JPC SYSTEMIC PATHOLOGY

Urinary System
 December 2023

U-M07

 

Signalment (JPC # 3062414): Two-year-old German shepherd dog

 

HISTORY: This 2-year-old male military working dog was diagnosed with end-stage renal disease with emesis. On gross necropsy, bilaterally, the kidneys were small with irregular surfaces and areas of fibrosis.

 

HISTOPATHOLOGIC DESCRIPTION: Kidney: Multifocally and segmentally, there are rays of fibrous connective tissue up to 3mm wide extending from the depressed capsular surface, to the corticomedullary junction. Within these areas there are fetal glomeruli and immature tubules. Fetal glomeruli are characterized by small, hypercellular glomerular tufts with inapparent capillaries and prominent peripheral nuclei along the visceral epithelium, and are surrounded by a dilated and cystic urinary space. Immature tubules are small and branching (adenomatoid) and lined by cuboidal basophilic epithelium with nuclei that are closely grouped together. There are also many small arterioles with mural thickening. Multifocally, there is a moderate lymphoplasmacytic cellular infiltrate expanding the fibrotic cortical areas. Abutting these areas at the corticomedullary junction and extending through the medulla are multifocal regionally extensive areas of primitive mesenchyme that are characterized by loose glassy, homogenous eosinophilic matrix populated by stellate cells. This mesenchyme widely separates remaining dilated tubules, which are lined by attenuated epithelium, and occasionally contain eosinophilic amorphous material (tubular proteinosis) or rarely contain basophilic granular material (mineral). Persistent metanephric ducts, characterized by ciliated cuboidal to columnar epithelium, are also present in low numbers and are often surrounded by mesenchyme. Glomeruli are multifocally mildly hypercellular, and there is mild multifocal periglomerular fibrosis and mild hypertrophy of the parietal epithelium of Bowman’s capsule. 

 

Ureter: Essentially normal tissue.

 

MORPHOLOGIC DIAGNOSIS: Kidney: Asynchronous maturation, with fetal glomeruli, immature tubules, primitive mesenchyme, persistent metanephric ducts, interstitial fibrosis, and lymphoplasmacytic nephritis, German Shepherd Dog, canine.

 

CONDITION: Progressive juvenile nephropathy, familial/hereditary nephropathy, familial renal disease

 

GENERAL DISCUSSION:

• Progressive juvenile nephropathy and renal dysplasia are described as two distinct disease entities, each with breed predilections; however, they have many similarities between the two and lesions can overlap
• Renal dysplasia is an overarching term referring to an abnormality of altered structural organization resulting from abnormal differentiation and the presence of structures not normally present in nephrogenesis; it is usually congenital and may be hereditary, but may be obscured by secondary compensatory, degenerative, or inflammatory changes; can be caused by various infectious, nutritional, and genetic diseases
• Progressive juvenile nephropathy includes non-inflammatory, degenerative, or developmental, chronic renal disease in young animals with vague or ill-defined pathogenesis; a few likely are examples of renal dysplasia
• Familial or breed nephropathy are more restrictive terms used to describe renal disease in families or breeds of animals
• Hereditary nephropathy is a definitive term used once inheritance has been determined via identification of underlying genetic abnormality

 

PATHOGENESIS:

• Hereditary nephropathies

• Dogs:

• Samoyed hereditary glomerulonephropathy: X-linked type IV collagen defect caused by mutation in exon 35 of the COL4A5 gene (result is multilamellar splitting of GMB aka “basket weaving”)

• A colony of mixed breed dogs experienced similar disease due to a10-base pair deletion in exon 9 that caused a frame shift and premature stop codon in exon 10 in the COL4A5 gene)

• miR-21 abnormally upregulated in kidneys of dogs with CKD caused by X-linked hereditary nephropathy (Clark, Vet Pathol 2019)

• Dalmatians and bull terriers: autosomal dominant (basket-weaving of GBM and polycystic kidney disease, respectively)
• French mastiff: simple autosomal recessive inheritance (glomerulocystic atrophy with hypercellular glomeruli and thickened capillary walls)
• Bullmastiff: simple autosomal recessive inheritance (uncharacterized glomerulonephropathy)
• Bernese Mountain dog: simple autosomal recessive inheritance (immune-complex–mediated membranoproliferative glomerulonephritis)
• Soft-coated Wheaten terrier: simple autosomal recessive inheritance (podocytopathy and segmental glomerulosclerosis)
• English cocker spaniel: simple autosomal recessive inheritance of a single nucleotide substitution that causes a premature stop codon in exon 3 of COL4A3 and COL4A4 genes (causes proliferative and sclerosing glomerulopathy with basket weaving of the GBM)
• Shih tzu: simple autosomal recessive inheritance (immature glomeruli and tubules, adenomatoid proliferation of tubular epithelium, metanephric tubules, cortical cysts, persistent mesenchyme, and interstitial fibrosis)

