Signalment:  

10-week-old male Sprague-Dawley rat (Rattus norvegicus)Tissue from a rat fed a high salt diet (8% NaCl) and infused with angiotensin II for 14 days.

Histopathologic Description:

Kidney: Multifocal glomeruli globally or segmentally have markedly thickened capillary loops and mesangial matrix expansion by homogeneous eosinophilic material (glomerular hyalinosis and sclerosis) resulting in glomerular tufts 50% to 100% larger than unaffected tufts. Multifocally, cells within affected glomerular tufts contain abundant hypereosinophilic cytoplasm and plump nuclei (hypertrophy) and some affected tufts contain pyknotic cellular debris (glomerulonecrosis). Other tufts contain cells with basophilic or vacuolated cytoplasm. Bowmans capsule parietal epithelium is hyperplastic with prominent, rounded nuclei and abundant slightly basophilic cytoplasm. Frequently, there is adhesion of the expanded glomerular tuft to the parietal epithelium (synechiae). Bowmans capsule basement membrane is variably thickened and surrounded by fibrous connective tissue (periglomerular fibrosis). The tunica media of small caliber vessels, particularly cortical and afferent and efferent juxtaglomerular arterioles and rarely arcuate and interlobar arteries, is multifocally expanded/ replaced by a homogenous, deeply eosinophilic material (fibrinoid necrosis) and occasionally contains basophilic cellular debris. Affected vessels in some areas are surrounded by concentric layers of loose fibrous connective tissue (fibrosis), small to moderate numbers of mononuclear leukocytes, and occasionally, extravasated erythrocytes (hemorrhage). Smooth muscle cells and endothelial cells are hypertrophic. Throughout the cortex are numerous regenerative tubules characterized by crowded tubular epithelial cells with basophilic (occasionally vacuolated) cytoplasm, deeply basophilic nuclei and rare mitotic figures. The tubular alteration is most prominent adjacent to affected glomeruli. Proximal tubules and collecting ducts frequently are ectatic and/or contain hypereosinophilic, homogenous proteinaceous fluid (proteinuria) or sloughed cells (cellular casts) and occasionally are lined by attenuated epithelium. The interstitium is multifocally expanded by loose fibrous connective tissue and small numbers of mononuclear leukocytes.

Morphologic Diagnosis:  

1. Glomerulonephropathy, multifocal, chronic with glomerular hyalinosis and sclerosis and tubular degeneration/ regeneration, atrophy, ectasia and proteinuria
2. Arteriolopathy, proliferative, chronic, multifocal with medial degeneration and fibrinoid necrosis

Condition:  

Hypertensive nephropathy

Contributor Comment:  

Hypertensive nephropathy is a common sequela to chronic high blood pressure in humans. One quarter of the US population is hypertensive and approximately 6% of affected individuals have chronic kidney disease with the risk of progression to end stage renal disease.(1) The relationship of hypertension and chronic renal disease is complex since hypertension is both a cause and consequence of renal disease.(6) In the human population, risk factors for hypertensive nephrosclerosis include African ancestry, severe and sustained hypertension, family history, microalbuminuria, diabetes mellitus, and left ventricular hypertrophy.(1) The morphological features of human hypertensive nephrosclerosis include vascular wall medial thickening with arteriolar hyaline deposits and intimal fibrosis as well as focal glomerular ischemic changes (retraction, wrinkling, and folding of the capillary walls) with basement membrane thickening, global or even segmental glomerulosclerosis and varying but subtotal foot process effacement (electron microscopy). Tubular atrophy and interstitial fibrosis also occur. This presentation of glomerular changes may be referred to as focal segmental glomerulosclerosis (FSGS) and may be attributed to hypertensive renal injury when accompanied by glomerular ischemic changes, periglomerular fibrosis, subtotal foot process effacement and disproportionate vascular sclerosis.5 When diagnosing the human patient, clinical history is critical and hypertension typically precedes renal insufficiency and proteinuria.(5)

In experimental medicine, rats are the most popular hypertensive model and the spontaneous hypertensive rat (SHR) is the most common model utilized.(9) Impaired endothelium dependent relaxation, cardiac hypertrophy and/or heart failure, cerebral hemorrhage, nephropathy and/or renal failure are features of most models of rat hypertension, mimicking the human spectrum of disease. Hypertension in rats is defined as sustained systolic blood pressure of greater than 150 mmHg.(2) The submitted case illustrates microscopic features that developed after 14 days of hypertension induced by high salt diet and angiotensin II infusion. Table 1 compares selected systemic hypertensive rat models.

