Bengtsson, U.

De Broe, M. E.

Elseviers, M. M.

Mihatsch, M. J.

Molzahn, M.

Pommer, W.

Ritz, E.

Schwarz, A.

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Nephrol Dial Transplant (1996) 11: 2407-2408StatementNephrologyDialysisTransplantationAnalgesic nephropathyM. E. De Broe1, M. M. Elseviers1, U. Bengtsson2, M. J. Mihatsch3, M. Molzahn4, W. Pommer4,E. Ritz5 and A. Schwarz6'Department of Nephrology, University of Antwerpen, Belgium, department of Nephrology, Sahlgren's UniversityHospital, Goteborg, Sweden, institute of Pathology, University of Basel, Switzerland, "Department of Nephrology,Humboldt-Krankenhaus, Berlin, department of Nephrology, Medizinische Universitat, Heidelberg, department ofNephrology, Universitatsklinikum Steglitz, Berlin, GermanyMore than 40 years after the first publication, analgesicnephropathy still remains a controversial issue. Duringthe 60s and 70s, phenacetin was singled out as thenephrotoxic culprit. Some countries reacted early bybanning all phenacetin-containing products from the'over-the-counter' market (Sweden, 1961; Canada,1973). In other countries phenacetin was removedfrom analgesic mixtures by the pharmaceutical industrylong before legislative measures were taken(Switzerland, Germany, Belgium). By 1996, phenacetinuse had ceased for more than 10 years in WesternEurope. Analgesic nephropathy however, remains acommon disease in several areas. Although a decreasein the national incidence has been observed in severalWest European countries, in Eastern Europe analgesicnephropathy has gained recognition. Unexpectedlyhigh incidences were recently measured in e.g. Czechand Slovak Republics [1].During the last decade, scientists demonstrated therenal risk of other analgesic mixtures not containingphenacetin and many clinicians diagnosed analgesicnephropathy in patients who never consumed phen-acetin. The recent publications investigating thenephrotoxic potential of paracetamol [2], the recom-mendations of the National Kidney Foundation of theUnited States [3] and the recent legislative actions inBelgium focused on all analgesic mixtures revived thediscussion concerning the nephrotoxicity of the manyanalgesic combinations currently available.The fact that analgesic nephropathy is one of thefew preventable renal diseases, makes worthy theinvestment to establish clear statements regarding thisissue. The statements presented here deal with and arelimited to 'classic' analgesic nephropathy. This particu-lar form of renal disease is characterized by renalpapillary necrosis and chronic interstitial nephritisassociated with prolonged and excessive consumptionof analgesic mixtures containing addictive substances.Correspondence and offprint requests to: M. E. De Broe, Universityof Antwerp, Department of Nephrology-Hypertension, p/aUniversity Hospital Antwerp, Wilrijkstraat 10, B 2650 Edegem/Antwerpen, Belgium.NSAID-related renal toxicity, mainly presented asacute renal failure and serious fluid and electrolytedisorders, is excluded from the discussion.The following statements represent our opinion con-cerning the current status of analgesic nephropathy:1. Attempts to evaluate the nephrotoxicity of differentanalgesics using experimental animal models haveyielded conflicting results. Experimental analgesicnephropathy and renal papillary necrosis can beinduced in animals with different kinds of analgesics.Moreover, the experimental data provide a biochem-ical and pathological basis for the enhanced renaltoxicity of analgesic mixtures compared with thatof single agents. The use of extremely high dosesand the aggravation of the renal effects by dehydra-tion or by introducing bacteria, however makes theextrapolation from the experimental data to anal-gesic nephropathy observed in humans difficult [4].2. In humans, there is overwhelming clinical evidencelinking analgesic abuse with a particular form ofchronic renal damage evolving towards end-stagerenal failure. The association between analgesicconsumption and the development of renal impair-ment was further investigated in the case-controlstudies published during the last decade [2,5,6,7].The strongest proof of causality came from the twoprospective studies published following the renalfunction of healthy abusers and controls during aperiod of several years [8,9].3. The long-standing excessive use of analgesicsobserved in patients with analgesic nephropathy isconcentrated on combination analgesics. Abusersprefer analgesic mixtures rather than single anal-gesics, taking these products rather for their mood-altering effects than for the relief of physical com-plaints. Hence, all these mixtures contain caffeineand/or codeine and it is clearly established that theaddition of these substances can create a psycholo-gical dependence towards these drugs [10].4. Analgesic nephropathy is caused by the abuse ofanalgesic mixtures containing two analgesic compon-ents combined with potentially addictive substances© 1996 European Renal Association-European Dialysis and Transplant Association2408 M. E. De Broe et al.