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Interaction of ischemic and antibiotic-induced injury in the rabbit kidney
Abstract:
The tubular necrosis produced by transient unilateral ischemia, three toxic cephalosporins, and the aminoglycoside neomycin were studied separately and in different combinations in the rabbit kidney. It was found that (1) mildly damaging transient ischemia (25 min) and a minimally toxic dose of the rapidly secreted cephalosporin cephaloglycin (60 mg/kg of body weight) are synergistically damaging; (2) there is no synergy between ischemia and the nonsecreted cephalosporin cephaloridine (90 mg/kg); and (3) ischemia and neomycin (100 mg/kg per day for three days) are not additively damaging, but the aminoglycoside has an additive effect with the combined insults of ischemia and cefazolin (500 mg/kg). Studies of transport showed that ischemia potentiates cephalosporin toxicity probably because it increases postischemic antibiotic concentrations in proximal tubular cells and that this increased uptake is the result of transiently augmented tubular secretion. Although this ischemic protocol reduced inulin clearance by 40%, it increased cephaloglycin secretion by an amount more than sufficient to overcome the decrease in filtration.
Insights
Transient kidney ischemia and certain cephalosporins cause synergistic damage, likely due to increased antibiotic uptake in kidney tubules. This interaction is crucial for understanding drug-induced kidney injury.
Area of Science:
- Nephrology
- Pharmacology
- Toxicology
Background:
- Kidney injury can result from ischemia and certain antibiotics.
- Understanding synergistic nephrotoxicity is vital for patient safety.
Purpose of the Study:
- To investigate the combined effects of transient ischemia and nephrotoxic drugs on rabbit kidneys.
- To elucidate the mechanisms underlying drug-induced kidney injury.
Main Methods:
- Inducing transient unilateral ischemia in rabbit kidneys.
- Administering cephalosporins (cephaloglycin, cephaloridine, cefazolin) and neomycin.
- Assessing kidney damage and drug transport mechanisms.
Main Results:
- Synergistic nephrotoxicity observed between mild ischemia and cephaloglycin.
- No synergy between ischemia and cephaloridine.
- Neomycin showed additive nephrotoxicity with combined ischemia and cefazolin.
- Ischemia potentiates cephalosporin toxicity by increasing tubular secretion and uptake.
Conclusions:
- Transient ischemia and specific cephalosporins can synergistically damage kidney tubules.
- Increased antibiotic concentration in proximal tubular cells, due to augmented secretion, underlies this potentiation.
- Findings highlight the importance of considering drug interactions and renal blood flow in nephrotoxicity.