Rat Model	Hyper-tension Etiology	Hypertension Mechanism of Action	Age of Onset	Blood Pressure Elevation (Systolic)	Comments
Stroke-prone Spontaneously Hypertensive Rat (SHRSP)(2,9)	Primary, genetic	Renally related -- Transplanting a kidney from SHR to a normotensive Wistar rat increases blood pressure in the recipient	Begins at 6-7 weeks of age	200 mmHg	80% die from stroke
Spontaneously Hypertensive Rat (SHR)(2,9)	Primary, genetic	Renally related -- Transplanting a kidney from SHR to a normotensive Wistar rat increases blood pressure in the recipient	Begins at 5-6 weeks of age, maximal by 12 weeks	180-200 mmHg	30% develop heart failure at 4-5 months of age
Dahl Salt Sensitive Rat(9)	Primary, genetic and dietary	High dietary sodium content increases circulating sodium causing osmotic pull into vasculature, elevating pressure on vessel walls	4-6 weeks of age	Increased even on normal diet; Steeply elevated on high salt diet	30% develop heart failure at 18 months of age
Transgenic TGR(mRen2)27 Rat(4,9)	Primary, genetic	Overexpression of the mouse Ren-2 gene (increased renin activity)	Begins at 5 weeks and maximal by 10 weeks of age	Heterozygous: 240 mmHg; Homozygous: 300 mmHg (high mortality)	Mortality from heart failure at 10 weeks of age
Double Transgenic (dTG) Rat(11)	Primary, genetic	Expresses both human renin and angiotensinogen genes	Early	200-220 mmHg	50% mortality by 7-8 weeks of age
Deoxycorticosterone Acetate (DOCA) + High Salt Diet(2,7, 9)	Secondary, endocrine/ dietary	Salt-dependent, mineralocorticoid (DOCA)-induced reabsorption of salt and water resulting in increased blood volume Also increased secretion of vasopressin = vasoconstriction + water retention	Hyper-tension begins 1-2 weeks after start of DOCA and high salt diet	200 mmHg	Mortality from brain, vascular, and renal lesions after 4-8 weeks of treatment
Ang II Infusion and High Salt Diet(10)	Secondary, endocrine	Daily infusion of angiotensin II via osmotic pump and high salt diet	Begins 1 day post infusion	130-200 mmHg	Mortality from renal glomerulosclerosis and vascular necrosis
Goldblatt Method: Two-Kidney One-Clip(2,9)	Secondary, renal	Clip on one renal artery increases circulating renin and angiotensin II	Develops 6 weeks post-surgery	160 - 190 mmHg	Mortality from renal failure and cardiovascular complications
Goldblatt Method: Two-Kidney Two-Clip(2)	Secondary, renal	Partial occlusion of both renal arteries (two stage surgery) increases circulating renin and aldosterone	Develops 4 weeks post-surgery	160 - 190 mmHg
Godlblatt Method: One-Kidney One Clip(2)	Secondary, renal	Uninephrectomy and clip on renal artery of remaining kidney with rapid salt and water retention; Plasma renin activity is normal	Within hours of surgery	160 - 190 mmHg
Renal Remnant(12)	Secondary, renal	Uninephrectomy and segmental 2/3 ablation of remaining kidney to 5/6 total renal mass	Within hours of surgery	170-190 mmHg	Mortality from renal failure with cardiovascular complications

