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Nephrotoxic injury by drugs (e.g., aminoglycosides, cyclosporine, amphotericin B, cisplatin) or contrast dyes seldom occurs unless coexisting risk factors exist.[10] Such factors may be acute (shock, hypovolemia, congestive heart failure) or chronic (advanced age, diabetes, chronic renal insufficiency). The risk of nephrotoxicity increases exponentially with the number of risk factors and nephrotoxic combinations.
Nephrotoxic acute renal failure is usually nonoliguric, with loss of concentrating ability and slowly progressive azotemia. As the GFR declines, accumulation of renally excreted drugs exacerbates nephrotoxicity unless drug levels are carefully monitored and the dosage repeatedly adjusted. However, the prognosis for recovery is good if these agents are discontinued in time and no coexistent organ failure is present.
Aminoglycosides (gentamicin, tobramycin, amikacin) are polycationic compounds that are filtered into the proximal tubule, where they bind to anionic brush border membrane phospholipids. Their nephrotoxicity is directly related to their polycationic status, so neomycin (six cationic sites) is more destructive than gentamicin (five sites) or streptomycin (three sites).[129] They are absorbed into intracellular lysosomes by endocytosis and thence released into the cytosol. Within the cell, they induce defects in lysosomes, plasma membranes, and mitochondria and, in particular, inhibit oxidative phosphorylation and the synthesis of high-energy phosphate compounds such as ATP.
Aminoglycoside-induced nephrotoxicity is directly related to sustained high trough serum levels, especially when associated with advanced age, preexisting renal disease, renal vasoconstrictive states (sepsis, hypovolemia, liver disease, congestive heart failure), adjuvant drug therapy (loop diuretics, vancomycin, cephalosporins, NSAIDs, cyclosporine, amphotericin B), and electrolyte disorders (hypokalemia, hypomagnesemia, hypercalcemia, and metabolic acidosis).[130]
Prevention of aminoglycoside nephrotoxicity depends on maintenance of adequate hydration, avoidance or removal of the risk factors enumerated earlier, and careful monitoring of serum aminoglycoside levels. A daily 2-hour creatinine clearance measurement can also be helpful in the early detection of aminoglycoside-induced nephrotoxicity and appropriate dose adjustment for GFR. Once-daily administration of aminoglycosides to achieve a high therapeutic level with an adequate trough period for renal recovery may limit the occurrence of nephrotoxicity.[131] Low-dose dopamine increases the renal clearance of aminoglycosides, but it is not known whether this increased clearance protects against tubular injury.
COX-1 is inhibited by NSAIDs such as indomethacin, meclofenamate, and ketorolac for about 8 to 24 hours. A single dose of aspirin causes irreversible acetylation of COX-1. In platelets, the impact lasts for the lifetime of these cells (7 to 10 days), but the kidney resynthesizes COX within 24 to 48 hours. The renal protective function of prostaglandins is "switched on" by injury, as illustrated by the fact that NSAIDs cause nephrotoxicity in ischemic, but not normal kidneys. During conditions of stress, impaired prostaglandin activity results in decreased RBF and GFR, increased renal vascular resistance, attenuated diuretic responsiveness, and hyperkalemia.
Adverse effects of NSAIDs and aspirin have been demonstrated in animal models of hemorrhage, endotoxemia, increased venous pressure, and low cardiac output and in humans with mild underlying renal dysfunction who also have congestive heart failure, ascites, or systemic lupus erythematosus.[132] However, in an individual patient, the risk of NSAIDs-induced nephrotoxicity is very much dependent on the milieu. Postoperative analgesia with a single agent such as ketorolac is extremely unlikely to cause injury in a relatively young, healthy, well-hydrated patient. The risk of nephrotoxic injury increases exponentially with the addition of concomitant nephrotoxins (e.g., contrast dye, aminoglycosides) in the presence of acute or chronic cardiovascular instability.
NSAIDs selective for COX-2 inhibitors appear to be less likely to cause gastric irritation and erosion. However, no evidence as yet indicates that they decrease the risk of nephrotoxic injury in comparison to nonselective COX inhibitors. Similar precautions regarding hydration and selection of low-risk patients should be taken.
Cyclosporine is a remarkably potent immunosuppressive agent and, together with steroids and azathioprine, is routinely used to prevent rejection after organ transplantation (see Chapter 56 ). Indeed, heart, lung, and liver transplantation increased exponentially after its release in 1981. It causes renal injury in part because it induces sympathetic hyperreactivity, hypertension, and renal vasoconstriction.
In patients undergoing cadaveric renal transplantation, the calcium channel blocker diltiazem was added to the graft preservative solution, infused into the donor for 48 hours, and then given orally.[133] The incidence of transplant acute tubular necrosis decreased from 41% to 10%, and when acute renal failure did occur, the hemodialysis requirement was significantly less. Diltiazem impairs cyclosporine metabolism, so plasma cyclosporine levels are higher, with fewer episodes of early acute rejection, but it protects against cyclosporine nephrotoxicity.[134] The cyclosporine dosage may be reduced by 30% to achieve the same drug levels and thus represents a substantial cost savings to patients.
The nephrotoxicity of contrast dyes probably involves microvascular obstruction by crenated red cells, as well as direct tubular toxicity by release of free oxygen radicals. The risk is markedly increased in diabetic renal insufficiency, hypovolemia, congestive heart failure, and myeloma.[135] Radiocontrast dyes are hypertonic and cause an osmotic diuresis, which induces a false sense of security but exacerbates hypovolemia and renal damage. Azotemia commences 24 to 48 hours after exposure and peaks at 3 to 5 days. Surgery performed during this period greatly increases the risk of perioperative acute renal failure.
