JPC SYSTEMIC PATHOLOGY

URINARY SYSTEM

JANUARY 2024

U-T03

 

SIGNALMENT (JPC# 2676774): 4.5 kg, 4-month-old male mixed breed dog.

 

HISTORY: This dog ingested 30 grams of rodent bait; 36 hours later he was depressed and anorectic. His condition continually deteriorated and he died of cardiac asystole approximately 72 hours after ingestion. 

 

HISTOPATHOLOGIC DESCRIPTION: Kidney: Multifocally, tubules within the cortex and medulla are filled or replaced by granular basophilic material (mineral) and cellular debris. Tubular epithelium exhibits one or more of the following changes: a hypereosinophilic cytoplasm with a shrunken, pyknotic nuclei (necrosis) admixed with mineral; or (in less affected areas) a pale, swollen, vacuolated cytoplasm (degeneration). Tubular lumina are often ectatic and contain eosinophilic homogenous to flocculent material (proteinosis) admixed with few necrotic neutrophils. There is multifocal mineralization of the basement membrane in less affected tubules, glomeruli, Bowman’s capsules and blood vessels. Multifocally there is necrosis and mineralization of blood vessel endothelium and walls, expanding the tunica media and tunica adventitia with mineral, fibrin, edema and necrotic debris. Multifocally, there are few neutrophils scattered throughout the cortical interstitium.

 

Lung: Multifocally, affecting up to 40% of the section, alveolar septa are fragmented and discontinuous or expanded by mineral, beaded to fibrillar eosinophilic material (fibrin), necrotic debris, and low numbers of neutrophils. Alveolar spaces are variably filled by necrotic cellular debris, fibrin, edema, hemorrhage and low numbers of neutrophils and alveolar macrophages. There is multifocal type II pneumocyte hyperplasia. Multifocally, there is mineralization of bronchiolar/bronchial walls, including terminal bronchioles, with loss of bronchiolar epithelium and low numbers of interepithelial or subepithelial neutrophils, and lumina contain scattered mineral, fibrin, neutrophils, edema and sloughed epithelial cells. There is multifocal mineralization in the subpleural connective tissue.

 

MORPHOLOGIC DIAGNOSIS: 1. Kidney: Mineralization, tubular, glomerular, and vascular, multifocal, moderate, with tubular necrosis and degeneration, mixed breed, canine.

 

2. Lung: Mineralization, multifocal, severe, with septal necrosis, type II pneumocyte hyperplasia, and hemorrhage.

 

ETIOLOGIC DIAGNOSIS: Renal and pulmonary hypervitaminosis D

 

SYNONYMS: Vitamin D nephropathy; vitamin D toxicity; vitamin D poisoning (intoxication)

 

GENERAL DISCUSSION:

• Vitamin D intoxication can occur in mammals, birds, and reptiles due to over supplementation (especially animals with low dietary vitamin D requirements, like rabbits) or intoxication (i.e. ingestion of rodenticide or vitamin D-containing plants)
• In general, Vitamin D functions to maintain serum calcium via 3 mechanisms:
  1. Increasing intestinal absorption of calcium (and phosphorus);
  2. Enhancing parathyroid hormone (PTH)-dependent renal tubular resorption of calcium (and excretion of phosphorus);
  3. Enhancing parathyroid hormone (PTH)-dependent mobilization of calcium (and phosphorus) from bone
• Vitamin D intoxication causes hypercalcemia, renal failure, metastatic mineralization in multiple tissues, and less commonly bony lesions (M-T03)

 

PATHOGENESIS:

