JPC SYSTEMIC PATHOLOGY

URINARY SYSTEM

December 2023

U-M18

 

SIGNALMENT (JPC#1549488): Dog, age and breed unknown

 

HISTORY: Dog was euthanized due to persistent vomiting and halitosis.

 

HISTOPATHOLOGIC DESCRIPTION: Kidney: Multifocally, glomeruli, tubules and vessels within both the cortex and medulla are widely separated, surrounded and replaced by fibroblasts and abundant collagen (interstitial fibrosis). Glomeruli often exhibit one or more of the following changes: periglomerular fibrosis and/or mineralization; hypertrophy of the parietal epithelium; adherence between the visceral epithelium and the parietal epithelium of Bowman’s capsule (synechia); and frequent segmental to global increases in mesangial matrix with obliteration of capillary lumina (glomerular sclerosis) progressing to shrunken, hyalinized and hypocellular glomerular tufts (obsolescence). Medullary and cortical tubules and collecting ducts contain one or more of the following changes: marked tortuosity; ectasia with attenuated epithelium; atrophy; epithelial degeneration characterized by swollen, vacuolated cells; epithelial necrosis characterized by shrunken and hypereosinophilic cells with pyknosis; crowded (hyperplastic) or hypertrophied epithelium with abundant basophilic cytoplasm and large vesiculate nuclei (regeneration); mineralization of the basement membrane; and lumina which contain varying amounts of brightly eosinophilic homogenous material (proteinosis), necrotic cellular debris, or occasional basophilic granular aggregates (mineral). Papillary ducts are often dilated and tortuous. Multifocally, primarily within the cortex, there are interstitial aggregates of few to moderate numbers of lymphocytes and plasma cells. The tunica muscularis of small to medium arterioles multifocally exhibits mild smooth muscle hypertrophy and hyperplasia and there is scattered perivascular edema. The capsule is irregular with multifocal mineralization.  

 

MORPHOLOGIC DIAGNOSIS: Kidney: Fibrosis, interstitial, chronic, multifocal to coalescing, marked, with tubular atrophy, necrosis, loss, regeneration, mineralization and proteinosis; glomerular sclerosis and obsolescence; periglomerular fibrosis and mineralization; and mild lymphoplasmacytic interstitial nephritis, breed unspecified, canine.

 

CONDITION: End stage kidney; chronic renal failure; end stage renal disease (ESRD)

 

GENERAL DISCUSSION:

• Not a specific entity but rather the end result of many chronic renal diseases; generalized, progressive and irreversible end stage kidney disease; encompassing inflammatory and ischemic renal diseases 
• Specific etiologies may be impossible to determine
• Chronic renal disease usually involves all four components of the kidney
  • Glomeruli, tubules, interstitium, and blood vessels
  • Resulting progressive interstitial fibrosis is final common pathway in chronic renal failure 
  • Renal fibrosis is a key characteristic finding in CKD; best correlates with renal function (Vet Pathol. 2019;56(1):93-105)
  • miR-21 indirectly increases fibrosis through TGF-β signaling pathway (possibly others) and is upregulated in X-linked hereditary nephropathy in dogs

 

PATHOGENESIS:

• Progressive, irreversible lesions initially localize in the renal vascular system, glomeruli, tubules, or interstitial tissue
• If any portion of the nephron is irreversibly destroyed, the distal portions (downstream) become nonfunctional
• Limited effective regeneration; repair occurs by replacement fibrosis and scarring
• With progressive loss of nephrons, the glomerular filtration rate (GFR) decreases
• Compensatory mechanisms (endogenous factors) to renal insufficiency, also contribute to progression of disease
  • Glomerular capillary hypertension, hyperfiltration, renal hypertrophy, increased oxygen consumption, increased production of ammonia and altered phosphate metabolism
• High dietary protein may increase renal blood flow and GFR
  • Hyperperfusion of glomeruli > tuft hypertrophy > glomerulosclerosis with proteinuria
• Failure to remove nitrogenous wastes results in azotemia when GFR is below 75%
  • Azotemia concurrent elevation of BUN and creatinine, without clinical disease
  • When these wastes produce clinical disease, the condition is known as uremia and is often accompanied by extrarenal lesions
  • Animals with dramatic uremia commonly die from terminal pulmonary edema
• Loss of function progresses through four overlapping stages:
  • Diminished Renal Reserve: GFR 50% of normal, serum BUN and creatinine are normal, and patient is asymptomatic but more susceptible to developing azotemia with additional renal insult
  • Chronic Renal Insufficiency: GFR 20-50% of normal; azotemia, anemia, polyuria, loss of concentrating ability (isosthenuria); increased susceptibility to developing uremia
    • GFR function 30-50% of normal, progression to end-stage renal failure tends to be inevitable
  • Chronic Renal Failure: GFR  < 20% of normal; edema, metabolic acidosis, hypocalcemia; overt uremia with gastrointestinal, cardiovascular, respiratory, skeletal, and neurologic complications
  • End-stage Renal Disease (ESRD):  GFR < 5% of normal; uremia
    • Pathogenesis of diffuse mineralization unclear, likely multifactorial
    • Decreased GFR > Phosphorus retention > Hyperphosphatemia
  • Decreased tubular resorption of calcium > Hypocalcemia
  • Hyperphosphatemia > hypocalcemia > increased PTH > production of Fibroblast Growth Factor 23 (FGF23) which inhibits renal 1-α-hydroxylase activity > decreased activation of 25‑hydroxycholecalciferol to active 1,25-hydroxycholecalciferol (calcitriol) > decreased intestinal absorption of calcium > hypocalcemia
• Hypocalcemia > parathyroid gland hyperplasia with increased synthesis and release of parathyroid hormone (PTH) > PTH attempts to increase blood calcium:

