1 Ospedale Civico, Lugano, 2 Stadtspital Waid, Zurich, 3 University Hospital, Zurich, 4 Hôpital de la Providence, Neuchatel and 5 University Hospital, Bern, Switzerland
Correspondence and offprint requests to: Dr Carlo Schönholzer, Capo Servizio, Reparto di Nefrologia, Dipartimento di Medicina Interna, Ospedale Regionale di Lugano (Sede Civico), CH-6900 Lugano, Switzerland. Email: carlo.schoenholzer{at}eoc.ch
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Abstract |
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Methods. On behalf of the Swiss Society of Nephrology, a survey was conducted in all the dialysis units of Switzerland in order to collect information on the occurrence, diagnostic and evolution data of the cases observed. A questionnaire was send to the nephrologists in charge of each of the 69 dialysis units in January 2003. The clinical and biological data of the suspected cases were analysed and compared with the data provided to health authorities and pharmaceutical companies.
Results. A total of five cases were identified as true PRCA with demonstrated positive anti-Epo antibodies. They occurred between November 1998 and February 2002, were all treated by haemodialysis and had received Epo subcutaneously. The median appearance time of refractory anaemia after Epo initiation was 10 months (range: 754 months). Two cases had been treated exclusively with epoietin-, one solely with epoietin-ß and the two others with a combination of both. With five cases out of a total of about 2500 dialysis patients and 2300 Epo-treated dialysis patients or an exposure rate to Epo of 9900 dialysis patient-years during a 4.3 year period, this prevalence is among the highest of those reported in European countries.
Conclusions. The prevalence of PRCA after Epo administration in dialysis patients appears particularly high in Switzerland. Among the potential explanations, the most plausible are the high percentage of dialysis patients treated with Epo, the almost exclusive subcutaneous administration, the larger market distribution of the epoietin- brand, the eventual disruption of the cold chain and the setting-up of a systematic national survey.
Keywords: anti-erythropoietin antibodies; chronic dialysis; chronic kidney failure; end-stage renal disease; erythropoietin; pure red-cell aplasia; renal anaemia
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Introduction |
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However, in February 2002, Casadevall et al. [6] published a series of 13 patients on chronic dialysis who developed pure red-cell aplasia (PRCA) due to neutralizing anti-Epo Ab while receiving Epo therapy. By now, over 200 cases of PRCA occurring after Epo administration have been reported, most often to the manufacturers and/or health authorities [79]. The presence of anti-Epo Ab was not documented in all of them. This occurrence has now led to important changes in the determination of Epo type and mode of administration (www.swissmedic.ch/cgi7news) [10,11].
When the first two cases were observed in Switzerland by one of the authors (C.S.), the Swiss Society of Nephrology asked through its Dialysis Committee, with the help of the Swissmedic Pharmacovigilance Section, for the setting up of a systematic survey of the observed cases among dialysis patients. We report here the results of this investigation.
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Subjects and methods |
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The clinical, diagnostic and therapeutic data of the suspected cases were collected and compared with the information already obtained by the Swissmedic Pharmacovigilance Section and by the national branches of the manufacturers. Only cases with positive anti-Epo Ab were considered for analysis. The antibody tests had been performed by either radioimmunoprecipitation or enzyme-linked immunosorbent assays in different laboratories (Service dHématologie Clinique, Hôpital Hôtel-Dieu, 75181 Paris, France; CLIA Laboratory, Immunochemistry Dept, PPD Development, 2244 Dabney Road, Richmond, VA 23230, USA; MDS, Pharma Services, 2350 rue Cohen, Saint-Laurent, Montreal, Quebec, H4R 2N6 Canada).
Just the Epo- and -ß brands were available during the survey period, since darbepoietin only became available in Switzerland in September 2002. According to different sources, the
brand constituted 70% and the ß brand 30% of the total sales for dialysis patients during the observation period.
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Results |
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According to our information, only Epo- had been used in two cases, one patient had received Epo-ß exclusively and in the two remaining cases both
and ß brands had been administered. In those last two cases, Epo-
had been given first at doses increasing from 7500 to 12 000 U/week for 2 and 5 months, respectively, and then replaced by Epo-ß at 7000 to 20 000 U/week for 5 and 7 months, respectively, before the diagnosis of PRCA was made.
