JPC SYSTEMIC PATHOLOGY

URINARY SYSTEM

January 2024

U-T07

 

Signalment (JPC # 2026604): A five-month-old beagle.

 

HISTORY: This beagle had a fever of 105^o 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 proximal renal tubules, there is complete loss of tubular epithelium, with lumens that contain amphophilic granular necrotic debris (granular casts), 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, tubular epithelium is swollen with vacuolated to granular eosinophilic 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, cortical tubules: Degeneration and necrosis, subacute, diffuse, severe with granular and cellular casts, beagle, canine.

 

ETIOLOGIC DIAGNOSIS: Acute tubular injury (ATI)

 

CAUSE: Aminoglycoside antibiotic

 

CONDITION: Nephrotoxic acute tubular injury

 

GENERAL DISCUSSION: 

• Acute Tubular Injury (ATI), previously referred to as “nephrosis” or “acute tubular necrosis” (ATN), is generally due to nephrotoxins (as with aminoglycosides) or ischemic damage and is an important cause of acute renal failure (ARF)
  1. Animals with ARF are often oliguric or anuric and die within a few days without treatment, however ATI, such as that caused by aminoglycosides, can cause polyuria
• Aminoglycosides (AG) are bactericidal antibiotics that work well against many gram-negative organisms
• All AGs are nephrotoxins causing ATI and direct toxic injury to proximal tubular epithelium in many species and foals are particularly sensitive
  1. AGs include gentamicin, neomycin, kanamycin, tobramycin, amikacin, and streptomycin
     • Neomycin is highly nephrotoxic; gentamicin is intermediate (although widely used in veterinary medicine, therefore a more common cause of ATI); streptomycin is the least nephrotoxic
  2. AGs are also ototoxic 

 

PATHOGENESIS:

• Nephrotoxic ATI: Renal tubules, especially proximal tubules, are particularly susceptible to certain toxicities due to a high metabolic activity and exposure to agents in the ultrafiltrate -> Cellular damage and necrosis
  1. Tubules and interstitium are intimately associated and damage to one affects the other; additionally, nephrotoxic ATI may lead to secondary ischemic injury (e.g., due to tubuloglomerular feedback)
• Aminglycoside ATI: 
  1. AGs are almost exclusively filtered by the glomerulus and excreted unchanged > Filtered aminoglycosides bind to phospholipids in the brush border > Enter and accumulate in proximal convoluted tubular epithelium > Inhibit lysosomal phospholipases > Lysosomal enzymes cannot degrade phospholipid-rich cell membranes (phospholipidosis) > Membranes accumulate in phagolysosome > Formation of myeloid bodies (lamellar structures containing undegraded phospholipids) and cytosegrosomes > Lysosomal leakage may lead to altered mitochondrial function and protein synthesis leading to cell injury and death
  2. AGs also inhibit Na-K-ATPase > Intracellular influx of hydrogen and sodium > Influx of water > cell swelling > cell death
  3. In absence of renal failure, toxicity is reversible as tubule epithelial cells regenerate, even in the face of continued aminoglycoside therapy, because regenerating 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:

• AGs ATI: 
  1. Polyuria (due to inability to concentrate urine), enzymuria, proteinuria, hematuria and azotemia
• ATI with ARF
  1. Listlessness, vomiting
  2. Azotemia, increased creatinine and BUN, hyperphosphatemia, hyperkalemia
  3. Proteinuria, isosthenuria, oliguria or anuria
• Novel urinary biomarkers that may demonstrate ATI prior to azotemia: retinol binding protein, neutrophil gelatinase-associated lipocalin, N-acetyl-β-D-glucosaminidase, β2-microglobulin, cystatin C, and kidney injury molecule-1

 

TYPICAL GROSS FINDINGS:  

• Pale, swollen kidneys
• Cut surface is pale and moist with bulging of the cortex

 

TYPICAL LIGHT MICROSCOPIC FINDINGS:

• ATI in general:
  1. Accumulation of hyaline droplets (lysosomes swollen with protein) within the cytoplasm of proximal convoluted tubules
  2. Damage and loss of brush border; degeneration and necrosis and sloughing of individual epithelial cells into tubular lumina (forming cellular or coarsely granular casts)
  3. Tubular regeneration
  4. Glomeruli vary from normal to slightly wrinkled from poor perfusion

• In nephrotoxic ATI there is usually preservation of basement membranes 
  1. In comparison to ischemic ATI (which may exhibit loss of basement membrane or tubulorrhexis) however, because of interaction of ischemia and nephrotoxicity, the presence of a tubular basement membrane is not pathognomonic for either pathogenesis

 

ULTRASTRUCTURAL FINDINGS:  

