nephrology, Toronto General Hospital, 101 College. St., Toronto, Ont. M5G I L7 ent hypertension, whichwas managed with 200 mg of hydralazine, 320 mg of.
Reversible azathioprine-induced erythrocyte aplasia in a renal transplant recipient D.E. HOGGE,* MD, FRCP[C] D.R. WILSON,t MD, FRCP[C] K.H. SHUMAK,4 MD, FRCP[C] D.C. CATTRAN,§ MD, FRCP[C] Long-term administration of azathioprine has been shown to produce toxic effects in the bone marrow in a number of ways. Leukopenia is common, and macrocytosis, with or without megaloblastic changes in the marrow, is also present in many patients.'"5 Selective erythrocyte hypoplasia is an important complication that has been previously reported in only four patients.6'7 We recently observed this disorder in a patient who had received a renal transplant 31/2 years earlier. We report this case to draw attention to reversible erythrocyte aplasia as a complication of azathioprine therapy, particularly in view of the increasing use of this drug in treating a variety of immunologic disorders. Case report A 30-year-old woman with hypertensive nephrosclerosis that had led to renal failure requiring peritoneal dialysis received a cadaveric renal transplant in July 1976. Analysis of a blood sample taken before the operation showed a hemoglobin level of 5.6 g/dl, a mean corpuscular volume of 89 fl, a leukocyte count of 15.4 X 109/l and a platelet count of 350 X 109/l. When discharged she was taking 75 mg of azathioprine, 55 mg of prednisone and 10 mg of folic acid daily, as well as 300 mg of ferrous sulfate three times a day. Following the transplant there was a gradual increase in the blood hemoglobin level to 13 g/dl; the mean corpuscular volume was 96 fl, and the leukocyte and platelet counts were normal. The daily dose of azathioprine was gradually increased to 125 mg, while that of prednisone was reduced to 15 mg. The patient's only other problem was persistFrom the department of medicine, Toronto General
Hospital and University of Toronto *Former resident
tDirector, division of nephrology and professor of medicine
tDirector of blood bank and associate professor of
medicine §Staff nephrologist and associate professor of medicine Reprint requests to: Dr. D.R. Wilson, Division of nephrology, Toronto General Hospital, 101 College St., Toronto, Ont. M5G I L7
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ent hypertension, which was managed with 200 mg of hydralazine, 320 mg of propranolol and 100 mg of hydrochlorothiazide daily. Five months after receiving the transplant the patient was admitted to hospital because of an obstruction of the small bowel; 36 cm of gangrenous jejunum was resected. At a routine followup visit shortly after discharge from hospital she was found to have a hemoglobin level of 8.5 g/dl, a mean corpuscular volume of 97 fl, a leukocyte count of 1.1 X 109/l and a normal platelet count. At this time the therapy with azathioprine and hydralazine was stopped. Within 1 week the leukocyte count was 3.2 X 109/l, the hemoglobin level was 8.4 g/dl and 7% of the erythrocytes were reticulocytes. Therapy with azathioprine was resumed at 50 mg/d; the leukocyte count continued to rise, and the hemoglobin level also began to rise into the normal range. The azathioprine dose was gradually increased to 100 mg daily, and her hemoglobin level remained between 12 and 13 g/dl, with a mean corpuscular volume of 95 fl and a leukocyte count of 5 to 6 X 109/l. Her renal function was normal, as indicated by a serum creatinine level of 1.4 mg/dl (124,mol/1). The patient felt well for almost 3 years, then began to note frequent dizziness as well as chest pain and shortness of breath with exertion. She had also noted increasing pallor of her skin unrelated to a history of blood loss. At this time she was taking 100 mg of azathioprine, 50 mg of hydrochlorothiazide and six tablets of slow-release potassium chloride (Slow-K) daily, as well as 25 mg of prednisone on alternate days. Her blood pressure was 120/75 mm Hg and her pulse rate 100 beats/min. Her skin and mucous membranes were pale. The chest was clear and her heart sounds were normal. There was a soft systolic murmur at the left sternal border and mild pitting edema of the ankles. The remainder of the examination showed no abnormalities. Laboratory investigation of the blood showed a hemoglobin level of 6.2 g/dl, a mean corpuscular volume of 107 fl, a
tration of 36.4 g/dl, an erythrocyte count of 1.6 X 10'2/1, a leukocyte count of 4.3 X 109/l (65% neutrophils) and a platelet count of 374 X 109/1. Fewer than 1% of the erythrocytes were reticulocytes. A smear of peripheral blood
