Analgesic nephropathy overview: Difference between revisions

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{{Analgesic nephropathy}}
{{Analgesic nephropathy}}
{{CMG}} {{AE}} {{SHA}}
{{CMG}} {{AE}} {{SHA}}
==Overview==
Analgesic nephropathy is a disorder caused by long-term use of analgesic drugs, mainly [[phenacetin]] and combinations containing [[phenacetin]]. This resulted in the withdrawal of [[phenacetin]] from most markets around the world since over 30 years ago, which has led to the disappearance of classic analgesic nephropathy caused by [[phenacetin]]. The main findings in analgesic nephropathy are [[renal papillary necrosis]] and chronic [[interstitial nephritis]]. The kidney injury may progress to [[End stage renal disease|end stage renal disease (ESRD)]]. 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.


==Overview==
==Historical Perspective==
<s>The term ''analgesic nephropathy'' usually refers to damage induced by excessive use of combinations of these medications, specifically combinations that include phenacetin. For this reason, it is also called '''analgesic abuse nephropathy'''. Others prefer the less judgmental '''analgesic-associated nephropathy'''. Both terms are abbreviated to the acronym '''AAN''', by which the condition is also commonly known.</s>


<s>'''Analgesic nephropathy''' is injury to the [[kidney]] caused by [[analgesic|analgesic medications]] such as [[aspirin]], [[phenacetin]], and [[paracetamol]]. The term usually refers to damage induced by excessive use of combinations of these medications, especially combinations that include phenacetin. It may also be used to describe kidney injury from any single analgesic medication.</s>
In 1953, the association between [[analgesic]] drugs and [[Chronic renal failure|chronic renal disease]] was first reported in German.<ref name="pmid13137299">{{cite journal |author=Spühler O, Zollinger HU |title=Die chronisch-interstitielle Nephritis. |language=German |journal=Z Klin Med |volume=151 |issue=1 |pages=1–50 |year=1953 |pmid=13137299 |doi= |url=}}</ref> In 1977, Australia was first to legally ban [[phenacetin]].<ref name="pmid11181803">{{cite journal| author=Michielsen P, de Schepper P| title=Trends of analgesic nephropathy in two high-endemic regions with different legislation. | journal=J Am Soc Nephrol | year= 2001 | volume= 12 | issue= 3 | pages= 550-6 | pmid=11181803 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11181803  }} </ref> In 1983, [[phenacetin]] was withdrawn from the US markets.<ref name="pmid10557618">{{cite journal| author=| title=List of drug products that have been withdrawn or removed from the market for reasons of safety or effectiveness.  Food and Drug Administration, HHS. Final rule. | journal=Fed Regist | year= 1999 | volume= 64 | issue= 44 | pages= 10944-7 | pmid=10557618 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10557618  }} </ref>


<s>The specific kidney injuries induced by analgesics are [[renal papillary necrosis]] and [[interstitial nephritis|chronic interstitial nephritis]]. They appear to result from decreased [[renal blood flow|blood flow to the kidney]], rapid consumption of [[antioxidant]]s, and subsequent [[oxidative stress|oxidative damage]] to the kidney. This kidney damage may lead to progressive [[chronic renal failure]], abnormal [[urinalysis]] results, [[hypertension|high blood pressure]], and [[anemia]]. A small proportion of individuals with analgesic nephropathy may develop [[end-stage kidney disease]].</s>
== Pathopysiology ==


<s>Analgesic nephropathy was once a common cause of kidney injury and end-stage kidney disease in parts of Europe, Australia, and the United States. In most areas, its incidence has declined sharply since the use of phenacetin fell in the 1970s and 1980s.</s>
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]].<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 | year= 1983 | volume= 20 | issue= 6 | pages= 285-301 | pmid=6641031 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=6641031  }} </ref><ref name="pmid16891638">{{cite journal| author=Mihatsch MJ, Khanlari B, Brunner FP| title=Obituary to analgesic nephropathy--an autopsy study. | journal=Nephrol Dial Transplant | year= 2006 | volume= 21 | issue= 11 | pages= 3139-45 | pmid=16891638 | doi=10.1093/ndt/gfl390 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16891638  }} </ref> [[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> 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.<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>  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, Delzell E, Deschepper PJ, Fox JM | display-authors=etal| 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 | year= 2000 | volume= 58 | issue= 6 | pages= 2259-64 | pmid=11115060 | doi=10.1046/j.1523-1755.2000.00410.x | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11115060  }} </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>


