Analgesic nephropathy pathophysiology

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Shakiba Hassanzadeh, MD[2]

Overview[edit | edit source]

The pathogenesis of analgesic nephropathy caused by phenacetin may be due to several reasons. Toxic metabolites of phenacetin cause capillary sclerosis in the renal medulla, which results in renal papillary necrosis, tubulointerstitial nephropathy and cortical atrophy. Renal ischemia and renal papillary necrosis may be result from the methemoglobinemia caused by phenacetin. Additionally, It has been reported that the concentration of phenacetin is higher at the papillary which is suggestive of direct damage to the renal papillary cells. Although non-phenacetin analgesics (such as NSAIDs, aspirin and acetaminophen) or their combinations have been reported in some studies as causes to analgesic nephropathy, but there is insufficient evidence that suggests these drugs cause analgesic nephropathy.

Pathophysiology[edit | edit source]

• There is a strong association between phenacetin and analgesic nephropathy.^[1]
• The classic analgesic nephropathy is disappearing after the removal of phenacetin from the markets over 30 years ago.^[2]
• Although non-phenacetin analgesics (such as NSAIDs, aspirin and acetaminophen) or their combinations have been reported in some studies as causes to analgesic nephropathy, but there is insufficient evidence that suggests these drugs cause analgesic nephropathy.^[3][4]

Phatogenesis of Analgesic Nephropathy Caused by Phenacetin[edit | edit source]

• Toxic metabolites of phenacetin cause capillary sclerosis in the renal medulla, which result in renal papillary necrosis, tubulointerstitial nephropathy and cortical atrophy.^[5][2]
• Renal ischemia and renal papillary necrosis may be result from the methemoglobinemia caused by phenacetin.^[6]
• It has been reported that the concentration of phenacetin is higher at the papillary which is suggestive of direct damage to the renal papillary cells.^[7]
• Acetaminophen is a metabolite of phenacetin.^[8]

Phatogenesis of Renal Papillary Necrosis Caused by Acetaminophen[edit | edit source]

• In renal cells, acetaminophen is converted to N-acetyl-p-benzoquinoneimine (NAPQI) which depletes glutathione. With depletion of glutathione, the reactive metabolite of acetaminophen produces lipid peroxides and arylation of tissue proteins, which result in oxidative stress and renal papilliary necrosis.^[8]  

Phatogenesis of Renal Papillary Necrosis Caused by NSAIDs and Aspirin[edit | edit source]

• NSAIDs and aspirin (ASA) inhibit the production of prostaglandin E2 (PGE2) in the kidneys (PGE2 regulates the renal blood flow).^[9]
• It has been reported that the concentration of salicylates is higher at the papillary compared to the cortex which is suggestive of direct damage to the renal papillary cells.^[10][7][9]

Gross Pathology[edit | edit source]

On gross pathology, the following findings are found in analgesic nephropathy:^[11]

• Decreased kidney size
• Adherent capsule and multiple cysts on the surface
• Scars on the surface (cortical atropy overlying papillary necrosis)
• Papillary necrosis (shrunken greyish black in appearance)

• Brownish-black papillae (due to products of phenacetin)
• Golden-brown streaks on the mucosal lining of the renal pelvis and the urinary tract

Microscopic Pathology[edit | edit source]

On microscopic histopathological analysis, the following are seen in analgesic nephropathy:^[11]

• Renal papillary necrosis
• Calcification in the necrotic medulla
• Chronic interstitial nephritis changes:
  • Tubular atrophy and dilatation  
  • Interstitial fibrosis 
  • Round cell infiltrate  
• Variable glomerular changes (normal to global sclerosis)
• Fibrosis of the periglomerular

Immunofluorescent Microscopy[edit | edit source]

On immunofluorescent microscopy, the following findings are seen:^[11]

• Segmental lesions show coarse blobs of C3
• Membranous lesions show granular deposits of IgG and C3 along glomerular capillary loops (epimembranous distribution)
• Arteries may be normal or show nephrosclerosis

References[edit | edit source]

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