Membranous Nephropathy with Chronic Graft-versus-Host Disease in a Bone Marrow Transplant Recipient

Dear Sir,Chronic graft-versus-host disease (GVHD) is multiple organ failure developing at least 100 days after allogeneic bone marrow transplantation, and frequently involves the skin, liver, gastrointestinal tract, eyes, and oral mucosa, but is not usually complicated by renal disease [1, 2]. We encountered a patient with membranous nephropathy developing about 11 months after allogeneic peripheral blood stem cell transplantation.A 39-year-old man was admitted to the Department of Hematology at Hiroshima University hospital in May 1995 with leukocytosis, and was diagnosed as having ph1 positive chronic myelocytic leukemia. Treatment with interferon-α was not effective. On May 16, 1996, the patient received allogeneic peripheral blood stem cell transplantation from his HLA-identical brother. On posttransplant day 17, diarrhea and rash occurred as symptoms of acute GVHD, but combined steroid and cyclosporine A therapy produced improvement. In April 1997, marked proteinuria, pleural effusion, and edema of the lower extremities were observed, suggesting the nephrotic syndrome, so the patient was readmitted. Investigations on admission showed urinary protein of 5.9 g/day, total protein of 4.4 g/dl, and serum albumin of 2.1 g/dl, indicating a diagnosis of nephrotic syndrome. On May 20, he underwent renal biopsy at the Second Department of Internal Medicine. Light microscopy showed localized hypertrophy of the basement membrane, but no spike formation was noted. Fluorescent antibody staining revealed deposition of IgG along the basement membrane. Electron microscopy disclosed subepithelial deposits sporadically, and fusion of the foot processes of podocytes was also observed (fig. 1). These findings indicated a diagnosis of early membranous nephropathy. Skin biopsies from the eyelid and lower limb disclosed granulomatous lesions composed of inflammatory cells, epithelioid cells, and multinucleated giant cells around the vessels in the epidermis, findings consistent with chronic GVHD.Thus, the diagnosis was nephrotic syndrome caused by membranous nephropathy complicating chronic GVHD. A combination of prednisolone (40 mg/day) and cyclophosphamide (100 mg/day) failed to achieve symptomatic improvement, so cyclosporine A was initiated at 150 mg/day. This reduced his edema and proteinuria, and the serum albumin increased.Various drugs and radiation therapy have frequently been reported to cause renal disease after bone marrow transplantation [3]. Sporadic cases of chronic vascular disease [4]associated with cyclosporine A and chronic proliferative nephritis complicating chronic myelocytic leukemia have been reported [5]. Recently, renal damage presumably caused by chronic GVHD has been reported after allogeneic bone marrow transplantation [6, 8]. The skin and renal biopsy data suggested that our patient had membranous nephropathy complicating chronic GVHD, and the clinical course resembled that reported by Barbara et al. [9]. Chronic GVHD has pathological features similar to those of autoimmune disease and is believed to be induced by the emergence of autoreactive T cells as a result of thymic dysfunction related to acute GVHD and pretreatment for bone marrow transplantation [10]. In our patient, the pretreatment CD4/CD8 ratio was a high 2.79, but decreased to 1.79 after the response to cyclosporine A therapy. Thus, an inhibitory effect of cyclosporine A on autoreactive T cells may have been responsible for his improvement.It was reported [11]that HLA DR2/DQ1 is commonly associated with membranous nephropathy in the Japanese, and the present patient had DR2, indicating that genetic factors may also have played a role in the development of this disease.