Acute Renal Failure
to disruption of cellular ion homeostasis with decreased cellularK
content, increased Na
content and membrane depolariza-tion. Increased cytosolic free Ca
concentrations can occur inthe early or late phase of cell injury and plays a critical role lead-ing to cell death. The increase in Ca
can activate calcium acti-vated neutral proteases (calpains) that appear to contribute tothe cell injury that occurs by a variety of toxicants. During thelate phase of cell injury, there is an increase in Cl
influx, fol-lowed by the influx of increasing larger molecules that leads tocell lysis. Two additional enzymes appear to play an importantrole in cell injury, particularly oxidative injury. Phospholipase A
consists of a family of enzymes in which the activity of thecytosolic form increases during oxidative injury and contributesto cell death. Caspases are a family of cysteine proteases that areactivated following oxidative injury and contribute to cell death.Following exposure to a chemical insult those cells sufficientlyinjured die by one of two mechanisms, apoptosis or oncosis.Clinically, a vast number of nephrotoxicants can produce avariety of clinical syndromes-acute renal failure, chronic renalfailure, nephrotic syndrome, hypertension and renal tubulardefects. The evolving understanding of the pathophysiology of toxicant-mediated renal injury has implications for potentialtherapies and preventive measures. This chapter outlines someof the mechanisms thought to be important in toxicant-mediat-ed renal cell injury and death that leads to the loss of tubularepithelial cells, tubular obstruction, “backleak” of the glomeru-lar filtrate and a decreased glomerular filtration rate. The recov-ery from the structural and functional damage following chemi-cal exposures is dependent on the repair of sublethally-injuredand regeneration of noninjured cells.
CLINICAL SIGNIFICANCE OFTOXICANT–MEDIATED RENAL FAILURE
Nephrotoxins may account for approximately 50%of all cases of acute and chronicrenal failure.Nephrotoxic renal injury often occurs in conjunction with ischemic acute renal failure.Acute renal failure may occur in 2%to 5%of hospitalized patients and 10%to 15%ofpatients in intensive care units.The mortality of acute renal failure is approximatley 50%which has not changedsignificantly in the last 40 years.Radiocontrast media and aminoglycosides are the most common agents associatedwith nephrotoxic injury in hospitalized patients.Aminoglycoside nephrotoxicity occurs in 5%to 15%of patients treated withthese drugs.
REASONSFOR THE KIDNEY’SSUSCEPTIBILITY TO TOXICANT INJURY
Receives 25%of the cardiac outputSensitive to vasoactive compoundsConcentrates toxicants through reabsorptive and secretive processesMany transporters result in high intracellular concentrationsLarge luminal membrane surface areaLarge biotransformation capacityBaseline medullary hypoxia
Clinical significance of toxicant-mediated renal failure.
Reasons for the kidney’s susceptibility to toxicant injury.
FACTORSTHAT PREDISPOSE THEKIDNEY TO TOXICANT INJURY
Preexisting renal dysfunctionDehydrationDiabetes mellitusExposure to multiple nephrotoxins
Factors that predispose the kidney to toxicant injury.
Clinical Significance of Toxicant-MediatedAcute Renal Failure