JPC SYSTEMIC PATHOLOGY
Signalment (AFIP #1801670): Sprague-Dawley rat
HISTORY: Sprague-Dawley rat kidney removed two days after a single intraperitoneal injection of 75 ug/kg body weight of gold sodium thiomalate.
HISTOPATHOLOGIC DESCRIPTION: Kidney: Multifocally, the epithelium lining of up to 60% of cortical tubules, and fewer medullary tubules, is lost with replacement by eosinophilic, granular necrotic debris or undergoes one or more of the following changes: loss of cellular detail with hypereosinophilic cytoplasm, pyknosis, karyorrhexis, and karyolysis (necrosis); swollen, vacuolated cytoplasm with faded nuclei (degeneration); or amphophilic cytoplasm and occasional mitotic figures (regeneration). Affected tubules and collecting ducts are often ectatic, and contain intraluminal eosinophilic, fibrillar to homogenous, proteinaceous fluid, which is often admixed with sloughed tubular epithelial cells and necrotic debris (granular casts). Scattered throughout the interstitium are low numbers of neutrophils and lymphocytes. Multifocally, the renal capsule is undulant, with depressions overlying aggregates of collapsed, necrotic tubules (stromal collapse).
MORPHOLOGIC DIAGNOSIS: Kidney, tubules: Necrosis, acute, multifocal, with degeneration and regeneration, Sprague-Dawley, rodent.
ETIOLOGIC DIAGNOSIS: Renal chrysotoxicosis
CAUSE: Gold sodium thiomalate
- Gold therapy (e.g., sodium aurothiomalate), also known as chrysotherapy, is used to treat certain immune-mediated diseases (e.g., rheumatoid arthritis, pemphigus)
- Therapeutic mechanism is uncertain (altered macrophage function suspected)
- Most common side effect of chrysotherapy is dermatitis
- Other side effects: nephrotoxicosis, stomatitis, hepatitis, interstitial pneumonia, diarrhea, bone marrow suppression (pancytopenia), and peripheral neuropathy
- Given therapeutically, the route of exposure is through injection or oral administration
- In humans, accidental exposure is through dermal contact, inhalation, or ingestion
- Gold and its salts are poorly absorbed from the gastrointestinal tract
- Soluble salts are excreted via urine; insoluble compounds are excreted in the feces
- Biological half-life is long, with slow accumulation in synovial membranes, macrophages, the reticuloendothelial system, skin, liver and kidney
- Renal damage occurs by two mechanisms:
- Direct toxicity to renal tubular epithelium: gold salts have high affinity for mitochondria of proximal convoluted tubule epithelium
- Immune-complex glomerulonephritis - two possible mechanisms:
- Gold acts as a hapten > formation antibodies against gold-protein complexes > subepithelial deposition in glomeruli
- Antibodies formed against damaged tubular mitochondria > antigen-antibody complexes deposited in glomeruli
TYPICAL CLINICAL FINDINGS:
- Most common: dermal rash and exfoliative dermatitis, often with pruritus
- Stomatitis and diarrhea also common
- Skin lesions may persist for months after discontinuing chrysotherapy
- Clinical Pathology: Proteinuria and the nephrotic syndrome are sequelae of glomerulonephritis
TYPICAL GROSS FINDINGS:
- Acute: bilaterally swollen, pale kidneys
- Chronic: small, white, granular, contracted kidneys with pitted surfaces
TYPICAL LIGHT MICROSCOPIC FINDINGS:
- Acute: degeneration and necrosis of proximal convoluted tubules with basement membrane preservation (differentiates from ischemic necrosis and facilitates regeneration); congestion; lymphocytic or neutrophilic interstitial nephritis
- Subacute: +/- regeneration of remaining tubule epithelial cells, +/- membranous or membranoproliferative glomerulonephritis
- Chronic: progressive interstitial fibrosis
- Not all parts of the kidney are equally affected because of the physiologic tendency of some nephrons to rest while others are active
DIFFERENTIAL DIAGNOSIS: Other nephrotoxins:
- Heavy metals (e.g., mercury, lead, arsenic, cadmium, thallium)
- Antimicrobials (e.g., aminoglycosides, tetracyclines, amphotericin B)
- Ionophores (e.g., monensin)
- Non-steroidal anti-inflammatory drugs
- Mycotoxins (e.g., ochratoxin A, citrinin)
- Plants (e.g., pigweed [Amaranthus retroflexus], oaks [Quercus], Isotropis sp., Yellow wood tree [Terminalia oblongata])
- Oxalates (e.g., ethylene glycol, halogeton [Halogeton glomeratus], sorrel or dock [Rumex sp.], rhubarb [Rheum rhaponticum], greasewood [Sarcobatus vermiculatus])
- Vitamin D (e.g., cholecalciferol, Cestrum diurnum, Solanum, Trisetum sp.)
- Antineoplastic compounds (e.g., cisplatin)
- Pet food contaminants (e.g., melamine, cyanuric acid)
- Endogenous (pigments):
- Bililrubin: young lambs, calves, and foals with immature hepatic conjugative mechanisms; associated with proximal tubular cellular swelling, degeneration, and pigmentation. Acute tubular necrosis seen with severe bilirubinemia (i.e. hepatorenal syndrome) is probably not caused by the bile acids, but by renal ischemia
- Hemoglobin: Not nephrotoxic itself but can increase tubular necrosis that occurs from renal ischemia
- Myoglobin: Similar to hemoglobin
- Bile: Animals with liver conditions which elevate circulating bile acid levels resulting in accumulation of bile pigment in tubular epithelium
COMPARATIVE PATHOLOGY: Examples of nephrotoxins in various species:
- Horse: Red maple leaf; monensin; aminoglycosides; cantharidin
- Ox: Oxalates (Halogeton , Rumex sp., Sarcobatus sp.); oak (Quercus sp.); monensin; plants with vitamin D-like toxicity (Cestrum diurnum)
- Sheep: Oxalates; copper
- Poultry: Monensin
- Rodents: Chloroform
- Dog: Ethylene glycol; NSAIDs; vitamin D; grapes and raisins
- Cat: Ethylene glycol; vitamin D; Easter lilies
- Pig: Pigweed (Amaranthus retroflexus); Ochratoxin A
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