Correspondence

High-Dose Erythropoietin for Unstable Hemoglobin Burke in a Patient Receiving Hemodialysis

N Engl J Med 1993; 328:1498-1499May 20, 1993

Article

To the Editor:

Rodgers et al. (Jan. 14 issue)1 report the use of erythropoietin to induce the fetal-hemoglobin response in patients with sickle cell disease (hemoglobin S: β6 Glu-to-Val) under treatment with hydroxyurea. We report an increased level of fetal hemoglobin in a patient with hemoglobin Burke (β107 Gly-to-Arg) undergoing hemodialysis who received a huge dose of erythropoietin alone.

A 66-year-old Japanese man receiving hemodialysis had severe anemia that necessitated multiple transfusions of up to 1600 ml of blood per month. Pretreatment hematologic data are shown in Table 1Table 1Effect of a Large Dose of Erythropoietin (873 U per Kilogram per Week) on Hematogic Variables in a Man with Hemoglobin Burke.. An undetectable serum level of haptoglobin, an increased level of lactate dehydrogenase (750 IU per liter), and a reticulocytosis of 88 per 1000 red cells indicated the presence of hemolytic anemia. Electrophoresis of hemolysate on cellulose acetate membrane showed an abnormal β-globin between normal α- and β-globins. Direct sequence measurement with reverse transcriptase-polymerase chain reaction and amino acid-sequence analysis of β-globin identified a mutation, a change from GGC(Gly) to CGC(Arg) at the position of β107. These results indicated that the patient had hemoglobin Burke,2,3 an unstable hemoglobin, superimposed on end-stage renal failure. A large dose of erythropoietin (Epoetin Alfa, 873 U per kilogram of body weight per week, administered subcutaneously) improved the patient's anemia so that he did not need transfusions after one month of treatment. The hemoglobin level was kept around 8 g per deciliter. The hemoglobin F level also increased, to 30.3 and 33.2 percent after 7 and 12 months of treatment, respectively (Table 1). The patient's general condition remained stable, and he was well for more than one year after erythropoietin treatment.

Our data suggest that erythropoietin given in high dosages as monotherapy, which was effective in a patient with hemoglobin Burke, should also be tested in patients with other types of abnormal β-globin. If successful, it may offer a way to avoid the possible side effects of hydroxyurea and other antineoplastic agents commonly used in these patients.

Kouju Kamata, M.D.
Naoyuki Sato, M.D.
Eiko Takahashi, M.D.
Kitasato University School of Medicine, Sagamihara, Kanagawa 228, Japan

3 References

1. 1

   Rodgers GP, Dover GJ, Uyesaka N, Noguchi CT, Schecter AN, Nienhuis AW. Augmentation by erythropoietin of the fetal-hemoglobin response to hydroxyurea in sickle cell disease. N Engl J Med 1993;328:73-80
   Full Text | Web of Science | Medline

2. 2

   Turner JW Jr, Jones RT, Brimhall B, DuVal MC, Koler RD. Characterization of hemoglobin Burke [β107(G9)Gly replaced by Arg]. Biochem Genet 1976;14:577-585
   CrossRef | Web of Science | Medline

3. 3

   Kobayashi S, Nara T, Nakano Y, et al. Hemoglobin Burke: an unstable hemoglobin rarely associated with hemolytic episodes. Hemoglobin 1986;10:661-666
   CrossRef | Web of Science | Medline

Author/Editor Response

Dr. Rodgers replies:

To the Editor: Kamata and associates provide convincing evidence that the administration of high doses of recombinant erythropoietin to a patient with an unstable hemoglobin (hemoglobin Burke) who had concomitant renal failure was associated with amelioration of the anemia, largely due to an enhancement in the production of fetal hemoglobin (hemoglobin F). The propitious association of this unstable hemoglobinopathy and the superimposed anemia of end-stage renal disease provided the justification to institute therapy with erythropoietin. Furthermore, previous observations that high doses of erythropoietin are necessary in animals1 and in patients with β-globin disorders2,3 to augment hemoglobin F levels established the rationale for giving higher doses of erythropoietin in the current case. Except in persons with sickle cell anemia or its genetic variants, the literature has not reported an increased prevalence of end-stage renal disease or the presence of clinically important anemia in many of the other β-globin structural variants4. Thus, it is uncertain whether trials of the type suggested by Kamata and coworkers would be medically justifiable in general. On the other hand, low doses of erythropoietin have been used in patients with sickle cell disorders who have renal failure before dialysis, and have been associated with a moderate improvement in hemoglobin levels5. Perhaps this subgroup might benefit from expanded trials of erythropoietin.

Griffin P. Rodgers, M.D.
National Institutes of Health, Bethesda, MD 20892

5 References

1. 1

   Al-Khatti A, Veith RW, Papayannopoulou T, Fritsch EF, Goldwasser E, Stamatoyannopoulos G. Stimulation of fetal hemoglobin synthesis by erythropoietin in baboons. N Engl J Med 1987;317:415-420
   Full Text | Web of Science | Medline

2. 2

   Rodgers GP, Dover GJ, Uyesaka N, Noguchi CT, Schechter AN, Nienhuis AW. Augmentation by erythropoietin of the fetal-hemoglobin response to hydroxyurea in sickle cell disease. N Engl J Med 1993;328:73-80
   Full Text | Web of Science | Medline

3. 3

   Nagel RL, Vichinsky E, Shah M, et al. F reticulocyte response in sickle cell anemia treated with recombinant human erythropoietin: a double-blind study. Blood 1993;81:9-14
   Web of Science | Medline

4. 4

   Bunn HF, Forget BG. Hemoglobin: molecular, genetic, and clinical aspects. Philadelphia: W.B. Saunders, 1986.
   

5. 5

   Steinberg MH. Erythropoietin for anemia of renal failure in sickle cell disease. N Engl J Med 1991;324:1369-1370
   Full Text | Web of Science | Medline