• Up-regulation of RANKL (receptor activator for nuclear factor kappa B ligand) on osteoblasts/stromal cells AND inhibition of osteoprotegerin (normally blocks RANK : RANKL interaction) > RANKL causes osteoclast differentiation > bone resorption/bone turnover 
• PTH inhibits sclerostin resulting in defective mineralization of new bone which then has features of both fibrous osteodystrophy and osteomalacia > renal osteodystrophy

 

TYPICAL CLINICAL FINDINGS:

• Polyuria:
  • Glomerular blood flow and amount of glomerular filtrate formed each minute by each nephron often increases to as much as twice the normal amount
  • Large amounts of excretory substances accumulate in the extracellular fluid, markedly increase the load on tubules, and are poorly reabsorbed
  • Volume of fluid entering the glomerulus and the osmotic effect of excretory substances overwhelm the compensated tubule; rapid flushing of fluid through the tubules does not allow time for concentration, so the specific gravity approaches that of the glomerular filtrate (isosthenuria)
• Neurologic abnormalities:
  • Depression: Increased uremic acids result in metabolic acidosis
  • Tetanic convulsions: Due to hypocalcemia, uncommon
  • Uremic encephalopathy (uncommon, reported in dogs, ruminants, horses)
• Gastrointestinal signs:
  • Oral and gastrointestinal ulcers: Ammonia released by bacterial action on urea or damage to endothelial cells
  • Mucosal lesions may induce vomiting, but a circulating “uremic toxin” 

• Hypertension common in dogs and cats with renal disease

 

TYPICAL GROSS FINDINGS:

• Kidneys:
  • Small, pale, firm, with pitted surface; usually bilateral
  • Capsule: Difficult to remove from the cortex because of adhesions
  • Cut surface: Thinned cortex, irregular scarring
  • Perirenal edema
• Gastrointestinal tract
  • Stomach: “Uremic gastritis”; attenuation of rugal folds, hyperemia, ulcerations, mucosal discoloration; initially non-inflammatory and marked mineralization
  • Oral cavity: Necrotic stomatitis/glossitis; lingual infarcts
• Widespread soft tissue mineralization
  • Intercostal muscles: most common in canine, mineralization beneath the parietal pleura, “ladder like” arrangement and necrosis in subpleural connective tissue
  • Lungs: “Uremic pneumonitis” with “pumice stone” appearance; extensive, with deposition particularly on reticulin of alveolar walls 
• Heart: Left atrial mural endocarditis and endothelial mineralization ; left ventricle may be hypertrophied and dilated, may be related to hypertension
• Bone: Fibrous osteodystrophy (especially bones of the head); osteopenia
• Parathyroid glands: Diffuse hyperplasia of all four glands

 

TYPICAL LIGHT MICROSCOPIC FINDINGS:

