The changing pattern of prevalence and age distribution of analgesic nephropathy as a cause of end-stage renal failure (ESRF) in patients on RRT was analysed using the EDTA-ERA Registry's files. Comparing 1990 to 1981, the percentage of patients with analgesic nephropathy decreased in many European countries and the Registry's average came down from 3 to 2%. The highest prevalence was noted for Switzerland, which showed a decrease from 28 in 1981 to 12% in 1990. During the same interval the age distribution shifted to the right with an increase in median age from 57 to 63 at start of RRT for analgesic nephropathy. In Switzerland the age-specific acceptance rate to RRT for patients with analgesic nephropathy decreased to less than 1/3 in the age cohorts below 55 but increased in those aged 65 or older. This increase in the elderly cohorts appeared to be related to the growing acceptance rate to RRT of elderly patients in general rather than to an increasing incidence of ESRF due to analgesic nephropathy. Mortality in general and death rates due to cardiovascular causes were found not to differ in RRT patients with analgesic nephropathy from that of other standard primary renal diseases (excluding diabetic nephropathy and systemic diseases). Some 20 years after withdrawal of phenacetin from the analgesic market, analgesic nephropathy all but disappeared as a cause of ESRF in Sweden and Denmark, and the same may be expected to occur in countries like Switzerland, Belgium, and others in the not too far distant futur

Brunner, F. P.

Selwood, Neville H.

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Nephrol Dial Transplant (1994) 9: 1371-1376Registry ReportNephrologyDialysisTransplantationEnd-stage renal failure due to analgesic nephropathy, its changingpattern and cardiovascular mortalityF. P. Brunner and Neville H. Selwood, on behalf of the EDTA-ERA Registry CommitteeDepartment fur Innere Medizin, Universitat Basel, Switzerland; and EDTA Registry, St Thomas' Hospital, London, UKAbstract. The changing pattern of prevalence and agedistribution of analgesic nephropathy as a cause ofend-stage renal failure (ESRF) in patients on RRTwas analysed using the EDTA-ERA Registry's files.Comparing 1990 to 1981, the percentage of patientswith analgesic nephropathy decreased in manyEuropean countries and the Registry's average camedown from 3 to 2%. The highest prevalence was notedfor Switzerland, which showed a decrease from 28 in1981 to 12% in 1990. During the same interval the agedistribution shifted to the right with an increase inmedian age from 57 to 63 at start of RRT for analgesicnephropathy. In Switzerland the age-specific accept-ance rate to RRT for patients with analgesic nephro-pathy decreased to less than 1/3 in the age cohortsbelow 55 but increased in those aged 65 or older. Thisincrease in the elderly cohorts appeared to be relatedto the growing acceptance rate to RRT of elderlypatients in general rather than to an increasing incid-ence of ESRF due to analgesic nephropathy. Mortalityin general and death rates due to cardiovascular causeswere found not to differ in RRT patients with analgesicnephropathy from that of other standard primary renaldiseases (excluding diabetic nephropathy and systemicdiseases). Some 20 years after withdrawal of phenacetinfrom the analgesic market, analgesic nephropathy allbut disappeared as a cause of ESRF in Sweden andDenmark, and the same may be expected to occur incountries like Switzerland, Belgium, and others in thenot too far distant future.Key words: EDTA Registry; analgesic nephropathy;cardiovascular mortality on renal replacement therapy;epidemiology of end-stage renal failure due to analgesicnephropathyIntroductionDuring the last three decades we have witnessed adecrease in the sale and abuse of mixed analgesic drugsCorrespondence and offprint requests to: Dr Neville Selwood, EDTARegistry, St Thomas' Hospital, London SE1 7EH, UKcontaining phenacetin in many European countriesdue to legal restriction, public education, and finallyby the pharmaceutical companies removing phenacetinfrom mixed preparations [1-3]. All these measuresshould have affected