Acute kidney injury mechanisms

Mechanisms of drug induced acute kidney injury... 

Traditionally, when searching for the etiology of AKI, the clinician s will subdivides the potential causes of a sudden decline of GFR into one of three general pathophysiologic processes pre renal failure, intrarenal failure or post renal failure [1]. Recently, Miet et al [ 52] in discussing drug-induce acute kidney injury detailed two additional mechanisms that need to be considered in addition to those outlined in Table 2. 

Crystal deposition Particularly important with acyclovir and indinavir, but also noted with sulfonamides, methotrexate and triamterene. This mechanism is becoming more recognized due to the rise in the incidence of tumor-lysis syndrome with AKI. Acute kidney injury caused by tubular obstruction can also occur with a number of drugs (Table 2), due to intratubular precipitation of the... 

Despite the significant progress made in understanding the biology and mechanisms of acute kidney injury (AKI) in animal models, translation of this knowledge into improved management and outcomes for patients has been limited. In fact, with few exceptions pharmacological therapies to prevent AKI have not been successful. Thus, prevention of AKI must be a priority to avoid the morbidity and mortality associated with this event. 

The mechanisms of the changes in cell viability during renal injury are incompletely understood. Most of the experimental data have been derived from the ischemia-reperfusion model of acute kidney injury and have focused on necrotic cell death. Because as many as 50% of patients have ischemia-induced acute kidney injury, the observations should be relevant to a large portion of the patients at risk. Also, different stresses initiate common biochemical events, so that understanding the relevant pathways of one stress will most likely be apphcable to others. What follows is a detailed analysis of some of the pathways currently thought to execute cell death in a variety of nephrotoxic insults. 

Ischemic, nephrotoxic, and septic rodent models of acute renal injury were developed to study mechanisms of acute kidney injury. Decreasing renal blood flow is critical in the pathophysiology of AKI in humans. Ischemic and other animal models are used to reproduce the morphological features of human disease. 

The mechanism of the acute kidney injury is thought to be multifactorial and similar to other cases of myoglobinuric renal failure [118, 121-126]. These factors include obstruction of tubules, toxic effects of the pigment or iron on renal tubular cells and altered hemodynamics in association with inhibition of the vasodilator nitric oxide by myoglobin. Experimental animals exposed to heme pigment have increases in the renal synthesis of both heme oxidase and ferritin [125]. This allows for more rapid heme degradation and greater sequestration of potentially toxic iron by the tubular cells [125]. Whether narcotics or the hypotensive, hypoxic environment associated with rhabdomyolysis interfere with these protective effects of the kidney is unknown. 

Vieira JM Jr., Castro I, Curvello-Neto A, et al. Effect of acute kidney injury on weaning from mechanical ventilation in critically ill patients. Crit Care Med 2007 35(1) 184—191. 

Clinical effects caused by acute tetrachloroethylene exposure include central nervous system depression, liver or kidney injury, and in severe cases even death from anesthetic effects (see Section 2.5). Other effects can include malaise, dizziness, fatigue, headache, and lightheadedness, all of which may disappear soon after the exposure is stopped (HSDB 1996). The mechanism of action for the central nervous system effects has not been clearly established but may be related to solvent effects on lipid and fatty acid compositions of membranes (Kyrklund et al. 1984, 1988, 1990). 

It is almost impossible to individualize the exact role of CSA-induced chronic nephrotoxicity in renal allograft outcomes. From the moment of implantation, the transplanted kidney will suffer from mechanical manipulation, ischemic injury and immunologic attack. Later on acute rejection, recurrent or de novo renal disease, hypertension, chronic viral infection, metabolic derangements (dyslipidemia, diabetes, and hyperuricemia), chronic rejection and aging may work in various combinations causing progressive structural damage and functional impairment. 

The general processes are manifested by various mechanisms, determined by the type and characteristics of the toxic noxa. Most often met with are a) heavy dehydratation by copious vomiting and diarrheas related to the local damages b) affection of the acid-alkaline and water-electrolytic balance c) acute blood circulation disorders as a consequence of the dehydratation, as well as of the direct injury by some poisons of the vasomotor centers d) syndromes of the central nervous system (consciousness disorders, convulsions, coma, etc.), the liver, the kidneys, the blood, etc., depending on the chemical character of the poison. 

Studies of the pathophysiology of acute renal failure has classically considered both tubular and vascular mechanisms [227,228]. In vitro techniques isolating either the vascular or tubular components have been developed. For example, the use of isolated proximal tubules in suspension or in culture allows the study of tubular mechanisms of injury in the absence of vascular factors [229] [230]. There are both in vitro and in vivo models to study vascular injury in the kidney. In vitro models include the study of vascular smooth muscle cells or endothelial cells in culture. In this section, the in vivo methods to evaluate the renal micro-circulation will be discussed. This is of relevance as many nephrotoxins exert their deleterious effects through pharmacologic actions on the resistance vasculature with parenchymal injury occurring as a consequence of ischemia. In clinical practice nephrotoxins may cause prerenal azotemia as a result of increased renal vascular resistance. Nephrotoxins that cause acute renal failure on a vascular basis include prostaglandin inhibitors e.g. aspirin, non-steroidal anti-... 

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