Membranous Glomerulonephritis and Nephrotic Syndrome as a Late Manifestation of Chronic Graft-Versus-Host Reaction Following Allogeneic Transplantation for Hematologic Malignancy.

Chronic GVHD is an immunologically mediated complication of allogeneic transplantation with multi-organ involvement and the presence of antibodies against host cell antigens, often requiring long-term immunosuppression for control of symptoms and disease. Although multiple organs can be involved, the major targets generally include skin, liver, GI tract, lung, bone marrow and oral mucosa associated with immunodeficiency independent of treatment. Renal manifestations of chronic GVHD are very unusual and generally caused by nephrotoxic medications used to treat the disease. Membranous glomerulonephritis is the most common cause of nephrotic syndrome in the adult, characterized by a thickening of the glomerular basement membrane, deposits of antibody and complement, and is associated with either infections, systemic autoimmune disease and medications. Although chronic GVHD is not generally associated with this syndrome, we have seen and evaluated eight patients who developed nephrotic syndrome as a late manifestation of chronic GVHD.

Eight patients (three males and five females), ages 44–60, presented with nephrotic syndrome (24 hour urine protein 7–18 grams/day) in the setting of pre-existing chronic GVHD with other manifestations, including skin, liver, oral mucosa and conjunctiva. One patient received an unrelated donor transplant and seven had related donors as treatment for hematologic malignancy (AML 3, MDS 3, CML 1, malignant histiocytosis 1). All patients underwent kidney biopsy which showed changes consistent with membranous glomerulonephritis with immunologic characterization consistent with this diagnosis. At the time of diagnosis all patients had 100% chimerism for T and B cells. In seven of eight cases the development of glomerulonephritis and nephrotic syndrome followed, sometimes by several years (range four months to eight years), other manifestations of chronic GVHD and in seven/eight patients it occurred while patients were on chronic immunosuppressive therapy. Treatment included the combination therapy of Prednisone and Cyclosporin, Prednisone, Cellcept and Cyclosporin or, in two cases, Rituxan targeted to the B cell component of the immunopathology. The overall response rate to treatment was 100% with all patients showing reduction in urine protein excretion (normal to 1.6 grams/day) with preservation of renal function. An evaluation for other causes, including systemic autoimmune disease, recurrent malignancy and infection, were negative and all patients remain alive and in remission. We conclude:

1. Nephrotic syndrome following allogeneic transplantation can be caused by membranous glomerulonephritis as a manifestation of chronic GVHD.

2. The syndrome generally occurs in the setting of existing well controlled chronic GVHD and can occur late in the course of the disease.

3. Membranous glomerulonephritis can be successfully treated with immunosuppressive therapy used in the treatment of other manifestations of GVHD, including Rituxan.