Nephrol Dial Transplant (2002) 17: 1119– 1121
Case Report
Prednisone-induced neutropenia after cadaveric kidney transplantation Stefan Schaub1, Michael Dickenmann1, Ewa Cynke1, Andreas Bircher2 and Ju¨rg Steiger1 1
Division of Transplantation Immunology and Nephrology and 2Division of Allergology, University Hospital Basel, Basel, Switzerland
Keywords: cadaveric kidney transplantation; deflazacort; leukopenia; methylprednisolone; neutropenia; prednisone
Introduction Leukopenia is a common problem after kidney transplantation, with a wide differential diagnosis. Usually it is induced by drugs (e.g. azathioprine, mycophenolate mofetil, ganciclovir, co-trimoxazole) or infections (e.g. cytomegalovirus). Rare causes are posttransplantation lymphoproliferative disease (PTLD) and recurrence of pre-existing autoimmune disorders like systemic lupus erythematosus (SLE) or Wegener’s granulomatosis.
Case A 44-year-old man was diagnosed with a biopsyproven p-ANCA-positive rapidly progressive glomerulonephritis in August 1996. His initial creatinine was 474 mmolul. He was treated with 1 g methylprednisolone intravenously for 3 days, followed by 75 mg prednisone (1 mgukg bodyweight) and 150 mg cyclophosphamide per day for 1 month without improvement of the renal function. Therapy was thereafter discontinued and dialysis treatment initiated in September 1996. During the steroiducyclophosphamide therapy and dialysis from September 1996 to August 1999, no leukopenia was observed. On 7 August 1999, the patient underwent cadaveric kidney transplantation. At this time he had a leukocyte count of 5.32 3 109ul (normal range 3.5–10 3 109ul) with
Correspondence and offprint requests to: Stefan Schaub, MD, Division of Transplantation Immunology and Nephrology, University Hospital, Petersgraben, CH-44031 Basel, Switzerland. Email:
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3.83 3 109ul neutrophils (normal range 1.3–6.7 3 109ul), a haemoglobin of 10.3 gudl (normal range 14–18 gudl), and a platelet count of 185 000 3 109ul (normal range 150 000–450 000 3 109ul). The p-ANCA were then negative. Primary graft function was excellent with a decrease of the creatinine from 885 mmolul to 96 mmolul 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 mgukg 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 nguml 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 3.28 3 109ul (neutrophils 1.84 3 109ul) to 1.47 3 109ul (neutrophils 0.3 3 109ul). 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 gudl and 150 000 and 250 000 3 109ul respectively (Figure 1). During this period, the patient had no signs or symptoms of an infection or a lymphoma. Repeated physical examinations were normal. Initially, a drug-induced neutropenia was considered and all drugs except tacrolimus and prednisone were stopped without success. Then an infectious aetiology of the neutropenia was suspected. But several measurements of the CMV-antigenaemia were negative (donor and recipient were both CMV negative), and repeated
2002 European Renal Association–European Dialysis and Transplant Association
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S. Schaub et al. Table 1. Differential diagnosis of neutropenia (adapted from 1 and 6)
Fig. 1. Changes transplantation.