the epidemiology of analgesicnephropathy, and the EDTA Registry's files affordeda unique opportunity to study any changes in theprevalence of ESRF caused by this condition. TheRegistry's files were also used to detect possible differ-ences in overall and cardiovascular mortality on RRT,comparing analgesic nephropathy to standard primaryrenal diseases.MethodsThe methods of data collection used by the EDTARegistry have been described previously [4]. Thisreport is based on data provided on individual patientquestionnaires and relates to treatment up to31 December 1990. The percentage of centres reportingtheir patients to the EDTA-ERA Registry variedbetween 50% and 100% for the countries mentionedspecifically in this report. The analyses were carriedout by the methodology developed by Dr NevilleSelwood as previously described [5]. Age and sexspecific acceptance rates to RRT were calculated forSwitzerland, where patient questionnaire returns havebeen 80% to 90% complete and where the total numberof new patients has been checked every year by tele-phone calls to non-reporting centres by FB.Results and commentsPrevalence and age distribution at start of RRTAs judged by the proportion of patients starting RRTdue to analgesic nephropathy and their age distribu-tion, the prevalence of analgesic nephropathy has beenchanging in Europe. Comparing 1990 to 1981, theproportion with analgesic nephropathy as a percentageof all patients starting RRT decreased in mostEuropean countries (Figure 1). The highest proportionwas noted for Switzerland, with 28% of patients in1981 and a lower but still remarkable 12% in 1990.© 1994 European Dialysis and Transplant Association-European Renal Association1372 F. P. Brunner and N. H. Selwood30% patients with AN at start of RRT2 5 -2 0 -1510-5"0-4wilt B Den A Neth W-Oerm CS S F IFig. 1. Proportion of patients with analgesic nephropathy at startof RRT shown for the total registry (EDTA), for all countries abovethe EDTA average (Switzerland, Belgium, Denmark, Austria,Netherlands, Germany, Czechoslovakia) and for selected countrieswith lower proportions (Sweden is shown because of its highprevalence of analgesic nephropathy in the 1960s and France andItaly were selected as the two countries with the largest number ofpatients on RRT and of inhabitants).For Belgium the percentage decreased from 16% to11%. In most other countries there was also a decreaseto be noted comparing 1990 to 1981. The EDTAaverage decreased from 3% in 1981 to 2% in 1990. Theproportion of patients with analgesic nephropathyaccepted for RRT was recorded for every EDTAcountry in the 1988 combined report [6]. The percent-age of patients accepted for RRT in 1987 with analgesicnephropathy for countries not listed in Figure 1 was3.2% in Portugal, 2.9% in Cyprus, 2.7% in the GermanDemocratic Republic, 1% in the United Kingdom, andless than 1% in all other countries [6].Analgesic abuse has been more prevalent amongfemales, and this is shown again as the female:maleratio for all patients starting RRT between 1970 and1990 (Figure 2). The EDTA average was 2.7 femalesfor 1 male, and Belgium had the highest preponderanceof females with a ratio of 4.9.AN female/male ratios-3 -2 -0-1—4.93 42.7 2.92 2 2 2W-Qerm Sweden EDTA Switzerl France BelgiumThe age distribution of all patients with analgesicnephropathy at start of RRT shifted to the rightcomparing 1990 to 1980 as shown in Figure 3. In 1980some 30% or more were in each of the cohorts aged45-54 and 55-64. In 1990 there were barely anypatients aged below 35, but over 30% were now in theage group 65-74 and 10% above age 75. Median agerose from about 57 in 1980 to 63 in 1990. Similarchanges in age distribution have been reported fromAustralia [7].The changing pattern of analgesic nephropathy canbe appreciated best in Switzerland where this diseasewas first described in 1953 [8] and where it has hadthe highest prevalence worldwide over the last decades.The age-specific acceptance rate for Swiss patients withanalgesic nephropathy is shown for 1980 and 1990 inFigure 4a (identical trends were observed regardingthe age-specific acceptance rates in both sexes). In 