A case of PLA2R-positive membranous nephropathy with subsequent development of IgG4-related disease

Abstract

Membranous nephropathy (MN) is a common cause of adult-onset nephrotic syndrome. It is also known as a minor but established renal manifestation of Immunoglobulin G4-related disease (IgG4-RD). Previous reports suggest that MN can also be an initial manifestation of IgG4-RD, all of which are phospholipase A2 receptor (PLA2R)-negative MN. We describe a case of PLA2R-positive MN that subsequently developed other manifestations of IgG4-RD. A 60-year-old male with nephrotic syndrome was diagnosed as primary MN with positive staining for PLA2R on the initial renal biopsy, which remained in partial remission with supportive therapy using angiotensin II receptor blocker (ARB) without steroid. About 1 year later, a renal mass was detected during an annual checkup, and contrast-enhanced computed tomography revealed low-density masses in bilateral kidneys and the head of the pancreas. The findings of endoscopic biopsy of the pancreatic mass were consistent with autoimmune pancreatitis (AIP) and the second renal biopsy showed the findings of MN with tubulointerstitial nephritis, both of which led to a diagnosis of IgG4-RD. The second renal biopsy also showed positive PLA2R. The patient received oral glucocorticoid therapy for IgG4-RD, which improved IgG4-related AIP and renal masses and also resulted in complete remission of MN. To our knowledge, this is the first reported case of PLA2R-positive MN with subsequent development of IgG4-RD. It is sometimes difficult to determine whether PLA2R-positive MN occurring with IgG4-RD is primary MN or secondary MN associated with IgG4-RD. The possibility of developing IgG4-RD should be considered even when preceding MN is PLA2R-positive, suggesting of primary MN.

Keywords: Autoimmune pancreatitis; IgG4-related disease; Membranous nephropathy; Nephrotic syndrome; Phospholipase A2 receptor (PLA2R); Primary membranous nephropathy.

Fig. 1

Abdominal ultrasound findings at the time of the initial renal biopsy. a, b No mass lesions were observed in the left kidney (a) and the right kidney (b)

Fig. 2

Histopathologic findings of the initial kidney biopsy at the onset of MN. a Scattered fluffing (yellow arrow) on the capillary walls was observed. The area enclosed by yellow square is shown enlarged. Periodic acid-methenamine-Masson trichrome (PAM) stain, × 400, scale bar 50 µm. b Granular deposits (yellow arrow) were detected. The area enclosed by yellow square is shown enlarged. Azan stain, × 400, scale bar 50 µm. c Immunofluorescence (IF) staining showed IgG(+), IgA(−), IgM(−), C1q(−), and C3(+) in the capillary walls. d IF staining showed PLA2R(+) in the capillary walls. e IF staining for IgG subclasses showed predominant positive staining for IgG4, followed by IgG1. C1q, complement C1q; C3, complement C3; IgA, immunoglobulin A; IgG, immunoglobulin G; IgM, immunoglobulin M; PLA2R

Fig. 3

Contrast-enhanced CT and MRI of the abdomen highlighting masses in the kidney and the pancreas. a, b Bilateral renal hypovascular masses (yellow arrow) were detected on a contrast-enhanced CT. c, d Pancreatic hypovascular mass in the head of the pancreas and a narrowing of the main pancreatic duct at the head of the pancreas were detected on MRI

Fig. 4

Histopathologic findings of the second kidney biopsy after the onset of IgG4-related AIP and renal masses. a The thickening of GBM was noted. Spike formation (yellow arrow), fluffing, and particle-like deposition were observed on the capillary walls. The area enclosed by yellow square is shown enlarged. PAM stain, × 400, scale bar 50 µm. b Granular deposits (yellow arrow) were observed on the capillary walls. The area enclosed by yellow square is shown enlarged. Masson’s trichrome stain, × 400, scale bar 50 µm. c No significant proliferation of mesangial cells or matrix were observed in glomeruli. PAS stain, × 400, scale bar 50 µm. d The tubulointerstitium was marked by a dense lymphoplasmacytic cell infiltration. Masson’s trichrome staining, × 100, scale bar 200 µm. e, f Immunohistochemical staining for IgG and IgG4 revealed increased number of IgG4-positive plasma cells of about 100 cells/HPF and an IgG4/IgG ratio of about 50% in the interstitium. × 400, scale bar 50 µm. g Immunofluorescence staining showed PLA2R(+) in the capillary walls. IgG, immunoglobulin G

Fig. 5

Changes in the amount of proteinuria (UPCR) and serum IgG4 level over time. Losartan alone did not induce remission of MN, but glucocorticoid therapy was initiated and proteinuria and IgG4 levels rapidly improved. EUS-FNA, endoscopic ultrasound-guided fine-needle aspiration; IgG, immunoglobulin G; UPCR, urinary protein creatinine ratio