analgesic nephropathy

Common findings in people with analgesic nephropathy include headache, anemia, high blood pressure (hypertension), and white blood cells in the urine (leucocyturia, pyuria).{{cite journal |vauthors=Murray TG, Goldberg M |title=Analgesic-associated nephropathy in the U.S.A.: epidemiologic, clinical and pathogenetic features |journal=Kidney Int. |volume=13 |issue=1 |pages=64–71 |date=January 1978 |pmid=713270 |doi= 10.1038/ki.1978.9|doi-access=free }} Some individuals with analgesic nephropathy may also have protein in their urine (proteinuria).{{cite journal |vauthors=Nanra RS, Stuart-Taylor J, de Leon AH, White KH |title=Analgesic nephropathy: etiology, clinical syndrome, and clinicopathologic correlations in Australia |journal=Kidney Int. |volume=13 |issue=1 |pages=79–92 |date=January 1978 |pmid=362034 |doi= 10.1038/ki.1978.11|doi-access=free }}

Complications of analgesic nephropathy include pyelonephritis{{cite journal |vauthors=Maisonneuve P, Agodoa L, Gellert R |title=Distribution of primary renal diseases leading to end-stage renal failure in the United States, Europe, and Australia/New Zealand: results from an international comparative study |journal=Am. J. Kidney Dis. |volume=35 |issue=1 |pages=157–65 |date=January 2000 |pmid=10620560 |doi= 10.1016/S0272-6386(00)70316-7|display-authors=etal}} and end-stage kidney disease. Risk factors for poor prognosis include recurrent urinary tract infection and persistently elevated blood pressure. Analgesic nephropathy also appears to increase the risk of developing cancers of the urinary system.{{cite journal |vauthors=Blohmé I, Johansson S |title=Renal pelvic neoplasms and atypical urothelium in patients with end-stage analgesic nephropathy |journal=Kidney Int. |volume=20 |issue=5 |pages=671–5 |date=November 1981 |pmid=7045494 |doi= 10.1038/ki.1981.192|doi-access=free }}

The scarring of the small blood vessels, called capillary sclerosis, is the initial lesion of analgesic nephropathy.{{cite journal |vauthors=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 |date=December 1983 |pmid=6641031 }} 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.{{cite journal |vauthors=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 |date=November 2006 |pmid=16891638 |doi=10.1093/ndt/gfl390 |doi-access=free }}

How phenacetin and other analgesics lead to this damage is incompletely understood. It is currently thought that the kidney 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.{{cite journal |vauthors=Feinstein AR, Heinemann LA, Curhan GC |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 |date=December 2000 |pmid=11115060 |doi=10.1046/j.1523-1755.2000.00410.x|display-authors=etal|doi-access=free }}

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.{{cn|date=April 2021}}

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, known as 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.

NSAIDs caused no adverse effects on renal function in healthy dogs subjected to anesthesia.{{cite journal|last1=Boström|first1=IM|last2=Nyman|first2=G|last3=Hoppe|first3=A|last4=Lord|first4=P|title=Effects of meloxicam on renal function in dogs with hypotension during anaesthesia.|journal=Veterinary Anaesthesia and Analgesia|date=January 2006|volume=33|issue=1|pages=62–9|pmid=16412133|doi=10.1111/j.1467-2995.2005.00208.x}}{{cite journal|last1=Frendin|first1=JH|last2=Boström|first2=IM|last3=Kampa|first3=N|last4=Eksell|first4=P|last5=Häggström|first5=JU|last6=Nyman|first6=GC|title=Effects of carprofen on renal function during medetomidine-propofol-isoflurane anesthesia in dogs.|journal=American Journal of Veterinary Research|date=December 2006|volume=67|issue=12|pages=1967–73|pmid=17144795|doi=10.2460/ajvr.67.12.1967|doi-access=free}}{{cite journal|last1=Boström|first1=IM|last2=Nyman|first2=GC|last3=Lord|first3=PE|last4=Häggström|first4=J|last5=Jones|first5=BE|last6=Bohlin|first6=HP|title=Effects of carprofen on renal function and results of serum biochemical and hematologic analyses in anesthetized dogs that had low blood pressure during anesthesia.|journal=American Journal of Veterinary Research|date=May 2002|volume=63|issue=5|pages=712–21|pmid=12013473|doi=10.2460/ajvr.2002.63.712|doi-access=free}}

