JPC SYSTEMIC PATHOLOGY

URINARY SYSTEM

December 2023

U-M11

 

Signalment (JPC #1565530): Rat

 

HISTORY: Tissue from an old laboratory rat 

 

HISTOPATHOLOGIC DESCRIPTION: Kidney: Diffusely, all levels of the nephron are moderately to severely affected by the changes listed below. There is a mild reduction in the number of glomeruli and multifocally those remaining have one or more of the following changes: Bowman’s capsule basement membrane is variably thickened and hyalinized and there is periglomerular fibrosis; the parietal epithelium of Bowman’s capsule is hypertrophied; there are multifocal adhesions of the glomerular tuft to Bowman’s capsule (synechiae); the uriniferous space is dilated; and there is segmental or global glomerulosclerosis with multifocal obsolescence of glomerular tufts. Diffusely within the cortex and medulla, tubules have one or more of the following changes:  swollen epithelium with indistinct cell borders and microvacuolated eosinophilic cytoplasm (degeneration); marked tubular ectasia with attenuation and/or loss of epithelium; abundant basophilic cytoplasm with vesiculate nuclei and rare mitotic figures (regeneration) that occasionally piles up and forms irregular tubules (hyperplasia), with multifocally thickened basement membranes; or shrunken atrophic tubules with attenuated epithelium. Ectatic tubular lumina often contain one or more of the following:  variable amounts of pale granular to brightly eosinophilic homogenous proteinaceous material (proteinosis, hyaline casts), deeply basophilic granular material (mineralization), sloughed epithelial cells with cellular and karyorrhectic debris (necrosis), few necrotic neutrophils, and rare erythrocytes. Tubular epithelia, primarily of the proximal convoluted tubule, multifocally contain variably distinct, irregularly round, intracytoplasmic 1-4µm diameter eosinophilic hyaline droplets. Diffusely, the interstitium is moderately expanded by fibrosis, edema, and multifocal infiltrates of low numbers lymphocytes and plasma cells. Multifocally there is a small amount of light golden-brown material (hemosiderin/lipofuscin) within the interstitium and tubules. Multifocally, the capsular surface is irregular and undulant.  

 

MORPHOLOGIC DIAGNOSIS: Kidney: Glomerulosclerosis, segmental to global, multifocal, chronic, marked, with synechiae, periglomerular fibrosis, tubular degeneration, necrosis, and regeneration, marked tubular ectasia with proteinosis, and lymphoplasmacytic interstitial nephritis, rat, rodent.

 

CONDITION: Chronic progressive nephropathy (CPN)

 

SYNONYMS: Glomerulosclerosis, progressive glomerulonephrosis, “old rat nephropathy”, protein overload nephropathy, chronic renal disease, chronic nephritis, dietary nephritis, glomerulonephritis, chronic progressive glomerulonephropathy, glomerular hyalinosis, progressive renal disease, spontaneous nephrosis

 

GENERAL DISCUSSION:

• The most common, life-limiting disease of aged rats, and the most important renal disease in rats and mice; prevalence may exceed 75% in susceptible strains
• Progressive disease that can lead to chronic renal failure and death
• Predisposing factors:
  • Age: Usually seen in rats >12 months old
  • Sex: More prevalent in males
  • Strain: Higher prevalence in Sprague-Dawley and Fischer 344 rats
  • Diet: High protein diets predispose to disease; total dietary caloric restriction (rather than dietary protein restriction alone) delays onset and reduces disease progression
  • Immunologic factors: Affected glomeruli have mesangial deposition of IgM consistent with non-complement-fixing immune complexes; however, CPN does not appear to be primarily an immune-mediated disease
  • Endocrine: Prolactin levels implicated as a contributing factor
  • Microbial status: Axenic rats tend not to develop CPN and therefore live much longer than microbe-associated rats
• Generally considered a degenerative to atrophic disease with compensatory regenerative hyperplasia
• Lesions can be evident as early as 3 months, but do not usually become severe until over 52 weeks of age; age of onset, incidence, and severity varies with stock/strain
• Lesions are typically bilaterally symmetric
• CPN contributes to hypertension and is often associated with polyarteritis nodosa
• Rats cope well with disease, but may rapidly decompensate and die
• Intrarenal Renin–Angiotensin System identified in having a central involvement in the mechanistic pathways such as hypoxia (hypoxia-inducible factor 1α), altered intrarenal renin–angiotensin system (RAS), oxidative stress (nitric oxide), and pro-inflammatory pathways (transforming growth factor β) resulting in CPN (Obert LA, Toxicol Pathol. 2019)