• Normal vitamin D metabolism:
  1. Vitamin D2 (ergocalciferol)
  2. Vitamin D3 (cholecalciferol) can be obtained from diet or generated by UV light
     • Cholesterol > 7-dehydrocholesterol > (with UV light) vitamin D3
  3. Cholecalciferol is converted to 25-hydroxycholecalciferol (HCC, calcidiol, 25-OH-D3) by 25-hydroxylase in liver; 25-HCC is 3x as potent as cholecalciferol
  4. 25 HCC is converted to 1,25 dihydroxycholecalciferol (DHCC, calcitriol) by 1ɑ-hydroxylase in renal tubular epithelial cells; 1,25 DHCC is 25 times as potent as 25-HCC
     • Horses lack renal 1ɑ-hydroxylase
     • Formation of 1,25 DHCC mainly controlled by [Ca++], less so by [PTH]
• Normal actions of vitamin D in dogs, cats, cattle
  1. Increased calbindin in intestinal mucosa > increased Ca++ uptake
  2. Increased osteoclastic activity > Ca++ and PO4 liberation
  3. Increased calbindin in renal tubular epithelium à increased Ca++ resorption
  4. Inhibition of PTH synthesis
  5. In horses, vitamin D only plays a minor role in regulation of [Ca++]
• Hypervitaminosis D > Hypercalcemia +/- hyperphosphatemia
  1. Exogenous vitamin D come from ingestion of 
     • Cholecalciferol rodenticides (converted to 25-HCC) (or carcasses containing rodenticides)
     • Ergocalciferol-containing plants (Cestrum diurnum, Solanum malacoxylon, Trisetum flavescens; toxic principle is 1,25 dihydroxycholecalciferol-glycoside)
     • Certain human ointments (tacalcitol, calcipotriol)
     • Misformulated feeds
  2. Endogenous vitamin D come from granulomatous inflammation (histiocytes produce vitamin D) or paraneoplastic syndrome (apocrine gland adenocarcinoma and lymphoma in dogs may have vitamin D activity)
• Hypercalcemia and hyperphosphatemia à mineralization of soft tissues (kidneys, gastric mucosa, lungs, endocardium, arterial walls) and death from renal failure
  1. [tCa++] x [Pi] > 70 à risk of mineralization (both in mg/dL)
  2. Alkaline tissues are most likely to mineralize (intima/media of arteries, endocardium, myocardium, gastric mucosa, lung and kidney)
• Hypercalcemic nephropathy (renal failure)
  1. Hypercalcemia causes decreased cAMP > impaired sodium transport in ascending LoH, DTs, CDs
  2. Hypercalcemia interferes with ADH receptors in CDs > renal diabetes insipidus
  3. Progressive mineralization of basement membrane and epithelium: Medulla > interstitium, vessels, glomeruli
  4. Tubular epithelial mineralization > casts > tubular obstruction > loss of nephrons
• Vitamin D is involved in mineralizing osteoid to form bone; lesions of toxicosis are uncommon but include sclerosis or rarefaction; initially there is intense osteoclast resorption followed by osteoblastic production of abundant basophilic matrix especially in long bones which may obliterate the marrow spaces (virtually pathognomonic); if exposure is intermittent, may have broad, basophilic resting lines 

 

TYPICAL CLINICAL FINDINGS:

• Depression
• Anorexia, weight loss
• Polyuria/polydipsia (due to nephrogenic diabetes insipidus)

 

TYPICAL GROSS LESIONS: 

• Acute cases: Kidneys have smooth capsular surface; in high doses may result in gastric, small intestinal, and myocardial hemorrhage
• Chronic cases: Renal surface appears finely granular due to fibrosis, chalky white deposits in cortex and medulla; soft tissue mineralization (lungs gritty and fail to collapse, pleural mineralization, arteriosclerosis, gastric mineralization)
  1. Lungs: Gritty texture, fail to collapse; pleural calcification
• Bone: Osteosclerosis in severe cases

 

TYPICAL LIGHT MICROSCOPIC FINDINGS: 

• Renal changes:
  1. Acute: Tubular necrosis and atrophy with scattered mineralization
  2. Chronic: Interstitial fibrosis, tubular dilation, glomerular atrophy, mineralization of basement membranes
• Cardiovascular: Myocardial necrosis; endocardial, myocardial, and arterial medial mineralization
• Pulmonary and gastric mucosal mineralization
• Bone: Deposition of abnormal basophilic matrix on trabeculae and in marrow spaces, resulting in obliteration (almost pathognomonic); usually seen at the ends of long bones (where most rapid growth occurs)

 

ADDITIONAL DIAGNOSTIC TESTS:

• Renal concentration of 25-hydroxyvitamin D, 25(OH)D3 
• Renal calcium to phosphorus ratio:
  1. <0.1 = normal
  2. 0.4-0.9 = cholecalciferol poisoning
  3. 2.5 = ethylene glycol poisoning

 

DIFFERENTIAL DIAGNOSIS

For hypercalcemia (HARD TIONS):

• Hyperparathyroidism: Hypercalcemia, hypophosphatemia
  1. Primary hyperparathyroidism: Hyperplasia, adenoma, adenocarcinoma of the parathyroid
  2. Secondary renal hyperparathyroidism
  3. Paraneoplastic syndrome: Leading cause of hypercalcemia in dogs is due to PTH-related protein (PTHrP), released in paraneoplastic syndromes of lymphoma and apocrine adenocarcinoma of the anal sac
• Acidosis: Decreased pH results in precipitated calcium
• Addison’s Disease/Hypoadrenocorticism: Increased tubular resorption of calcium
• Renal failure in horses; hypercalcemia, familial disease in young dogs
• Vitamin D intoxication (this case)
• Thiazide diuretics
• Immobilization
• Osteolytic lesions of bone
• Neoplasia: Lymphosarcoma, plasma cell myeloma, adenocarcinoma of the apocrine gland of the anal sac, tumors metastatic to bone
• Spurious: Granulomatous diseases:  systemic canine blastomycosis or paecilomycosis, bovine paratuberculosis, hyperproteinemia, hemoconcentration

 

COMPARATIVE PATHOLOGY:

