Recovery from Aminoglycoside Nephrotoxicity with Continued Drug Administration

Abstract

To examine the nephrotoxicity of prolonged gentamicin administration compared to the effect obtained when a less toxic aminoglycoside is substituted during the course of treatment, we gave gentamicin (67.5 mg/kg per day) to rats for 21 days, gentamicin for 14 days followed by either netilmicin or tobramycin for 7 days, or gentamicin for 14 days followed by saline diluent. After initial tubular, necrosis, the animals recovered from renal injury whether the drug was continued or discontinued or another drug was substituted. These data are consistent with the observation that regenerating renal epithelium is resistant to continued or additional nephrotoxic insults. These findings suggest that improvement in renal function during aminoglycoside therapy cannot necessarily be attributed to the substitution of another aminoglycoside or other therapeutic interventions.Aminoglycoside antibiotics differ in their propensity to cause renal damage in experimental animals. Previous studies have shown that tobramycin and netilmicin are less nephrotoxic than gentamicin in rats (1, 3, 7). Should nephrotoxicity occur during gentamicin therapy in humans, clinicians have the option of changing their therapy to an aminoglycoside purported to be less nephrotoxic. In all likelihood any improvement in renal function would be attributed to the drug substitution. We studied the course of prolonged gentamicin administration in rats with or without substitution of another aminoglycoside late in the course of treatment. After 2 weeks, renal function and structure recovered whether the gentamicin, was continued or another drug was substituted. These studies indicate that, in rats, recovery from aminoglycoside nephrotoxicity may occur despite continued administration of the same, or a different, aminoglycoside. MATERIALS AND METHODSAdult, male Sprague-Dawley rats (Cox Laboratories, Indianapolis, Ind.), weighing 225 to 250 g, were housed and fed as described elsewhere (4). Ten groups of 12 rats each were studied. Four groups were given gentamicin, 67.5 mg/kg per day, as a daily subcutaneous injection in 1 ml of saline diluent for 14 days. Thereafter, group 1 received saline diluent, group 2 received netilmicin (90 mg/kg per day), group 3 received tobramycin (67.5 mg/kg per day), and group 4 received gentamicin (67.5 mg/kg per day) for an additional 7 days, after which the animals were sacrificed.

Correlation between renal membrane binding and nephrotoxicity of aminoglycosides

“…Renal membranes from young rats exhibited a lower affinity for [3H]amikacin binding in (14,32). The regenerated tubules resulting from repair of damaged tissue with continuous aminoglycoside treatment may be reflective of an immature stage of development, particularly since the regenerated tubules become sensitive with time (14).…”

Increased renal DNA synthesis in vivo after administration of low doses of gentamicin to rats

“…We believe that the focal necrotic process occurring at low doses of gentamicin is actually underestimated because dead cells are quickly swept away in the tubular fluid. When animals are treated with higher doses, large zones of necrosis and adjacent zones of regeneration are easily seen during treatment (9,20) even upon continuous drug administration. High doses are also associated with plugging of tubules by cellular impaction, causing a rise in intratubular pressure (6).…”

“…High doses of gentamicin induce considerable postnecrotic regeneration, even under continuous drug administration (9,20). Tubular regeneration is also observed after treatment at low doses, but becomes unambiguously detectable by conventional histology only after prolonged treatment (28 days or more) (4,11).…”

Influence of Hydrocortisone on Gentamicin-Induced Nephrotoxicity in Rats

“…These drugs induce a lysosomal phospholipidosis characterized by inhibition of sphingomyelinase and phospholipase A1 activity and by phospholipid accumulation into lysosomes (17). This lysosomal phospholipidosis is accompanied by cellular necrosis and postnecrotic cell regeneration (10,18,20).Many risk factors associated with aminoglycoside nephrotoxicity have been identified in humans. They are an initial high rate of creatinine clearance, high initial peak levels in serum, age, sex, duration of treatment, and liver disease (23,26).…”

“…These drugs induce a lysosomal phospholipidosis characterized by inhibition of sphingomyelinase and phospholipase A1 activity and by phospholipid accumulation into lysosomes (17). This lysosomal phospholipidosis is accompanied by cellular necrosis and postnecrotic cell regeneration (10,18,20).…”