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.{{cn|date=April 2021}}

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.{{cite journal |vauthors=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 |date=October 1985 |pmid=3910912 |doi= 10.1038/ki.1985.172|doi-access=free }}

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).{{cite journal |vauthors=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 |date=November 1981 |pmid=6798713 |doi= 10.1016/0041-008X(81)90415-4}} NAPQI depletes glutathione via non-enzymatic conjugation with glutathione, a naturally occurring antioxidant.{{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 |date=July 1996 |pmid=8669429 |doi= 10.1016/S0272-6386(96)90568-5}} With depletion of glutathione, cells of the kidney become particularly sensitive to oxidative damage.{{cn|date=April 2021}}

Diagnosis is traditionally based on the clinical findings above in combination with excessive analgesic use. Once suspected, analgesic nephropathy can be confirmed with relative accuracy using computed tomography (CT) imaging without contrast.{{cite journal |vauthors=de Broe ME, Elseviers MM |title=Analgesic nephropathy |journal=N. Engl. J. Med. |volume=338 |issue=7 |pages=446–52 |date=February 1998 |pmid=9459649 |doi= 10.1056/NEJM199802123380707}} One trial demonstrated that the appearance of papillary calcifications on CT imaging was 92% sensitive and 100% specific for the diagnosis of analgesic nephropathy.{{cite journal |vauthors=Elseviers MM, De Schepper A, Corthouts R |title=High diagnostic performance of CT scan for analgesic nephropathy in patients with incipient to severe renal failure |journal=Kidney Int. |volume=48 |issue=4 |pages=1316–23 |date=October 1995 |pmid=8569094 |doi= 10.1038/ki.1995.416|display-authors=etal|doi-access=free }}

Treatment of analgesic nephropathy begins with the discontinuation of analgesics, which often halts the progression of the disease and may even result in normalization of kidney function.{{cite journal |author =Linton AL |title=I. Recognition of the problem of analgesic nephropathy |journal=Can Med Assoc J |volume=107 |issue=8 |pages=749–51 |date=October 1972 |pmid=4638849 |pmc=1941002 }} In Stage 5 chronic kidney disease patients renal replacement therapy may become necessary.{{cn|date=April 2021}}

{{main|Phenacetin|Analgesic}}

Analgesics are a class of medications widely used in the treatment of pain. They include aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs),{{cite journal | vauthors = Buer JK | title = Origins and impact of the term 'NSAID' | journal = Inflammopharmacology | volume = 22 | issue = 5 | pages = 263–7 | date = Oct 2014 | pmid = 25064056 | doi = 10.1007/s10787-014-0211-2 | url = http://urn.nb.no/URN:NBN:no-49638 | hdl = 10852/45403 | s2cid = 16777111 | hdl-access = free }} as well as the antipyretics paracetamol (known as acetaminophen in the United States) and phenacetin. Introduced in the late 19th century, phenacetin was once a common component of mixed analgesics in parts of Europe, Australia, and the United States.{{cite journal |vauthors=McLaughlin JK, Lipworth L, Chow WH, Blot WJ |title=Analgesic use and chronic renal failure: a critical review of the epidemiologic literature |journal=Kidney Int. |volume=54 |issue=3 |pages=679–86 |date=September 1998 |pmid=9734593 |doi=10.1046/j.1523-1755.1998.00043.x|doi-access=free }} These analgesics contained aspirin or other NSAIDs combined with phenacetin, paracetamol, or salicylamide, and caffeine or codeine.{{cite book |last=de Broe |first=Marc E |editor=Curhan, Gary C |title=UpToDate |year=2008 |location=Waltham, MA |chapter=Analgesic nephropathy}}

