PMID- 9579027 OWN - NLM STAT- MEDLINE DCOM- 19980619 LR - 20181201 IS - 1096-6080 (Print) IS - 1096-0929 (Linking) VI - 42 IP - 2 DP - 1998 Apr TI - Short communication: renal tubular vacuolation in animals treated with polyethylene-glycol-conjugated proteins. PG - 152-7 AB - During toxicologic evaluation of a dimeric PEG-linked protein, tumor necrosis factor binding protein (TNF-bp), vacuolation of renal cortical tubular epithelium was seen in male and female Sprague-Dawley rats (200-300 g) given i.v. 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 months were only partially reversible after a 2-month recovery period. Despite the presence of marked vacuolation, there were no changes in BUN, creatinine, urinalysis parameters, urinary NAG, urinary B2-microglobulin, or fractional sodium excretion. Single i.v. doses > or = 20 mg/kg TNF-bp caused similar but milder changes. However, equivalent doses of PEG alone or the non-PEG-linked TNF-bp did not cause light microscopic evidence of vacuolation. Treatment of rats with another PEG-linked protein of similar molecular weight resulted in similar changes. Immunostaining for TNF-bp revealed positivity in the apical cytoplasm of renal tubular epithelium within 1 h of i.v. dosing. Immunostaining of kidneys from chronically dosed rats indicated that protein was present in some vacuoles as long as dosing continued; however, kidneys from animals on a reversibility study had vacuoles but no immunostaining for TNF-bp. These results, along with a study that showed more severe lesions with PEG-linked proteins of lower molecular weight and minimal if any lesions with PEG-linked proteins > 70 kDa, suggest that TNF-bp is filtered through the glomerulus and that the protein with attached PEG is reabsorbed by the proximal tubules. Vacuolation may be a result of fluid distension of lysosomes due to the hygroscopic nature of PEG. These studies demonstrated that PEG-linked proteins have the capacity to induce renal tubular vacuolation at high doses. However, the change was not associated with alteration of clinical pathology or functional markers. FAU - Bendele, A AU - Bendele A AD - Amgen Inc., Boulder, Colorado 80301, USA. FAU - Seely, J AU - Seely J FAU - Richey, C AU - Richey C FAU - Sennello, G AU - Sennello G FAU - Shopp, G AU - Shopp G LA - eng PT - Journal Article PL - United States TA - Toxicol Sci JT - Toxicological sciences : an official journal of the Society of Toxicology JID - 9805461 RN - 0 (Carrier Proteins) RN - 0 (Receptors, Tumor Necrosis Factor) RN - 0 (Receptors, Tumor Necrosis Factor, Type I) RN - 0 (Tumor Necrosis Factor Decoy Receptors) RN - 1IEO802L3J (recombinant human tumor necrosis factor-binding protein-1) RN - 3WJQ0SDW1A (Polyethylene Glycols) SB - IM MH - Animals MH - Carrier Proteins/chemistry/*toxicity MH - Female MH - Kidney Tubules/*drug effects/pathology/ultrastructure MH - Male MH - Molecular Weight MH - Polyethylene Glycols/*chemistry MH - Rats MH - Rats, Sprague-Dawley MH - *Receptors, Tumor Necrosis Factor MH - Receptors, Tumor Necrosis Factor, Type I MH - Tumor Necrosis Factor Decoy Receptors MH - Vacuoles/*drug effects EDAT- 1998/05/14 00:00 MHDA- 1998/05/14 00:01 CRDT- 1998/05/14 00:00 PHST- 1998/05/14 00:00 [pubmed] PHST- 1998/05/14 00:01 [medline] PHST- 1998/05/14 00:00 [entrez] AID - S1096-6080(97)92396-9 [pii] AID - 10.1006/toxs.1997.2396 [doi] PST - ppublish SO - Toxicol Sci. 1998 Apr;42(2):152-7. doi: 10.1006/toxs.1997.2396.