Renal Pathophysiology

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include (1) loop diuretics to inhibit metabolic demands and promote cell preservation; (2) forced diuresis to wash out cellular debris; and (3) atrial na triuretic peptide (ANP), mannitol, dopamine, and calcium channel blockers to modulate renal hemodynamics. Aminoglycoside-Induced Acute Tubular Necrosis The major causes of nephrotoxic ATN are listed in Table 11.1. One of the best understood is the renal injury that may follow prolonged administration of an aminoglycoside antibiotic such as gentamicin or tobramycin. Although newer, less toxic antibiotics have been developed in recent years, aminogly cosides remain an important class of antimicrobials. It has been estimated, for example, that an elevation in the plasma creatinine concentration of more than 0.5 to 1.0 mg/dL occurs in 10% to 20% of patients treated with these drugs. ATN can occur even if the plasma drug levels are closely monitored, al though the risk is clearly greater in those patients with high-peak drug levels. Pathogenesis The aminoglycosides are freely filtered across the glomerulus; most of the drug is then excreted with a small amount being taken up by and stored in the tubular cells, particularly those in the proximal tubule. Experimental studies suggest that intracellular aminoglycoside accumulation persists for as long as 4 to 6 weeks after therapy is discontinued. The number of cationic amino groups (NH 3 + ) per molecule appears to be an important determinant of nephrotoxicity. Neomycin (six per molecule), gentamicin (five), and tobramycin (five) produce the most renal injury; strep tomycin (three) the least. The role of molecular charge seems to be related to the binding of the cationic drug to receptors in the apical and subcellular membranes. At the apical mem brane, the aminoglycoside may bind to anionic phospholipids, thereby promoting drug entry into the tubular cell. Within the cell, the aminoglycoside accumulates within lysosomes, an effect that may also be dependent on charge. Inhibition of ly sosomal functions (such as decreased synthesis of the proteolytic enzymes cathep sin B and cathepsin L) may then be responsible for the associated cellular injury. The likelihood of developing renal injury is dependent on the dose and the duration of therapy. The plasma creatinine concentration does not usu ally begin to rise until the aminoglycoside has been given for at least 7 days in patients who are otherwise well. However, the latent period may fall to as little as 2 days if there is concurrent renal ischemia (due to volume depletion or hypotension) or sepsis with endotoxemia. Prevention Careful monitoring of drug levels and minimizing the duration of drug ther apy are at present the primary methods used to reduce the incidence of aminoglycoside nephrotoxicity. Studies indicate that aminoglycoside neph rotoxicity can be minimized by giving the entire dose once a day (4 mg/kg in

CHAPTER 11 Acute Kidney Injury

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