The nephrotoxicity and histology of cephaloridine and its polymers in rats.

Abstract Cephaloridine nephrotoxicity for female Sprague-Dawley rats has been confirmed, but can be reduced by administering the drug in dilute rather than concentrated solution. The commercial preparation contains polymers which show varying nephrotoxicity. Mixing the fractions in pairs fails to cause the damage seen after giving the commercial preparation. Mixing the 3 major fractions to reconstitute the commercial preparation only produces about half of the expected damage. If each fraction is given at high dosage, 2·2 g./kg., different degrees of damage result, least with the large polymer, greater with the medium-size polymer, and greatest with the fraction whose molecular weight is less than 1000 and which contains monomers and dimers of cephaloridine, and probably degradation products. The damage is almost comparable with that due to commercial cephaloridine. Pyridine causes minimal nephrotoxicity at equimolar dose levels. Histology shows proximal tubule cell coagulative necrosis, followed by colliquative necrosis, and repair firstly by flattened, later by cubical then columnar epithelium, finally with a brush border. The groups given smaller doses of the drug or its fractions show a subtle sleeving effect of the brush borders which detach from the underlying cell bodies, individual cell necrosis, and exfoliation or enucleation of cells. Cytoplasmic vacuolation is prominent occasionally. There is no sharp distinction between nephrotoxicity and the normal processes of exfoliation and repair. Granular precipitate and PAS positive homogeneous casts accompany severe damage. The chemical and histological results suggest that the pathogenic mechanisms responsible for damage to the tubules may be (a) precipitation of drug (or its fractions) from concentrated solution, (b) polymerization, which may be more likely to cause damage of the brush borders than precipitation since polymer is less able to redissolve than pure drug. These processes could be aggravated by other nephrotoxic agents (including diuretics), pH of tubular contents, anatomical differences between proximal convoluted tubules of the 2 sexes, and a vascular component which from histological observation does not clearly implicate renin.