• Cats: 

• Persians: Polycystic kidney disease caused by mutation in Pkd1
• Abyssinian: Amyloidosis (medullary and glomerular); suspected autosomal dominant genetic defect

• Renal dysplasia

• In normal embryogenesis development of the metanephros (the definitive kidney) begins as an evagination from the mesonephric duct (ureteric bud); this bud grows into a mass of mesenchymal cells (the metanephric blastema); normal renal and ureteral development depends on the interaction of the ureteric bud and the metanephric blastema
• Renal dysplasia is a developmental disorder caused by improper interaction between the ureteric bud and the metanephric blastema; small foci can be found as an incidental finding on necropsy
• Rapid growth of fetus/newborn and increased renin-angiotensin activity may cause increased susceptibility to permanent renal injury

 

TYPICAL CLINICAL FINDINGS:

• Canine familial renal disease

• Characterized clinically by renal failure in a group of related immature to young adult dogs (typically 4-18 months old)
• Inheritance and pathogenesis often uninvestigated

• Renal failure: Vomiting, diarrhea, depression, anorexia, weight loss, PU/PD
• Extrarenal anomalies may occur concurrently (e.g. imperforate anus, ureteral agenesis)
• Clinical pathology:

• Azotemia, hyperphosphatemia, hypercholesterolemia, hypercalcemia, non-regenerative anemia
• Isosthenuria, proteinuria

 

TYPICAL GROSS FINDINGS:  

• Progressive juvenile nephropathy findings are variable among different breeds

• Kidneys are notably shrunken, pale tan to white, and firm
• Diffusely pitted renal surface with a fine granular pattern
• Numerous small cortical cysts may be present due to dilation of Bowman’s capsule
• Renal surface may have patchy, deeply depressed cortical scarring if tubular or dysplastic lesions predominate
• On cut surface, cortex is thin with linear radial scars with a fibrotic medulla

• Renal dysplasia

• Kidneys are normally small, misshapen, or both and fibrosed with thick-walled cysts and dilated tortuous ureters; may affect one or both kidneys, lesions may be diffuse or focal
• Unilateral lesions: Ipsilateral ureter should be examined for congenital defects; bilateral lesions: Bladder and lower urinary tract should be examined

• +/- pyelonephritis associated with ureteral anomalies
• Findings consistent with chronic renal failure: Gastric and left atrial mineralization, fibrous osteodystrophy, parathyroid gland hyperplasia

 

TYPICAL LIGHT MICROSCOPIC FINDINGS:

• Progressive juvenile nephropathy:

• Type IV collagen defect in the glomerular basement membrane; lamellation of GBM
• Membranoproliferative glomerulonephritis
• Tubular atrophy and interstitial fibrosis
• Renal dysplasia findings (see below)

• Renal dysplasia:

• Fetal or immature glomeruli with peripheral nuclei and inapparent capillaries in the cortex of adult or adolescent animals
• Primitive/undifferentiated mesenchyme (interstitium has a myxomatous appearance)
• Collecting tubules ending blindly 
• Persistent metanephric ducts lined by cuboidal or columnar epithelium
• Adenomatoid/atypical epithelial proliferation in collecting tubules 
• Osseous or cartilaginous metaplasia (rare)
• Secondary interstitial fibrosis, renal cysts, and hypercellular compensatory glomeruli

 

ULTRASTRUCTURAL FINDINGS:  

Renal dysplasia:

• Lamellation and thickening of the glomerular basement membrane
• Fusion of visceral epithelial cell foot processes

 

DIFFERENTIAL DIAGNOSIS:

• For small kidneys:

• Progressive juvenile nephropathy and renal dysplasia can have similar gross features
• Renal fibrosis, acquired scarring with entrapped glomeruli, numerous etiologies
• Renal hypoplasia, numerous etiologies

 

COMPARATIVE PATHOLOGY:

• Dogs: Congenital, induced by drug therapy, or secondary to neonatal herpesvirus infection

• β-Mannosidosis reported in 3 German shepherd puppies (previously reported in Saliers calves) -> lysosomal storage disease, causes lesions in the kidneys as well as severe neuro defects