== Causes ==
There is a strong association between [[phenacetin]] and analgesic nephropathy which has led to the disappearing of classic analgesic nephropathy after the removal of [[phenacetin]] from the markets over 30 years ago.<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><ref name="pmid16891638">{{cite journal| author=Mihatsch MJ, Khanlari B, Brunner FP| title=Obituary to analgesic nephropathy--an autopsy study. | journal=Nephrol Dial Transplant | year= 2006 | volume= 21 | issue= 11 | pages= 3139-45 | pmid=16891638 | doi=10.1093/ndt/gfl390 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16891638  }} </ref> Although non-phenacetin [[Analgesic|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, Delzell E, Deschepper PJ, Fox JM | display-authors=etal| 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 | year= 2000 | volume= 58 | issue= 6 | pages= 2259-64 | pmid=11115060 | doi=10.1046/j.1523-1755.2000.00410.x | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11115060  }} </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>


== Differentiating Analgesic nephropathy from other Diseases ==
Analgesic nephropathy should be differentiated with other disorders that cause [[renal papillary necrosis]], such as: [[diabetic nephropathy]], renal crisis in [[Sickle-cell disease|sickle cell disease]], [[pyelonephritis]], obstructive uropathy, [[renal tuberculosis]], alcohol-induced nephropathy, systemic [[vasculitis]] and [[renal vein thrombosis]].<ref name="pmid31082145">{{cite journal| author=| title=StatPearls | journal= | year= 2020 | volume=  | issue=  | pages=  | pmid=31082145 | doi= | pmc= | url= }} </ref><ref name="pmid26184064">{{cite journal| author=Chalhoub NE, Riley K, Siddiqui N, Assaly R, Shahrour K, Booth R | display-authors=etal| title=Renal Papillary Necrosis Due to Invasive Candida Infection in a Morbidly Obese Patient. | journal=J Urol | year= 2015 | volume= 194 | issue= 4 | pages= 1107-8 | pmid=26184064 | doi=10.1016/j.juro.2015.07.036 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=26184064  }} </ref><ref name="pmid29984778">{{cite journal| author=Kawaguchi Y, Mori H, Izumi Y, Ito M| title=Renal Papillary Necrosis with Diabetes and Urinary Tract Infection. | journal=Intern Med | year= 2018 | volume= 57 | issue= 22 | pages= 3343 | pmid=29984778 | doi=10.2169/internalmedicine.0858-18 | pmc=6288002 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=29984778  }} </ref>


== Risk Factors ==
[[Risk factor|Risk factors]] for renal insufficiency from [[Non-steroidal anti-inflammatory drug|NSAIDs]] include: history of [[Kidney|renal]] disorder, older age, [[Congestive heart failure|congestive heart failure (CHF)]], [[cirrhosis]] with [[ascites]], [[nephrotic syndrome]], history of [[Bleeding|hemorrhage]] or [[surgery]], [[Nausea and vomiting|vomiting]] and  [[diarrhea]].<ref name="pmid9601134">{{cite journal| author=Henrich WL| title=Analgesic nephropathy. | journal=Trans Am Clin Climatol Assoc | year= 1998 | volume= 109 | issue=  | pages= 147-58; discussion 158-9 | pmid=9601134 | doi= | pmc=2194329 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9601134  }} </ref>


==Overview==
== Screening ==
There is insufficient evidence to recommend routine [[Screening (medicine)|screening]] for analgesic nephropathy.


