Renal pathophysiologic role of cortical tubular inclusion bodies.
Renal tubular inclusion bodies are rarely associated with drug administration. The authors describe the finding of renal cortical tubular intranuclear and intracytoplasmic inclusion bodies associated with the oral administration of a norepinephrine/serotonin reuptake inhibitor (NSRI) test article in Sprague-Dawley (SD) rats. Rats were given an NSRI daily for 4 weeks, and kidney histopathologic, ultrastructural pathology, and immunohistochemical examinations were performed. Round eosinophilic intranuclear inclusion bodies were observed histologically in the tubular epithelial cells of the renal cortex in male and female SD rats given the NSRI compound. No evidence of degeneration or necrosis was noted in the inclusion-containing renal cells. By ultrastructural pathology, inclusion bodies consisted of finely granular, amorphous, and uniformly stained nonmembrane-bound material. By immunohistochemistry, inclusion bodies stained positive for d-amino acid oxidase (DAO) protein. In addition, similar inclusion bodies were noted in the cytoplasmic tubular epithelial compartment by ultrastructural and immunohistochemical examination.  This is the first description of these renal inclusion bodies after an NSRI test article administration in SD rats. Such drug-induced renal inclusion bodies are rat-specific, do not represent an expression of nephrotoxicity, represent altered metabolism of d-amino acids, and are not relevant to human safety risk assessment.
Pfizer Worldwide Research and Development, Drug Safety R&D, Cambridge, MA 02140, USA. zaher.radi@pfizer.com
Zaher A
ZA
Radi
Zachary S
ZS
Stewart
Felicity A
FA
Grzemski
Walter F
WF
Bobrowski
D000818:Animals; D003605:D-Amino-Acid Oxidase / Q000737:chemistry / Q000378:metabolism; D005260:Female; D007150:Immunohistochemistry; D002479:Inclusion Bodies / Q000737:chemistry / Q000378:metabolism / Q000473:pathology* / Q000648:ultrastructure; D007668:Kidney / Q000737:chemistry / Q000166:cytology / Q000473:pathology; D007672:Kidney Cortex / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D007674:Kidney Diseases / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D007684:Kidney Tubules / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D008297:Male; D009336:Necrosis / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley
D003605:D-Amino-Acid Oxidase