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{{Analgesic nephropathy}}
{{Analgesic nephropathy}}
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==Overview==
== Overview ==
==Pathophysiology==
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 [[Salicylic acid|phenacetin]] is higher at the papillary which is suggestive of direct damage to the renal papillary cells. Although non-[[phenacetin]] analgesics (such as [[Non-steroidal anti-inflammatory drug|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.
The scarring of the small blood vessels, called capillary sclerosis, is the initial lesion of analgesic nephropathy.<ref name="pmid6641031">{{cite journal |author=Mihatsch MJ, Hofer HO, Gudat F, Knüsli C, Torhorst J, Zollinger HU |title=Capillary sclerosis of the urinary tract and analgesic nephropathy |journal=Clin. Nephrol. |volume=20 |issue=6 |pages=285–301 |year=1983 |month=December |pmid=6641031 |doi= |url=}}</ref> Found in the [[renal pelvis]], [[ureter]], and capillaries supplying the [[nephron]]s, capillary sclerosis is thought to lead to [[renal papillary necrosis]] and, in turn, [[interstitial nephritis|chronic interstitial nephritis]].<ref name="pmid16891638">{{cite journal |author=Mihatsch MJ, Khanlari B, Brunner FP |title=Obituary to analgesic nephropathy--an autopsy study |journal=Nephrol. Dial. Transplant. |volume=21 |issue=11 |pages=3139–45 |year=2006 |month=November |pmid=16891638 |doi=10.1093/ndt/gfl390 |url=http://ndt.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=16891638}}</ref><ref name="pmid6641031"/>


How phenacetin and other analgesics lead to this damage is incompletely understood. It is currently thought that the renal toxicities of NSAIDs and the antipyretics phenacetin and paracetamol may combine to give rise to analgesic nephropathy. A committee of investigators reported in 2000 that there was insufficient evidence to suggest that non-phenacetin analgesics by themselves are associated with analgesic nephropathy.<ref name="pmid11115060">{{cite journal |author=Feinstein AR, Heinemann LA, Curhan GC, ''et al'' |title=Relationship between nonphenacetin combined analgesics and nephropathy: a review. Ad Hoc Committee of the International Study Group on Analgesics and Nephropathy |journal=Kidney Int. |volume=58 |issue=6 |pages=2259–64 |year=2000 |month=December |pmid=11115060 |doi=10.1046/j.1523-1755.2000.00410.x |url=http://dx.doi.org/10.1046/j.1523-1755.2000.00410.x}}</ref>
== Pathophysiology ==


===Aspirin and NSAIDs===
* There is a strong association between [[phenacetin]] and analgesic nephropathy.<ref name="pmid27900067">{{cite journal| author=Yaxley J| title=Common Analgesic Agents and Their Roles in Analgesic Nephropathy: A Commentary on the Evidence. | journal=Korean J Fam Med | year= 2016 | volume= 37 | issue= 6 | pages= 310-316 | pmid=27900067 | doi=10.4082/kjfm.2016.37.6.310 | pmc=5122661 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=27900067  }} </ref>
Proper [[Renal function|kidney function]] depends upon adequate blood flow to the kidney. [[Renal blood flow|Kidney blood flow]] is a complex, tightly regulated process that relies on a number of [[hormone]]s and other small molecules, such as [[prostaglandin]]s. Under normal circumstances, [[prostaglandin E2]] (PGE<sub>2</sub>) produced by the kidney is necessary to support adequate blood flow to the kidney. Like all prostaglandins, PGE<sub>2</sub> synthesis depends upon the [[cyclooxygenase]]s.
*The classic analgesic nephropathy is disappearing after the removal of [[phenacetin]] from the markets over 30 years ago.<ref name="pmid16891638">{{cite journal |author=Mihatsch MJ, Khanlari B, Brunner FP |title=Obituary to analgesic nephropathy--an autopsy study |journal=Nephrol. Dial. Transplant. |volume=21 |issue=11 |pages=3139–45 |year=2006 |month=November |pmid=16891638 |doi=10.1093/ndt/gfl390 |url=http://ndt.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=16891638}}</ref>
* Although non-[[phenacetin]] analgesics (such as [[Non-steroidal anti-inflammatory drug|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.<ref name="pmid11115060">{{cite journal |author=Feinstein AR, Heinemann LA, Curhan GC, ''et al'' |title=Relationship between nonphenacetin combined analgesics and nephropathy: a review. Ad Hoc Committee of the International Study Group on Analgesics and Nephropathy |journal=Kidney Int. |volume=58 |issue=6 |pages=2259–64 |year=2000 |month=December |pmid=11115060 |doi=10.1046/j.1523-1755.2000.00410.x |url=http://dx.doi.org/10.1046/j.1523-1755.2000.00410.x}}</ref><ref name="pmid9556702">{{cite journal| author=Delzell E, Shapiro S| title=A review of epidemiologic studies of nonnarcotic analgesics and chronic renal disease. | journal=Medicine (Baltimore) | year= 1998 | volume= 77 | issue= 2 | pages= 102-21 | pmid=9556702 | doi=10.1097/00005792-199803000-00003 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9556702  }} </ref>


