NDT Advance Access originally published online on April 3, 2008
Nephrology Dialysis Transplantation 2008 23(7):2416-2418; doi:10.1093/ndt/gfn051
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Successful re-challenge with darbepoetin in a patient with rHu-EPO-induced pure red cell aplasia refractory to immunosuppressive drugs
1 Association pour l’Utilisation du Rein Artificiel 2 Service d’Hématologie Biologique (Hôtel-Dieu), Paris, France
Correspondence and offprint requests to: B. Viron, Centre Pasteur Vallery-Radot (AURA), 26 rue des Peupliers 75013-Paris, France. Tel: +33-1-53-62-6674; Fax: +33-1-53-62-6626; E-mail: beatrice.viron{at}auraparis.org
Keywords: anti-erythropoietin antibody; darbepoetin alpha; immunosuppressive treatments; pure red cell aplasia
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Introduction |
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Pure red cell aplasia (PCRA) due to allo-immunization is a rare, severe complication of recombinant human erythropoietin (rHu-EPO) therapy [1]. It was mostly observed in patients treated with epoetin alpha in some countries where, starting in 1998, human albumin was substituted as a stabilizer with polysorbate 80 that can interact with leachates from uncoated rubber stoppers [2]. In France, this ‘epidemic’ stopped as soon as subcutaneous administration of epoetin alpha was banned (in 2002). Recently, the SC route was able to be resumed, after the technical process of fabrication had been modified.
Most patients were cured by immunosuppressive drugs, given either alone or after renal transplantation [3]. Reintroduction of the same or another erythropoiesis-stimulating agent (ESA), especially darbepoetin, was thus proposed [4]. Noticeably, most re-challenged patients had become antibody free, either spontaneously after stopping epoetin, or thanks to transplantation or to immunosuppressive treatment alone [5].
We report a patient with life-threatening PCRA due to the persistence of antibody in spite of different successive immunosuppressive regimens, in whom nevertheless, darbepoetin proved effective.
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Case presentation |
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This man, born in 1927, has been haemodialysed since 1993 for hypertensive nephropathy. From the initiation of dialysis, he received epoetin beta. Thereafter haemoglobin remained stable (11–12 g/dl), except for the occurrence in 1996 of massive gastric ulcus bleeding (16 packed cells units transfused over 2 days).
In October 1997, for logistic reasons epoetin beta was substituted with epoetin alpha. From May 1998, a poor response was observed in spite of a progressive increase of epoetin alpha; the patient became transfusion dependent, with shortly recurrent severe anaemia (spontaneous value of Hb 6 g/dl). Step-by-step investigations [1] led in March 1999 to the disclosure of a strong neutralizing antibody (initial titre = 55 U EPO fixed per ml); it could be demonstrated that this was directed against the peptidic moiety [1]. During this time lapse, epoetin, which had proved totally inefficient, was finally stopped in November 1998. A few weeks later, the antibody titre fell dramatically, and in the course of the following years reached a nadir of 0.8 ± 0.2 U/ml (Figure 1). Nevertheless, later on the patient remained transfusion-dependent (2–8 packed cells units monthly). In spite of infusion of desferrioxamine during each dialysis session, ferritin stayed over 3000 mg/ml and clinically patent haemosiderosis appeared. Left ventricular hypertrophy increased strikingly; the patient exhibited perdialytic haemodynamic instability and angina pectoris, resulting in 2004 in inferior myocardial infarction.
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Several immunosuppressive regimens were successively tried (Table 1): IV immunoglobulins, mycophenolate mofetil (limited to 1 g/day because of poor digestive tolerance), cyclophosphamide, calcineurin inhibitors (cyclosporine, then tacrolimus). None of them had any effect. The patient never received steroids, in account first of the history of gastric ulcus, then of the disclosure of intestinal angiodysplasiae that caused recurrent bleeding, punctually increasing the need for transfusions.
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In March 2005 the patient was given a test dose of 150 µg darbepoetin IV. As subsequently the antibody titre did not rise, from July 2005 the same dosage was administered weekly (Figure 2). From June 2005, no more transfusion was required; after 3 months anaemia was corrected. This time lapse resulted from latent folate depletion that had been overlooked before erythropoiesis resumed. Since then, Hb has remained stable. In July 2006, after a 1-year survey and in spite of persistent antibody (0.1–0.2 mU/ml), tacrolimus was stopped with regard to patient's age and poor general condition; nevertheless, since January 2007 there has been no detection of antibodies.
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Discussion |
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This patient was the first French case of EPO-induced PCRA ‘epidemics’ [1], but its singularity dwells in its peculiar severity.