The clinical evolution was interesting in several aspects: in two cases a remission occurred spontaneously 3 and 6 months after Epo withdrawal without any immunosuppressive therapy; in another case PRCA persisted clinically after kidney transplantation, requiring blood transfusions for 6 months, however, the anti-Epo Ab are still positive, despite immunosuppressive therapy, 3 years after transplantation and 3.5 years after Epo withdrawal. Cases 2 and 3 are reported in detail elsewhere [12,13].
Since all the dialysis units responded to this survey, the prevalence of PRCA due to anti-Epo Ab in Switzerland could be calculated. With 69 dialysis units in a country of 7.3 million inhabitants, Switzerland has a high density of dialysis centres. During 2002, the incidence and prevalence of chronic dialysis patients were 115 and 343 per million inhabitants, respectively. According to our survey, at the end of 2002, a total of 2555 patients were treated by chronic dialysis: 2237 by haemodialysis (among which 27 were haemodialyzed at home) and 318 by peritoneal dialysis. These numbers had been increasing only slowly over the preceding 4 years. This means that with five cases for around 2500 dialysis patients, Switzerland has a higher prevalence (1/500) than its surrounding countries: France with 33 cases out of 28 000 chronic dialysis patients (1/848), Germany with six out of 58 000 (1/9666) and Italy with four out of 36 000 (1/9000) [8,14].
Those diverse prevalences can be explained, at least partly, by the varying uses of Epo in the different countries and their administration mode [10]. According to our survey, during the first part of 2002, 90% of the total dialysis population was treated with Epo, among which 79.4% were treated subcutaneously (s.c.) and 20.6% intravenously (i.v.). Based on those results it appears that, when considering the two Epo brands together, the five cases were observed in a weighted chronic dialysis population of 2500, in an Epo-treated dialysis population of around 2300 patients or in about 9900 dialysis patient-years of exposure to Epo during a 4.3 year period. According to various sources, during the survey period the
brand constituted 70% of the sales to the chronic dialysis units in Switzerland. When restricted to the pure cases, this prevalence becomes 1/1150 for only Epo-
-treated patients and 1/2300 for only Epo-ß patients.
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Discussion |
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The most interesting observation of this survey is the high prevalence of PRCA due to anti-Epo Ab observed in Switzerland: five cases for a chronic dialysis population receiving Epo of 2300 and an exposure rate of 9900 patient-years during a 4.3 year period. Even if this total population remains low when compared with other countries, it has to be noted that in France, despite the initial report by Casadevall et al. [6] and the subsequent increased awareness, a lower prevalence is observed [10]. The prevalence is also much lower in other neighbouring countries, such as Germany and Italy. It is presently estimated that the incidence of PRCA due to anti-Epo Ab is one to two per 10 000 dialysis patients receiving Epo by the s.c. route [11]. Due to the changes in the manufacturing, handling and prescription mode introduced for the Epo- brand during summer 2002, the occurrence of new cases seems to be decreasing.
The national discrepancies appear multifactorial. In France, the patient has to go to the pharmacy in person to obtain the product with a subsequent greater risk of cold-chain disruption, while in Germany and Italy, Epo is routinely administered by the dialysis staff and much more often by the i.v. route. In Switzerland, Epo is generally ordered and stocked directly by the dialysis unit or hospital pharmacy and administered most often s.c., directly by the dialysis staff.
Several factors can be put forward to explain the high frequency of PRCA cases due to anti-Epo Ab observed in Switzerland:
It must also be added that due to the mandatory declaration to Swiss health authorities of any clinical syndrome suspected of PRCA during Epo administration and the simultaneous 100% response rate of the present survey, the prevalence reported here corresponds to the real prevalence, which is not necessarily the case in other countries.
Indeed, a recent Editorial proposed the setting up of a dedicated independent registry devoted to the Epo-induced PRCA syndrome, in order to obtain a clearer view of its occurrence and outcome [11]. Our survey appears as an original step in this direction and seems to indicate that the prevalence might be underestimated at present.
In conclusion, the prevalence of PRCA after Epo administration in dialysis patients appears particularly high in Switzerland. Among the potential explanations, the most plausible are the large use of Epo in dialysis patients, the almost exclusive s.c. administration, the larger market distribution of the Epo- brand, the eventual disruption of the cold chain and the setting up of a systematic national survey.
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Acknowledgments |
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Conflict of interest statement. Several authors participated in experts meetings and/or multicenter studies financed by Janssen-Cilag or Roche; the present study did not receive any financial support.
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References |
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