Hypertensive nephropathy pathophysiology

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Aarti Narayan, M.B.B.S [2] Nasrin Nikravangolsefid, MD-MPH [3]

Pathophysiology

• Hypertension can involve any compartment of the kidney  :
  • Vessels
    • Intimal thickening of small arterioles due to migration of myofibroblasts from media into intimal layer and secretion of collagen which leads to narrowing of the afferent arterioles.
    • thining of media layer and hyalinosis of the afferent arteriole due to loss of smooth muscle cells, which have been changed into myofibroblasts, leads to a reduction in glomerular filtration rate (GFR).
  • Glomerules
    • Constriction of intraglomerular capillaries due to hyalinosis causes glomerular ischemia and reduced filtration which induce accumulation of Extracellular Matrix (ECM).
    • Hypertrophy of the remaining healthy glomerules maintains filtration but increases intra-glomerular pressure and developing microalbuminuria.
    • Podocyte loss due to hyperfiltration and glomerulosclerosis leads to destroying the filtration barrier and developing proteinuria.
  • Tubulointerestitium
    • Dilatation, flattening and loss of epithelial tubular cells
      • overexpression of fibrogenic and angiogenic factors such as transforming growth factor b1 (TGF-b1), Endothelin 1 (ET-1), and vascular endothelial growth factor (VEGF) results in disruption of tubular cells junction, transition of epithelial into mesenchymal cells, production of metalloproteinases, cell migration, production of collagen by myofibroblasts in the interstitial and subsequent tubulointerstitial fibrosis.
    • Activation of Renin - Angiotensin - Aldosterone system further contributes to vasoconstriction, cell proliferation, reactive oxygen species production,inducing inflammation and ECM production.
      • Angiotensin II induces differentiation of fibroblasts into myofibroblasts, which synthesize collagen in the periglomerular and peritubular regions.

Changes of kidney compartments induced by Hypertension
Compartment	Changes	Final effects
Vessels	Myofibroblasts migration from media into intimal layer Collagen secretion by myofibroblasts Smooth muscle cells loss in media layer	Intimal thickening of small arterioles Arteriolar narrowing Thining of media layer Arteriolar hyalinosis
Glomerules	Intraglomerular capillaries constriction Glomerular ischemia Reduced GFR Remained glomerules hypertrophy Podocyte loss	ECM accumulation Glomerulosclerosis Increased Intraglomerular pressure Microalbuminuria
Tubulointerestitium	Transition of epithelial into mesenchymal cells Dilatation and loss of epithelial tubular cells Collagen secretion by myofibroblasts RAS activation	Tubulointerstitial fibrosis Vasoconstriction Inflammation induction ECM accumulation

• In patients with primary hypertension, intra-glomerular hemodynamic studies show a reduction in renal blood flow. This leads to increased permeability of glomerular capillaries to plasma components like plasma proteins especially fibrin, initiating the clotting cascade and subsequently microangiopathic hemolytic anemia.

Gross Pathology

• Benign nephrosclerosis:
  • The size of the kidneys is reduced or shrunken with loss of cortical mass and fine granularity.
• Malignant nephrosclerosis:
  • Hemorrhages from surface capillaries gives the kidney a "flea-bitten" appearance.

Microscopic Pathology

• Benign nephrosclerosis:
  • Afferent arterioles have eosinophilic fibrin deposits in the wall, causing hyaline arteriosclerosis
• Malignant nephrosclerosis:
  • Fibrinoid necrosis in afferent arteriole
  • Hyperplastic arteriosclerosis in inter-lobar arterioles
  • Sclerosis in glomeruli and renal tubules