==Historical Perspective==
== Natural History, Complications and Prognosis ==


In 1953, the association between [[analgesic]] drugs and [[Chronic renal failure|chronic renal disease]] was first reported in German.<ref name="pmid13137299">{{cite journal |author=Spühler O, Zollinger HU |title=Die chronisch-interstitielle Nephritis. |language=German |journal=Z Klin Med |volume=151 |issue=1 |pages=1–50 |year=1953 |pmid=13137299 |doi= |url=}}</ref> In 1977, [[phenacetin]] became legally banned in Australia.<ref name="pmid11181803">{{cite journal| author=Michielsen P, de Schepper P| title=Trends of analgesic nephropathy in two high-endemic regions with different legislation. | journal=J Am Soc Nephrol | year= 2001 | volume= 12 | issue= 3 | pages= 550-6 | pmid=11181803 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11181803 }} </ref> In 1978 and 1983, [[phenacetin]] was withdrawn from the Canadian and US markets, respectively.<ref name="pmid6937434">{{cite journal| author=| title=Some pharmaceutical drugs. | journal=IARC Monogr Eval Carcinog Risk Chem Hum | year= 1980 | volume= 24 | issue= | pages= 1-337 | pmid=6937434 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=6937434 }} </ref><ref name="pmid10557618">{{cite journal| author=| title=List of drug products that have been withdrawn or removed from the market for reasons of safety or effectiveness.  Food and Drug Administration, HHS. Final rule. | journal=Fed Regist | year= 1999 | volume= 64 | issue= 44 | pages= 10944-7 | pmid=10557618 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10557618  }} </ref>
The prognosis of analgesic nephropathy depends on the scarring and damage to the renal tissue.<ref name="pmid31082145" /> Most patients in early stages recover to normal [[renal function]] after stopping the [[analgesic]] drug, however some may progress to [[End stage renal disease|end stage renal disease (ESRD)]].<ref name="pmid31082145" /> Complications of analgesic nephropathy include: [[Urinary tract infection|urinary tract infections]], varying degrees of [[Renal insufficiency|renal failure]] and [[End stage renal disease|end stage renal disease (ESRD)]].<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><ref name="pmid362034">{{cite journal| author=Nanra RS, Stuart-Taylor J, de Leon AH, White KH| title=Analgesic nephropathy: etiology, clinical syndrome, and clinicopathologic correlations in Australia. | journal=Kidney Int | year= 1978 | volume= 13 | issue= 1 | pages= 79-92 | pmid=362034 | doi=10.1038/ki.1978.11 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=362034 }} </ref><ref name="pmid31082145">{{cite journal| author=| title=StatPearls | journal= | year= 2020 | volume= | issue= | pages= | pmid=31082145 | doi= | pmc= | url= }} </ref>


== Epidemiology and Demographics ==
== Epidemiology and Demographics ==
There is insufficient evidence about the [[incidence]], [[prevalence]] and racial predilection of analgesic nephropathy. Most patients with analgesic nephropathy have been reported to be middle age or older with a history of chronic pain.<ref name="pmid28582877">{{cite journal| author=Yaxley J| title=Common analgesic agents and their role in analgesic nephropathy: A commentary of the evidence. | journal=Int J Risk Saf Med | year= 2016 | volume= 28 | issue= 4 | pages= 189-196 | pmid=28582877 | doi=10.3233/JRS-170735 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=28582877  }} </ref> There is insufficient evidence that suggests gender predilection in analgesic nephropathy. However, some studies suggest that analgesic nephropathy is more conman in females than males.<ref name="pmid713269">{{cite journal| author=Gault MH, Wilson DR| title=Analgesic nephropathy in Canada: clinical syndrome, management, and outcome. | journal=Kidney Int | year= 1978 | volume= 13 | issue= 1 | pages= 58-63 | pmid=713269 | doi=10.1038/ki.1978.8 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=713269  }} </ref>
There is insufficient evidence about the [[incidence]], [[prevalence]] and racial predilection of analgesic nephropathy. However, 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 | year= 2006 | volume= 21 | issue= 11 | pages= 3139-45 | pmid=16891638 | doi=10.1093/ndt/gfl390 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16891638  }} </ref> Most patients with analgesic nephropathy have been reported to be middle age or older with a history of chronic pain.<ref name="pmid28582877">{{cite journal| author=Yaxley J| title=Common analgesic agents and their role in analgesic nephropathy: A commentary of the evidence. | journal=Int J Risk Saf Med | year= 2016 | volume= 28 | issue= 4 | pages= 189-196 | pmid=28582877 | doi=10.3233/JRS-170735 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=28582877  }} </ref> Studies suggest that analgesic nephropathy is more conman in females than males.<ref name="pmid713269">{{cite journal| author=Gault MH, Wilson DR| title=Analgesic nephropathy in Canada: clinical syndrome, management, and outcome. | journal=Kidney Int | year= 1978 | volume= 13 | issue= 1 | pages= 58-63 | pmid=713269 | doi=10.1038/ki.1978.8 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=713269  }} </ref>


