JPC SYSTEMIC PATHOLOGY
Signalment (JPC Accession #1949349): A 10-month-old, feedlot calf
HISTORY: This calf was one of 25 calves treated for signs of anorexia and respiratory disease with oxytetracycline (OTC). This calf did not respond to treatment and died four days after the initiation of therapy. A total of 12 of the 25 calves died and were presented for necropsy with similar lesions.
HISTOPATHOLOGIC DESCRIPTION: Kidney: Diffusely, tubular epithelium shows one or more of the the following changes: necrosis characterized by loss of cellular detail, indistinct cell borders, hypereosinophilic cytoplasm, karyolysis, pyknosis or karyorrhexis, and epithelial detachment from intact basement membranes; degeneration characterized by swollen, pale, vacuolated cytoplasm; or regeneration characterized by basophilic cytoplasm, large vesiculate nuclei with a prominent nucleolus, and rare mitotic figures. Lesser affected tubules are often ectatic, lined by attenuated epithelium and contain either an eosinophilic homogeneous material (proteinaceous fluid), or amorphous granular eosinophilic material that is occasionally admixed with sloughed epithelial cells and cellular debris (hyaline and cellular casts). Rarely, medullary tubule lumina contain granular basophilic material (mineral). The interstitium is multifocally expanded by low numbers of lymphocytes, plasma cells, and occasional neutrophils with mild edema, congestion and hemorrhage.
MORPHOLOGIC DIAGNOSIS: Kidney: Tubular degeneration and necrosis, multifocal, marked, with intratubular protein, hyaline and cellular casts, and mild lymphoplasmacytic interstitial nephritis, breed unspecified, bovine.
ETIOLOGIC DIAGNOSIS: Antibiotic-induced nephrosis
CAUSE: Oxytetracycline toxicosis
- High doses of oxytetracycline can cause acute tubular necrosis, resulting in acute renal failure
- Tetracyclines are excreted from the body primarily by the kidneys; any degree of renal dysfunction leads to increased serum drug concentrations and enhanced nephrotoxic potential; thus tetracyclines are contraindicated in renal failure
- Most cases involve feedlot cattle treated with tetracyclines for bacterial pneumonia
- Doxycycline, a semisynthetic tetracycline, is not reported to be nephrotoxic
- Other antibiotics that can cause acute tubular necrosis (foals especially susceptible) include aminoglycosides; sulfonamides (newer sulfonamides have greater solubility); cephalosporins; and polymixins
- Amphotericin B is an antifungal, polyene antibiotic, which can also cause acute tubular necrosis
- High doses of tetracyclines impair mitochondrial oxidative phosphorylation in tubular epithelial cells (possibly by calcium/magnesium chelation) > necrosis
- Tetracycline degradation products (outdated formulations) block tubular resorption sites and inhibit tubules from concentrating urine > loss of protein, potassium, bicarbonate > metabolic acidosis and dehydration
- Tetracyclines may inhibit amino acid incorporation into proteins > increased nitrogenous compounds in kidneys > azotemia
- Decreased production of lipoprotein lipase > triglyceride accumulation, fatty change in hepatocytes
- Several binding products in tetracyclines are harmful:
- propylene glycol induces systemic hypotension, decreased renal arterial blood flow
- polyvinylpyrrolidone increases systemic vascular resistance by constriction of peripheral arterioles
TYPICAL CLINICAL FINDINGS:
- Acute renal failure: depression, emesis, diarrhea, oliguria or anuria
- Proximal tubular nephropathy is characterized by renal tubular acidosis, glucosuria, proteinuria, aminoaciduria, hyperphosphaturia, hypokalemia
- Rapid intravenous injection of tetracyclines can cause acute collapse syndrome (cattle and horses)
- Gastrointestinal disorders are due to the irritant effect of the drug (especially oxytetracycline); GI signs are most common in horses and cats
TYPICAL GROSS FINDINGS:
- Pale swollen kidneys, peri-renal edema and hemorrhage
TYPICAL LIGHT MICROSCOPIC FINDINGS:
- Tubular epithelial degeneration and necrosis with intact basement membranes
- Cells of proximal convoluted tubules are sloughed segmentally forming intraluminal granular debris
- Distal convoluted tubules and collecting ducts contain hyaline, granular or cellular casts
ULTRASTRUCTURAL FINDINGS: Swelling of mitochondria, hydropic degeneration of tubule cells
ADDITIONAL DIAGNOSTIC TESTS:
- History of administration of oxytetracycline
- Serum biochemistry values consistent with acute renal failure (azotemia, hyperphosphatemia, hypocalcemia, hyperkalemia)
- Urinalysis: isosthenuria, proteinuria, hematuria, casts, glucosuria
Acute tubular necrosis in cattle due to nephrotoxins with similar histologic and gross findings:
- Redroot pigweed (Amaranthus retroflexus): Toxic principle not yet identified
- Oak (Quercus ): Toxic substances are gallotannins
- Oxalate containing plants: More common in sheep
- Metals (arsenic, mercury, lead, cadmium)
- Ischemic acute tubular necrosis: Patchy necrosis of entire nephrons (especially proximal tubules) with disruption of tubule basement membranes (tubulorrhexis)
- Canine (Basenji dogs): Overdosing can cause acute tubular injury and renal failure in dogs
- Calves: Acute tubular injury & death (due to tetracycline degradation product)
- Equine: Anaphylaxis
- Feline: Anaphylaxis
- Human: Degraded (outdated) tetracyclines:
- Reversible diabetes insipidus
- Reversible Fanconi-like syndrome
- Breshears MA, Confer AW. The urinary system. In: Zachary JF, ed. Pathologic Basis of Veterinary Disease. 6th ed. St. Louis, MO: Mosby/Elsevier; 2017:654-655.
- Cianciolo RE, Mohr FC. Urinary system. In: Maxie MG,ed. Jubb, Kennedy, and Palmer’s Pathology of Domestic Animals. 6th ed. Vol. 2. Philadelphia, PA:Elsevier; 2016: 424.
- Lairmore M.D, Alexander A.F, Powers B.E., et al. Oxytetracycline-associated nephrotoxicosis in feedlot calves. J Am Vet Med Assoc. 1984;185:793-795.
- Moalli M.R, Dysko R.C, Rush H.G., et al,. Oxytetracycline-induced nephrotoxicosis in dogs after intravenous administration for experimental bone labeling. Lab An Sci. 1996;46:497-502.
- TerHune NT, Upson WD. Oxytetracycline pharmacokinetics, tissue depletion, and toxicity after administration of a long-acting preparation at double the label dosage. J Am Vet Med Assoc. 1989;194:911-917.