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Saudi Journal of Kidney Diseases and Transplantation
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Year : 1999  |  Volume : 10  |  Issue : 4  |  Page : 498-502
Analgesic Nephropathy

Department of Pathology, University of Melbourne, Grattan Street, Parkville Vic 3052, Australia

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How to cite this article:
Kincaid-Smith P. Analgesic Nephropathy. Saudi J Kidney Dis Transpl 1999;10:498-502

How to cite this URL:
Kincaid-Smith P. Analgesic Nephropathy. Saudi J Kidney Dis Transpl [serial online] 1999 [cited 2020 Jun 2];10:498-502. Available from: http://www.sjkdt.org/text.asp?1999/10/4/498/37208
In a paper on chronic interestitial nephritis published in 1953,[1] Spuhler and Zollinger described a chronic progressive from of tubular interstitial disease which led to death from renal failure. They implied that phenacetin or sulphonamides might cause this condition. They mentioned papillary necrosis as a finding in some kidneys but did not recognize this as a primary factor in the pathogenesis of the chronic interstitial nephritis, nor as a frequent or characteristic lesion in their cases.

In the late 1950s and early 1960s reports of the association of a high intake of analgesics and renal failure appeared from Scandinavia and Australia. For a period of time, it was implied that phenacetin was the cause of these lesion, however, this was based on the "common denominator theory" as phenacetin was in ingredient of most of the analgesic mixtures or compounds associated with these cases of renal failure. In the Scandinavian and Australian reports renal papillary necrosis was recognized as a common feature. [2],[3],[4] Lindeneg suggested at that time that papillary necrosis may be terminal manifestation of chronic interstitial nephritis. [5]

Subsequent clinico-pathological studies demonstrated that renal papillary necrosis was the primary lesion. This was followed by atyroph of relted renal cortical lobes and hypertrophy of adjacent areas in Bertin's columns leading to the characteristic lesions. [6]

The changes in the calyces on the intravenous pyelogram are characteristic [4] although in early cases before separation of the papille the pyelogram may be normal.[7]

Analgesic nephropathy was a common cause of renal failure in Australia, Scandinavia and Switzerland forty years ago but was subsequently recognized in many countries in the USA and Europe. More recently it has appeared in developing countries.

In early years some controversy existed as to which of the many ingredients of analgesic mixtures may be responsible for the renal papillary necrosis and subsequent interstitial nephritis and the renal failure. Mixtures taken in various countries have included phenazone, dextropropoxphene, amidopyrine, aspirin, phenacetin, paracetamol, caffeine and codeine.

Clinical studies showed that mixtures were commonly taken as a "habit" and for their mood-altering qualities, rather than for the relief of pain. [4] Encouragement to workers to take mixtures and compounds was provided by free supplies being available in factories. Many of the early cases in Switzerland worked in watch factories where free analgesics were provided.

Powerful advertising encouraged frequent use, and at least in Australia this dated back to a publication in a magazine in 1907 but was greatly increased in the 1920-1950 period. In the middle of this century it was common practice for housewives to purchase a gross (144) powders of aspirin, phenacetin and caffeine with the weekly groceries.

Australia appears to have had a particular problem with 25% of cases of end-stage renal failure here attributed to analgesic nephropathy in the early 1970s.

At that time the autopsy prevalence of renal papillary necrosis was reported to be 21.4% a remarkable figure and much higher than that in other countries [Table - 1].

Other features seen in patients with analgesic nephropathy were physhosis or physhoneurosis, peptic ulceration [8] and premature atherosclerosis and renal artery stenosis. [9] Myocardial infarction was a common cause of death.[8]

Perhaps the most important feature about the epidemic of analgesic nehropathy, which occurred in Australia in the mid­century was the lesson which it has taught us for prevention. Removal of phenacetin from most mixtures and compound in the early 1960s achieved no noticeable change in the prevalence of analgesic nephropathy. Legislation introduced in all states between 1979 and 1980 has led to the virtual disappearance of analgesic nephropathy due to common over-the counter analgesic mixtures and compounds. This legislation prohibited the sale of mixtures, which contained aspirin together with paracetamol (or phenacetin, which had already disappeared). Legislation also prohibited over-the-counter sales of analgesics containing caffeine. It also prohibited the sale of packs containing more than 25 tables or powders.

This legislation was dramatically effective. Essentially the only form of renal failure due to papillary necrosis now encountered by nephrologists in Australia is that dating back for many years prior to the introduction of legislation, or, that associated with chronic used of non.­steroidal anti-inflammatory drugs.