showed abnormally shaped erythrocytes, including oval, bizarre and a few target cells. A test of the stool for occult blood was negative on three occasions. Roentgenographic studies of the upper gastrointestinal tract and colon, as well as a proctosigmoidoscopic examination, yielded normal results, as did chest roentgenography. Serum levels of vitamin B,2 and folate, and folate levels in the erythrocytes were normal. The serum iron concentration was 262 ug/dl (46.9 gmol/l) and the total iron binding capacity 338 jAg/dl (60.5 Mmol/l). The results of the direct antiglobulin test were negative, the serum level of haptoglobin was normal and the serum level of bilirubin was 0.4 mg/dl (6.8 ,umol/l). Within 1 week her hemoglobin level had fallen to 4.1 g/dl, with a mean corpuscular volume of 106 fl and a leukocyte count of 3.5 X 109/l (85% neutrophils). A bone marrow aspirate was moderately hypocellular and showed normal maturation of granulocytes and occasional giant metamyelocytes. No erythroid precursors were seen. The iron stores were graded 4/6 (normal 2/6 to 3/6). The patient was given three units of packed red cells, which raised the hemoglobin level to 8.2 g/dl. The dose of azathioprine was reduced to 50 mg/d and the hydrochlorothiazide therapy was stopped. She was discharged from hospital feeling much improved. However, 3 weeks later her symptoms had returned and her hemoglobin level had dropped to 5.5 g/dl; fewer than 1% of the erythrocytes were reticulocytes. The leukocyte count was 5.8 X 109/l (80% neutrophils) and the platelet count 338 X 109/1. Her hemoglobin level continued to drop to 4.0 g/dl. She was given three more units of blood, which raised her hemoglobin level to 10.3 g/dl. Azathioprine therapy was stopped. Within 3 weeks the hemoglobin level had stabilized at 9 to 10 g/dl; the leukocyte count mean corpuscular hemoglobin concen- was 8.1 X 109/l and the platelet count
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520 X 10./l. Therapy with cyclophosphamide was started, at a dose of 25 mg/d. The hemoglobin level continued to rise; 2 months later it had reached 13.1 g/dl. Unfortunately, despite increases in the dose of cyclophosphamide the patient underwent recurrent episodes of renal transplant rejection over the next 2 months, and the serum creatinine level gradually increased to 5.5 to 6.5 mg/dl (486.2 to 574.6 Mmol/l). At the same time, the hemoglobin level gradually fell, although there was no evidence of hematologic toxic effects from cyclophosphamide. The patient's course up to this point is summarized in Fig. 1. Shortly thereafter continuous ambulatory peritone.l dialysis was begun because of the onset of uremic symptoms, and after 5 months the patient received a second cadaveric renal allograft. Two months later she showed good renal function, with a serum creatinine level of 1.3 mg/dl (114.9 jsmol/l). She had been given antilymphocyte globulin for 2 weeks, prednisone, 25 mg on alternate days and cyclophosphamide, 50 mg daily. She received no azathioprine, and showed no evidence of hematologic toxic effects. The patient continued to take cyclophosphamide and prednisone; her renal function 10 months after receiving the second transplant was excellent. Discussion Leukopenia is common in patients taking azathioprine. The leukopenia and anemia occurring together 6 months after renal transplantation in the patient we have described were probably induced by azathioprine. When the patient stopped taking this drug for 1 week her leukocyte count began to rise. She re-
sumed therapy with azathioprine and tolerated it well for the next 3 years. In contrast, the progressive anemia that developed 3 years later was not associated with leukopenia. There was reticulocytopenia, and the bone marrow showed no evidence of erythropoiesis. Reducing the dose of azathioprine did not help; only after complete withdrawal of this agent did the erythrocyte hypoplasia reverse. The patient worked as a computer programmer, and no exposure to bone marrow toxins could be identified. Although she was receiving hydrochlorothiazide and slow-release potassium chloride when the decrease in the hemoglobin level was first noted, neither drug is recognized as a cause of erythrocyte aplasia, and when the patient stopped taking these drugs she showed no improvement until the azathioprine was also discontinued, 3 weeks later. The mean corpuscular volume was raised in our patient, as it has been in most renal transplant recipients taking azathioprine, according to several groups of investigators.'5 The marked increase in this measure that McGrath and colleagues6 observed in two cases of azathioprine-induced erythrocyte aplasia led them to suggest that such an increase be used as a marker for impending erythrocyte aplasia in monitoring the effects of azathioprine therapy. More recently, however, Old and associates7 reported two cases of erythrocyte aplasia in which the mean corpuscular volume was normal. We conclude that azathioprine toxicity should be considered in the renal transplant recipient in whom unexplained anemia develops, even in the absence of leukopenia. Reticulocytopenia may be an important clue to
1614'
8-
Total Neutrophlls. .
