JPC SYSTEMIC PATHOLOGY
URINARY SYSTEM
January 2024
U-T01 (NP)
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 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 and nuclear pyknosis, karyorrhexis, or karyolysis (necrosis); or swollen, vacuolated cytoplasm with faded nuclei (degeneration). 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.
MORPHOLOGIC DIAGNOSIS: Kidney, tubules: Necrosis, acute, multifocal, with degeneration and regeneration, Sprague-Dawley, rodent.
ETIOLOGIC DIAGNOSIS: Renal chrysotoxicosis
CAUSE: Gold sodium thiomalate
GENERAL DISCUSSION:
- 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
- Heavy metals such as gold, lead, mercury (organic), nickel, and chromium have been shown to be carcinogenic in a dose-dependent fashion in rodent models
- Mechanisms of action across heavy metals are incompletely understood, but the valence state of the metals and ability to act as electrophiles leads to interaction with electron-rich DNA and/or proteins – this in turn alters binding affinity/and or function through changes in enzyme activity or gene expression
- Glomeruli and proximal convoluted tubule are frequent sites of injury in heavy metal toxicoses
PATHOGENESIS:
- 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 preferentially (>60%); insoluble compounds are excreted in the feces (via biliary excretion)
- 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; can see karyomegalic and or cytomegalic cells (low, persistent doses) that may be precursors or pre-malignant changes
DIFFERENTIAL DIAGNOSIS:
Other nephrotoxins:
- Exogenous:
- Heavy metals (e.g., mercury, lead (U-T02), arsenic, cadmium, thallium)
- Antimicrobials (e.g., aminoglycosides (U-T07), tetracyclines (U-T08), 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 sp.], Isotropis sp., Yellow wood tree [Terminalia oblongata])
- Oxalates (e.g., ethylene glycol (U-T05), halogeton [Halogeton glomeratus], sorrel or dock [Rumex sp.], rhubarb [Rheum rhaponticum], greasewood [Sarcobatus vermiculatus])
- Vitamin D (e.g., cholecalciferol, Cestrum diurnum, Solanum sp., Trisetum sp.) (U-T03)
- Antineoplastic compounds (e.g., cisplatin)
- Pet food contaminants (e.g., melamine (U-T18), 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 (U-T10): 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 (U-T12); monensin; aminoglycosides; cantharidin
- Ox: Oxalates (Halogeton sp., Rumex sp., Sarcobatus sp.); oak (Quercus sp.); monensin; plants with vitamin D-like toxicity (Cestrum diurnum)
- Sheep: Oxalates (U-T06); copper
- Poultry: Monensin
- Rodents: Chloroform
- Dog: Ethylene glycol; NSAIDs; vitamin D; grapes and raisins
- Cat: Ethylene glycol; NSAIDs; vitamin D; Easter lilies
- Pig: Pigweed (Amaranthus retroflexus) (U-T13); Ochratoxin A
REFERENCES:
1. Cianciolo RE, Mohr FC. Urinary system. In: Maxie MG, ed., Jubb, Kennedy, and Palmer’s Pathology of Domestic Animals. Vol. 2. 6th ed. St. Louis, MO: Elsevier; 2016:422-428.
2. Diamond GL, Zalups RK. Understanding renal toxicity of heavy metals. Toxicol Pathol. 1998;26(1):92-103.
3. Khan KMN, Hard GC, Li X, Alden CL. Urinary System. In: Wallig MA, Haschek WM, Rousseaux CG, Bolon, B, Mahler BW eds. Fundamentals of Toxicologic Pathology. Cambridge, MA: Academic Press; 2018: 263.
4. Payne BJ, Saunders LZ. Heavy metal nephropathy of rodents. Vet Pathol. 1978 ;15 Suppl 5:51-87
5. Sula MM, Lane LV. The urinary system. In: Zachary JF, ed. Pathologic Basis of Veterinary Disease. 7th ed. St. Louis, MO: Elsevier; 2022:734-736.
6. Ufelle AC, Barchowsky A. Toxic effects of metals. In: Klaassen CD, ed. Casarett and Doull’s Toxicology: The Basic Science of Poisons, 9th ed., New York, NY: McGraw-Hill; 2019:1107-1115, 1142.