Experience in Scandinavia has been similar to that in Australia. In Belgium, as in Australia, the removal of phenacetin has had no impact on the prevalence of analgesic nephropathy. [10]

While analgesic nephropathy remains an important cause of end-stage renal failure in Belgium, Switzerland, Germany and Austria, it is less frequent in the United Kingdom and in southern countries in Europe. The prevalence of analgesic nephropathy in Europe is correlated with analgesic sales.[11]

Geographic variation has been observed both between different countries as occurs in Europe and within countries as in Australia.[12] in the United States it is reported predominantly from the South Eastern States. There has been some suggestion that climate and dehydration may have an impact on geographic variations in the prevalence, however, climate cannot account for the current prevalence in certain European countries. The increased prevalence in Scotland compared to England appears to be related to a higher analgesic intake [11] and perhaps to the mood altering properties of the powders containing aspirin, paracetamol and caffeine. Such preparations encourage frequent use and in both Australia and in Glasgow have been the most frequently used preparations.

Earlier controversy about the role of phenacetin in analgesic nephropathy [13] has been clearly resolved. Not only did removal of phenacetin in Australia and Belgium achieve no benefit but also more recently case control studies have clearly implicated paracetamol in analgesic nephropathy. [14]

A very important feature about analgesic nephropathy is its reversibility if analgesic intake ceases. We recognized at an early state that it was necessary to stop intake of aspirin and paracetamol as well as phenacetin to achieve this recovery.[15]

Where rigorous counseling and monitoring of continuing analgesic intake is undertaken, almost all people who stop taking analgesics recover even if they have quite advanced renal failure. [15] A more recent study where users were monitored for chemical markers of analgesic intake showed continuing deterioration in patients who continued drug abuse when advised to stop. [16]

Interest on the nephrotoxicity of non­steroidal anti-inflammatory drugs as a cause of papillary necrosis dates back 28 years. [17] The frequency of renal papillary necrosis in rheymatoid arthiritis [18] is almost certainly attributable in part to non-steroidal anti­inflammaatory drugs, although large doses of aspirin could contribute.

The subject of analgesic nephropathy related to non-steroidal anti-inflammatory drugs has been the subject of a recent extensive review.[10]

There is now sufficient epidemiological data to confirm the role of analgesicd in causing end-stage renal disease. Dubach's study published in 1991 provided the first evidence of this casual relationship.[19]

Elseviers and De Broe in a matched study of analgesic abusers and controls showed a relative risk of 6.1 in analgesic abusers. [20] Mortality was also higher in the abusers (RR +1.8 corrected for smoking) perhaps reflecting their premature althrosclerosis. We identified premature coronary artery disease as part of the analgesic syndrome and a frequent cause of death in 1964.[18]

The study by elseviers and De Broe et al is important because it documents clearly that phenacetin is not necessary for patients to develop analgesic nephropathy or the analgesic syndrome. [20]

Many experiments have been conducted in this field. Renal papillary necrosis was produced in rats with aspirin alone but not with phenacetin alone, however, over-the­counter analgesic mixture and compounds much readily produced renal papillary necrosis and the subsequent cortical atrophy which characterizes this disease in man. [21]

More recently, experiments have demonstrated that caffeine increases the likelihood of renal papillary necrosis in animals administered with a non-steroidal anti-inflammatory drug such as mefenamic acid.[22]

Essentially all the data that could be derived from animal studies is now available in human studies.

In patients with end-stage renal failure a computerized tomography (CT) Scan of the kidneys demonstrating renal papillary necrosis and calcification provides the most accurate diagnosis of analgesic nephropathy. Elseviers and De Broe compared different imaging techniques in this situation and found CT scanning the most accurate.[23]

Analgesic nephropathy recognized 50 years ago has been virtually eliminatedin some countries such as Australia by control of the ingredients of and numbers of analgesics available over-the counter. In other countries, it remains an important and costly cause of end-stage renal disease. Not only could this disease be eliminated worldwide by introducing similar controls to those introduced in Australia, but even late cases with renal failure may show remarkable recovery when analgesics are withdrawn.[15]

