Analgesic nephropathy pathophysiology

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

## Overview

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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

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* 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

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* 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

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* 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

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* 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

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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

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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

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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

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1. ↑ Yaxley J (2016). "Common Analgesic Agents and Their Roles in Analgesic Nephropathy: A Commentary on the Evidence". Korean J Fam Med. 37 (6): 310–316. doi:10.4082/kjfm.2016.37.6.310. PMC 5122661. PMID 27900067.
2. ↑ 2.0 2.1 Mihatsch MJ, Khanlari B, Brunner FP (2006). "Obituary to analgesic nephropathy--an autopsy study". Nephrol. Dial. Transplant. 21 (11): 3139–45. doi:10.1093/ndt/gfl390. PMID 16891638. Unknown parameter `|month=` ignored (help)CS1 maint: Multiple names: authors list (link)
3. ↑ Feinstein AR, Heinemann LA, Curhan GC; et al. (2000). "Relationship between nonphenacetin combined analgesics and nephropathy: a review. Ad Hoc Committee of the International Study Group on Analgesics and Nephropathy". Kidney Int. 58 (6): 2259–64. doi:10.1046/j.1523-1755.2000.00410.x. PMID 11115060. Unknown parameter `|month=` ignored (help)CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
4. ↑ Delzell E, Shapiro S (1998). "A review of epidemiologic studies of nonnarcotic analgesics and chronic renal disease". Medicine (Baltimore). 77 (2): 102–21. doi:10.1097/00005792-199803000-00003. PMID 9556702.
5. ↑ Mihatsch MJ, Hofer HO, Gudat F, Knüsli C, Torhorst J, Zollinger HU (1983). "Capillary sclerosis of the urinary tract and analgesic nephropathy". Clin. Nephrol. 20 (6): 285–301. PMID 6641031. Unknown parameter `|month=` ignored (help)CS1 maint: Multiple names: authors list (link)
6. ↑ Gault MH, Shahidi NT, Barber VE (1974). "Methemoglobin formation in analgesic nephropathy". Clin Pharmacol Ther. 15 (5): 521–7. doi:10.1002/cpt1974155521. PMID 4827469.CS1 maint: Multiple names: authors list (link)
7. ↑ 7.0 7.1 Bluemle LW, Goldberg M (1969). "Renal accumulation of salicylate and phenacetin: possible mechanisms in the nephropathy of analgesic abuse". J Clin Invest. 47 (11): 2507–14. doi:10.1172/JCI105932. PMC 297415. PMID 5813230.
8. ↑ 8.0 8.1 Duggin GG (1996). "Combination analgesic-induced kidney disease: the Australian experience". Am. J. Kidney Dis. 28 (1 Suppl 1): S39–47. PMID 8669429. Unknown parameter `|month=` ignored (help)
9. ↑ 9.0 9.1 Sabatini S (1996). "Pathophysiologic mechanisms in analgesic-induced papillary necrosis". Am J Kidney Dis. 28 (1 Suppl 1): S34–8. doi:10.1016/s0272-6386(96)90567-3. PMID 8669428.
10. ↑ Beyer KH, Gelarden RT (1978). "Renal concentration gradients of salicylic acid and its metabolic congeners in the dog". Arch Int Pharmacodyn Ther. 231 (2): 180–95. PMID 25632.
11. ↑ 11.0 11.1 11.2 Nanra RS (1980). "Clinical and pathological aspects of analgesic nephropathy". Br J Clin Pharmacol. 10 Suppl 2: 359S–368S. doi:10.1111/j.1365-2125.1980.tb01824.x. PMC 1430193. PMID 7002190.

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