 

PATHOGENESIS:

• Pathogenesis is complex and exact mechanism is unknown; essentially any nephrotoxic insult can result in CPN; it is suggested that glomeruli are the initial site of injury
• Fibrosis: 
  • Macrophages and myofibroblasts appear to play an important role in the development of interstitial fibrosis, likely through production of TGF-β
• In advanced cases, secondary hyperparathyroidism often develops, resulting in metastatic mineralization in multiple organs (e.g. kidney, gastric mucosa, lungs, and media of larger arteries) and osteodystrophy with fibroplasia
• Increased glomerular protein loss à functional overload of nephrons à“hyaline” droplets in tubular epithelial cells with associated increased lysosomal activity 

 

TYPICAL CLINICAL FINDINGS:

• Weight loss, proteinuria
• Advanced cases: Elevated plasma creatinine (renal insufficiency)
• Nephrotic syndrome in advanced cases: marked proteinuria, hypoalbuminemia, edema, hypercholesterolemia
  • Elevated serum cholesterol and marked proteinuria (>300mg/dL) are useful diagnostic parameters

 

TYPICAL GROSS FINDINGS:

• Renal cortices pitted, sometimes irregular, with irregularities and linear streaks in the cortex and medulla on cut surface with varying degrees of brown pigmentation
• Kidneys variably enlarged, pale

 

TYPICAL LIGHT MICROSCOPIC FINDINGS:

• Changes consistent with chronic glomerulonephropathy are present at all levels of the nephron; lesions depend on chronicity
  • Early lesions: Focal to multifocal foci of tubule basophilia, nuclear crowding, peritubular basement membrane thickening, variable infiltration by mononuclear inflammatory cells
  • With progression: Amount of affected renal parenchyma increases, individual components of CPN become more severe, and hyaline casts are prominent, as well as development of glomerular changes such as capillary tuft thickening, adhesions between glomerular epithelium and Bowman’s capsule (synechiae), and glomerulosclerosis; there may be a small but significant increase in proliferative lesions of the proximal tubule
• Tubules: 
  • Intraluminal proteinaceous or hyaline casts in dilated tubules of the cortex and medulla
  • Eosinophilic PAS-positive and iron-positive resorption droplets (“hyaline” droplets) frequently present in tubular epithelium of affected nephrons
  • Tubules often either ectatic and lined by attenuated epithelium, or contracted and lined by poorly differentiated cuboidal basophilic epithelium, or sclerotic 
  • Variable thickening and splitting of proximal tubular basement membrane
• Glomeruli: 
  • Lesions vary from minimal basement membrane thickening to marked thickening of glomerular tufts with segmental glomerulosclerosis and adhesions to Bowman’s capsule (synechiae)
  • Variable thickening and splitting of Bowman’s capsular basement membrane
• Interstitium: 
  • Interstitial fibrosis
  • Mononuclear cell infiltration
• Renal papilla: Epithelial hyperplasia with advanced disease 
• Other Tissues: Metastatic mineralization of the kidney, gastric mucosa, lungs, and media of larger arteries in severe cases due to renal secondary hyperparathyroidism

 

ULTRASTRUCTURAL FINDINGS:  

• Thickened capillary basement membranes
• Distorted, fused, and enlarged podocyte foot processes distort distortion, enlargement, and fusion of podocyte foot processes in multiple areas

 

DIFFERENTIAL DIAGNOSIS: 

Histologic:

• Chronic bacterial pyelonephritis: Medullary necrosis, patchy fibrosis in outer medulla and cortex, inflammatory exudate within renal pelvis
• Renal ischemic injury: Necrosis (acute) or fibrosis (chronic) of entire nephrons 
• Nephrosis associated with toxic insults (e.g. aminoglycosides): cortical tubules uniformly affected
• Atypical tubule hyperplasia and adenoma: CPN can have tubular proliferative lesions; atypical hyperplasia or adenoma are expansive with complex proliferation of tubules and no thickened basement membrane

