Membranous-Like Glomerulopathy with Masked IgG Deposits in a Case of Plasma Cell Dyscrasia: A Case Report

Introduction

“Masked deposits” refers to immunoglobulins that exhibit false-negative staining under routine frozen immunofluorescence but demonstrate positivity when immunofluorescence is performed on formalin-fixed, paraffin-embedded tissue. In 2014, Larsen et al. described a rare entity termed membranous-like glomerulopathy with masked IgGĸ deposits (MGMID).¹ This condition is characterized by a membranous pattern of glomerular injury on light microscopy, absence of IgG staining on direct immunofluorescence (DIF) of fresh tissue (masked deposit), but positivity for IgG when DIF is performed on proteinase-K-treated formalin-fixed, paraffin-embedded (FFPE) tissue.² MGMID has been observed more frequently in young females with positive autoimmune markers, normal complement levels, absence of an M band on serum protein electrophoresis (SPEP), and a lack of clonal plasma cells in the bone marrow.³ The deposition of serum amyloid P (SAP) in the glomerulus is a recognized distinctive feature of MGMID.⁴ We report a case with membranous-like glomerulopathy with masked IgG deposits in a case of plasma cell dyscrasia with some novel features.

Case Report

A 51-year-old man presented with fever, anemia, and weakness. Evaluation revealed renal dysfunction, with a serum creatinine of 2.69 mg/dL and a 24-hour urine protein of 2.5g. SPEP demonstrated an M band with a quantification of 0.6 g/dL, and serum immunofixation electrophoresis showed IgG with ĸ-restriction. Bone marrow examination revealed 3% clonal plasma cells with ĸ-restriction and a 17p13 deletion on cytogenetics. Complement levels were normal. Notably, autoimmune markers (ANA, anti-dsDNA) and serologies for HIV, hepatitis B, and hepatitis C were negative.

Renal biopsy showed diffuse and global basement membrane thickening with 3+ intense granular deposits of IgM along the capillary walls. IgG, IgA, C3, and C1q were negative on DIF performed on fresh tissue. DIF on proteinase-K-treated FFPE tissue showed segmental granular positivity for IgG with ĸ-restriction and IgG1 subtyping. Immunohistochemistry for PLA2R and NELL-1 was negative. Immunohistochemistry for SAP revealed focal and segmental positivity along the capillary walls. Electron microscopy showed immune complex-type deposits in subepithelial, intramembranous, and subendothelial locations [Figure 1].

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Figure 1:

(a) Renal biopsy showing global thickening of glomerular basement membranes (Periodic Acid Schiff, 400x). (b) Direct Immunofluorescence (DIF) on fresh tissue showing negative fluorescence for IgG (400x) and (c) diffuse granular positivity for IgM (400x). (d-f) DIF on Proteinase-k treated paraffin-embedded tissue shows focal and segmental granular positivity for IgG (400x) and ĸ (e: 400x); negative for lambda (f: 400x). (g) Immunohistochemistry for Phospholipase A2 receptor (PLA2R) shows no granular positivity along the capillary wall (400x); (h) positive expression for Serum Amyloid P (SAP) in the capillary wall and the mesangium (400x). (i) Ultrathin examination shows immune complex-type deposits in the sub-epithelium, intramembranous, and sub-endothelial locations (4000x).

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Discussion

Our case shares features with those described by Larsen et al.,³ such as membranous-like glomerular morphology with masked IgG ĸ deposits; IgG1 subtyping; SAP positivity; and similar immune complex-type deposits on electron microscopy. However, this case has several novel features that are worth highlighting. This patient was male, lacked autoimmune marker positivity, demonstrated clonality on immunofixation electrophoresis and bone marrow examination, and fulfilled the criteria for monoclonal gammopathy of renal significance. In the case series by Larsen et al.,³ MGMID presented with a membranous pattern without hypercellularity in 50% of cases. The remaining 50% exhibited either mesangial hypercellularity, focal segmental glomerulosclerosis (FSGS), or focal or diffuse crescentic glomerulonephritis. However, endocapillary proliferation, wire-loop lesions, hyaline thrombi, thrombotic microangiopathy, or arteritis was absent. All cases were negative for PLA2R and THSD7A.

Notably, 68% of cases showed C3 positivity on frozen DIF and revealed masked IgGĸ on paraffin IF, with all cases exclusively showing IgG1 positivity. This highlights the importance of unmasking in all cases, showing only C3 positivity on frozen IF to prevent a false diagnosis of C3 glomerulonephritis in MGMID cases, cryoglobulinemic glomerulonephritis, and membranoproliferative glomerulonephritis with masked Ig deposits. Interestingly, our case showed IgM positivity along the capillary walls on DIF performed on fresh tissue. The glomerular deposition of IgM might have masked the cryptic antigenic site of IgG. The exact source of IgM is unknown, although the patient presented with fever. Other postulated mechanisms for masked IgG deposits include the tertiary/quaternary arrangement of immunoglobulin molecules and abnormal glycosylation of immunoglobulins, which hinder antibody binding and cause false negativity on DIF performed on fresh tissue.⁵

Because this entity is not well established, past patients have received various regimens, including Renin Angiotensin System (RAS) blockers, combinations of steroids with calcineurin inhibitors, mycophenolate mofetil, hydroxychloroquine, rituximab, azathioprine, or rituximab alone. Outcomes have varied. Among the available follow-up data on 22 patients, 15 achieved complete remission, and 12 progressed to ESKD. One patient experienced biopsy-proven relapse 42 months post-transplant. Our patient is currently on a RAS blocker and is being followed. Our case has morphologic features resembling MGMID but with several significant dissimilarities.

To conclude, whether this case represents a new category of monoclonal gammopathy of renal significance or another form of MGMID remains a dilemma. Nephrologists and nephropathologists should be aware of this rare entity, and larger studies of similar cases are required.