RIBBON-LIKE ELECTRON-DENSE DEPOSITS IN NELL1-POSITIVE MEMBRANOUS NEPHROPATHY

Neural epidermal growth factor-like 1 (NELL-1) was identified as a novel antigen in membranous nephropathy (MN) in 2020, accounting for 5-10% of PLA2R-negative and THSD7A-negative cases. Previous reports have characterized NELL-1-positive MN by segmental electron-dense deposits (EDD) in the subepithelial region. We report an unusual case of NELL-1-positive MN with ribbon-like continuous subepithelial EDD throughout the glomerular basement membrane, a pattern that has not been previously described.

An 88-year-old man with chronic heart failure, chronic obstructive pulmonary disease, and peripheral arterial disease presented with lower extremity edema and right pleural effusion. Laboratory findings revealed nephrotic syndrome with urinary protein 7.4 g/day, serum albumin 1.6 g/dL, total cholesterol 443 mg/dL, and serum creatinine 1.18 mg/dL (eGFR 44.7 mL/min/1.73m²). Autoantibodies including antinuclear antibodies, rheumatoid factor, and ANCA were negative. Extensive malignancy screening including CT imaging and endoscopy was negative. A renal biopsy was performed for a definitive diagnosis. Light microscopy, immunofluorescence, and electron microscopy were performed. Immunofluorescence staining was performed for IgG subclasses and target antigens (PLA2R, THSD7A, NELL-1, EXT1).

The renal biopsy contained 22 glomeruli with 5 globally sclerotic glomeruli (22.7%). Light microscopy revealed spike formation on the glomerular capillary walls without mesangial proliferation or crescent formation. Marked interstitial fibrosis (50%) and fibrous arteriosclerosis were also observed. Immunofluorescence revealed granular deposits of IgG, C3, and C4 along the capillary walls with IgG4 predominance. PLA2R and THSD7A were negative, while NELL-1 was strongly positive. EXT1 was negative. The difference was not significant for κ and λ staining. Electron microscopy revealed stage II MN with discontinuous subepithelial deposits embedded within the lamina densa of the capillary loops. Notably, diffuse and global ribbon-like continuous EDD were observed in the subepithelial layer between the lamina rara externa and lamina densa throughout the glomerular basement membrane. No organized deposits were identified at high magnification.These extremely rare global ribbon-like linear electron-dense deposits could not be classified into any typical MN stage described by Churg and Ehrenreich because they lacked the characteristic spike formations of stages II and III. NELL-1 positivity was confirmed by immunohistochemistry using frozen sections, consistent with true NELL-1-related MN rather than an artifact. Differential diagnoses included monoclonal immunoglobulin deposition disease (MIDD) and membranoproliferative glomerulonephritis (MPGN) type II, which were excluded based on negative κ/λ staining, absence of Bence-Jones protein, subepithelial location of deposits, and normal complement levels.  The patient was treated with prednisolone (20 mg/day), rituximab (500 mg), and cyclosporine (100 mg/day). However, the patient experienced progressive cognitive decline and died of heart failure 12 months after diagnosis.

This case demonstrates an extremely rare NELL-1-positive membranous nephropathy with ribbon-like continuous subepithelial deposits throughout the glomerular basement membrane, unlike the typical segmental pattern. This novel morphological variant expands our understanding of NELL-1-positive MN and requires further investigation.