Prevention of nephrotoxicity depends on adequate hydration and deferral of elective surgical procedures until the effects of the dye have been evaluated and treated.[136] Nonionic, low-osmolar radiocontrast agents are less nephrotoxic, but they are expensive and offer an optimal cost-benefit ratio only when used in high-risk situations, such as diabetic nephropathy.[131]
A number of pharmacologic agents have possible roles in preventing or attenuating contrast nephropathy, but none replace hydration as first-line protection (see later). Intravenous mannitol has been used for many years but may exacerbate injury if it induces dehydration through excessive osmotic diuresis. Some evidence indicates that calcium channel blockers may be protective, but recent interest has focused on antioxidants and dopaminergic agonists.
Tepel and coauthors reported that prophylactic administration of the antioxidant N-acetylcysteine (600 mg orally twice daily) attenuated renal injury in a study of 83 patients with chronic renal insufficiency (mean serum creatinine, 2.4 mg/dL) undergoing contrast radiography. [137] Only 2% of patients receiving N-acetylcysteine had an increase in serum creatinine of greater than 0.5 mg/dL versus 21% of patients receiving saline placebo, and mean serum creatinine concentrations actually decreased. However, in a subsequent study of 183 patients with less severe renal dysfunction (mean serum creatinine, 1.5 mg/dL), Briguori and colleagues found that N-acetylcysteine provided better protection than did saline alone only when a low dose of contrast dye was used.[138]
A number of retrospective reviews or case series have been published that attest to the benefit of prophylactic fenoldopam infusion (<0.1 µg/kg/min) in preventing or attenuating contrast nephropathy in high-risk patients. This benefit has not yet been confirmed by randomized prospective trials. In a double-blind randomized study of 45 patients, Tumlin and coworkers found that fenoldopam infusion prevented a contrast-induced decrease in RBF, but the study was underpowered to detect differences in renal outcome.[139]
A randomized prospective study was designed by Allaqaband and colleagues to compare N-acetylcysteine, fenoldopam, and placebo in 123 high-risk patients undergoing contrast radiography for cardiovascular procedures.[49] No difference was found in the incidence of increased serum creatinine (>0.5 mg/dL) in any of the groups, and the authors concluded that neither N-acetylcysteine nor fenoldopam offered any benefit over saline.
Pigment nephropathy implies acute renal injury as a result of the nephrotoxic effect of the heme pigments myoglobin, hemoglobin, and bilirubin.
Muscle necrosis (rhabdomyolysis) occurs most commonly with direct trauma involving major crush or thermal injury. However, it also occurs with acute muscle ischemia induced by vascular disease or injury or by prolonged immobilization. Compartment syndromes exacerbate rhabdomyolysis. They are particularly likely to occur with major hemorrhage in an extremity or when vascular insufficiency coexists with tissue edema (e.g., femoral placement of an intra-aortic balloon after vein harvesting). Dramatic increases in metabolic rate (severe exercise, prolonged fever, status epilepticus or myoclonus), severe hypophosphatemia, or direct proteolysis (acute pancreatitis) can all precipitate rhabdomyolysis.[140]
Myoglobin, the oxygen-carrying heme pigment of muscle, is released into the bloodstream (myoglobinemia) and rapidly excreted by the glomerulus at a plasma threshold of 0.03 mg/dL. Delivery of myoglobin to the proximal tubule is greater in a well-muscled individual with normal GFR than in a cachectic patient with low GFR. At a urine pH of less than 5.6, myoglobin is transformed into ferrihematin, which precipitates in the proximal tubule.[141] Renal damage is facilitated by hypovolemia (i.e., low tubular flow) and acidic urine. Because of the associated hypercatabolic state, oliguria is associated with acute hyperkalemia, hypocalcemia, anion-gap metabolic acidosis, and rapid azotemia. Serum creatinine and BUN increase very rapidly (1.0 to 1.5 mg/dL/day and 20 to 30 mg/dL/day, respectively).
The most important aid to the diagnosis of rhabdomyolysis is a high index of suspicion. The affected muscle
Prevention of acute nephrotoxic tubular necrosis is dependent on maintenance of high RBF and tubular flow. Urine flow should be kept between 100 and 150 mL/hr by osmotic diuresis with intravenous mannitol, 6.25 to 12.5 g every 6 hours, with or without intravenous furosemide, 10 to 20 mg as required.[143] Urine pH should be kept above 5.6 with intravenous sodium bicarbonate, 50 mEq intravenously, as required, or acetazolamide, 250 mg every 6 hours, or both. However, because no prospective data have confirmed the beneficial effect of urinary alkalinization, urine pH should not be increased at the expense of causing significant acid-base imbalance. Calcium should be given to treat hyperkalemia only.
Acute intravascular hemolysis caused by mismatched blood transfusion (ABO incompatibility) is a direct and devastating renal insult. The renal damage is thought to be predominantly due to red blood cell stroma rather than free hemoglobin. Management is essentially the same as for rhabdomyolysis.
A direct correlation has been found between the degree of preoperative obstructive jaundice and postoperative renal dysfunction.[144] When cholestasis causes conjugated bilirubin to increase above 8 mg/dL, bile salt excretion effectively ceases, and portal septicemia and renal damage ensue. This situation is analogous to hepatorenal syndrome and sepsis, in which circulating endotoxins induce renal vasoconstriction and damage (vasomotor nephropathy).
Administration of preoperative oral bile salts (e.g., sodium taurocholate) or intravenous mannitol may provide perioperative renal protection in patients with severe obstructive jaundice. In a prospective, randomized study in patients with obstructive jaundice undergoing surgery, Plusa and Clark[145] found no difference in renal outcome between these two regimens. However, mannitol provokes a brisk osmotic diuresis, and it is important to replace urinary losses appropriately. Diuresis-induced hypovolemia negates the protective effect of mannitol. [146]
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