1980some 40 patients per million population aged 45-54and about 60 patients p.m.p. aged 55-64 (or morethan 100 per million females aged 55-64 and over 30per million males aged 55-64) were accepted for RRTwith ESRF attributed to analgesic nephropathy. Tenyears later, in 1990, not a single patient starting RRTfor analgesic nephropathy was below age 35, and veryfew were in the cohorts 35-44 and 45-54. A definitedecrease is also demonstrated for the cohort aged55-64. However, the number of patients aged 65-74more than doubled and there were some 10 per millionpopulation aged above 75 who started dialysis forESRF due to analgesic nephropathy in 1990. Almostidentical numbers and trends in the age-specific accept-ance rates have been recorded in Australia between1981 and 1991 [7].One explanation for this increasing incidence inelderly patients could be the well-known fact thatmany patients discontinued analgesic abuse with phen-acetin-containing mixed analgesics once renal diseasehad been detected or when phenacetin was more diffi-cult to obtain. This could have lessened further damageto the kidneys and delayed the appearance of ESRFfrom age 40-50 to age 70 or 80. Another explanation5040302 0 -% patients with AN at start of RRTTotal Registry373033• 35 35 - 44 45 - 54 55 - 64 65 - 74age cohortsFig. 2. Female:male ratio of patients starting RRT for end-stagerenal failure due to analgesic nephropathy in 1970-1990, shown for Fig. 3. Age distribution of patients starting RRT for end-stage renalselected countries. failure due to analgesic nephropathy in 1980 and in 1990.EDTA Registry report on analgesic nephropathynew patients with AN per million pop137370% patients with AN at start of RRTeo-60-40-30-20-10-0ammi i«go Switzerland4636 - 44 46 - 64 66 - 64age cohorts' 36 36 - 44 46 - 64 66 - 64 66 - 74age cohortsFig. 4. End-stage renal failure due to analgesic nephropathy in Switzerland, a. Age-specific acceptance rate (per million general populationof same age cohort); b. patients with analgesic nephropathy as a percentage of all patients accepted for for RRT.is suggested by Figure 4b, which shows the percentageof patients with analgesic nephropathy as a proportionof all patients starting RRT in each age cohort separ-ately for 1979/80 and for 1989/90. It is important tonote that the percentage in the age group 65-74 andabove 75 did not change over this 10-year interval.There is no doubt, therefore, that the number ofpatients with end-stage renal failure due to analgesicnephropathy has been decreasing during the 1980s inSwitzerland at least up to the age of 65. In patientsabove the age of 65, the true incidence of end-stagerenal failure due to analgesic nephropathy has prob-ably remained stable, and the increased acceptancerate was the result of an increased acceptance rate ofelderly patients in general.Mortality and death rates due to cardiovascular causesAccelerated artherosclerosis with coronary, carotid,renal, and peripheral arterial occlusive disease has beenreported to cause serious morbidity and prematuremortality in patients with analgesic nephropathy,mainly from Australia [9] but also from Switzerland[10]. The study from Australia [9] compared patientswith analgesic nephropathy to patients with glomerulo-nephritis accepted for RRT during the same 5-yearperiod. Overall mortality was significantly higher inthe former group with 50.8 versus 15.8%. However,no details regarding age distribution and other pro-gnostic features of the two patient groups were given.In the 20-year longitudinal study of initially healthyfemale factory workers without renal disease fromSwitzerland [10] a group with analgesic abuse wascompared to a matched control group without abuse.The risk of renal or cardiovascular disease wasincreased in the group with analgesic abuse but end-stage renal disease was a rare event. It seemed import-ant therefore to analyse overall mortality and deathrates due to cardiovascular causes in typicallyEuropean patient cohorts on RRT with analgesicnephropathy in comparison to all patients with stand-ard primary renal diseases (glomerulonephritis,pyelonephritis/interstitial nephritis, polycystic