• Extensive renal fibrosis, mineralization, global glomerulosclerosis, mixed tubular atrophy and hypertrophy 
• Gastrointestinal ulceration; mucosal infarction, mineralization of middle and deep zones of gastric mucosa
• Parathyroid glands: Chief cell hyperplasia/hypertrophy, often bilateral
• Mineralization: Vascular subintima, kidney (glomerular/tubular basement membrane or corticomedullary junction), lung (alveolar/bronchiolar walls), gastric mucosa (middle and deep zones), subpleural intercostal musculature 
• Bone: Fibrous osteodystrophy: Lamellar bone replaced by fibrous connective tissue and poorly mineralized immature bone; osteopenia
• Arteriolar hyaline degeneration, hyperplastic arteriosclerosis (due to hypertension)
• CNS: Rare white-matter spongiform degeneration (uremic encephalopathy)
• Lung: Pulmonary edema and fibrin in alveolar lumina, mineral in walls of alveolar ducts and arterioles

 

ULTRASTRUCTURAL FINDINGS:

• Tubular and glomerular basement membranes are thickened in early stages and condensed into amorphous material in later stages
• Loss and internalization of tubular cell apical microvilli; apical membrane blebbing

 

ADDITIONAL DIAGNOSTIC TESTS:

• Urine specific gravity: 1.007–1.013 in oliguric animal, indicative of renal failure or end-stage renal disease or renal failure 
  • Can also occur with acute renal disease or urinary tract obstruction
• Complete blood count
  • Normocytic, normochromic (non-regenerative) anemia; multifactorial but in part to decreased erythropoietin production from the kidneys and chronic disease
• Serum biochemistry panel may detect azotemia: Not specific and only occurs after 75% of nephrons have been lost
  • BUN and creatinine: Elevated (azotemia, failure to excrete metabolic wastes)
  • Electrolyte abnormalities:
    • Hypochloridemia: Due to vomiting, diarrhea 
    • Hypoproteinemia: Due to glomerular disease
      • Edema occurs because of inability to regulate volume and solute composition and hypoproteinemia
    • Hyperkalemia: Decreased excretion and increased exchange of intracellular potassium for extracellular hydrogen in metabolic acidosis; not expected in polyuric chronic renal failure
      • Cats with chronic renal failure develop hypokalemia due to tbK⁺ depletion
    • Hyperphosphatemia: Decreased excretion due to decreased GFR; not a consistent indicator in herbivores due to digestive elimination; FGF23 is an important component of phosphorus regulation (phosphatonin system), it increases as phosphorus or vitamin D levels increase, and plays a role in the pathogenesis of chronic kidney disease (and hereditary hypophosphatemic rickets) with the kidney being the main target
  • Serum calcium is variable depending on species
    • Cow: Normocalcemia
    • Horse: Hypercalcemia
    • Dog and cat: Slight hypocalcemia (occasionally may be hypercalcemic and hypophosphatemic) 
  • Young dogs with familial renal disease: Hypercalcemia 
  • Metabolic acidosis: Decreased bicarbonate (titration by uremic acids and impaired resorption); retention of hydrogen ions
• Water deprivation test: evaluate urine concentrating ability
  • Not specific, more than two thirds of the nephrons must be lost before concentrating ability is altered

 

DIFFERENTIAL DIAGNOSIS:

• Normal aging changes
• Idiopathic (inherited or congenital) generalized renal disease of young dogs
• Chronic, generalized pyelonephritis, glomerulonephritis, or inflammatory disease
• Renal amyloidosis
• Progressive renal ischemia due to vascular disease

 

COMPARATIVE PATHOLOGY:

