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Ann Thorac Surg 2003;76:607-610
© 2003 The Society of Thoracic Surgeons
a Heart Failure Department, Heart Institute, University of São Paulo Medical School, São Paulo, Brazil
Accepted for publication January 19, 2003.
* Address reprint requests to Dr Bacal, Rua João Castaldi, 217 Apto 42, Moema, São Paulo–SP 04517-050, Brazil
e-mail: fbacal{at}uol.com.br
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Abstract |
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Introduction |
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A relationship has previously been shown between the consequences of episodes of humoral rejection on the durability of grafts and the development of coronary artery disease in transplanted organs. It has been shown that they were more aggressive and precocious than those mediated through T-lymphocytes, which significantly changed a patient’s prognosis [1].
New approaches, such as plasmapheresis, or cyclophosphamide therapy [2], and the use of high doses of human intravenous immunoglobulin (Ig) have been proposed to treat patients with humoral graft rejection in association, or not, with cellular rejection. However, some patients have persistent graft rejection or recurrent episodes with a humoral component of the immune response (findings which are probably related to a shorter surveillance of the transplanted organ, high mortality, cost of treatment, and development of graft coronary artery disease), reflecting a poor prognosis.
Antimetabolite effects of methotrexate, through its potent inhibition of dihydrofolate reductase and interruption in purine synthesis, promote a breakdown in replication and function of T lymphocytes, and possibly B cells, because of relatively selective action on DNA replication [3–5]. The latter should be the principal component in modulation of humoral response.
In a previous article [6], our group reported on 6 patients with persistent acute cellular rejection treated with methotrexate who experienced an important reduction in episodes of graft rejection. Therefore, a reduction in the number of recurrences of humoral-mediated immune response against a transplanted heart must be expected.
The aim of this report is to show the first use of methotrexate, as a rescue treatment, in recurrent humoral rejection of a patient undergoing standard treatment. The transplant recipient is a white man, 33 years old, who had idiopathic dilated cardiomyopathy. His blood type is AB negative. He never received blood transfusions, and serologies for cytomegalovirus, toxoplasmosis, hepatitis B and C, and human immunodeficiency virus-1 and 2 were negative. Panel reaction was 0%.
The donor, a black woman, age 46, blood type B, died as consequence of stroke. She was hypertensive; other comorbidities and her obstetric history were not described. She had never received blood components. Serologies for Chagas disease, cytomegalovirus, toxoplasmosis, hepatitis B and C, and human immunodeficiency virus-1 and -2 were negative. A crossmatch was performed and all studies were negative
An orthotopic heart transplant was performed on December 26, 2000, without sequelae. The patient received standard treatment with corticosteroids, cyclosporine (4 mg/kg/d), and azathioprine (2.5 mg/kg/d) to prevent rejection. His serum level of cyclosporine was 549 ng/mL on the seventh day after transplantation.
On postoperative day 9, the echocardiogram showed mild left ventricular hypertrophy with normal function, mild global dysfunction of the right ventricle, and mild tricuspid and mitral insufficiency. An endomyocardial biopsy was performed on the same day, and the sample showed acute cellular rejection grade IIIB (ISHLT [International Society of Heart–Lung Transplantation]) with an associated humoral immunity component: IgG negative, IgM++, C3+++ and fibrinogen +++ (Fig 1).
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The patient was removed to the intensive care unit and underwent four sessions of plasmapheresis, methylprednisolone pulse therapy (1 g/d); immunosuppressive drugs had been changed to cyclophosphamide (200 mg/d), tacrolimus (0.16 mg/kg/d), and OKT3 (Orthoclone, Janssen-Cilag, Brazil) (monoclonal antibodies, 5 mg/d). The patient had febrile episodes occur, but without evidence of infectious illness. No changes occurred in the patient’s clinical state or in the hemodynamic findings.
On postoperative day 29, a new biopsy showed improvement in histologic findings, with grade IA (ISLHT) cellular rejection, and a mild humoral response on immunofluorescence. The serum level of FK506 (Prograf, Janssen-Cilag, Brazil) (tacrolimus) was 9.4 ng per mL.
On postoperative day 30, cyclophosphamide was replaced by mycophenolate mofetil (CellCept, Roche, Brazil) (1 g/d). The patient remained asymptomatic. Another biopsy was performed on postoperative day 40 after the transplantation showed a mild progression in the cellular grade of rejection grade IB (ISLHT), and recurrent humoral findings were graded as IgG negative on immunofluorescence, IgM+/III, C3+/III, and fibrinogen +++.
On postoperative day 49, another endomyocardial biopsy showed acute cellular rejection grade IIIA (ISHLT); humoral rejection was graded as IgG negative, IgM+/IV, C3++/IV, and fibrinogen ++/IV. Methylprednisolone pulse therapy was tried again, and antimetabolite methotrexate was included in the therapeutic regimen. A dosage of 15 mg per week was used the first week, then 10 mg per week thereafter. The patient remained asymptomatic without changes in echocardiographic findings.
A biopsy was performed on postoperative day 55, which showed a cellular rejection grade A (ISLHT), and immunofluorescence of IgG+/IV, IgM+/IV, C3+/IV, and fibrinogen +/IV. A week later, an endomyocardial biopsy showed no evidence of rejection (humoral or cellular), and the echocardiography study was normal. Histologic findings remained without alterations, and the patient was stable and asymptomatic in ambulatory care at 24 months of follow-up.
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The treatment performed was validated by literature data. Prophylaxy was used in the postoperative period, with a triple-drug immunosuppressive regimen added of corticosteroids, azathioprine, and cyclosporine. Standard treatment was maintained during the first episode of acute rejection, when methylprednisolone pulse therapy and monoclonal antibodies were prescribed; however, biopsies were still showing acute rejection patterns.
Based on the patient’s response, we decided to gear the therapeutic goal to the humoral branch of immune response. Cyclophosphamide and plasmapheresis were then tried, as other authors had previously advocated [2]. The lack of efficacy for a standard treatment and the persistence of humoral and cellular response led us to initiate a new immunosuppressive regimen.
Despite no reports in the literature pertaining to the use of methotrexate in humoral rejection treatment, we aimed at a new approach that allowed prolongation of xenograft survival to guarantee the patient’s well being. We took into account previous reports about the association of methotrexate as an adjuvant therapy in persistent acute cellular rejection. Therefore, we initiated a folic acid analogue that would play an important role by inhibiting T lymphocytes through interruption of purine synthesis, reducing cellular response [3, 4], as well as B cells, inhibiting humoral factors [4]. Results of the present case have reflected our expectations; reverse of rejection and maintenance of this pattern thus far (24 months after institution of this new therapy).
It is clear that the case reported in this article cannot lead us to hasty conclusions. Further studies are needed to determine the real effectiveness and reliability of the proposed regimen. However, this report may have important implications involving a novel therapeutic treatment.
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