== Diagnosis ==
== Diagnosis ==


=== Diagnostic Study of Choice ===
=== Diagnostic Study of Choice ===
Renal [[biopsy]] is the diagnostic study of choice, however, since it is an [[Invasive (medical)|invasive]] procedure, [[Computed tomography|CT scan]] without [[Contrast medium|contrast]] of the abdomen is usually preferred.<ref name="Keen Aeddula 2020 p.">{{cite | last=Keen | first=MU | last2=Aeddula | first2=NR | title=Analgesic Nephropathy | chapter=article-17511 | publisher=StatPearls Publishing | publication-place=Treasure Island (FL) | year=2020 | pmid=31082145 | url=http://www.ncbi.nlm.nih.gov/books/NBK541101/ | access-date=2020-07-06 | page=}}</ref><ref name="pmid9459649">{{cite journal |author=de Broe ME, Elseviers MM |title=Analgesic nephropathy |journal=N. Engl. J. Med. |volume=338 |issue=7 |pages=446–52 |year=1998 |month=February |pmid=9459649 |doi= |url=http://content.nejm.org/cgi/pmidlookup?view=short&pmid=9459649&promo=ONFLNS19}}</ref>
Renal [[biopsy]] is the diagnostic study of choice, however, since it is an [[Invasive (medical)|invasive]] procedure, [[Computed tomography|CT scan]] without [[Contrast medium|contrast]] of the abdomen is usually preferred.<ref name="urlAnalgesic Nephropathy - StatPearls - NCBI Bookshelf">{{cite web |url=https://www.ncbi.nlm.nih.gov/books/NBK541101/ |title=Analgesic Nephropathy - StatPearls - NCBI Bookshelf |format= |work= |accessdate=}}</ref><ref name="pmid9459649">{{cite journal |author=de Broe ME, Elseviers MM |title=Analgesic nephropathy |journal=N. Engl. J. Med. |volume=338 |issue=7 |pages=446–52 |year=1998 |month=February |pmid=9459649 |doi= |url=http://content.nejm.org/cgi/pmidlookup?view=short&pmid=9459649&promo=ONFLNS19}}</ref>


=== History and Symptoms ===
=== History and Symptoms ===
Common findings in patients with analgesic nephropathy include: [[headache]], upper gastrointestinal disease (such as [[peptic ulcer]]), [[anemia]], [[Urinary tract infection|urinary tract infections]], [[pyuria]] and [[hypertension]].<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><ref name="pmid362034">{{cite journal| author=Nanra RS, Stuart-Taylor J, de Leon AH, White KH| title=Analgesic nephropathy: etiology, clinical syndrome, and clinicopathologic correlations in Australia. | journal=Kidney Int | year= 1978 | volume= 13 | issue= 1 | pages= 79-92 | pmid=362034 | doi=10.1038/ki.1978.11 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=362034  }} </ref>


=== Physical Examination ===
=== Physical Examination ===
In [[physical examination]] of patients with analgesic nephropathy checking for the followings should be considered: [[headache]], upper gastrointestinal disease (such as [[peptic ulcer]]), [[anemia]], [[Urinary tract infection|urinary tract infections]], and [[hypertension]].<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><ref name="pmid362034">{{cite journal| author=Nanra RS, Stuart-Taylor J, de Leon AH, White KH| title=Analgesic nephropathy: etiology, clinical syndrome, and clinicopathologic correlations in Australia. | journal=Kidney Int | year= 1978 | volume= 13 | issue= 1 | pages= 79-92 | pmid=362034 | doi=10.1038/ki.1978.11 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=362034  }} </ref>