• Cats: Type III Collagen Glomerulonephropathy; cause of end-stage glomerular kidney disease (Guillame et al, J Comp Path 2021) 
  • Gross: Kidneys enlarged, pale, firm
  • Histo: Diffuse global enlargement of glomeruli with massive deposition of extracellular pale, eosinophilic, amorphous to fibrillar material within the mesangial and capillary loops. Mesangial hypercellularity, hyperplasia of podocytes, synechia, and periglomerular fibrosis. Tubular ectasia and flattening of tubular epithelium, with abundant proteinaceous material within tubules. Multifocal moderate tubular mineralization, moderate interstitial fibrosis, and multifocal lymphoplasmacytic infiltration.
    • Lesions consistent with acute injury following chronic kidney disease
• Shetland pony: Pyelonephritic end-stage kidney and ureterocutaneous fistula (Schinköthe et. al, J Vet Diagn Invest. 2023).
  • Affected kidney markedly atrophic and fibrotic, with thickened capsule, non-identifiable corticomedullary junction
  • Severe glomerular and tubular atrophy, interstitial fibrosis, intimal and medial vascular fibrosis 
  • Lymphohistioplasmacytic to granulomatous pyelonephritis with few dilated to amorphous proteinaceous secretion-filled tubules (thyroidization)  
  • Atrophic, sclerotic, and hyalinized glomeruli present in cortex
• Mouse model for Diabetic Kidney Disease (leading cause of end-stage kidney disease in humans in developed countries) (Cohen, Toxico Pathol. 2018)
• Rodents (and humans): Numerous substances produce urinary calculi when administered at a dose above which crystallization occurs; chronic administration leads to changes including retrograde nephropathy, chronic hydronephrosis, pyelonephritis, and eventually end-stage kidney (Cohen, Toxicol Pathol. 2018).
  • Toxic end point in rodents (but not humans or other species including cats) is urothelial tumor formation
• Rodents: Chronic progressive nephropathy (CPN) (U-M11)
• Bears: End-stage renal disease (ESRD) is a common finding and cause for euthanasia in captive bears; best described in polar bears 
• Aged rhinos: Mononuclear interstitial nephritis and fibrosis with tubular degeneration and loss, with secondary changes, such as uremic mineralization in the lungs or stomach and gastric ulcers
• Captive anurans: Chronic renal disease is common cause of edema syndrome; most cases evaluated by pathologists are end-stage, and characterized by extensive fibrosis and tubular loss, +/- membranous glomerulonephropathy or glomerulonephritis 
• All artiodactyls and captive pygmy hippos: Leptospira sp. - important cause of chronic renal disease including severe end-stage disease with extensive fibrosis

 

REFERENCES:

1. Barthold SW, Griffey SM, Percy DH, eds. Pathology of Laboratory Rodents and Rabbits. 4^th ed. Ames, IA: Wiley Blackwell; 2016: 102, 157.
2. Sula MM, Lane LV. The Urinary System. In: Zachary JF, ed. Pathologic Basis of Veterinary Disease. 7th ed. St. Louis, MO: Elsevier; 2022:708-709, 717.
3. 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: 378, 383-387, 407-409.
4. Cohen SM. Crystalluria and Chronic Kidney Disease. Toxicol Pathol. 2018;46(8)949-955.
5. Clark SD, Abnormal Expression of miR-21 in Kidney Tissue of Dogs With X-Linked Hereditary Nephropathy: A Canine Model of Chronic Kidney Disease. Vet Pathol. 2019;56(1):93-105.
6. 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: 61-64, 74-75, 77.
7. Duncan M. Perissodactyls. In: Terio et al., eds. Pathology of Wildlife and Zoo Animals. San Diego, CA: Elsevier; 2018: 439-440.
8. Guillame E, Zacharopoulou M, Reynolds B, et al. Additional Value of Second Harmonic Generation Microscopy in the Diagnosis of Feline Collagen Type III Glomerulonephropathy. J Comp Pathol. 2021;188:37-43.
9. Jones MEB, Gasper DJ, Mitchell E. Bovidae, Antilocapridae, Giraffidae,Tragulidae, Hippopotamidae. In: Terio KA, McAloose D, St. Leger J, eds. Pathology of Wildlife and Zoo Animals. London, UK: Academic Press; 2018:117-148.
10. Keel KK, Terio, KA, McAloose D. Canidae, Ursidae, and Ailuridae. In: Terio et al., eds. Pathology of Wildlife and Zoo Animals. San Diego, CA: Elsevier; 2018: 235.
11. Miller MA. Endocrine System. In: Zachary JF, ed. Pathologic Basis of Veterinary Disease. 7th ed. St.    Louis, MO: Elsevier; 2022:790.
12. P Pessier AP. Amphibia. In: Terio KA, McAloose D, St. Leger J, eds. Pathology of Wildlife and Zoo Animals. London, UK: Academic Press; 2018:915-944. 
13. Pessier AP. Amphibia. In: Terio KA, McAloose D, St. Leger J, eds. Pathology of Wildlife and Zoo Animals. London, UK: Academic Press; 2018:915-944.
14. Rosol TJ, Grone 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: 291-296.
15. Schinköthe J, Gerlach K, Ulrich RG, Brehm W. Pyelonephritic end-stage kidney and ureterocutaneous fistula in a Shetland pony. J Vet Diagn Invest. 2023;35(5)577-580.
16. Stockham SL, Scott MA. Fundamentals of Veterinary Clinical Pathology. 2nd ed. Hoboken, NJ: Wiley; 2013.
17. Sula MM, Lane LV. The Urinary System. In: Zachary JF, ed. Pathologic Basis of Veterinary Disease. 7^th ed. St. Louis, MO: Elsevier;2022:706-709.

 

          

 

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