IgG4-related kidney disease: the effects of a Rituximab-based immunosuppressive therapy

Abstract

IgG4-related disease (IgG4-RD) is a recently recognized disorder, characterized by elevated serum IgG4 concentrations, dense tissue infiltration of IgG4-positive plasma cells and storiform fibrosis. Treatment is usually based on steroids, however, relapses and long-term adverse effects are frequent. We prospectively studied 5 consecutive patients with histologically-proven IgG4-RD and renal involvement, treated with an extended Rituximab protocol combined with steroids. Two doses of intravenous cyclophosphamide were added in 4 patients. Five patients with IgG-RD were investigated: three had tubulointerstitial nephritis (TIN), while two had retroperitoneal fibrosis (RPF). In the patients with TIN, renal biospy was repeated after 1 year. In the patients with TIN, estimated glomerular filtration rate (eGFR) at 12 months increased from 9 to 24 ml/min per 1.73 m²; IgG/IgG4 decreased from 3,236/665 to 706/51 mg/dl; C3/C4 increased from 49/6 to 99/27 mg/dl; CD20⁺ B-cells decreased from 8.7% to 0.5%; Regulatory T-cells decreased from 7.2% to 2.5%. These functional and immunologic changes persisted at 24 months and in two patients at 36 months. A repeat renal biopsy in the patients with TIN showed a dramatic decrease in interstitial plasma cell infiltrate with normalization of IgG4/IgG positive plasma cells. The patients with RPF showed a huge regression of retroperitoneal tissue. In this sample of patients with aggressive IgG4-RD and renal involvement, treatment aimed at depleting B cells and decreasing antibody and cytokine production was associated with a substantial, persistent increase in eGFR, and a definite improvement in immunologic, radiologic and histological parameters.

Keywords: IgG4-related disease; IgG4-related kidney disease; Rituximab; retroperitoneal fibrosis; tubulointerstitial nephritis.

Figure 1. Light microscopy and immunohistochemistry findings in patient #1

Plasma cell infiltrate before (A) and after (B) intensive B cell depletion therapy (IBCDT). IgG⁺ plasma cells before (C) and after (D) IBCDT. (A) Masson's trichrome (original magnification ×100); (B) Periodic acid-Schiff solution (PAS) (original magnification ×100); (C, D) Immunohistochemical staining (original magnification ×200).

Figure 2. Light microscopy and immunohistochemistry findings in patient #2

Plasma cell infiltrate and storiform fibrosis before (A) and after (B) intensive B cell depletion therapy (IBCDT). IgG⁺ plasma cells before (C) and after (D) IBCDT. (A) Periodic acid-Schiff solution (PAS) (original magnification ×100); (B) Masson's trichrome (original magnification ×200); (C, D) Immunohistochemical staining (original magnification ×200).

Figure 3. Light microscopy and immunohistochemistry findings in patient #4

Dense plasma cell infiltrate (A) and storiform fibrosis (B) in surgical periaortic tissue biopsy, typical of IgG4-related retroperitoneal fibrosis. IgG⁺ plasma cells (C), and IgG4⁺ plasma cells (D). (A) hematoxylin and eosin (original magnification ×100); (B) Masson's trichrome (original magnification ×100); (C, D) Immunohistochemical staining (original magnification ×400).

Figure 4. Radiologic features of patient #4

Magnetic resonance and PET/CT imagings before (A, B), 5 months (C), and 16 months (D) after treatment: (A and B) abnormal periaortic soft tissue, axial diameter 17 mm, showing high metabolic activity; (C) 60% reduction of tissue axial thickness; (D) 80% increase of periaortic mass axial diameter.

Figure 5. Radiologic features of patient #5

CT scan and PET/CT imagings before starting therapy (A, C) and at 6 months (B, D): (A) retroperitoneal and perivascular fibroinflammatory tissue, with (C) high metabolic activity; (B) complete disappearance of abnormal tissue, with (D) persistence of residual minimal pelvic metabolic activity.