, ischemia and reperfusion (I/R), pre-eclampsia/eclampsia, sepsis, major burns and pancreatitis [62].
ARF is classically divided into pre-renal, renal (intrinsic) and post-renal failure. Pre-renal ARF is a consequence of decreased renal perfusion (due to hypovolemia/shock or ischemia), which leads to a reduction in GFR. Intrinsic renal failure occurs when there is a damage to the structures of the nephron such as the glomeruli, tubules, vessels, or interstitium. The major cause of intrinsic ARF is acute tubular necrosis (ATN) that results from ischemic or nephrotoxic injury. Pre-renal ARF and ischemic ATN may occur as a continuum of the same pathophysiological process, and together account for 75% of the causes of ARF [73]. Post-renal ARF follows obstruction of the urinary collection system with an increase in pressure within the renal collecting systems resulting in reduced GFR and renal failure.
In clinical setup, the etiology of ARF is multifold and complex. Rhabdomyolysis is the syndrome characterized by breakdown of striated muscle with massive release of myoglobulin into the extracellular fluid and circulation leading to filtration of myoglobulin to renal tubules [126]. Rhabdomyolysis provokes ATN because myoglobin forms obstructing tubular casts and myoglobin also leads to intra-renal vasoconstriction due to nitric oxide scavenging and through hypovolemia. I/R-induced renal injury is also very important cause of ARF in clinical setup. Antibiotics such as gentamicin [92], anticancer agents such as cisplatin [61, 89, 94] and ifosfamide [145], radio contrast media, non-steroidal anti-inflammatory drugs (NSAIDS), osmotic changes, dietary or endogenous agents such as folic acid are the important causes of ARF [42, 51, 75, 129]. In order to understand the pathophysiology of onset of ARF in these different conditions and to explore the drug therapeutics, researchers have developed different animal models of ARF (Tab. 1 ). The present review discusses these different animal models of acute renal failure.
Section snippets
Glycerol-induced ARF
Glycerol-induced ARF is characterized by myoglobinuria, tubular necrosis [66] and enhanced renal vasoconstriction. The pathogenic mechanisms involved in glycerol-induced renal failure include ischemic injury, tubular nephrotoxicity caused by myoglobin, and the renal actions of cytokines released after rhabdomylosis [34, 135]. The large numbers of disorders known to cause rhabdomyolysis include intrinsic muscle dysfunction (including trauma, burns, intrinsic muscle disease, and excessive
Conclusions
The development of different animal models of acute renal failure, especially those closely simulating clinical conditions, has contributed immensely in understanding the pathophysiology underlying the onset of renal failure. Since the etiology for induction of renal failure is multifold, therefore, a large number of animal models have been developed to mimic the clinical conditions of renal failure. Glycerol-induced renal failure closely mimics the rhabdomyolysis; ischemiareperfusion-induced
Acknowledgment
The authors are grateful to Department of Pharmaceutical Sciences & Drug Research, Punjabi University, Patiala, India for providing technical facilities.
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