(2+ analgesics). Evidence came in the first placefrom the clinicians confronted with the history ofabuse obtained from their patients with analgesicnephropathy. Further evidence came from the casecontrol study of Pommer et al. showing an increasedodds ratio for all combined analgesics but not forthe single ones [6]. Moreover, Elseviers and DeBroe reported that in 219 out of 226 patients withanalgesic nephropathy diagnosed according toobjective renal imaging criteria, the abuse was con-centrated on analgesic mixtures [11].5. Last year the ad hoc committee of the NationalKidney Foundation in the US examined data avail-able from the peer-review medical literature in form-ing opinions regarding analgesic nephropathy [3].The available information, gathered from hundredsof peer-reviewed articles, suggests that habitual con-sumption of both phenacetin-containing mixtures andnon-phenacetin-containing mixtures is associated withanalgesic nephropathy. Phenacetin can no longer beconsidered as the only nephrotoxic culprit in analgesicmixtures. Clinical observations in countries whereanalgesics without phenacetin are on the market fora period of more than 20 years (e.g. Australia,Belgium, Germany) learned that identical renalpathology is observed in patients abusing analgesicmixtures which never contained phenacetin. Thediagnostic criteria studies documented the nephro-toxicity of the combinations of salicylic acid-paracetamol, salicylic acid-pyrazolones, paracet-amol-pyrazolones, and two pyrazolones [11].6. The problem of chronic analgesic toxicity can beprevented efficaciously by curtailing heavy con-sumption. That educational and voluntary restraintalike should have but little effect on analgesic abuseis understandable, even predictable, given theaddictive nature of analgesic mixtures. The mostrational approach to prevention of classical analgesicnephropathy is the prohibition of 'over-the-counter'sales of any analgesic mixture containing two anal-gesic components combined with caffeine and/or cod-eine. The Australian experience learned that bylimiting the 'over-the-counter' availability of anal-gesic mixtures, the disease almost disappeared [12].References1. Matousovic K, Elseviers MM, Devecka D et al. Incidence ofanalgesic nephropathy among patients undergoing renal replace-ment therapy in Czech republic and Slovak republic. NephrolDial Transplant 1996; 11: 1048-10512. Perneger TV, Whelton PK, KJag MJ. Risk of kidney failureassociated with the use of acetaminophen, aspirin and nonster-oidal antiinflammatory drugs. iV Engl J Med 1994; 331:1675-16793. Henrich WL, Agodoa LE, Barrett B et al. Analgesics and theKidney: Summary and Recommendations to the ScientificAdvisory Board of the National Kidney Foundation From anAd Hoc Committee of the National Kidney Foundation. AmJ Kidn Dis 1996; 27: 162-1654. Nanra RS, Kincaid-Smith P. Experimental evidence for nephro-toxicity of analgesics. In: Stewart JH, ed. Analgesic and NSAID-induced Kidney Disease. Oxford University Press, 1993; 17-315. Sandier DP, Smith JC, Weinberg CR et al. Analgesic use andchronic renal disease. New Engl J Med 1989; 320: 1238-12436. Pommer W, Bronder E, Greiser E et al. Regular analgesic intakeand the risk of end-stage renal failure. Am J Nephrol 1989;9: 403-4127. Morlans M, Laporte JR, Vidal X et al. End-stage renal diseaseand non-narcotic analgesics: A case-control study. Brit J ClinPharmaco 1990; 30: 717-7238. Dubach UC, Rosner B, Pfister E. Epidemiologic study of abuseof analgesics containing phenacetin. Renal morbidity and mor-tality (1968-1979). New Engl J Med 1983; 308: 357-3629. Elseviers MM, De Broe ME. A long-term prospective controlledstudy of analgesic abuse in Belgium. Kidney Int 1995; 48:1912-191910. Murray RM. Genesis of analgesic nephropathy in the UnitedKingdom. Kidney Int 1978; 13: 50-5711. Elseviers MM, De Broe ME. Combination analgesic involvementin the pathogenesis of analgesic nephropathy: The EuropeanPerspective. Am J Kidn Dis 1996; 28: S48-S5512. Stewart JH. The analgesic syndrome. In: Stewart JH, ed.Analgesic and NSAID-induced Kidney Disease. Oxford UniversityPress, 1993; 58-66Editor's notePlease see also the letter to the Editor by Fox (pp. 2519-2520 inthis issue).

Analgesic nephropathy

Analgesic nephropathy

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