kidneydiseases) as shown in Figures 5-8. These analyses wererestricted to Belgium, The Netherlands, Germany,Switzerland, and Austria, i.e. countries with a sizeableproportion of patients with analgesic nephropathy. Incontrast to the findings reported from Australia [9]mortality did not differ appreciably between thecohorts with analgesic nephropathy as compared tothose with other standard primary renal diseases.Furthermore mortality in females with analgesicnephropathy was slightly lower compared to males, ashas been reported for European patients with othercommon renal diseases [11].Cardiovascular mortality including death rates dueto myocardial ischaemia and infarction have long beenknown to be increased in patients on RRT as recordedagain in recent EDTA reports [11,12]. Of particularinterest were the geographical differences in the coron-ary death rates on RRT, which reflected the pattern inthe general population of higher death rates due tomyocardial ischaemia and infarction in Northernversus Southern Europe. These geographical differ-ences made it important to restrict the analyses ofcardiovascular death rates in patients with analgesicnephropathy to countries in central Europe with similarrisks of cardiovascular death in the general population.Death rates due to myocardial ischaemia and infarction(Figure 6) were slightly higher in male patients thanin female patients but did not differ appreciablybetween patients with analgesic nephropathy as com-pared to patients with other primary renal diseases.The same was true for other cardiac causes (Figure 7).Lethal cerebrovascular accidents (Figure 8) had notonly a similar incidence in males compared to femalesbut also occurred at similar rates in patients withanalgesic nephropathy.Hence we may conclude that patients on RRT dueto analgesic nephropathy have an overall mortalityand cardiovascular death rates related to end-stagerenal failure in general, as observed in other patientgroups with standard primary renal diseases.Conclusions regarding the incidence of analgesicnephropathy as a cause of end-stage renal failureThe sale of phenacetin-containing mixed analgesicswas discontinued in the early 1960s in Sweden [1]. The1374260-200-160-100-6 0 -0mortality per• AN ^M1000 patient yearsStandard PRD 1BPJF. P. Brunner and N. H. Selwoodmortality per 1000 patient years200-46 - 64 66 - 64age cohorts45 - 54 66 - 74Fig. 5. Average yearly mortality during the first 5 years of RRT in patients starting treatment in 1980-1985 in Austria, Belgium, FRG,Netherlands, and Switzerland. Mortality per thousand patient years at risk is shown separately for patients with analgesic nephropathy(AN) and for patients with all other standard primary renal diseases.Mvocardial Ischaemia and Infarctiondeath rate per 1000 patient years4 0 -3 0 -20 -10-0 -death•LirateAN*per 1000 patient years§ 2 Standard PRD 1 female/—zdT1I I45 - 54 45 - 64 66 - 64age cohortsFig. 6. Average annual death rates per 1000 patient years due to myocardial ischaemia and infarction (same patient groups, countries, andperiods of time as Figure 5).death rate per 1000 patient yearsCardiac (excl MI)death rate per 1000 patient years46 - 64Fig. 7. Average annual death rates per 1000 patient years due to cardiac causes excluding myocardial ischaemia and infarction (samepatient groups, countries, and periods of time as Figure 5).proportion of patients with analgesic nephropathy as decreased further to 2% in 1980 (Figure 9). Analgesica cause of end-stage renal failure in Sweden had nephropathy has now almost disappeared in Swedenprobably decreased slightly by 1970, with 10% of all and there was only a small number of old patientspatients accepted for RRT at that time, and this starting RRT for analgesic nephropathy in 1990 inEDTA Registry report on analgesic nephropathyCerebro-Vascular Accident1375death rate per 1000 patient years death rate per 1000 patient years45 - 64 66 - 74 66 - 74Fig. 8. Average annual death rates per 1000 patient years due to cerebrovascular accident (same patient groups, countries, and periods oftime as Figure 5).