• Cats: May be more sensitive to vitamin D toxicosis than dogs
• Cattle: Therapeutic administration of Vitamin D for milk fever can cause soft tissue mineralization; condition is also known as “enzootic calcinosis”, Manchester wasting disease (Jamaica), Naalehu disease (Hawaii), enteque seco (Argentina), espichamento (Brazile)
• Rabbits are prone to over-supplementation due to low dietary requirements; characteristically develop mineralization of the aorta
• Naked mole rats, beavers, and woodchucks do not require dietary vitamin D; can develop toxicity if fed rodent chow; naked mole rats can develop calcinosis cutis due to toxicosis
• New world monkeys can’t synthesize vitamin D in skin; require supplementation
• Birds/reptiles can’t fully use D2; require UV light access or D3 supplementation
• Birds: Cockatiels, macaws may be predisposed to over supplementation; tubular necrosis and basement membrane mineralization may be accompanied by secondary urate deposition (tophi); mineralization also occurs in proventriculus, lungs, myocardium; can also cause premature lymphoid depletion in the bursa of Fabricius; macaw and cockatiel fetuses may also have mineralization due to over-supplementation of hen; bone lesions have not been seen in pet/aviary birds
• Captive non-human primates and green iguanas also occasionally develop hypervitaminosis D due to over supplementation
• Black rhinoceros: Vitamin D3 toxicosis occurred due to misformulated feed; developed renal failure and soft tissue mineralization

 

REFERENCES:

1. Barthold SW, Griffey SM, Percy DH, eds. Pathology of Laboratory Rodents and Rabbits. 4^th ed. Ames, IA: Wiley Blackwell; 2016:315. 
2. 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: 441.
3. Craig LE, Dittmer KE, Thompson KG. Bones and joints. In: Maxie MG, ed. Jubb, Kennedy, and Palmer’s Pathology of Domestic Animals. Vol 1. 6th ed. St. Louis, MO: Elsevier; 2016: 89.
4. Delaney MA, Treuting PM, Rothenburger JL. Lagomorpha. In: Terio KA, McAloose D, St. Leger J, eds. Pathology of Wildlife and Zoo Animals. Cambridge, MA: Academic Press. 2018: 483.
5. Delaney MA, Treuting PM, Rothenburger JL. Rodentia. In: Terio KA, McAloose D, St. Leger J, eds. Pathology of Wildlife and Zoo Animals. Cambridge, MA: Academic Press. 2018: 502.
6. Duncan M. Perissodactyls. In: Terio KA, McAloose D, St. Leger J, eds. Pathology of Wildlife and Zoo Animals. Cambridge, MA: Academic Press. 2018: 438.
7. Gal A, Castillo-Alcala F. Cardiovascular System, Pericardial Cavity, and Lymphatic Vessels. In: Zachary JF, ed. Pathologic Basis of Veterinary Disease. 7th ed. St. Louis, MO: Elsevier; 2022: 652, 656, 673.
8. López A, Martinson SA. Respiratory system, mediastinum, and pleurae. In: Zachary JF, ed. Pathologic Basis of Veterinary Disease. 7th ed. St. Louis, MO: Elsevier; 2022: 571, 595. 
9. Miller MA, Lyle T, Zachary JF. Mechanisms and morphology of cellular injury, adaptation, and death. In: Zachary JF, ed. Pathologic Basis of Veterinary Disease. 7th ed. St. Louis, MO: Elsevier. 2022: 48.
10. Origgi FC. Lacertilia. In: Terio KA, McAloose D, St. Leger J, ed. Pathology of Wildlife and Zoo Animals. Cambridge, MA: Academic Press. 2018:875-876.
11. Reavill DR, Dorrestein G. Psittacines, Coliiformes, Musophagiformes, Cuculiformes. In: Terio KA, McAloose D, St. Leger J, eds. Pathology of Wildlife and Zoo Animals. Cambridge, MA: Academic Press. 2018: 780.
12. Robinson WF, Robinson NA. Cardiovascular system. In: Maxie MG, ed. Jubb, Kennedy, and Palmer’s Pathology of Domestic Animals. Vol 3. 6th ed. St. Louis, MO: Elsevier; 2016: 61. 
13. Rosol TJ, Gröne  A. Endocrine glands. In: Maxie MG, ed. Jubb, Kennedy, and Palmer’s Pathology of Domestic Animals. Vol 3. 6th ed. St. Louis, MO: Elsevier; 2016:302, 309.
14. Schmidt RE, Reavill DR, Phalen DN. Pathology of Pet and Aviary Birds. 2^nd ed. Ames, IO: John Wiley and Sons, Inc. 2015: 9, 45, 69, 119, 139-140, 158, 180, 212.
15. Stockham SL, Scott MA. Fundamentals of Veterinary Clinical Pathology. 2^nd ed. Ames, IO: Blackwell Publishing. 2008: 596, 597, 600-601, 629-630. 
16. Sula MM, Lane LV. The urinary system. In: Zachary JF, ed. Pathologic Basis of Veterinary Disease. 7th ed. St. Louis, MO: Elsevier; 2022; 737.

 

 

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