1 Division of Transplantation Immunology and Nephrology and 2 Division of Allergology, University Hospital Basel, Basel, Switzerland
Keywords: cadaveric kidney transplantation; deflazacort; leukopenia; methylprednisolone; neutropenia; prednisone
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Introduction |
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Case |
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Primary graft function was excellent with a decrease of the creatinine from 885 µmol/l to 96 µmol/l within 24 days. Immunosuppression, started on the day of transplantation, consisted of oral therapy with tacrolimus (12 mg twice a day) and azathioprine (150 mg per day). Methylprednisolone was given intravenously, 1 g on day zero, 500 mg on day 1 and 250 mg on day 2, followed by 40 mg (0.5 mg/kg bodyweight) prednisone orally. The prednisone dosage was tapered every 2 weeks by 10 mg down to 30 mg, then by 5 mg down to 15 mg, and then by 2.5 mg. Tacrolimus trough levels were between 10 and 15 ng/ml during the first 3 months after transplantation. In addition, a Pneumocystis carinii prophylaxis with co-trimoxazole three times a week was started on the day of transplantation. The patient left hospital on day 16 after transplantation with the medication stated above. At the first visit after discharge from hospital, leukocytes had decreased from 3.28x109/l (neutrophils 1.84x109/l) to 1.47x109/l (neutrophils 0.3x109/l). Therefore, azathioprine was discontinued, which resulted in a recovery of the leukocyte count. Therapy with azathioprine was reinitiated, but the patient developed neutropenia again. After definitively discontinuing azathioprine, the patient remained neutropenic. It was an isolated neutropenia, since haemoglobin and platelets were stable between 11 and 14 g/dl and 150000 and 250000x109/l respectively (Figure 1). During this period, the patient had no signs or symptoms of an infection or a lymphoma. Repeated physical examinations were normal.
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Because neutropenia is a rare but known side-effect of tacrolimus, we switched the calcineurin inhibitor therapy from tacrolimus to cyclosporin A. However, there was no improvement of the neutropenia. Thorax and abdomen CT scan performed for lymphoma screening showed no splenomegaly; it did show a slightly enlarged axillary lymph node, which was removed, but was histologically normal.
To differentiate production deficiency from peripheral destruction of the neutrophils, a bone marrow biopsy was performed, which showed no evidence of a lymphoproliferative disease or an EBV infection. Myelopoiesis was normal, yet left-shifted. In the stem-cell culture taken from the bone marrow, neutrophil growth was found to be extremely stimulated. Therefore, neutropenia was considered to be of peripheral aetiology (Table 1).
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During the following months, we tapered deflazacort to zero and re-initiated therapy with azathioprine. From the time prednisone was stopped (5.5 months post-transplantation) until 12 months after transplantation, the patient always had a normal leukocyte and neutrophil count under an immunosuppressive therapy with cyclosporin A and azathioprine.
Skin-prick and intradermal tests with corticosteroids including hydrocortisone, methylprednisolone, triamcinolone, dexamethasone, prednisolone, betamethasone, and prednisone were negative. A drug lymphocyte stimulation test (DLST) with prednisone yielded a stimulation index (SI) of 1.3 and was considered to be negative (positive: SI >2). A controlled re-exposure to prednisone was refused by the patient. Although the DLST and skin tests were negative for prednisone, there was strong clinical evidence, that neutropenia was induced by prednisone.
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Discussion |
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Many drugs are associated with neutropenia [1]. The highest risks were found for thyroid inhibitors, co-trimoxazole, sulphasalazine, and clomipramine hydrochloride [2]. Several pathogenic mechanisms for drug-induced neutropenia are postulated or supported by experimental evidence [1,3]. These mechanisms include immune-mediated destruction of granulocytes or granulocytic precursors, dose-dependent inhibition of the granulopoiesis, and direct toxic effect on myeloid precursors or the marrow microenvironment.
The mechanism of peripheral destruction of neutrophils by prednisone is not clear. We could not identify evidence for an immune-mediated destruction process by skin-prick tests, intradermal tests and DLST, although these tests cannot rule out such a pathogenesis. Unfortunately, a re-exposure to prednisone was refused by the patient. Interestingly, despite the wide use of corticosteroids, there are only two case reports of steroid-induced leukopenia. Maeshima et al. [4] reported on one patient with SLE, who had a leukopenia due to prednisolone and methylprednisolone. In this case, DLST was positive, suggesting an immune-mediated pathogenesis. Rokseth [5] reported on one patient with erythema multiforme with prednisolone-associated leukopenia.
Probably the first episode of neutropenia, which was reversible after discontinuation of azathioprine, was due to toxic effect on the bone marrow of this drug. However, the second, long-lasting episode of neutropenia could not have been caused by azathioprine toxicity, because no myelotoxic effect in the bone marrow biopsy was observed, as is typical for azathioprine toxicity. In recent years it has been shown that patients with thiopurine methyltransferase (TPMT) deficiency are at greater risk for developing haematopoietic toxicity from therapy with azathioprine [7,8]. We do not think that our patient has a TPMT deficiency, because after recovery of leukopenia he always had normal leukocyte counts under a therapy with 150 mg azathioprine for 6 months.
Autoimmune disorders can induce neutropenia. In our case, there was no evidence for a recurrence of the initial disease, namely p-ANCA-positive rapidly progressive glomerulonephritis, because urine sediment was always normal, proteinuria was absent, and p-ANCA were negative. Moreover, the fast recovery of neutropenia within 5 days after replacement of prednisone with an equivalent dose of deflazacort (with the same immunosuppressive power) does not point to an antibody-mediated autoimmune disease.
In conclusion, there are a number of causes for leukopenia/neutropenia after kidney transplantation. After excluding common causes, one should also consider prednisone-induced neutropenia, although this aetiology is rare.
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Notes |
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References |
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