JPC SYSTEMIC PATHOLOGY
Signalment (JPC Accession # 2026604): A five-month-old beagle
HISTORY: This beagle had a fever of 105o F and was treated with gentamicin. It died 14 days after treatment began.
HISTOPATHOLOGIC DESCRIPTION: Kidney: Diffusely within the cortex, in approximately 50% of the renal proximal tubules, there is complete loss of tubular epithelium, with lumens that contain amphophilic granular necrotic debris, or cellular casts composed of sloughed epithelial cells that are shrunken with hypereosinophilic cytoplasm and karyorrhectic or karyolytic nuclei (necrosis). Multifocally, cortical tubules are ectatic with attenuated epithelium and lumina are infrequently expanded by granular, basophilic, acellular material (mineral). Multifocally within less affected renal tubules, epithelium are swollen with vacuolated to granular eosinophilic granular cytoplasm and loss of cellular detail (degeneration), or is piled up with a moderate amount of amphophilic cytoplasm and large, irregularly round, more densely basophilic nuclei with rare mitotic figures (regeneration). Multifocally, medullary collecting ducts contain a moderate amount of eosinophilic, globular material (proteinosis). Diffusely, Bowman's space is expanded, and multifocally, glomeruli are mildly congested.
MORPHOLOGIC DIAGNOSIS: Kidney, cortex, tubules: Degeneration and necrosis, subacute, diffuse, severe with granular and cellular casts, beagle, canine.
ETIOLOGIC DIAGNOSIS: Toxic nephrosis
CAUSE: Aminoglycoside antibiotic
CONDITION: Nephrotoxic tubular necrosis
- Aminoglycosides (AG) are bactericidal for many gram-negative organisms
- AGs are obligate nephrotoxins
- In cats, are also ototoxic
- Degree of nephrotoxicity: Neomycin > kanamycin > gentamycin > streptomycin > tobramycin > amikacin
- Cause direct toxic injury to proximal tubular epithelium
- AGs are almost exclusively filtered by the glomerulus and excreted unchanged (not metabolized)
- Filtered aminoglycosides bind to phospholipids in the brush border -> enter and accumulate in proximal convoluted tubular epithelial cells via pinocytosis -> vesicles fuse rapidly with lysosomes -> inhibit lysosomal enzymes (phospholipases and sphingomyelinase) -> lysosomal enzymes cannot degrade phospholipid-rich cell membranes (phospholipidosis) -> membranes accumulate in phagolysosome -> formation of myeloid bodies (lamellar structures that contain undegraded phospholipids) -> lysosomes enlarge and rupture -> enzyme leakage causes cellular degeneration and necrosis
- Aminoglycosides also inhibit Na-K-ATPase -> intracellular influx of hydrogen and sodium -> influx of water -> cellular swelling -> cell death
- In absence of renal failure, toxicity is reversible
- Proximal convoluted tubule epithelial cells regenerate, even in the face of continued aminoglycoside therapy, because cells have increased resistance to AGs
- As these cells mature (7-14 days), they become susceptible to the toxic effects of AGs
TYPICAL CLINICAL FINDINGS:
- Typical of acute renal failure:
- Anorexia, listlessness, vomiting
- Azotemia, increased creatinine and BUN, hyperphosphatemia, hyperkalemia
- Proteinuria, isosthenuria, oliguria or anuria
- Factors enhancing AG nephrotoxicosis:
- Fever, dehydration, sepsis
- Preexisting renal and hepatic disease
- Combined therapy with cephalosporin antibiotics
- Animals with enteric disease (ie. parvovirus-infected dogs) given AG orally: Normally these are poorly absorbed, except when GI mucosal integrity is compromised
TYPICAL GROSS FINDINGS:
- Pale, swollen kidneys
- Cut surface is pale and moist with bulging of the cortex
TYPICAL LIGHT MICROSCOPIC FINDINGS:
- Initial accumulation of hyaline globules within the cytoplasm of proximal convoluted tubules
- Damage and loss of brush border
- Necrosis and sloughing of individual epithelial cells into tubular lumina
- Presence of myeloid bodies and cytosegrosomes (inclusions that contain cellular organelles) in damaged proximal tubular epithelium
- Formation of hyaline, granular, and/or mineralized casts
- Can progress to necrosis of entire segments of proximal tubules
- Preservation of basement membranes (differentiated from ischemic necrosis which exhibits loss of basement membranes, ie tubulorrhexis)
- Tubular regeneration
- The hallmark finding is concentric multilaminated phospholipid membrane whorls in the phagolysosome (myeloid bodies)
- Loss of microvilli
- Glomeruli are spared
ADDITIONAL DIAGNOSTIC TESTS:
- Biomarkers: cystatin C is the most sensitive index of kidney injury
Other nephrotoxic agents:
- Exogenous: Antimicrobials, chemotherapeutic agents, heavy metals, paraquat, monensin, ethylene glycol, chlorinated hydrocarbons, mycotoxins, NSAIDS, vitamin D, venoms, canthardins
- Endogenous: Bile, hemoglobin, myoglobin
- Specific examples of nephrotoxins in various species:
- Equine: Monensin; foals and older, sick foals particularly susceptible to aminoglycoside toxicity
- Bovine: Oxalate toxicity (Halogeton , Rumex sp., Sarcobatus sp.; Quercus sp.); monensin; plants with vitamin D-like toxicity (Cestrum diurnum)
- Sheep: Oxalate toxicity
- Poultry: Monensin
- Rodents: Chloroform
- Canine: Ethylene glycol; NSAIDs; Tibetan spaniels with inherited hyperoxaluria; vitamin D nephropathy
- Feline: Ethylene glycol; vitamin D nephropathy; Easter lilies
- Porcine: Pigweed (Amaranthus retroflexus); Ochratoxin A
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