=== Laboratory Findings ===
=== Laboratory Findings ===
The laboratory tests and findings in analgesic nephropathy may include: urinary examination (sterile [[pyuria]], [[hematuria]], [[proteinuria]] and [[bacteriuria]]) and blood tests ([[anemia]] and [[Renal insufficiency|renal failure]]).<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><ref name="pmid362034">{{cite journal| author=Nanra RS, Stuart-Taylor J, de Leon AH, White KH| title=Analgesic nephropathy: etiology, clinical syndrome, and clinicopathologic correlations in Australia. | journal=Kidney Int | year= 1978 | volume= 13 | issue= 1 | pages= 79-92 | pmid=362034 | doi=10.1038/ki.1978.11 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=362034  }} </ref><ref name="pmid31082145">{{cite journal| author=| title=StatPearls | journal= | year= 2020 | volume=  | issue=  | pages=  | pmid=31082145 | doi= | pmc= | url= }} </ref>


=== Electrocardiogram ===
=== Electrocardiogram ===
There are no [[The electrocardiogram|ECG]] findings associated with analgesic nephropathy.


=== X-ray ===
=== X-ray ===
A pyelogram is not helpful in the diagnosis of analgesic nephropathy and may worsen the renal injury due to [[Contrast medium|contrast]] utilization.<ref name="Keen Aeddula 2020 p.">{{cite | last=Keen | first=MU | last2=Aeddula | first2=NR | title=Analgesic Nephropathy | chapter=article-17511 | publisher=StatPearls Publishing | publication-place=Treasure Island (FL) | year=2020 | pmid=31082145 | url=http://www.ncbi.nlm.nih.gov/books/NBK541101/ | access-date=2020-07-06 | page=}}</ref>
A pyelogram is not helpful in the diagnosis of analgesic nephropathy and may worsen the renal injury due to [[Contrast medium|contrast]] utilization.<ref name="urlAnalgesic Nephropathy - StatPearls - NCBI Bookshelf">{{cite web |url=https://www.ncbi.nlm.nih.gov/books/NBK541101/ |title=Analgesic Nephropathy - StatPearls - NCBI Bookshelf |format= |work= |accessdate=}}</ref>


=== Ultrasound ===
=== Ultrasound ===
There are no [[ultrasound]] findings associated with analgesic nephropathy. However, [[ultrasound]] of the [[abdomen]], [[Kidney|kidneys]] and the [[urinary bladder]] could be helpful in ruling out other causes of [[nephropathy]] ([[obstruction]] or [[infection]]).<ref name="pmid31082145">{{cite journal| author=| title=StatPearls | journal= | year= 2020 | volume=  | issue=  | pages=  | pmid=31082145 | doi= | pmc= | url= }} </ref>


=== CT Scan ===
=== CT Scan ===
[[Computed tomography|CT scan]] without [[Contrast medium|contrast]] of the abdomen is usually preferred for diagnosing analgesic nephropathy, the findings include: decrease in [[Kidney|renal]] size, bumpy contours and papillary calcifications.<ref name="pmid9459649">{{cite journal |author=de Broe ME, Elseviers MM |title=Analgesic nephropathy |journal=N. Engl. J. Med. |volume=338 |issue=7 |pages=446–52 |year=1998 |month=February |pmid=9459649 |doi= |url=http://content.nejm.org/cgi/pmidlookup?view=short&pmid=9459649&promo=ONFLNS19}}</ref>
[[Computed tomography|CT scan]] without [[Contrast medium|contrast]] of the abdomen is usually preferred for diagnosing analgesic nephropathy, the findings include: decrease in [[Kidney|renal]] size, irregular contours and papillary [[Calcification|calcifications]].<ref name="pmid9459649">{{cite journal |author=de Broe ME, Elseviers MM |title=Analgesic nephropathy |journal=N. Engl. J. Med. |volume=338 |issue=7 |pages=446–52 |year=1998 |month=February |pmid=9459649 |doi= |url=http://content.nejm.org/cgi/pmidlookup?view=short&pmid=9459649&promo=ONFLNS19}}</ref>


=== MRI ===
=== MRI ===
There is insufficient evidence suggesting [[Magnetic resonance imaging|MRI]] findings associated with analgesic nephropathy.


