Toxic and Vascular Nephropathy Associated with Orotic Acid Administration in Laboratory Cats

Dr. Donna S. Dimski, Department of Veterinary Clinical Sciences, School of Veterinary Medicine, Louisiana State University, Baton Rouge, LA 70803-8422 (USA) Dear Sir, Orotic aciduria with subsequent orotate crystalluria occasionally has resulted in ureteral or urethral obstruction in humans with hereditary orotic aciduria or other disorders of pyrimidine metabolism. Oral adminis-trationof orotic acid (OA) can result in uroli-thiasis in mice [1]. We serendipitously noted renal and urinary tract complications in a group of cats with experimentally induced orotic aciduria. Our research group has been studying the idiopathic hepatic lipidosis syndrome in cats, which is the most common hepatic disease seen by veterinarians in feline practice. One theory on the pathogenesis of this disease is that cats may develop arginine deficiency, which could result in impaired urea synthesis and alterations in nitrogen metabolism. When urea cycle function is impaired, nitrogen is shunted into the pyrimidine pathway, increasing endogenous concentrations of orotic acid, a pyrimidine precursor. OA is known to induce hepatic lipidosis in rats. In humans, hereditary orotic aciduria may occur with defects in pyrimidine synthesis, leading to marked crystalluria with sedimentation of urine, occasionally resulting in ureteral or urethral obstruction. Feeding OA to mice induces urolithiasis. As part of this ongoing study 20 cats were treated with 0.3-0.6 g OA/kg metabolic body weight (MBW) for 29 days [Dimski DS, et al., unpublished data]. The OA was given either in a liquid suspension (13 cats) or a capsule (7 cats). Serum urea, creatinine, and urine orotate: creatinine ratios (OACR) were evaluated weekly throughout this period. The 7 cats treated with 0.6 g/kg MBW OA in a capsule developed depression, dehydration, and anorexia within 1 week after OA administration was begun. Laboratory evaluation identified azotemia and increased urinary OACR. One cat died on day 28 of the study. The remaining 6 cats were euthanized on day 29. Necropsy examination revealed wedge-shaped, depressed areas of the renal cortex, which corresponded to interstitial fibrosis and inflammation (fig. 1). Histopathologic changes seen in the kidneys included toxic tubular-nephrosis and vasculitis with thrombosis (fig. 2). The tubular changes consisted of epithelial necrosis, degeneration with