Aspirin and other NSAIDs are inhibitors of the cyclooxygenases. In the kidney, this inhibition results in decreased PGE<sub>2</sub> concentration causing a reduction in blood flow. Because blood flow to the kidney first reaches the [[renal cortex]] (outside) and then the [[renal medulla]] (inside), the deeper structures of the kidney are most sensitive to decreased blood flow. Thus the innermost structures of the kidney, called the [[renal papilla]]e, are especially dependent on prostaglandin synthesis to maintain adequate blood flow. Inhibition of cyclooxygenases therefore rather selectively damages the renal papillae, increasing the risk of [[renal papillary necrosis]].<ref name="an-utd"/>
=== Phatogenesis of Analgesic Nephropathy Caused by Phenacetin ===


Most healthy kidneys contain enough physiologic reserve to compensate for this NSAID-induced decrease in blood flow. However, those subjected to additional injury from phenacetin or paracetamol may progress to analgesic nephropathy.
* Toxic metabolites of [[phenacetin]] cause capillary sclerosis in the [[renal medulla]], which result in [[renal papillary necrosis]], tubulointerstitial nephropathy and cortical [[atrophy]].<ref name="pmid6641031">{{cite journal |author=Mihatsch MJ, Hofer HO, Gudat F, Knüsli C, Torhorst J, Zollinger HU |title=Capillary sclerosis of the urinary tract and analgesic nephropathy |journal=Clin. Nephrol. |volume=20 |issue=6 |pages=285–301 |year=1983 |month=December |pmid=6641031 |doi= |url=}}</ref><ref name="pmid16891638" />
* [[Renal ischemia]] and [[renal papillary necrosis]] may be result from the [[methemoglobinemia]] caused by [[phenacetin]].<ref name="pmid4827469">{{cite journal| author=Gault MH, Shahidi NT, Barber VE| title=Methemoglobin formation in analgesic nephropathy. | journal=Clin Pharmacol Ther | year= 1974 | volume= 15 | issue= 5 | pages= 521-7 | pmid=4827469 | doi=10.1002/cpt1974155521 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=4827469  }} </ref>
*It has been reported that the concentration of [[Salicylic acid|phenacetin]] is higher at the papillary which is suggestive of direct damage to the renal papillary cells.<ref name="pmid5813230">{{cite journal| author=Bluemle LW, Goldberg M| title=Renal accumulation of salicylate and phenacetin: possible mechanisms in the nephropathy of analgesic abuse. | journal=J Clin Invest | year= 1969 | volume= 47 | issue= 11 | pages= 2507-14 | pmid=5813230 | doi=10.1172/JCI105932 | pmc=297415 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=5813230  }} </ref>
*[[Acetaminophen]] is a metabolite of [[phenacetin]].<ref name="pmid8669429">{{cite journal |author=Duggin GG |title=Combination analgesic-induced kidney disease: the Australian experience |journal=Am. J. Kidney Dis. |volume=28 |issue=1 Suppl 1 |pages=S39–47 |year=1996 |month=July |pmid=8669429 |doi= |url=}}</ref>


===Phenacetin and paracetamol===
=== Phatogenesis of Renal Papillary Necrosis Caused by Acetaminophen ===
It is unclear how phenacetin induces injury to the kidney.<ref name="an-utd"/> Bach and Hardy have proposed that phenacetin's metabolites lead to [[lipid peroxidation]] that damages cells of the kidney.<ref name="pmid3910912">{{cite journal |author=Bach PH, Hardy TL |title=Relevance of animal models to analgesic-associated renal papillary necrosis in humans |journal=Kidney Int. |volume=28 |issue=4 |pages=605–13 |year=1985 |month=October |pmid=3910912 |doi= |url=}}</ref>


[[Paracetamol]] is the major metabolite of phenacetin and may contribute to kidney injury through a specific mechanism. In cells of the kidney, cyclooxygenases catalyse the conversion of paracetamol into [[NAPQI|''N''-acetyl-''p''-benzoquinoneimine]] (NAPQI).<ref name="pmid6798713">{{cite journal |author=Mohandas J, Duggin GG, Horvath JS, Tiller DJ |title=Metabolic oxidation of acetaminophen (paracetamol) mediated by cytochrome P-450 mixed-function oxidase and prostaglandin endoperoxide synthetase in rabbit kidney |journal=Toxicol. Appl. Pharmacol. |volume=61 |issue=2 |pages=252–9 |year=1981 |month=November |pmid=6798713 |doi= |url=http://linkinghub.elsevier.com/retrieve/pii/0041-008X(81)90415-4}}</ref> NAPQI depletes glutathione via non-enzymatic conjugation to [[glutathione]], a naturally occurring [[antioxidant]].<ref name="pmid8669429">{{cite journal |author=Duggin GG |title=Combination analgesic-induced kidney disease: the Australian experience |journal=Am. J. Kidney Dis. |volume=28 |issue=1 Suppl 1 |pages=S39–47 |year=1996 |month=July |pmid=8669429 |doi= |url=}}</ref> With depletion of glutathione, cells of the kidney become particularly sensitive to [[oxidative stress|oxidative damage]].
* In renal cells, [[acetaminophen]] is converted to [[NAPQI|''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 papillary necrosis|renal papilliary necrosis]].<ref name="pmid8669429" />  
 