=== Other Imaging Findings ===
=== Other Imaging Findings ===
There are no other [[imaging]] findings associated with analgesic nephropathy.


=== Other Diagnostic studies ===
=== Other Diagnostic studies ===
There are no other diagnostic studies associated with analgesic nephropathy.


== Treatment ==
== Treatment ==


=== Medical therapy ===
=== Medical therapy ===
Medical treatment of analgesic nephropathy may include: discontinuation of [[Analgesic|analgesics]], adequate hydration with normal [[Saline (medicine)|saline]] and treatment of [[Infection|infections]] with [[Antibiotic|antibiotics]].<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><ref name="pmid31082145">{{cite journal| author=| title=StatPearls | journal= | year= 2020 | volume=  | issue=  | pages=  | pmid=31082145 | doi= | pmc= | url= }} </ref>
=== Interventions ===
Patients with analgesic nephropathy that present with [[Acute kidney injury|acute renal failure]] or progression to [[End stage renal disease|end stage renal disease (ESRD)]] may require [[renal replacement therapy]] with [[dialysis]].<ref name="pmid4638849">{{cite journal |author=Linton AL |title=Renal disease due to analgesics. I. Recognition of the problem of analgesic nephropathy |journal=Can Med Assoc J |volume=107 |issue=8 |pages=749–51 |year=1972 |month=October |pmid=4638849 |pmc=1941002 |doi= |url=}}</ref><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>
=== Surgery ===
Patients with analgesic nephropathy that progress to [[End stage renal disease|end stage renal disease (ESRD)]] may require [[renal replacement therapy]] with [[Kidney transplantation|renal transplantation]].<ref name="pmid4638849" />


=== Prevention ===
=== Prevention ===
It has been suggested that in clinical practice, non-[[opioid]] analgesics, when possible, should be avoided for prolonged use due to their [[nephrotoxicity]].<ref name="pmid28582877">{{cite journal| author=Yaxley J| title=Common analgesic agents and their role in analgesic nephropathy: A commentary of the evidence. | journal=Int J Risk Saf Med | year= 2016 | volume= 28 | issue= 4 | pages= 189-196 | pmid=28582877 | doi=10.3233/JRS-170735 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=28582877  }} </ref>
It has been suggested that in clinical practice, non-[[opioid]] analgesics, when possible, should be avoided for long-term use due to their [[nephrotoxicity]].<ref name="pmid28582877">{{cite journal| author=Yaxley J| title=Common analgesic agents and their role in analgesic nephropathy: A commentary of the evidence. | journal=Int J Risk Saf Med | year= 2016 | volume= 28 | issue= 4 | pages= 189-196 | pmid=28582877 | doi=10.3233/JRS-170735 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=28582877  }} </ref>
 
=== Cost-Effectiveness of Therapy ===
There is insufficient evidence about the cost-effectiveness of therapy in analgesic nephropathy.


=== Future or Investigational Therapies ===
=== Future or Investigational Therapies ===
Further randomized trials are required to assess the incidence of renal injury and analgesic nephropathy caused by certain drugs.<ref name="pmid28582877">{{cite journal| author=Yaxley J| title=Common analgesic agents and their role in analgesic nephropathy: A commentary of the evidence. | journal=Int J Risk Saf Med | year= 2016 | volume= 28 | issue= 4 | pages= 189-196 | pmid=28582877 | doi=10.3233/JRS-170735 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=28582877  }} </ref>
No further or investigational therapies have been suggested in analgesic nephropathy.


==References==
==References==

Latest revision as of 06:28, 8 July 2020

Analgesic nephropathy Microchapters

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Overview

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Natural History, Complications and Prognosis

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Physical Examination

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CT

Treatment

Medical Therapy

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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

Analgesic nephropathy is a disorder caused by long-term use of analgesic drugs, mainly phenacetin and combinations containing phenacetin. This resulted in the withdrawal of phenacetin from most markets around the world since over 30 years ago, which has led to the disappearance of classic analgesic nephropathy caused by phenacetin. The main findings in analgesic nephropathy are renal papillary necrosis and chronic interstitial nephritis. The kidney injury may progress to end stage renal disease (ESRD). 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.

