Correspondence
Resolution of Recurrent Focal Segmental Glomerulosclerosis Proteinuria after Rituximab Treatment
N Engl J Med 2006; 354:1961-1963May 4, 2006
- Article
To the Editor:
Focal segmental glomerulosclerosis recurs in about 30 percent of patients who undergo kidney transplantation for this condition and leads to the nephrotic syndrome and accelerated graft loss.1 Cyclosporine, cyclophosphamide, plasmapheresis, protein A immunoabsorption, and mycophenolate mofetil have been variably effective.1,2
We report the case of a seven-year-old boy who presented with immediate recurrence of focal segmental glomerulosclerosis after transplantation that subsequently resolved only after rituximab treatment of a transplantation-related lymphoma that occurred five months after the surgery. This child originally had biopsy-proven primary focal segmental glomerulosclerosis with the nephrotic syndrome. After 4.5 years, he progressed to renal failure with a need for dialysis despite therapy with prednisone, cyclophosphamide, and mycophenolate mofetil. Then, 1.25 years after starting dialysis (the patient had anuria), he received a kidney transplant from a deceased adult donor with no HLA-AB matches and one HLA-DR match. His immunosuppressive therapy consisted of tacrolimus, mycophenolate mofetil, corticosteroids at a tapered dose (with discontinuation after seven days), and daclizumab.
Although the initial renal function of the patient was excellent, by two weeks after transplantation, the creatinine level had increased to 2.4 mg per deciliter, and the serum albumin level had fallen to 1.5 mg per deciliter (Figure 1Figure 1
Serum Levels of Creatinine and Albumin and the Urinary Protein:Creatinine Ratio in the Index Patient after the Initiation of Treatment.). Biopsy of the transplant showed minimal pathological changes without evidence of rejection. Electron microscopy was not performed. Recurrent focal segmental glomerulosclerosis was diagnosed; oral corticosteroids were resumed, and plasmapheresis with 5 percent albumin replacement, performed three times a week, was begun.Five months after transplantation, because of fever, enlarged tonsils, and cervical adenopathy, adenotonsillectomy was performed, and a diffuse large-cell lymphoma associated with the Epstein–Barr virus (EBV) that was positive for latent membrane protein and CD20 protein (post-transplantation lymphoproliferative disease [PTLD]) was diagnosed. Six weekly doses of intravenous rituximab were administered (375 mg per square meter of body-surface area; actual dose received, 285 mg), resulting in rapid clearing of circulating CD19-positive B cells (from 9.4 percent [158 cells per microliter] to 0 percent [1 cell per microliter]) and CD20-positive B cells (from 7.5 percent [127 cells per microliter] to 0.2 percent [3 cells per microliter]). At present, the patient is doing well and is receiving cyclosporine (at a dose of 75 mg twice daily) and prednisone (at a dose of 5 mg daily). The ratio of urinary protein to creatinine is 0.5, and the serum albumin level is 3.4 g per deciliter.
This child's proteinuria abated only after treatment of his PTLD with rituximab. Focal segmental glomerulosclerosis has been associated with viral infections,3 but it is unlikely that this case was simply associated with EBV, since the focal segmental glomerulosclerosis recurred immediately after transplantation, antedating the PTLD. The presence of EBV was first determined at the time of adenopathy, some seven months later. Rituximab has been used with increased frequency in various autoimmune diseases, including those that are thought to be primarily mediated by either T cells4 or B cells. The mechanism of action is postulated to be either the elimination of circulating autoantibody or interference with the presentation of B-cell antigens.5 This case suggests that B cells play a central role in some cases of focal segmental glomerulosclerosis.
Given the lack of viable treatments for recurrent cases of this disorder and the overall excellent safety profile of rituximab, a small pilot trial of rituximab might be considered among patients who are awaiting transplantation but are not receiving dialysis or in whom standard treatment has failed after transplantation. If efficacy could be demonstrated in these cases, then selected patients who have lost renal allografts because of early recurrence of focal segmental glomerulosclerosis might be treated with rituximab before or at the time of subsequent transplantation. The optimal timing of such therapy is unknown.
Mark D. Pescovitz, M.D.
Benita K. Book, M.S.
Richard A. Sidner, Ph.D.
Indiana University, Indianapolis, IN 46202
mpescov@iupui.edu Dr. Pescovitz reports having received consulting fees, lecture fees, and grant support from Genentech and Roche.
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