=== Phatogenesis of Renal Papillary Necrosis Caused by NSAIDs and Aspirin ===
 
* [[Non-steroidal anti-inflammatory drug|NSAIDs]] and [[Aspirin|aspirin (ASA)]] inhibit the production of [[prostaglandin]] E2 (PGE2) in the kidneys (PGE2 regulates the [[renal blood flow]]).<ref name="pmid8669428">{{cite journal| author=Sabatini S| title=Pathophysiologic mechanisms in analgesic-induced papillary necrosis. | journal=Am J Kidney Dis | year= 1996 | volume= 28 | issue= 1 Suppl 1 | pages= S34-8 | pmid=8669428 | doi=10.1016/s0272-6386(96)90567-3 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8669428  }} </ref>
* It has been reported that the concentration of [[Salicylic acid|salicylates]] is higher at the papillary compared to the cortex which is suggestive of direct damage to the renal papillary cells.<ref name="pmid25632">{{cite journal| author=Beyer KH, Gelarden RT| title=Renal concentration gradients of salicylic acid and its metabolic congeners in the dog. | journal=Arch Int Pharmacodyn Ther | year= 1978 | volume= 231 | issue= 2 | pages= 180-95 | pmid=25632 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=25632  }} </ref><ref name="pmid5813230">{{cite journal| author=Bluemle LW, Goldberg M| title=Renal accumulation of salicylate and phenacetin: possible mechanisms in the nephropathy of analgesic abuse. | journal=J Clin Invest | year= 1969 | volume= 47 | issue= 11 | pages= 2507-14 | pmid=5813230 | doi=10.1172/JCI105932 | pmc=297415 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=5813230  }} </ref><ref name="pmid8669428">{{cite journal| author=Sabatini S| title=Pathophysiologic mechanisms in analgesic-induced papillary necrosis. | journal=Am J Kidney Dis | year= 1996 | volume= 28 | issue= 1 Suppl 1 | pages= S34-8 | pmid=8669428 | doi=10.1016/s0272-6386(96)90567-3 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8669428  }} </ref>
 
== Gross Pathology ==
On [[gross pathology]], the following findings are found in analgesic nephropathy:<ref name="pmid7002190">{{cite journal| author=Nanra RS| title=Clinical and pathological aspects of analgesic nephropathy. | journal=Br J Clin Pharmacol | year= 1980 | volume= 10 Suppl 2 | issue=  | pages= 359S-368S | pmid=7002190 | doi=10.1111/j.1365-2125.1980.tb01824.x | pmc=1430193 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=7002190  }} </ref>
 
* Decreased kidney size
* Adherent [[Capsule (anatomy)|capsule]] and multiple [[Cyst|cysts]] on the surface
*[[Scar|Scars]] on the surface (cortical atropy overlying [[Renal papillary necrosis|papillary necrosis]])
*[[Renal 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 system|urinary tract]]
 
== Microscopic Pathology ==
On [[microscopic]] [[Histopathology|histopathological]] analysis, the following are seen in analgesic nephropathy:<ref name="pmid7002190" />
 
*[[Renal papillary necrosis]]
*[[Calcification]] in the necrotic medulla
* Chronic [[interstitial nephritis]] changes:
** Tubular [[atrophy]] and [[Dilation|dilatation]]  
** Interstitial [[fibrosis]] 
** Round cell infiltrate  
* Variable [[Glomerulus|glomerular]] changes (normal to global [[sclerosis]])
*[[Fibrosis]] of the periglomerular
 
== Immunofluorescent Microscopy ==
On [[Immunofluorescence|immunofluorescent]] microscopy, the following findings are seen:<ref name="pmid7002190" />
 
* Segmental lesions show coarse blobs of [[C3 (complement)|C3]]
* Membranous lesions show granular deposits of [[Immunoglobulin G|IgG]] and [[C3 (complement)|C3]] along glomerular capillary loops (epimembranous distribution)
* Arteries may be normal or show [[nephrosclerosis]]


==References==
==References==

Latest revision as of 06:18, 8 July 2020

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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

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

  • 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

Phatogenesis of Renal Papillary Necrosis Caused by Acetaminophen

Phatogenesis of Renal Papillary Necrosis Caused by NSAIDs and Aspirin

Gross Pathology

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

Microscopic Pathology

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

Immunofluorescent Microscopy

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

  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)
  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)
  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)
  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.
  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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