Historical Perspective

In 1953, the association between analgesic drugs and chronic renal disease was first reported in German.[1] In 1977, Australia was first to legally ban phenacetin.[2] In 1983, phenacetin was withdrawn from the US markets.[3]

Pathopysiology

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.[4][5] Renal ischemia and renal papillary necrosis may be result from the methemoglobinemia caused by phenacetin.[6] 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.[7] 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.[8][9]

Causes

There is a strong association between phenacetin and analgesic nephropathy which has led to the disappearing of classic analgesic nephropathy after the removal of phenacetin from the markets over 30 years ago.[10][5] 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.[8][9]

Differentiating Analgesic nephropathy from other Diseases

Analgesic nephropathy should be differentiated with other disorders that cause renal papillary necrosis, such as: diabetic nephropathy, renal crisis in sickle cell disease, pyelonephritis, obstructive uropathy, renal tuberculosis, alcohol-induced nephropathy, systemic vasculitis and renal vein thrombosis.[11][12][13]

Risk Factors

Risk factors for renal insufficiency from NSAIDs include: history of renal disorder, older age, congestive heart failure (CHF), cirrhosis with ascites, nephrotic syndrome, history of hemorrhage or surgery, vomiting and diarrhea.[14]

Screening

There is insufficient evidence to recommend routine screening for analgesic nephropathy.

Natural History, Complications and Prognosis

The prognosis of analgesic nephropathy depends on the scarring and damage to the renal tissue.[11] Most patients in early stages recover to normal renal function after stopping the analgesic drug, however some may progress to end stage renal disease (ESRD).[11] Complications of analgesic nephropathy include: urinary tract infections, varying degrees of renal failure and end stage renal disease (ESRD).[15][16][11]

Epidemiology and Demographics

There is insufficient evidence about the incidence, prevalence and racial predilection of analgesic nephropathy. However, the classic analgesic nephropathy is disappearing after the removal of phenacetin from the markets over 30 years ago.[5] Most patients with analgesic nephropathy have been reported to be middle age or older with a history of chronic pain.[17] Studies suggest that analgesic nephropathy is more conman in females than males.[18]

Diagnosis

Diagnostic Study of Choice

Renal biopsy is the diagnostic study of choice, however, since it is an invasive procedure, CT scan without contrast of the abdomen is usually preferred.[19][20]

History and Symptoms

Common findings in patients with analgesic nephropathy include: headache, upper gastrointestinal disease (such as peptic ulcer), anemia, urinary tract infections, pyuria and hypertension.[15][16]

Physical Examination

In physical examination of patients with analgesic nephropathy checking for the followings should be considered: headache, upper gastrointestinal disease (such as peptic ulcer), anemia, urinary tract infections, and hypertension.[15][16]

Laboratory Findings

The laboratory tests and findings in analgesic nephropathy may include: urinary examination (sterile pyuria, hematuria, proteinuria and bacteriuria) and blood tests (anemia and renal failure).[15][16][11]

Electrocardiogram

There are no ECG findings associated with analgesic nephropathy.

X-ray

A pyelogram is not helpful in the diagnosis of analgesic nephropathy and may worsen the renal injury due to contrast utilization.[19]

Ultrasound

There are no ultrasound findings associated with analgesic nephropathy. However, ultrasound of the abdomen, kidneys and the urinary bladder could be helpful in ruling out other causes of nephropathy (obstruction or infection).[11]

CT Scan

CT scan without contrast of the abdomen is usually preferred for diagnosing analgesic nephropathy, the findings include: decrease in renal size, irregular contours and papillary calcifications.[20]

MRI

There is insufficient evidence suggesting MRI findings associated with analgesic nephropathy.

Other Imaging Findings

There are no other imaging findings associated with analgesic nephropathy.

Other Diagnostic studies

There are no other diagnostic studies associated with analgesic nephropathy.