First, the antibody was extremely powerful; the strikingly high initial level can be explained by the delay of diagnosis in this early case of anti-EPO immunization, hence sustained administration of rHu-EPO at increasing dosage during the first 6 months.
It is in the course of this initial evaluation that the neutralizing capacity of the antibody was established. It was shown that the antibody recognized the peptidic, and not any glycosylated, moiety of erythropoietin [1]. Nevertheless, after alpha and beta epoetins, darbepoetin alpha was also tested; the antibody neutralized all three ESA [6]. We did not perform these tests repeatedly in the course of evolution, since the characterization of the antibody was clear; besides, it would not have been feasible in the presence of low antibody titres [6].
Therefore, both recombinant and endogenous EPO were neutralized, causing severe anaemia. Blood transfusions had to be repeatedly scheduled, yielding overt haemosiderosis. Nevertheless, it was not sufficient to ensure stable Hb, hence the life-threatening cardiac complications.
Moreover, the lack of effect of any classes of immunosuppressants is quite unusual in this setting [3]. On the other hand, all successive treatment trials were steroid-free. This point may be relevant, since in one recent report the antibody reappeared as soon as steroids were withdrawn [7].
We have long been hesitating about re-challenging a patient with detectable antibody persisting after 7 years. In most similar cases, patients had become antibody free before any ESA was reintroduced [5]. Besides, in a series of more than 80 patients with EPO-induced PCRA, similar and even lower titres of anti-EPO have been observed by one of us immediately following onset of PCRA [6], proving the clinical significance of a low antibody level.
Nonetheless, in a recent report the reintroduction of ESA proved effective in the presence of detectable antibody and did not induce any upsurge of the plasma titre [8].
Aranesp® was chosen because the patient had been previously exposed to both other available ESA, although the initial results showed that the antibody, being directed against the common peptidic chain, neutralized this molecule also. Thus, one could expect that darbopoetin would be inefficient; this proved not to be the case. Furthermore, not only did allo-immunization not increase but also after 6 months the antibody disappeared. One can object that at the time of re-challenge the titre had dropped low enough to allow any ESA to be reintroduced. In a similar case [9], Aranesp® proved efficient, although introduced 5 months after in vitro testing had shown that the antibody also neutralized darbopoetin-alpha. Nevertheless, as already mentioned, the residual titre in our patient was greater than the level initially recorded in some patients with clinically overt EPO-induced PCRA [6]. We hypothesize that the high dose of ASE administered caused sufficient antigen excess to prevent any relapse of allo-immunization.
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Conclusion |
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In patients with EPO-induced PCRA, the long-term persistence of a sustained, but low titre of anti-EPO antibody must not prevent from trying to reintroduce ESA.
Conflict of interest statement. None declared.
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References |
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TopIntroductionCase presentationDiscussionConclusionReferences |
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- Casadevall N, Nataf J, Viron B, et al. Pure red-cell aplasia and antierythropoietin antibodies in patients treated with recombinant erythropoietin. N Engl J Med (2002) 346:469–475.
[Abstract/Free Full Text] - Boven K, Knight J, Rossert J, et al. Epoetin-associated pure red cell aplasia in patients with chronic kidney disease: solving the mystery. Nephrol Dial Tranplant (2005) 20:33–40.[Web of Science]
- Verhelst D, Rossert J, Casadevall C. for the PRCA Study Group. Treatment of epoetin-induced pure red cell aplasia. Lancet (2004) 363:1768–1771.[CrossRef][Web of Science][Medline]
- Asari A, Gokal R. Pure red cell aplasia secondary to epoetin alpha responding to darbopoetin alpha in a patient on peritoneal dialysis. J Am Soc Nephrol (2004) 15:2204–2207.
[Abstract/Free Full Text] - Rossert J, Macdougall I, Casadevall N. Antibody-mediated pure red cell aplasia treatment and re-treatment: multiple options. Nephrol Dial Transplant (2005) 20:23–26.[Web of Science]
- Casadevall N. Personal communication.
- Andrade JA, Taylor PA, Love JM, et al. Successful reintroduction of a different erythropoiesis-stimulating agent after pure red cell aplasia: relapse after successful therapy with prednisone. Nephrol Dial Transplant (2005) 20:2548–2551.
[Abstract/Free Full Text] - Macdougall IC, Roche A, Rossert J, et al. Re-challenging patients who developed pure red cell aplasia with epoetin: can it be done? Nephrol Dial Transplant (2004) 19:2901–2905.
[Free Full Text] - Varta A, Asola MR, Tertti R. Two haemodialysis patients with epoetin alfa-induced pure red-cell aplasia recovered despite treatment with another epoetin preparation. Nephrol Dial Transplant (2007) 19:1313–1316.
Accepted in revised form: 23. 1.08
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