• ATI: Irregular apical microvillus brush border, abundant electron-dense cellular debris within lysosomes, paucity of intact mitochondria, and interstitial edema
• AG: Hallmark finding is myeloid bodies (Concentric multilamellated phospholipid membrane whorls in the phagolysosome)
  1. Loss of proximal convoluted tubule microvilli
  2. Glomeruli are spared

 

DIFFERENTIAL DIAGNOSIS:

Other nephrotoxic agents:  

• Exogenous: Antimicrobials, chemotherapeutic agents, heavy metals, paraquat, monensin, ethylene glycol, chlorinated hydrocarbons; Ochratoxin A (OTA) or other mycotoxins such as other ochratoxins, citrinin, fumonisin, oxalate, and viridicatumtoxin (produced by Aspergillus and Penicillium); NSAIDS, vitamin D, venoms, canthardins 
• Endogenous: Bile, hemoglobin (U-T10), myoglobin 

 

COMPARATIVE PATHOLOGY:

Other aminoglycoside toxicities

• In addition to nephrotoxicity, AGs are also ototoxic, targeting the hair cells, and may lead to vestibular disease and/or acquired deafness (cats, dogs, and pig)
  1. The AG antibiotic and anthelmintic hygromycin B has been shown to induce posterior cortical and subcapsular cataracts in sows, but not boars 
  2. Demonstrated to cause injury to some neurons in the dorsal root ganglia, trigeminal ganglia, other sensory ganglia (Bennet, Toxicol Pathol. 2023)

Specific examples of nephrotoxins in various species:

• Equine: Monensin; foals and older, sick foals particularly susceptible to aminoglycoside toxicity
• Bovine: Oxalate toxicity (Halogeton sp., Rumex sp., Sarcobatus sp.; Quercus sp.) (U-T06); monensin; plants with vitamin D-like toxicity (Cestrum diurnum)
• Sheep: Oxalate toxicity (U-T06)
• Avians:
  1. Toxic nephropathy kidneys often contain fine white to pale yellow linear striations from tubules dilated with urates (also present on serosa) (U-M08 – Gout)
  2. Poultry: Monensin
• Lab animal
  1. Rodents: Chloroform
  2. Rabbits: Telazol 
• Canine: Ethylene glycol (U-T05); NSAIDs; vitamin D nephropathy (U-T03)
• Feline: Ethylene glycol; vitamin D nephropathy; Easter lilies
• Porcine: Pigweed (Amaranthus retroflexus) (U-T13); Ochratoxin A

 

References:

1. Barthold SW, Griffey SM, Percy DH. Pathology of Laboratory Rodents and Rabbits. 4th ed. Ames, IA: Wiley Blackwell; 2016: 140, 209, 316.
2. Bennet BM, Pardo ID, Assaf BT, et al. Scientific and Regulatory Policy Committee Technical Review: Biology and Pathology of Ganglia in Animal Species Used for Nonclinical Safety Testing. Toxicol Pathol. 2023;51(5):278-305.
3. Cheville, Norman F. Nephrotoxins. In: Ultrastructural Pathology: The Comparative Cellular Basis of Disease. 2nd ed. John Wiley & Sons, 2009:701.
4. Cianciolo RE, Mohr FC. Urinary system. In: Maxie MG, ed. Jubb, Kennedy, and Palmer's Pathology of Domestic Animals. 6th ed. Vol 2. St. Louis, MO: Elsevier; 2016:421-424, 427.
5. Cline JM, Brignolo L, Ford EW. Urogenital system. In: Abee CR, Mansfield K, Tardiff S, Morris T, eds. Nonhuman Primates in Biomedical Research: Disease. Vol. 2. London, UK: Academic Press, 2012:492.
6. Njaa BL. The Ear. In: Zachary JF, ed. Pathologic Basis of Veterinary Disease. 7th ed. St. Louis, MO: Elsevier; 2022:1369-1370.
7. Noga EJ. Pharmacopoeia. In: Fish Disease: Diagnosis and Treatment. 2nd ed. Ames, IA: Wiley Blackwell; 2010: 380.
8. Schmidt R, Reavill DR, Phalen DN. Urinary System. In: Pathology of Pet and Aviary Birds. 2nd ed. Ames, IA: John Wiley & Sons, Inc.; 2015:140.
9. Sula MM, Lane LV. The Urinary System. In: Zachary JF, ed. Pathologic Basis of Veterinary Disease. 7th ed. St. Louis, MO: Elsevier; 2022:706, 711, 734-736, 754.
10. Wilcock BP, Njaa BL. Special Senses. In: Maxie MG, ed. Jubb, Kennedy & Palmer's Pathology of Domestic Animals. Vol 1. 6th ed. St. Louis, MO: Elsevier; 2016:444, 494. 

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