Angiotensin II has a wide array of biological effects including (from Kobori et. al(3)):
1. Arteriolar vasoconstriction (in the glomerulus, efferent > afferent)
2. Stimulation of aldosterone secretion (zona glomerulosa of the adrenal cortex)
-Ç-ó Acts on distal convoluted tubules and collecting ducts → reabsorb sodium and water from urine (exchange for potassium which is excreted in urine) → ↑blood volume → ↑blood pressure
3. Secretion of anti-diuretic hormone from the pituitary
a. Vasoconstriction
b. Reabsorption of water in the kidneys
c. Stimulation of thirst and salt appetite
4. Regulation of sodium transport by renal and intestinal epithelium
-Ç-ó In the kidney, stimulation of Na+/H+ exchange on proximal tubules, thick ascending limb of the loop of Henle, and collecting ducts → increased sodium resorption
5. Hypertrophy of renal tubular epithelium
6. Release of prostaglandins → counteracts renal vasoconstriction
7. Reduced renal medullary blood flow
8. Increases tubuloglomerular feedback sensitivity → lower tubular perfusion (prevents excessive rise in glomerular filtration rate)
9. Other actions
a. Enhanced cardiomyocyte growth and contractility
b. Stimulation of release of catecholamines (norepinephrine from adrenal medulla)
c. Increases sympathetic nervous system activity

JPC Diagnosis:  

1. Kidney, arterioles: Arteriopathy, proliferative and necrotizing.
2. Glomerulosclerosis, multifocal, moderate, with tubular degeneration, regeneration, and protein casts.

Conference Comment:  

Differential diagnoses discussed during conference included chronic progressive nephropathy (CPN) and polyarteritis nodosa (PAN). CPN generally does not include a vascular component centered on small arterioles as in this case, and CPN typically has conspicuous basement membrane thickening, which is absent in this case. Polyarteritis nodosa tends to affect vessels of a larger caliber than is typical with hypertensive nephropathy and to affect vessels more randomly. As the name indicates, CPN becomes progressively more severe with age, and PAN is typically a disease of aged rats. 

The contributor has provided an excellent comparative review of hypertensive nephropathy, a condition that is morphological similar in most affected species. 

References:

1 Barri YM: Hypertension and kidney disease: a deadly connection. Curr Hypertens Rep 10: 39-45, 2008
2 Doggrell SA, Brown L: Rat models of hypertension, cardiac hypertrophy and failure. Cardiovasc Res 39: 89-105, 1998
3 Kobori H, Nangaku M, Navar LG, Nishiyama A: The intrarenal renin-angiotensin system: from physiology to the pathobiology of hypertension and kidney disease. Pharmacol Rev 59: 251-287, 2007
4 Langheinrich M, Lee MA, Bohm M, Pinto YM, Ganten D, Paul M: The hypertensive Ren-2 transgenic rat TGR (mREN2)27 in hypertension research. Characteristics and functional aspects.Am J Hypertens 9: 506-512, 1996
5 Marcantoni C, Fogo AB: A perspective on arterionephrosclerosis: from pathology to potential pathogenesis. J Nephrol 20: 518-524, 2007
6 Navar LG: The kidney in blood pressure regulation and development of hypertension. Med Clin North Am 81: 1165-1198, 1997
7 Park CG, Leenen FH: Effects of centrally administered losartan on deoxycorticosterone-salt hypertension rats. J Korean Med Sci 16: 553-557, 2001
8 Percy DH, Barthold SW. Pathology of Laboratory Rodents and Rabbits. 3rd ed., Ames, Iowa:Blackwell Publishing; 2007: 161-4.
9 Pinto YM, Paul M, Ganten D: Lessons from rat models of hypertension: from Goldblatt to genetic engineering. Cardiovasc Res 39: 77-88, 1998
10 Rugale C, Delbosc S, Cristol JP, Mimran A, Jover B: Sodium restriction prevents cardiac hypertrophy and oxidative stress in angiotensin II hypertension. Am J Physiol Heart Circ Physiol 284: H1744-1750, 2003
11 St-Jacques R, Toulmond S, Auger A, Binkert C, Cromlish W, Fischli W, Harris J, Hess P, Lan J, Liu S, Riendeau D, Steiner B, Percival MD: Characterization of a stable, hypertensive rat model suitable for the consecutive evaluation of human renin inhibitors. J Renin Angiotensin Aldosterone Syst, 2011
12 Sviglerova J, Kuncova J, Nalos L, Tonar Z, Rajdl D, Stengl M: Cardiovascular parameters in rat model of chronic renal failure induced by subtotal nephrectomy. Physiol Res 59 Suppl 1: S81-88, 2010

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3-1. Kidney

3-2. Kidney

3-2. Kidney

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