Adult male Sprague-Dawley rat, Rattus norvegicus.This transgenic rat for the mouse Ren2 gene was found dead.
The small intestinal mesenteric arteries were diffusely dark red, nodular, tortuous and measured up to 5mm in diameter. Both kidneys had many 0.5mm round indentations on their surfaces.
The renal changes are consistent with an end stage kidney with polyarteritis nodosa and hypertensive arterial disease. The renal capsule is irregularly indented throughout. The underlying interstitium has tubular loss with replacement by fibrous connective tissue and infiltration by lymphocytes and plasma cells. The glomerular mesangium is regularly thickened by pale eosinophilic amorphous material, the tufts are large and prominently segmented, and periglomerular fibrosis is prominent. Occasional glomeruli are shrunken, have synechia or are sclerotic. The cortical renal tubules are dilated, up to 1mm across, by eosinophilic amorphous material, and are lined by attenuated epithelium. Tubular epithelial cells are occasionally swollen with vacuolated cytoplasm, and some have hypereosinophilic cytoplasm and pyknotic nuclei. The tunica media of medium-sized arteries is thickened by concentric rings of excessive smooth muscle and sometimes fibrous connective tissue, and the walls are infiltrated by lymphocytes and fewer macrophages. Hypereosinophilic amorphous material obscures the tunica media in some slides (fibrinoid change).
1. Glomerulonephropathy, diffuse, chronic, severe with tubular proteinosis and interstitial lymphocytic nephritis and fibrosis (chronic progressive nephropathy).
2. Arteritis, segmental, chronic, moderate to severe, lymphohistiocytic with fibrinoid change, kidney (polyarteritis nodosa).
3. Smooth muscle hyperplasia, segmental, chronic, moderate, arterial tunica media, kidney (hypertensive change).
Chronic progressive nephropathy, polyarterits nodosa, hypertension
This case demonstrates three histological renal lesions in a hypertensive rat: chronic progressive nephropathy (CPN), polyarteritis nodosa and hypertensive arterial disease. CPN is a common age-related lesion most common in males, with increased incidences in Sprague-Dawley and Fischer 344 rats. Grossly, the renal cortices are irregular and pitted, as in this case. The kidneys may be enlarged, pale and have linear streaks in the cortex and medulla. Histologically, glomerular changes include basement membrane and mesangial thickening, segmental sclerosis, and synechia. Tubules are regularly dilated, protein-filled, and lined by flattened epithelial cells. Interstitial fibrosis and inflammation are common. Advanced cases may also have secondary hyperparathyroidism with metastatic calcification in the kidneys, gastric mucosa, lungs and/or tunica media of larger arteries. Late-stage CPN has been associated with hypertension and polyarteritis nodosa.(7)
Similar to CPN, polyarteritis nodosa is a chronic progressive degenerative disease occurring most frequently in aged Sprague-Dawley rats, spontaneous hypertensive rats, and rats with late-stage chronic nephropathy. At necropsy the mesenteric vessels are often enlarged, tortuous and segmentally thickened, as in this case. Polyarteritis nodosa is characterized histologically by fibrinoid degeneration and thickening of the tunica media of medium-sized arteries with infiltrating mononuclear cells and fewer neutrophils. The lumina may vary in size and have thromboses, some of which may recanalize. Polyarteritis nodosa has also been reported in mice,(7) cats,(1) dogs,(11) pigs,(2,4) cynomolgus macaques(9) and foxes.(6) Although the cause is uncertain, the lymphohistiocytic inflammation suggests it may have an immune-mediated basis.(4,7,9)
The rat is a common animal model of hypertension. Spontaneously hypertensive Wistar rats, Dahl-salt sensitive rats, transgenic mREN2 rats, and rats administered deoxycorticosterone acetate (DOCA) in combination with a high salt diet are the most common models.(3,8) In all of these models, the hypertensive animals have impaired endothelium-dependent relaxation and vascular remodeling which lead to increased vascular resistance and renal damage.(3,8) Severe end-organ damage involving the heart, brain and kidney is only seen in a subset of animals within some models. This rat was transgenic (TGR[mREN2]27), with over-expression of the mouse Ren-2 gene which increases renin activity. Renin catalyzes the conversion of angiotensinogen to angiotensin I, which is then converted to angiotensin II by angiotensin-converting enzyme. Angiotensin II causes vasoconstriction and increased blood pressure. Hypertensive changes are further exacerbated by angiotensin II-induced aldosterone secretion which increases mineralocorticoid levels and sodium reabsorption, thus increasing blood volume osmotically and further increasing blood pressure.(10)
1. Kidney, arteries: Arteritis, proliferative and necrotizing, multifocal, severe, with fibrinoid necrosis.
2. Kidney, arteries: Arteriosclerosis, multifocal, moderate.
3. Kidney: Glomerulonephritis, diffuse, with tubular degeneration, necrosis and regeneration, proteinosis, and chronic interstitial nephritis.
The contributor provides an excellent summary of the various changes observed in this animal model of hypertension. Veterinary species are not as commonly affected with idiopathic (essential) hypertension as humans; however, several species, including cats and dogs, develop systemic hypertension which is often secondary to other conditions. In the cat, hypertension is often associated with hyperthyroidism and chronic renal failure; whereas in the dog, it is more likely to be associated with chronic renal failure, hyperadrenocorticism, or pheochromocytomas.(5)
Conference participants discussed the vessel wall changes observed in this case, noting that hypertension results in several pathologic changes in the walls of small arteries and arterioles, including two types of arteriolosclerosis: hyaline and hyperplastic. Small blood vessels in hyaline arteriolosclerosis exhibit a homogeneous, eosinophilic thickening of the wall and narrowing of the lumen due to endothelial cell damage and the subsequent increased vascular permeability and plasma protein leakage into the vessel wall. Hyperplastic arteriolosclerosis, on the other hand, is characterized by a concentric, laminated thickening of the wall (onion skinning) and narrowing of the lumen which is due to smooth muscle cell hyperplasia and reduplication of basement membranes. Hyperplastic arteriolosclerosis can also be associated with fibrinoid necrosis in the vessel walls.(10)
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