SHORT COMMUNICATION - RENAL TUBULAR VACUOLATION IN ANIMALS TREATED WITH POLYETHYLENE-GLYCOL-CONJUGATED PROTEINS

During toxicologic evaluation of a dimeric PEG-linked protein, tumor n ecrosis factor binding protein (TNF-bp), vacuolation of renal cortical tubular epithelium was seen in male and female Sprague-Dawley rats (2 00-300 g) given iv doses of 40, 20, or 10 mg/kg every other day for 3 months. Tubular lesions in rats treated with 20 or 40 mg/kg for 3 mont hs were only partially reversible after a 2-month recovery period. Des pite the presence of marked vacuolation, there were no changes in BUN, creatinine, urinalysis parameters, urinary NAG, urinary B-2-microglob ulin, or fractional sodium excretion. Single iv doses greater than or equal to 20 mg/kg TNF-bp caused similar but milder changes. However, e quivalent doses of PEG alone or the non-PEG-linked TNF-bp did not caus e light microscopic evidence of vacuolation. Treatment of rats with an other PEG-linked protein of similar molecular weight resulted in simil ar changes. Immunostaining for TNF-bp revealed positivity in the apica l cytoplasm of renal tubular epithelium within 1 h of iv dosing. Immun ostaining of kidneys from chronically dosed rats indicated that protei n was present in some vacuoles as long as dosing continued; however, k idneys from animals on a reversibility study had vacuoles but no immun ostaining for TNF-bp. These results, along with a study that showed mo re severe lesions with PEG-linked proteins of lower molecular weight a nd minimal if any lesions with PEG-linked proteins >70 kDa, suggest th at TNF-bp is filtered through the glomerulus and that the protein with attached PEG is reabsorbed by the proximal tubules. Vacuolation may b e a result of fluid distension of lysosomes due to the hygroscopic nat ure of PEG. These studies demonstrated that PEG-linked proteins have t he capacity to induce renal tubular vacuolation at high doses. However , the change was not associated with alteration of clinical pathology or functional markers. (C) 1998 Society of Toxicology.