JPC SYSTEMIC PATHOLOGY

URINARY SYSTEM

January 2024

U-T08 (NP)

 

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, cortical and medullary tubular epithelium shows one or more of the following changes: Necrosis characterized by loss of  cellular detail, indistinct cell borders, hypereosinophilic cytoplasm, nuclear 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. Less affected tubules are often ectatic, lined by attenuated epithelium and contain either an eosinophilic homogeneous material (proteinosis), or amorphous granular eosinophilic material that is occasionally admixed with sloughed epithelial cells and cellular debris (granular and cellular casts). Rarely, medullary tubule lumina contain granular basophilic material (mineral) or similar proteinosis and casts. The interstitium is multifocally expanded by low numbers of lymphocytes, plasma cells, and occasional neutrophils with mild edema, congestion, and hemorrhage.                      

 

MORPHOLOGIC DIAGNOSIS: Kidney, cortical and medullary tubules: Degeneration and necrosis, acute, diffuse, severe, with proteinosis, granular and cellular casts, and mild lymphoplasmacytic interstitial nephritis, breed unspecified, bovine.

 

ETIOLOGIC DIAGNOSIS: Antibiotic-induced nephrosis

 

CAUSE: Oxytetracycline toxicosis

 

GENERAL DISCUSSION: 

•    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 (U-T07); sulfonamides (newer sulfonamides have greater solubility); cephalosporins; and polymixins
• Amphotericin B is an antifungal, polyene antibiotic, which can also cause acute tubular necrosis

 

PATHOGENESIS:

• 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:

 

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: 

 

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

 

DIFFERENTIAL DIAGNOSIS:

Acute tubular necrosis in cattle due to nephrotoxins with similar histologic and gross findings:

• Redroot pigweed (Amaranthus retroflexus) (U-T13): Toxic principle not yet identified
• Oak (Quercus sp.) (U-T14): Toxic substances are gallotannins
• Oxalate containing plants (U-T06): More common in sheep
• Metals (arsenic, mercury, lead (U-T02), cadmium)
• Ischemic acute tubular necrosis: Patchy necrosis of entire nephrons (especially proximal tubules) with disruption of tubule basement membranes (tubulorrhexis)

 

COMPARATIVE PATHOLOGY:

• 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

REFERENCES:

1. 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.   
2. 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.
3. 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.
4. Sula, MM and Lane, LV. The urinary system. In: Zachary JF, McGavin MD, eds. Pathologic Basis of Veterinary Disease. 7th ed. St. Louis, MO: Elsevier; 2022:736. 
5. 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.

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