Onset of Graves' disease during long-term immunosuppressive therapy in a patient with membranous nephropathy

A 67-year-old man was referred to our department for thyrotoxicosis with intermittent palpitation and 4-kg weight loss during the previous month. At the first visit, the patient was treated with cyclosporine A (CyA) for membranous nephropathy during the last 3 years and 8 months. Laboratory studies revealed that the serum TSH level was <0.005 μU/ml, and free thyroxine (fT(4)) and triiodothyronine (fT(3)) levels were elevated at 2.76 ng/dl and 5.96 pg/ml respectively. Anti-TSH receptor antibody (TRAb) level was increased at 26.4%. A clinical diagnosis of Graves' hyperthyroidism was given, and then thyrostatic treatment with thiamazole (MMI) at a dose of 10 mg daily was initiated after CyA withdrawal. After the initiation of MMI therapy, serum fT(4) and fT(3) attained the normal level within 1.5 months, with relief of symptoms followed by a remarkable decrease in urinary protein excretion from 2.0–5.2 g/day to ≤0.03 g/day. The patient maintained euthyroid with a low titre of TRAb for the succeeding 2 years and then MMI was finally stopped. Neither a relapse of hyperthyroidism nor a flare-up of nephrotic syndrome was observed for 3 years after MMI discontinuation. CyA has conflicting effects on immunologic self-tolerance by modulation of self-reactive T cells and natural CD4(+)CD25(+)Foxp3(+) regulatory T cell (Treg) functions, and possibly becomes a triggering factor in the development of autoimmune disorders. This case may be interesting when considering the effect of each T cell subset on the development of Graves' disease. LEARNING POINTS: The balance between intrathyroidal self-reactive T cell and natural CD4(+)CD25(+)Foxp3(+) Treg functions determine self-tolerance in the thyroid. CyA not only halts the expansion of self-reactive T cells but also impairs the function of Treg, which can provoke an unwanted immune response. A change in thyroid autoimmunity during treatment with CyA may result in the development of autoimmune thyroid diseases (AITD). Renal involvement in AITD frequently manifests as nephrotic syndrome, and thyrostatic treatment with thiamazole may be effective for excessive proteinuria.