of
leukocyte
and
neutrophil
counts
after
serologies for herpes-simplex virus, varicella zoster virus, Epstein–Barr-virus (EBV), human herpes virus 6, parvovirus B19 (including PCR), measles, mumps, toxoplasmosis, and human immunodeficiency virus also proved negative. There was also no evidence for an autoimmune disease, e.g. for a recurrence of the p-ANCA-positive rapidly progressive glomerulonephritis. Urine sediment was normal (0–2 leukocytes per high-power field, 0–1 erythrocytes per high-power field), and proteinuria was absent. Antinuclear antibodies, extractable nuclear antibodies, anti-DNS, c-ANCA, p-ANCA, and anticardiolipin antibodies were negative. Because neutropenia is a rare but known sideeffect 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 stemcell 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). Because there was no clinical or serological evidence of an autoimmune or infectious disorder, we suspected a drug-induced peripheral destruction of the neutrophils. The only drug that had not been altered 5.5 months after transplantation was prednisone. We therefore discontinued prednisone (12.5 mguday) and started a therapy with an equivalent dose of deflazacort (15 mguday). Five days later, the leukocyte count
1. Decreased production Drug-induced: e.g. azathioprine, mycophenolate-mofetil, cyclophosphamide, methotrexate, ganciclovir, tacrolimus, and many more (for details see references [1] and [2]) Infections: viruses (cytomegalovirus, EBV, herpes simplex virus, varicella zoster virus, human immunodeficiency virus, hepatitis virus, influenza A and B, measles, mumps), bacterial (brucellosis, tuberculosis, typhoid fever, Gram-negative septicaemia), fungal, protozoal Nutritional deficiency: folate, vitamin B12, copper Tumour invasion of bone marrow, PTLD, myelofibrosis Congenital or chronic neutropenias: severe congenital neutropenia (Kostmann syndrome), cyclic neutropenia, idiopathic chronic severe neutropenia 2. Peripheral destruction Drug-induced Infections Autoimmune disorders: Felty’s syndrome, SLE, Wegener’s granulomatosis, Antineutrophil antibodies Splenic sequestration 3. Peripheral pooling (transient neutropenia) Overwhelming bacterial infection (acute endotoxaemia) Haemodialysis, cardiopulmonary bypass, apheresis
rose from 2.6 3 109ul (0.55 3 109ul neutrophils) to 6.59 3 109ul (4.02 3 109ul neutrophils) (Figure 1). 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.
Discussion After gastrointestinal absorption prednisone is transferred in the liver through reduction on C11-keto group into biologically active prednisolone. Deflazacort differs from prednisolone by an oxazolin ring on C16–C17. Prednisone (Prednison Streuli1; Streuli) uses lactose, magnesium stearate, talc, and potato starch as additives, deflazacort (Calcort1; Aventis) uses lactose,
Prednisone-induced neutropenia after cadaveric kidney transplantation
magnesium stearate, cellulose, and corn starch. To our knowledge, there is no known association between neutropenia and talc or potato starch, which are the only differences in the additives. 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
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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 leukopeniauneutropenia after kidney transplantation. After excluding common causes, one should also consider prednisone-induced neutropenia, although this aetiology is rare.
References 1. Watts RG. Neutropenia. In: Richard LG et al., eds. Wintrobe’s Clinical Hematology, 10th edn. Williams & Wilkins, Philadelphia, 1999; 1862–1887 2. van der Klauw MM, Goudsmit R, Halie MR et al. A populationbased case-cohort study of drug-associated agranulocytosis. Arch Intern Med 1999; 159: 369–374 3. Guest I. Drugs that induce neutropeniauagranulocytosis may target specific components of the stromal cell extracellular matrix. Med Hypotheses 1999; 53: 145 4. Maeshima E, Yamada Y, Yukawa S. Fever and leucopenia with steroids. Lancet 2000; 355: 198 5. Rokseth R. Aganulocytosis and sepsis associated with prednisolone. Lancet 1960; 26: 680 6. Holland SM, Gallin JI. Disorders of granulocytes and monocytes. In: Isselbacher KJ et al., eds. Harrison’s online (http:uuwww. harrisonsonline.com), chapter 62. McGraw-Hill, 1999 7. Evans WE, Hon YY, Bomgaars L et al. Preponderance of thiopurine S-methyltransferase deficiency and heterozygosity among patients intolerant to mercaptopurine or azathioprine. J Clin Oncol 2001; 19: 2293–2301 8. Sebbag L, Boucher P, Davelu P et al. Thiopurine S-methyltransferase gene polymorphism is predictive of azathioprineinduced myelosuppression in heart transplant recipients. Transplantation 2000; 69: 1524–1527 Received for publication: 16.9.01 Accepted in revised form: 13.12.01
