Analgesic nephropathy pathophysiology: Difference between revisions
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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]].<ref name="pmid6641031" /><ref name="pmid16891638" /> | * 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" /><ref name="pmid16891638" /> | ||
* [[Renal ischemia]] and [[renal papillary necrosis]] may be result from the [[methemoglobinemia]] caused by [[phenacetin]]. | * [[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> | ||
* Acetaminophen is a metabolite of [[phenacetin]].<ref name="pmid8669429" /> | * Acetaminophen is a metabolite of [[phenacetin]].<ref name="pmid8669429" /> | ||
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* 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" /> | * 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" /> | ||
* It has been reported that he concentration of both [[Salicylic acid|salicylates]] and [[acetaminophen]] are several times higher at the papillary of the kidney compared to the cortex. | * It has been reported that he concentration of both [[Salicylic acid|salicylates]] and [[acetaminophen]] are several times higher at the papillary of the kidney compared to the cortex.<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> This is suggestive of direct damage to the renal papillary cells.<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> | ||
=== Phatogenesis of Renal Papillary Necrosis Caused by NSAIDs and Aspirin === | === 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) and [[prostacyclin]] in the kidneys, which regulate the [[renal blood flow]]. (sbatini) | * [[Non-steroidal anti-inflammatory drug|NSAIDs]] and [[Aspirin|aspirin (ASA)]] inhibit the production of [[prostaglandin]] E2 (PGE2) and [[prostacyclin]] in the kidneys, which regulate the [[renal blood flow]]. (sbatini) | ||
* It has been reported that he concentration of both [[Salicylic acid|salicylates]] and [[acetaminophen]] are several times higher at the papillary compared to the cortex. | * It has been reported that he concentration of both [[Salicylic acid|salicylates]] and [[acetaminophen]] are several times higher at the papillary compared to the cortex.<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> This is suggestive of direct damage to the renal papillary cells.<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 == | == Gross Pathology == | ||
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Overview
Pathophysiology
The scarring of the small blood vessels, called capillary sclerosis, is the initial lesion of analgesic nephropathy.[1] Found in the renal pelvis, ureter, and capillaries supplying the nephrons, capillary sclerosis is thought to lead to renal papillary necrosis and, in turn, chronic interstitial nephritis.[2][1]
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.[3]
Aspirin and NSAIDs
Proper kidney function depends upon adequate blood flow to the kidney. Kidney blood flow is a complex, tightly regulated process that relies on a number of hormones and other small molecules, such as prostaglandins. Under normal circumstances, prostaglandin E2 (PGE2) produced by the kidney is necessary to support adequate blood flow to the kidney. Like all prostaglandins, PGE2 synthesis depends upon the cyclooxygenases.
Aspirin and other NSAIDs are inhibitors of the cyclooxygenases. In the kidney, this inhibition results in decreased PGE2 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 papillae, 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.
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.
Phenacetin and paracetamol
It is unclear how phenacetin induces injury to the kidney. Bach and Hardy have proposed that phenacetin's metabolites lead to lipid peroxidation that damages cells of the kidney.[4]
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 N-acetyl-p-benzoquinoneimine (NAPQI).[5] NAPQI depletes glutathione via non-enzymatic conjugation to glutathione, a naturally occurring antioxidant.[6] With depletion of glutathione, cells of the kidney become particularly sensitive to oxidative damage.
Overview
Pathophysiology
- There is a strong association between phenacetin and analgesic nephropathy.[7]
- 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][8]
Phatogenesis of Analgesic Nephropathy Caused by Phenacetin
- Toxic metabolites of phenacetin cause capillary sclerosis in the renal medulla, which result in renal papillary necrosis, tubulointerstitial nephropathy and cortical atrophy.[1][2]
- Renal ischemia and renal papillary necrosis may be result from the methemoglobinemia caused by phenacetin.[9]
- Acetaminophen is a metabolite of phenacetin.[6]
Phatogenesis of Renal Papillary Necrosis Caused by Acetaminophen
- 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.[6]
- It has been reported that he concentration of both salicylates and acetaminophen are several times higher at the papillary of the kidney compared to the cortex.[10][11] This is suggestive of direct damage to the renal papillary cells.[12]
Phatogenesis of Renal Papillary Necrosis Caused by NSAIDs and Aspirin
- NSAIDs and aspirin (ASA) inhibit the production of prostaglandin E2 (PGE2) and prostacyclin in the kidneys, which regulate the renal blood flow. (sbatini)
- It has been reported that he concentration of both salicylates and acetaminophen are several times higher at the papillary compared to the cortex.[10][11] This is suggestive of direct damage to the renal papillary cells.[12]
Gross Pathology
On gross pathology, the following findings are found in analgesic nephropathy:[13]
- Decreased kidney size
- Adherent capsule and multiple cysts on the surface
- Scars on the surface (cortical atropy overlying necrotic papillae)
- Necrotic papillae (shrunken greyish black in appearance)
- Brownish-black appearance of the papillae (due to products of phenacetin)
- Golden-brown streaks on the mucosal lining of the renal pelvis and the urinary tract
Microscopic Pathology
On microscopic histopathological analysis, the following are seen in analgesic nephropathy:[13]
- Renal papillary necrosis
- Calcification in the necrotic medulla
- Chronic interstitial nephritis changes:
- Tubular atrophy and dilatation
- Interstitial fibrosis
- Nonspecific round cell infiltrate
- Variable glomerular changes (normal to global sclerosis)
- Periglomerular fibrosis
Immunofluorescent Microscopy
On immunofluorescent microscopy, the following findings are seen:[13]
- 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
- ↑ 1.0 1.1 1.2 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) - ↑ 2.0 2.1 2.2 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) - ↑ 3.0 3.1 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) - ↑ Bach PH, Hardy TL (1985). "Relevance of animal models to analgesic-associated renal papillary necrosis in humans". Kidney Int. 28 (4): 605–13. PMID 3910912. Unknown parameter
|month=ignored (help) - ↑ Mohandas J, Duggin GG, Horvath JS, Tiller DJ (1981). "Metabolic oxidation of acetaminophen (paracetamol) mediated by cytochrome P-450 mixed-function oxidase and prostaglandin endoperoxide synthetase in rabbit kidney". Toxicol. Appl. Pharmacol. 61 (2): 252–9. PMID 6798713. Unknown parameter
|month=ignored (help) - ↑ 6.0 6.1 6.2 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) - ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 10.0 10.1 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.
- ↑ 11.0 11.1 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.
- ↑ 12.0 12.1 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.
- ↑ 13.0 13.1 13.2 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.