Departments of Nephrology, 1 Haematology, 2 Pneumology and 3 Pathology, Hospital Universitario, Insular de Gran Canaria
Sir,
Mycophenolate mofetil is a well known drug that has been recently introduced as an immunosuppressive agent for solid organ transplants [1]. It has been also used in the treatment of several autoimmune mediated diseases such as systemic lupus erythematosus [2], rheumatoid arthritis [3], systemic vasculitis [4] and some primary glomerular diseases [5].
Goodpasture's syndrome is an antibody-mediated disease directed against basement membranes. It can be defined by the triad of glomerulonephritis, which is usually rapidly progressive with crescent formation, lung haemorrhage and the presence of anti-glomerular basement membrane (GBM) antibodies. To our knowledge the use of this drug in the treatment of anti-GBM disease has not been reported. We present a case of lifethreatening Goodpasture's syndrome with renal failure and relapsing pulmonary haemorrhage despite conventional therapy which then responded to treatment with mycophenolato mofetil.
Case.
A 19-year-old man presented with oliguric acute renal failure, severe anaemia, cough, haemoptysis and dyspnea. Past medical history was unremarkable. On admission his haematocrit was 15.6%; haemoglobin 5.4 g/dl; serum urea 200 mg/dl; serum creatinine 8 mg/dl and potassium 5.6 meq/l with normal serum immunoglobulins and complement components. Antinuclear antibodies, antiDNA antibodies, cryoglobulins and antineutrophil cytoplasmic autoantibodies were negative while anti-GBM antibodies were positive (7.56).
A renal biopsy revealed extracapillary glomerulonephritis with crescents in 13 out of 16 glomeruli with fibrin in the crescents and linear deposits of IgG. Immunofluorescent examinations were negative for IgA, IgM and C3. Respiratory symptoms, chest X-ray and bronchofibroscopy were indicative of pulmonary haemorrhage. Goodpasture's syndrome was diagnosed and treatment with oxygen, blood transfusion, haemodialysis, three 1 g methylprednisolone boli followed by prednisone 1 mg/kg/day and 100 mg/day of cyclophosphamide was given. He recovered from lung haemorrhage and was discharged with established chronic renal failure. He remained on haemodialysis three times a week and treated with oral prednisone and cyclophosphamide.
One month later he was admitted because of cough, haemoptysis shortness of breath, bilateral alveolar shadowing on a chest X-ray, hypoxia and severe anaemia. A bronchoscopy confirmed a relapse of the pulmonary haemorrhage. Anti-GBM antibodies were positive (3.59). Plasma exchange at 1.5 times plasma volume was done every day for 3 days and then every other day until 14 sessions were completed, resolving the lung haemorrhage. Three months later he presented again with pulmonary haemorrhage and positive for anti-GBM antibodies which responded to another 14 plasma exchange sessions. Two months later another pulmonary haemorrhage recurred that initially improved with plasma exchange but relapsed before 14 sessions were completed.
Because of the lack of response to usual therapy and because it was a life threatening condition, we decided to stop cyclophosphamide and started therapy with 1 g mycophenolate mofetil every 12 h. Since the start of treatment with mycophenolate mofetil, no other episode of pulmonary haemorrhage has developed and anti-GBM antibodies have continued to be negative, allowing us to decrease steroid doses to 10 mg every other day. Eight months later the mycophenolate dose was reduced to 500 mg every 12 h. After one year on haemodialysis there were no further haemorrhages and the anti-GBM antibodies remained negative allowing us to carry out a successful kidney transplant (Figure 1).
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Comment.
Without therapy Goodpasture's syndrome is a rapidly fatal disease [6]. Treatment based on aggressive non-specific immunosuppression has reduced overall mortality from 96% to 1121%. Conventional therapy includes a combination of plasma exchange with intensified immunosuppression, the most frequently used protocols include pulse intravenous corticosteroid therapy (methylprednisolone 1 g/day intravenously for three consecutive days), prednisolone (12 mg/kg/day), cyclophosphamide (23 mg/kg/day) and plasma exchange [7]. However, despite this aggressive therapy the mortality remains high. Other therapeutic options include the use of immuno-absorption, cyclosporin and, experimental monoclonal antibodies and immunomodulatory therapy.
Mycophenolate mofetil is a derivative of mycophenolic acid that blocks de novo purine synthesis and inhibits specific proliferative responses of both T and B cells to antigens [8]. It has been used in solid organ transplants and in the treatment of several autoimmune-mediated diseases. To our knowledge the use of this drug in the treatment of anti-GBM disease has not been reported. The rational basis for its use is that through its effect on B cells, it can inhibit humoral immune response and antibody production [9]. Moreover it also inhibits the generation of cytotoxic T cells that have been recently shown to play an important role in the immunoregulation of the disease [10].
We do not suggest that mycophenolate mofetil should be a first line treatment in Goodpasture's syndrome and obviously its place should be defined by further clinical experience. Although anecdotal, we think that it is worth communicating this case because it shows an alternative when there is no response to conventional therapy in life threatening anti-GBM disease with renal and lung involvement.
Acknowledgments
We are grateful to Peter Mangiaracina for his assistance in the preparation of this manuscript.
References