In the 1950s, Spühler and Zollinger reported an association between kidney injury and the chronic use of phenacetin.{{cite journal |vauthors=Spühler O, Zollinger HU |title=Die chronisch-interstitielle Nephritis. |language=de |journal=Z Klin Med |volume=151 |issue=1 |pages=1–50 |year=1953 |pmid=13137299 }} They noted that chronic users of phenacetin had an increased risk of developing specific kidney injuries, namely renal papillary necrosis and chronic interstitial nephritis. This condition was dubbed analgesic nephropathy and was attributed to phenacetin, although no absolute causative role was demonstrated. With further reports of the increased risk of kidney injury with prolonged and excessive phenacetin use, however, phenacetin was banned in several countries between the 1960s and 1980s.

As the use of phenacetin declined, so too did the prevalence of analgesic nephropathy as a cause of end-stage kidney disease. Data from Switzerland, for example, demonstrated a decline in the prevalence of analgesic nephropathy among people with end-stage kidney disease, from 28% in 1981 to 12% in 1990.{{cite journal |vauthors=Brunner FP, Selwood NH |title=End-stage renal failure due to analgesic nephropathy, its changing pattern and cardiovascular mortality. EDTA-ERA Registry Committee |journal=Nephrol. Dial. Transplant. |volume=9 |issue=10 |pages=1371–6 |year=1994 |pmid=7816247 |doi= 10.1093/ndt/9.10.1371|url=http://doc.rero.ch/record/303453/files/9-10-1371.pdf }} An autopsy study performed in Switzerland suggested that the prevalence of analgesic nephropathy in the general population has likewise decreased; the prevalence was 3% in 1980 and 0.2% in 2000.

While these data demonstrate that analgesic nephropathy has been all but eliminated in some regions, in other regions the condition persists. Notably, in Belgium, the prevalence of analgesic nephropathy among people having dialysis was 17.9% in 1984 and 15.6% in 1990.{{cite journal |vauthors=Elseviers MM, de Broe ME |title=Analgesic nephropathy in Belgium is related to the sales of particular analgesic mixtures |journal=Nephrol. Dial. Transplant. |volume=9 |issue=1 |pages=41–6 |year=1994 |pmid=8177475 }}{{cite journal |vauthors=Noels LM, Elseviers MM, de Broe ME |title=Impact of legislative measures on the sales of analgesics and the subsequent prevalence of analgesic nephropathy: a comparative study in France, Sweden and Belgium |journal=Nephrol. Dial. Transplant. |volume=10 |issue=2 |pages=167–74 |year=1995 |pmid=7753450 }} Michielsen and de Schepper suggest that analgesic nephropathy persists among people in Belgium having dialysis not due to non-phenacetin analgesics, but because Belgium accepts a higher proportion of elderly people for dialysis. According to these authors, a greater proportion have analgesic nephropathy because a greater percentage of people in Belgium having dialysis have been exposed to long-term use of phenacetin.{{cite journal |vauthors=Michielsen P, de Schepper P |title=Trends of analgesic nephropathy in two high-endemic regions with different legislation |journal=J. Am. Soc. Nephrol. |volume=12 |issue=3 |pages=550–6 |date=March 2001 |doi=10.1681/ASN.V123550 |pmid=11181803 |url=http://jasn.asnjournals.org/cgi/pmidlookup?view=long&pmid=11181803|doi-access=free }}

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. Murray prefers the less judgmental analgesic-associated nephropathy. Both terms are abbreviated to the acronym AAN, by which the condition is also commonly known.{{cn|date=April 2021}}

{{Reflist}}

{{Medical resources

| DiseasesDB =

| ICD10 = {{ICD10|N|14|0|n|10}}

| ICD9 = {{ICD9|583.89}}, {{ICD9|584.7}}

| ICDO =

| OMIM =

| MedlinePlus = 000482

| eMedicineSubj = med

| eMedicineTopic = 2839

| MeshID =

}}

{{Nephrology}}

Category:Kidney diseases

Category:Pain management