Proteinuria in a patient with Graves’ disease: Answers

Histopathologic examination of the renal biopsy was consistent with membranous nephropathy (MN) which was characterized by diffuse thickening of the glomerular basement membrane (GBM) by light microscopy and a diffuse granular deposition of IgG and C3 along the GBM on immunofluorescence.

In childhood, secondary membranous nephropathies are significantly more common, associated with systemic autoimmune diseases, infections, drugs, and malignancies, whereas primary MN is uncommon [1‐3]. The distinction between primary and secondary forms of MN is of great importance for the diagnosis and clinical management. Antibodies to M type phospholipase A2 receptors (PLA2R) is valuable for diagnosing primary MN with a high rate of sensitivity (> 75%) and specificity (100%) [4, 5]. PLA2R staining on renal biopsies is reported as 45–100% in children and adolescents with MN [6, 7]. Our patient had serum anti-PLA2R antibody (1:320 IG G titers) and diagnosed as primary MN. We were unfortunately not able to perform PLA2R staining on biopsy specimens.

Membranous nephropathy has been reported in several cases with Graves’ disease [8‐14]. Although rare, membranoproliferative glomerulonephritis, IgA nephropathy, and minimal change disease have also been reported with Graves’ disease [15‐17]. Anti-neutrophil cytoplasmic antibody (ANCA)-positive glomerulonephritis as a complication of treatment with propylthiouracil [18, 19] and thiamazole [20], and lupus nephritis associated with methimazole treatment have previously been reported in the literature [21, 22]. Additionally, Reynold et al. [23] reported a case of methimazole-related nephrotic syndrome that was resolved after discontinuation of the drug without intervention. They hypothesized a direct toxic effect of methimazole to the GBM and epithelial podocytes.

There is very limited data for the optimal treatment of children with MN; therefore, a more personalized therapeutic approach is required [24]. The standard therapy for adults with MN and nephrotic proteinuria is usually a combination of oral corticosteroids and alkylating agents (chlorambucil or cyclophosphamide), cyclosporine, and mycophenolate [25]. However, serious side effects including malignancy, lymphoproliferative disease, gonadal toxicity, myelotoxicity, and opportunistic infections are main limitations of these agents [26]. Rituximab was first used in the treatment of idiopathic MN in 2002 and since then has been successfully used without serious side effect for treatment in adults [27‐30]. The rationale of rituximab treatment is to deplete B cells and thus prevent the production of nephritogenic antibodies like anti-PLA2R [31]. In our case, rituximab was given as the first-line therapy considering the positivity of both PLA2R and thyroid antibodies and considering potential side effects of conventional treatments. The patient received four doses of rituximab (375 mg/m²) with 4-week interval. Urticarial lesions developed during the first infusion; thus, the following doses were given with antihistaminic treatment. Thereafter, no other short-term side effects were observed. Proteinuria decreased to 0.15 g/m²/day and the serum levels of anti-PLA2R antibodies normalized (< 1:10 IG G titers) 3 months after rituximab therapy. Furthermore, the serum levels of anti-TPO [30.4 (< 34) IU/mL] and anti-thyroglobulin [10 (< 115) IU/mL] were normalized and the serum level of TRAB was significantly decreased [2.13 (< 0.55) IU/L]. Methimazole doses were gradually tapered to 1.25 mg/day to maintain euthyroid state at the third month of rituximab. Currently, 1 year after rituximab therapy, the level of proteinuria is 0.05 g/m²/day and she is still euthyroid with this dose of methimazole.