Animal models of acute renal failure

Abstract

The animal models are pivotal for understanding the characteristics of acute renal failure (ARF) and development of effective therapy for its optimal management. 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; ischemia-reperfusion-induced ARF simulate the hemodynamic changes-induced changes in renal functioning; drug-induced such as gentamicin, cisplatin, NSAID, ifosfamide-induced ARF mimics the renal failure due to clinical administration of respective drugs; uranium, potassium dichromate-induced ARF mimics the occupational hazard; S-(1,2-dichlorovinyl)-Lcysteine-induced ARF simulate contaminated water-induced renal dysfunction; sepsis-induced ARF mimics the infection-induced renal failure and radiocontrast-induced ARF mimics renal failure in patients during use of radiocontrast media at the time of cardiac catheterization. Since each animal model has been created with specific methodology, therefore, it is essential to describe the model in detail and consequently interpret the results in the context of a specific model.

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.