Treatment

Medical therapy

Medical treatment of analgesic nephropathy may include: discontinuation of analgesics, adequate hydration with normal saline and treatment of infections with antibiotics.[15][11]

Interventions

Patients with analgesic nephropathy that present with acute renal failure or progression to end stage renal disease (ESRD) may require renal replacement therapy with dialysis.[21][15]

Surgery

Patients with analgesic nephropathy that progress to end stage renal disease (ESRD) may require renal replacement therapy with renal transplantation.[21]

Prevention

It has been suggested that in clinical practice, non-opioid analgesics, when possible, should be avoided for long-term use due to their nephrotoxicity.[17]

Cost-Effectiveness of Therapy

There is insufficient evidence about the cost-effectiveness of therapy in analgesic nephropathy.

Future or Investigational Therapies

No further or investigational therapies have been suggested in analgesic nephropathy.

References

  1. ↑ Spühler O, Zollinger HU (1953). "Die chronisch-interstitielle Nephritis". Z Klin Med (in German). 151 (1): 1–50. PMID 13137299.
  2. ↑ Michielsen P, de Schepper P (2001). "Trends of analgesic nephropathy in two high-endemic regions with different legislation". J Am Soc Nephrol. 12 (3): 550–6. PMID 11181803.
  3. ↑ "List of drug products that have been withdrawn or removed from the market for reasons of safety or effectiveness. Food and Drug Administration, HHS. Final rule". Fed Regist. 64 (44): 10944–7. 1999. PMID 10557618.
  4. ↑ 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.
  5. ↑ 5.0 5.1 5.2 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.
  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. ↑ 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 Feinstein AR, Heinemann LA, Curhan GC, Delzell E, Deschepper PJ, Fox JM; 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.
  9. ↑ 9.0 9.1 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.
  10. ↑ 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.
  11. ↑ 11.0 11.1 11.2 11.3 11.4 11.5 11.6 "StatPearls". 2020. PMID 31082145.
  12. ↑ Chalhoub NE, Riley K, Siddiqui N, Assaly R, Shahrour K, Booth R; et al. (2015). "Renal Papillary Necrosis Due to Invasive Candida Infection in a Morbidly Obese Patient". J Urol. 194 (4): 1107–8. doi:10.1016/j.juro.2015.07.036. PMID 26184064.
  13. ↑ Kawaguchi Y, Mori H, Izumi Y, Ito M (2018). "Renal Papillary Necrosis with Diabetes and Urinary Tract Infection". Intern Med. 57 (22): 3343. doi:10.2169/internalmedicine.0858-18. PMC 6288002. PMID 29984778.
  14. ↑ Henrich WL (1998). "Analgesic nephropathy". Trans Am Clin Climatol Assoc. 109: 147–58, discussion 158-9. PMC 2194329. PMID 9601134.
  15. ↑ 15.0 15.1 15.2 15.3 15.4 15.5 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.
  16. ↑ 16.0 16.1 16.2 16.3 Nanra RS, Stuart-Taylor J, de Leon AH, White KH (1978). "Analgesic nephropathy: etiology, clinical syndrome, and clinicopathologic correlations in Australia". Kidney Int. 13 (1): 79–92. doi:10.1038/ki.1978.11. PMID 362034.
  17. ↑ 17.0 17.1 Yaxley J (2016). "Common analgesic agents and their role in analgesic nephropathy: A commentary of the evidence". Int J Risk Saf Med. 28 (4): 189–196. doi:10.3233/JRS-170735. PMID 28582877.
  18. ↑ Gault MH, Wilson DR (1978). "Analgesic nephropathy in Canada: clinical syndrome, management, and outcome". Kidney Int. 13 (1): 58–63. doi:10.1038/ki.1978.8. PMID 713269.
  19. ↑ 19.0 19.1 "Analgesic Nephropathy - StatPearls - NCBI Bookshelf".
  20. ↑ 20.0 20.1 de Broe ME, Elseviers MM (1998). "Analgesic nephropathy". N. Engl. J. Med. 338 (7): 446–52. PMID 9459649. Unknown parameter |month= ignored (help)
  21. ↑ 21.0 21.1 Linton AL (1972). "Renal disease due to analgesics. I. Recognition of the problem of analgesic nephropathy". Can Med Assoc J. 107 (8): 749–51. PMC 1941002. PMID 4638849. Unknown parameter |month= ignored (help)

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