% patients with AN at start of RRTJO -30 -2 5 -2 0 -1 5 -1 0 -5 -o-(MS! Sweden ^M Denmark fSSM Switzerland2617i IHIII in9 I! 1 llII J•Wii MWMl—1980 1990Fig. 9. Proportion of patients with analgesic nephropathy at startof RRT in Sweden, Denmark, and Switzerland in 1970, 1980,and 1990.Sweden. In Denmark, the restriction to the sales ofphenacetin-containing mixed analgesics came intoeffect during the early 1960s but phenacetin continuedto be available on prescription only until 1984. Thepercentage of Danish patients with analgesic nephro-pathy at start of RRT decreased from 14% in 1970 to9% in 1980 and was as low as 3% in 1990. InSwitzerland the highest proportion was recorded in1980 and 1981 with some 26-28% of patients startingRRT during those years. Phenacetin has been disap-pearing rather slowly from the market in Switzerlandand was still available in a few mixed analgesics in thelate 1980s. We may expect that some 10-20 years henceanalgesic nephropathy will no longer be a significantcause of end-stage renal failure in Switzerland andother countries as was the case in Sweden some 20years after the disappearance of phenacetin.Acknowledgements. This work was supported by grants from thegovernments and National Societies of Nephrology of Austria,Cyprus, Denmark, Finland, France, Germany, Iceland, Ireland,Israel, The Netherlands, Norway, Switzerland, and United Kingdom.Grants were also made by the AKZO Group (Fibres and PolymersDivision), Asahi Medical Co. Ltd., Baxter Healthcare Corporation,Bellco SpA, Braun Melsungen AG., Cilag AG Research, CobeInternational Ltd., Fresenius Ltd., Gambro, Hospal Ltd, andSandoz AG.We gratefully acknowledge the collaboration of the Nationalregistries of Bulgaria, Hungary and the Netherlands (Renine) andthe regional registries of Lombardy, Italy, Catalunia, and Andalucia,Spain, in providing patient data to the EDTA Registry. Theco-operation of UK Transplant Service, Bristol, United Kingdom isalso acknowledged.We thank those doctors and their staff who have completedquestionnaires. Without their collaboration, this report could nothave been prepared.The hard work and dedication of the staff of the EDTA Registry:Dr Elizabeth Jones, Mrs Lynne Saker, Miss Tamara Sobel, and MrsLinda Carter, in the preparation of this report is gratefullyacknowledged.References1. Bengtsson U. Analgetika-Nephropathie—Langfristige Erfahr-ungen aus Schweden. Zeilschr Urol Nephrol 1989; 82:121-1252. Pommer W, Glaeske G, Molzahn M. Analgetika-Verbrauch inder Bundesrepublik Deutschland. Deutsch Med Wochemschr1987; 112: 787-7903. Elseviers MM., De Broe ME. Analgesic nephropathy in Belgiumis related to the sales of particular analgesic mixtures. NephrolDial Transplant 1994; 9: 41-464. Demography of dialysis and transplantation in Europe, 1984.Report from the European Dialysis and Transplant AssociationRegistry. Nephrol Dial Transplant 1986; 1: 1-85. Kramer P, Broyer M, Brunner FP et al. Combined Report onRegular Dialysis and Transplantation in Europe, XIV, 1983.Proc Eur Dial Transplant Assoc—ERA 1985; 21: 2-686. Tufveson G, Geerlings W, Brunner FP et al. Combined reporton regular dialysis and transplantation in Europe, XIX, 1988.Nephrol Dial Transplant 1989; 4 [Suppl 4]: 5-297. Australia and New Zealand Dialysis and Transplant Registry.Disney APS, ed. ANZDATA Report 1992. Adelaide, SouthAustralia8. Spiihler O, Zollinger HU. Die chronisch-interstitielle Nephritis.Z Klin Med 1953; 151: 1-499. Nanra RS. Analgesic nephropathy: etiology, clinical syndrome,and clinicopathologic correlations in Australia. Kidney Int 1978;13: 79-921376 F. P. Brunner and N. H. Selwood10. Dubach UC, Rosner B, StUrmer T. An epidemiologic study ofabuse of analgesic drugs. Effects of phenacetin and salicylate onmortality and cardiovascular morbidity, (1968 to 1987). N EnglJ Med 1991; 324: 155-16011. Fassbinder W, Brunner FP, Brynger H et al. Combined Reporton Regular Dialysis and Transplantation in Europe, XX, 1989.Nephrol Dial Transplant 1991; 6 [Suppl 1]: 5-3512. Raine AEG, Margreiter R, Brunner FP et al. Report onManagement of Renal Failure in Europe, XXII, 1991. NephrolDial Transplant 1992; 7 [Suppl 2]: 7-35Received: 2.12.93

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