 

COMPARATIVE PATHOLOGY:

• Mice, hamsters, gerbils, guinea pigs: Age-related chronic renal disease morphologically similar to CPN of rats has been diagnosed in a variety of laboratory rodents; in rats, basement membrane thickening occurs in the absence of vascular lesions, which is unlike these rodents; mice have less severe renal and secondary systemic changes (e.g. metastatic calcification); any strain of mice is susceptible to CPN, but specifically described in B6C3F1 mice; metastatic calcification of tissue usually not a feature in mice
  1. CD-1 mice: The major nonneoplastic causes of death in a retrospective study of young CD-1 mice were obstructive uropathy (39/192, 20.3%) in males and chronic progressive nephropathy (40/198, 20.2%) in females.
• Humans: Diabetic glomerulopathy and end-stage renal disease
• Common marmosets: Spontaneous progressive glomerulonephropathy dominated by glomerular lesions with secondary tubulointerstitial lesions is similar to CPN in rodents; pathogenesis unknown 
• Dogs: X-linked hereditary nephropathy (XLHN) of Navasota dogs: miR-21 upregulation in the kidney may play an important pathologic role in the progression of XLHN by dysregulating multiple pathways – Genes associated with fibrosis:  COL1A1, TGFB1 and its receptor, TGFB2, and Serpine1 were upregulated (Clark SD, Vet Pathol. 2019)
• Mice, Naked mole rat and Australian rodents (stick-nest rat):  Gross lesion: Bilateral pale kidney, enlarged or shrunken with numerous pinpoint to large 1mm cortical microcysts (nodular surface); Histo lesions: markedly ectatic and tortuous renal tubules with intraluminal bright eosinophilic fluid (proteinosis); adenoma formation (predominately in rats); glomeruli variably affected
• Key Largo woodrat: Similar disease
• Marmoset: “Wasting Marmoset Syndrome” (WMS) - Inflammatory non-infectious disease entities; etiology undetermined; syndrome is primarily associated with chronic lymphocytic enteritis (CLE), inflammatory bowel disease (IBD) or chronic renal disease characterized by severe interstitial nephritis, mesangioproliferative, or membranoproliferative glomerulonephritis

 

REFERENCES:

1. Apreutese A, Levi M, Taylor I, Apreutese R, Mukaratirwa S, Mowat V. Causes of Mortality and Profile of Spontaneous Tumors in Young CD-1 Mice. Toxicol Pathol. 2022 Aug;50(6):776-786.
2. Barthold SW, Griffey SM, Percy DH. Pathology of Laboratory Rodents and Rabbits. 4th ed. Ames, IA: Blackwell Publishing; 2016: 102, 157-158.
3. Clark SD, Wenping S, Cianciolo R, Lees G, Nabity M, Liu S. 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.
4. Delaney MA, Trueting PM, Rothenburger JL. Rodentia. In: Terio KA, McAloose D, St. Leger J ed. Pathology of Wildlife and Zoo Animals. Cambridge, MA: Elsevier Inc. 2018: 503.
5. Gutsol AA, Hale TM, Thibodeau JF, Holterman CE, Nasrallah R, Correa JWN, Touyz RM, Kennedy CRJ, Burger D, Hébert RL, Burns KD. Comparative Analysis of Hypertensive Tubulopathy in Animal Models of Hypertension and Its Relevance to Human Pathology. Toxicol Pathol. 2023 Jun;51(4):160-175.
6. Matz-Rensing K, Lowenstine L. New world and old world monkeys. In: Terio KA, McAloose D, St. Leger J ed. Pathology of Wildlife and Zoo Animals. Cambridge, MA: Elsevier Inc. 2018: 347.
7. Obert LA, Frazier KS. Intrarenal renin–angiotensin system involvement in the pathogenesis of chronic progressive nephropathy—bridging the informational gap between disciplines. Toxicol Pathol. 2019; 47(7): 799-816. 

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