Rejection
100. (mg/d)..............................,....................................,,.......
Cyclophosphamid (mg/d)
[
Prednlsone
2OLR 7/78
HULME B: Obaervations on the incidence and cause of macrocytoaja in patients on azathioprine therapy follow. ing renal tranaplantation. Transplantation 1974; 18: 443-446 2. KLIPPEL JH, DECKER JL: Relative macrocytoaja in cyclophoaphamide and azathioprine therapy. JAMA 1974; 229: 180-181 3. PROCTOR Si, WALKER w, RAI C: Imuran-induced macrocytoais and splenectomy following renal transplantation. Transplantation 1976; 22: 404-406 4. WILLIAMS D, Va.ICKRAMASINGHE SN, HYLME B: EU
fecta of azathioprine therapy on the MCv of patients with renal grafta: evidence for alterations in the kinetics of erythropoiesia over a prolonged period. Scand J Haematol 1978; 20: 258-264 5. NICHOLLS AJ, DAVIDSON Ri: Development of macrocyscais during azathioprine therapy after renal trana. plantation. A correlation of renal function with MCv. Transplantation 1979; 27: 220-221 6. MCGRATH BP, IBELS IS, RAIK E, HARORAVE M,
MAHONY iF, STEWART JH: Erythroid toxicity of azathioprine. Macrocytoaia and selective marrow hypoplasia. Q J Med 1975; 44: 57-63 7. OLD Cw, FLANNERY EP, GROGAN TM, STONE WH,
SAN ANTONIO RP: Azathioprine-induced pure red blood cell aplatia. JAMA 1978; 240: 552-555
NEUROPSYCHIATRIC FEATURES OF MEDICAL DISORDERS. Critical Issues in
Creatinine (mg/d) muran
1. wICKRAMASINGHE SN, DODSWORTH H, RAULT RMJ,
continued from page 508
64215 r Leukocyte count 10(o10/l)
References
Books
Transfusions:
10HemoglobIn (g/dl)
azathioprine-induced erythrocyte aplasia. Other immunosuppressives, such as cyclophosphamide, seem to be well tolerated by such patients. In order to minimize the risk of transplant rejection, therapy with cyclophosphamide should probably be started within 1 to 2 weeks after azathioprine therapy is stopped. Another approach, used successfully by McGrath and colleagues,6 is to reinstitute azathioprine therapy at a lower dose following erythroid recovery. In our patient, therapy with cyclophosphamide and prednisone was not adequate to prevent progressive transplant rejection. However, she received a second renal allograft, along with antilymphocyte globulin (for 2 weeks), cyclophosphamide and prednisone postoperatively as immunosuppressive agents, and showed good renal function at the last follow-up assessment.
1/77
1/78
1/79 12/79 DATE
1/80
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4/80
5/80
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7/80
FIG. 1-Hemoglobin level and leukocyte count in peripheral bloods serum creatinine leveln and daily doses of Imuran (azathiopnne), cyclophosphamide and prednisone after patient received cadaveric renal allograft (7/76). Transfusions consisted of three units of packed red cells on each occasion.
Psychiatry. An Educational Series for Residents and Clinicians. James W. Jefferson and John R. Marshall. 383 PP. Plenum Publishing Corporation, New York, 1981. $24.50. ISBN 0-306-40674-8 OPTOMETRY HANDBOOK. 2nd ed. Leroy Rubin. 374 pp. lIlust. Butterworths & Co. (Publishers) Ltd., Woburn, Massachusetts, 1981. $34.95. ISBN 0-40995180-3 ORGAN PRESERVATION FOR TRANSPLANTATION. 2nd ed. Revised and Expanded. Edited by Armand M. Karow, Jr. and David E. Pegg. 705 pp. Illust. Marcel Dekker, Inc., New York, 1981. $69.25. ISBN 0-8247-1083-5
PAEDIATRIC ANAESTHESIA. Trends in Current Practice. G. Jackson Rees and T. Cecil Gray. 194 pp lIlust. Butterworth & Co. (Publishers) Ltd., London, 1981.
$39.95. ISBN 0-407-00 1 14-X
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