Nivolumab-induced membranous nephropathy in a patient with stage IV lung adenocarcinoma

Abstract

Immune check point inhibitors (ICIs) are now increasingly used for cancer therapy. At the same time, by activating the immune system, ICIs induce unique side effects, termed immune-related adverse events (irAEs). Renal irAEs, although uncommon, result in acute tubulointerstitial nephritis. Recently, because of an increase in ICI administration, renal irAEs, including glomerulonephritis, are being increasingly reported. A 69-year-old man presented with nephrotic syndrome after use of the ICI nivolumab. He underwent renal biopsy and was diagnosed with membranous nephropathy (MN) without acute tubulointerstitial nephritis. Immunofluorescence staining was negative for IgG4 and phospholipase A2 receptor (PLA2R), suggesting a malignancy-associated pattern. Oral glucocorticoid therapy was started as the standard treatment for irAEs, which resulted in complete remission of the nephrotic syndrome in 20 months. We suggest his MN was induced or accelerated by immune activation due to nivolumab. It means that ICIs possibly induce not only acute tubulointerstitial nephritis but also nephrotic syndrome due to MN as renal irAEs which is treatable with glucocorticoid.

Keywords: IgG subclass; Immune check point inhibitors (ICIs); Immune-related adverse events (irAEs); Membranous nephropathy (MN); Nephrotic syndrome; Nivolumab; Phospholipase A2 receptor (PLA2R).

Fig. 1

Clinical course of urinary protein quantitative data and serum total protein levels after use of nivolumab

Fig. 2

Microscopic examination of renal biopsy specimens. The basement membrane was diffusely thickened (a Periodic acid-Schiff (PAS) staining, original magnification ×400). Periodic acid-methenamine silver (PAM) staining (b original magnification ×400, c original magnification ×1000) revealed spike formation (arrow). No substantial tubulointerstitial inflammation was observed at a lower magnification (d Masson’s trichrome staining original magnification ×100)

Fig. 3

Immunofluorescence staining of renal biopsy specimens. IgG and C3 granular depositions were observed along the capillary loop (a, d). IgM (b), IgA (c), C4 (e) and C1q (f) were not stained

Fig. 4

Electron microscopic examination. Electron microscopy revealed subepithelial electron-dens deposits and adjacent projections of basement membrane material (original magnification ×3000)

Fig. 5

Immunofluorescence staining for IgG subclass and phospholipase A2 receptor (PLA2R). The tissue was positive for IgG1 (a), and negative for other IgG subclasses and PLA2R (b–e)

Fig. 6

Clinical course of urinary protein levels (dotted line) and serum albumin (solid line) after admission

Fig. 7

Clinical course of urinary protein levels after discharge