JPC SYSTEMIC PATHOLOGY
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 following changes. There is a mild reduction in the number of glomeruli and multifocally those remaining have one or more of the following changes: The basement membrane of Bowman’s capsule 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 (synechia); the uriniferous space is dilated; there is segmental or global glomerulosclerosiswith 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 (regeneration) that occasionally piles up and forms irregular tubules (hyperplasia), with multifocally thickened basement membranes; or shrunken atrophic tubules with attenuated epithelium. Ectatic tubule lumina often contain one or more of the following: variable amounts of pale granular to brightly eosinophilic homogenous proteinaceousmaterial (proteinosis, hyaline casts), deeply basophilic granular material (mineralization), sloughed epithelial cells with cellular and karyorrhectic debris (necrosis), few degenerate neutrophils, and rare erythrocytes. Tubular epithelia, primarily of the proximal convoluted tubule, multifocally contain variably distinct, irregularly round, intracytoplasmic 1-4um 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) within the interstitium and tubules. Multifocally, the capsular surface is irregular and undulant.
MORPHOLOGIC DIAGNOSIS: Kidney: Glomerulosclerosis, segmental to global, multifocal, marked, with synechia, periglomerular fibrosis, tubular degeneration, necrosis, and regeneration, marked tubular ectasia with proteinosis, and chronic 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, others
- 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 noncomplement-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
- 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
- Macrophages and myofibroblasts appear to play an important role in the development of interstitial fibrosis, likely through production of TGF-β
- TGF-β plays an important role in the development of fibrosis, which can be minimized with sirtuin therapy (AJP 2017)
- 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
- 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
- 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
- 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
- Thickened capillary basement membranes
- Distorted, fused, and enlarged podocyte foot processes distort distortion, enlargement, and fusion of podocyte foot processes in multiple areas
- 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
- 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)
- 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 of Navasota dogs due to a genetic defect resulting in defective production of type IV collagen, resulting in similar disease with mesangioproliferative glomerulopathy and progressive proteinuria with glomerular loss, interstitial fibrosis, tubular necrosis, and variable inflammation
- Naked mole rat: Similar progressive chronic nephritis/nephropathy is common in aging animals of this long-lived species; glomerular changes are less severe than in rats and mice with CPN and characterized predominantly by membranous glomerulopathy, Bowman capsule dilation is not a feature; secondary hyperparathyroidism is not a feature of this disease
- Key Largo woodrat: similar disease
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- Terrell SP, Origgi FC, Agnew D. Glomerulonephropathy in aged captive Key Largo woodrats (Neotoma floridana smalli). Vet Pathol. 2012;49(4):710-716.
- Zhang Y, Connelly KA, et. al. Sirtuin 1 activation reduces transforming growth factor-β1-induced fibrogenesis and affords organ protection in a model of progressive, experimental kidney and associated cardiac disease. Am Jour Pathol. 2017;187(1):80-90.