• Cats: Fetal infection with panleukopenia virus (parvovirus)
• Bovine:  

• Renal dysplasia with hydronephrosis and congenital ureteral stricture reported in two Holstein-Freisan calves
• Fetal infection with bovine virus diarrhea virus (pestivirus)

• Pigs: Renal dysplasia attributed to hypovitaminosis A 
• Sheep: Autosomal dominant form of cystic renal dysplasia in Suffolk breed
• Pygmy hippopotamuses: Polycystic kidney disease in over 35% of captive adults/geriatric animals 
• Captive springbok: Neonatal polycystic kidney disease (lethal) documented to affect up to 18% of live births
• White-tailed and roe deer: Polycystic kidneys regularly reported
• Peccaries: Polycystic kidney disease reported; assumed to be acquired, not inherited
• Pallas’ cats: Captive animals from North American zoo populations have been diagnosed with polycystic kidney disease (in adulthood); familial inheritance suspected
• Mink: Fatal polycystic kidney disease reported in kits
• Racoon, dwarf mongoose: Polycystic kidney disease reported in one aged raccoon; reported occasionally in dwarf mongoose 
• Brazilian agoutis: Polycystic kidney disease reported; many affected animals have no clinical signs
• Non-human primates: Polycystic kidney disease, renal aplasia, other congenital defects possible

• Cynomolgus monkey: Unilateral renal aplasia (spontaneous) reported at the termination of a toxicology study

 

REFERENCES:

1. Abee CR, Mansfield K, Tardif S, Morris T. Nonhuman Primates in Biomedical Research: Volume 2: Diseases. 2nd ed. San Diego, CA: Elsevier; 2012.

2. Bilgen N, Türkmen MB, Kul BC, et al. Prevalence of PKD1 gene mutation in cats in Turkey and pathogenesis of feline polycystic kidney disease. J Vet Diagn Invest. 2020;32(4):549-555.

3. Church ME, Terio KA, Keel MK. Procyonidae, Viverridae, Hyenidae, Herpestidae, Eupleridae, and Prionodontidae. In: Terio KA, McAloose D, St. Leger J, eds. Pathology of Wildlife and Zoo Animals. London, UK: Academic Press; 2018:308.

4. 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: 388-394, 395-396, 415-417. 

5. Clark SD, Song W, Ciancolo R, et al. 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. Delaney MA, Treuting PM, Rothenburger JL. Rodentia. In: Terio KA, McAloose D, St. Leger J, eds. Pathology of Wildlife and Zoo Animals. London, UK: Academic Press; 2018:502.

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8. Jolly RD, Dittmer KE, Garrick DJ, et al. β-Mannosidosis in German Shepherd Dogs. Vet Pathol. 2019;56(5):743-748.

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10. Martinez MAJ, Gasper DJ, Mucino MCC, Terio KA. Suidae and Tayassuidae. In: Terio KA, McAloose D, St. Leger J, eds. Pathology of Wildlife and Zoo Animals. London, UK: Academic Press; 2018:208.

11. Obert LA, Suttie A, Abdi M, et al. Congenital Unilateral Renal Aplasia in a Cynomolgus Monkey (Macaca fasicularis) With Investigation Into Potential Pathogenesis. Toxicol Pathol. 2020;48(6):766-783.

12. Sula MM, Lane LV . The Urinary System. In: Zachary JF, ed. Pathologic Basis of Veterinary Disease. 7th ed. St. Louis, MO: Elsevier; 2022:717, 722-725, 753.

13. Takehana K, Moresco A, Johnson III JG, et al. Severe Hydroxyapatite Deposition Disease in Binturongs (Arctictis binturong). Vet Pathol. 2021;58(6):1147-1151.

13. Terio KA, McAloose D, Mitchell E. Felidae. In: Terio KA, McAloose D, St. Leger J, eds. Pathology of Wildlife and Zoo Animals. London, UK: Academic Press; 2018:266.

14. Williams BH, Burek-Huntington KA, Miller M. Mustelids. In: Terio KA, McAloose D, St. Leger J, eds. Pathology of Wildlife and Zoo Animals. London, UK: Academic Press; 2018:292.

15. Yoshida K, Takezawa S, Itoh M, et al. Renal Dysplasia with Hydronephrosis and Congenital Ureteral Stricture in Two Holstein-Friesian Calves. J Comp Pathol. 2022;193:20-24.

 

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