| Analgesic nephropathy | |
|---|---|
 | |
| Classically caused by mixed analgesics containingphenacetin, analgesic nephropathy was once a common cause ofacute kidney injury. | |
| Specialty | Nephrology  |
Analgesic nephropathy is injury to thekidneys caused byanalgesic medications such asaspirin,bucetin,phenacetin, andparacetamol. 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.
The specific kidney injuries induced by analgesics arerenal papillary necrosis andchronic interstitial nephritis. They appear to result from decreasedblood flow to the kidney, rapid consumption ofantioxidants, and subsequentoxidative damage to the kidney. This kidney damage may lead to progressivechronic kidney failure, abnormalurinalysis results,high blood pressure, andanemia. A small proportion of individuals with analgesic nephropathy may developend-stage kidney disease.
Analgesic nephropathy was once a common cause of kidney injury and end-stage kidney disease in parts ofEurope,Australia, and theUnited States. In most areas, its incidence has declined sharply since the use of phenacetin fell in the 1970s and 1980s.[citation needed]
| Finding | Proportion affected |
|---|---|
| Headache | 35-100% |
| Pyuria | 50-100% |
| Anemia | 60-90% |
| Hypertension | 15-70% |
| Gastrointestinal symptoms | 40-60% |
| Urinary tract infection | 30-60% |
Common findings in people with analgesic nephropathy includeheadache,anemia, high blood pressure (hypertension), and white blood cells in the urine (leucocyturia,pyuria).[1] Some individuals with analgesic nephropathy may also have protein in their urine (proteinuria).[2]
Complications of analgesic nephropathy includepyelonephritis[3] andend-stage kidney disease.[4] Risk factors for poor prognosis include recurrent urinary tract infection and persistently elevated blood pressure.[5] Analgesic nephropathy also appears to increase the risk of developing cancers of theurinary system.[6]
The scarring of the small blood vessels, called capillary sclerosis, is the initial lesion of analgesic nephropathy.[7] Found in therenal pelvis,ureter, and capillaries supplying thenephrons, capillary sclerosis is thought to lead torenal papillary necrosis and, in turn,chronic interstitial nephritis.[8][7]
How phenacetin and other analgesics lead to this damage is incompletely understood. It is currently thought that the kidney toxicities ofNSAIDs 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.[9]
Properkidney function depends upon adequate blood flow to the kidney.Kidney blood flow is a complex, tightly regulated process that relies on a number ofhormones and other small molecules, such asprostaglandins. 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 thecyclooxygenases.[citation needed]
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 therenal cortex (outside) and then therenal medulla (inside), the deeper structures of the kidney are most sensitive to decreased blood flow. Thus the innermost structures of the kidney, known as therenal 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 ofrenal papillary necrosis.[10]
NSAIDs caused no adverse effects on renal function in healthy dogs subjected to anesthesia.[11][12][13]Most healthy kidneys contain enoughphysiologic 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.[citation needed]
It is unclear how phenacetin induces injury to the kidney.[10] Bach and Hardy have proposed that phenacetin's metabolites lead tolipid peroxidation that damages cells of the kidney.[14]
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 intoN-acetyl-p-benzoquinoneimine (NAPQI).[15] NAPQI depletes glutathione via non-enzymatic conjugation withglutathione, a naturally occurringantioxidant.[16] With depletion of glutathione, cells of the kidney become particularly sensitive tooxidative damage.[citation needed]
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 usingcomputed tomography (CT) imaging withoutcontrast.[17] One trial demonstrated that the appearance of papillary calcifications on CT imaging was 92%sensitive and 100%specific for the diagnosis of analgesic nephropathy.[18]
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.[5] In Stage 5chronic kidney disease patientsrenal replacement therapy may become necessary.[citation needed]
Analgesics are aclass of medications widely used in the treatment ofpain. They includeaspirin and othernon-steroidal anti-inflammatory drugs (NSAIDs),[19] as well as theantipyreticsparacetamol (known as acetaminophen in the United States) andphenacetin. Introduced in the late 19th century, phenacetin was once a common component of mixed analgesics in parts of Europe, Australia, and the United States.[20] These analgesics contained aspirin or other NSAIDs combined with phenacetin, paracetamol, or salicylamide, andcaffeine orcodeine.[10]
In the 1950s, Spühler and Zollinger reported an association between kidney injury and the chronic use of phenacetin.[21] They noted that chronic users of phenacetin had an increased risk of developing specific kidney injuries, namelyrenal papillary necrosis andchronic 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.[20]
As the use of phenacetin declined, so too did the prevalence of analgesic nephropathy as a cause of end-stage kidney disease. Data fromSwitzerland, 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.[4] 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.[8]
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.[22][23] 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.[24]
The termanalgesic 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 calledanalgesic abuse nephropathy. Murray prefers the less judgmentalanalgesic-associated nephropathy.[1] Both terms are abbreviated to the acronymAAN, by which the condition is also commonly known.[citation needed]
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