   References Top

1.Spuhler O, Zolinger HU, Die chroniseh interstitielle nephritis. Z Kin Med 1953;151:1.  Back to cited text no. 1    
2.Lindvall N. Renal papillary necrosis. A reoentgenographics study of 155 cases. Acta Radiol 1960:Suppl 192:1.  Back to cited text no. 2    
3.Bengtsson U. A comparative study of chronic non-obtructive pyelonephritis and renal papillary necrosis. Acta Med Scan 1962(Suppl 388)172:1.  Back to cited text no. 3    
4.Dawborn JK, Kincaid-Smith P, McLaren J. The effect of aspirin and phenacetin on ascending infection in the rat kidney Australasian Ann Med 1964;13:217-21.  Back to cited text no. 4    
5.Lindeneg O, fischer S, Pedersen J, Nissen NI. Necrosis of the renal papillae and prolonger abuse of phenacetin. Acta Med Scan 1959;165:321.  Back to cited text no. 5    
6.Kincaid-Smith P. Pathogenesis of the renal lesion associated with the abuse of analgesics. Lancet 1967;1:859-62.  Back to cited text no. 6  [PUBMED]  
7.Fairley KF, Kincaid-Smith P. Renal papillary encrosis with anormal pyelograjm. Brit Med J 1968;1:156-7.  Back to cited text no. 7    
8.Dawborn JK, Fairely KF, Kincaid-Smith P, King WE. The association of peptic ulceration, chronic renal disease and analgesic abuse. QJ Med 1966;35:69-83.  Back to cited text no. 8    
9.Kincaid-Simth P. Analgesic nephropathy in Australia. Contrib. Nephrol 1979;16:57-64.  Back to cited text no. 9    
10.Bennett WM, Porter GA. Analgesic nephropathy and the use of non­steroidal anti-inflammatory drugs in renal patients: new insight. J Nephrol 1998;11:70-5.  Back to cited text no. 10    
11.Elseviers MM, De Broe ME. Analgesic nephropathy in Belgium is related to the sales of particular analgesic mixtures. Nephrol Dial Transplant 1994;9:41-6.  Back to cited text no. 11  [PUBMED]  [FULLTEXT]
12.Kincaid-Smith P. analgesic nephropathy. Kidney Int 1978;13:1-4.  Back to cited text no. 12  [PUBMED]  
13.Kincaid-Smith P. Analgesic nephropathy. Ann Internal Medicine 1968;68:949-53.  Back to cited text no. 13    
14.Perneger TV, Whelton PK, Klag MJ, Risk of kidney failure associated with the use of acetaminophen, aspirin and non-stroidal antiiflammatory drugs. N Engl J Med 1994;331:1675-9.  Back to cited text no. 14    
15.KincaidSmith P, Nanra RS, Fiarley KF. Analgesic nephropathy: a recoverable form of chronic renal failure. In: Renal infection and renal scarring. Editors: Kincaid-Sith P, Fiarley KF. Mercedes Publishing Services, Melbourne 1971;385-400.  Back to cited text no. 15    
16.Hauser AC, Derfler K, Balcke P. Progression of renal insufficiency in analgesic nephropthy: Impact of continuous drug abuse J clin Epidemiol 1991;44:53-6.  Back to cited text no. 16    
17.Nanra RS, Kincaid-Smith P. Experimental renal papillary necrosis (RPN) with non-steroid anti-inflam­matory analgesics. In: Phenacetin Abuses 1973. Editor: Haschek H. Facta Publications, Vienna 1973;67-88.  Back to cited text no. 17    
18.Nanra RS. Renal papillary necrosis in rheumatoid arthritis. Med J Aust 1975;1:194-7.  Back to cited text no. 18  [PUBMED]  
19.Dubach UC, Rosner B, Sturmer T. An epidemiologic study of abuse of analgesic drugs. Effects of phenacetin and salicylate on mortality. N Engl J Med 1991;324:155-60.  Back to cited text no. 19    
20.Elseviers MM, De Broe ME. A long­term prospective controlled study of analgesic abuse in Belgium. Kidney Int 1995;48:1912-9.  Back to cited text no. 20  [PUBMED]  
21.Saker BM, Kincaid Smith P. Papillary necrosis in experimental analgesic nephropathy. Br Med J 1969;1:161-2.  Back to cited text no. 21    
22.Champion de Crespigny P, Hewitson T, Birchall I, Kincaid-Smith P. Caffeine potentiates the nephrotoxicity of mefenamaic acid on the rat renal papilla. Am J Nephrol 1990;10:311-5.  Back to cited text no. 22  [PUBMED]  
23.Elseviers MM, Waller I, Nenoy D, et al. Evaluation of diagnostic criteria for analgestic nephropathy in patients with end-stage renal failure: results of the ANNE study. Analgesic Nephropathy Network of Europe. Nephrol Dial transplant 1995;10:808-14.  Back to cited text no. 23    

Correspondence Address:
Priscilla Kincaid-Smith
Department of Pathology, University of Melbourne, Grattan Street, Parkville Vic 3052
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