A Clinicopathologic Study of Neural Epidermal Growth Factor-Like 1-Associated Membranous Nephropathy in a Chinese...

Neural epidermal growth factor-like 1 (NELL-1)-associated membranous nephropathy (MN), first described in 2020, represents a common subtype among >20 target antigens; however, its clinicopathologic features and long-term prognosis are poorly characterized.

Consecutive biopsy-proven MN cases (2006-2025) were retrospectively analyzed at Ruijin Hospital, Shanghai. NELL-1 immunostaining was performed in M-type phospholipase A₂ receptor (PLA2R)- and thrombospondin type-1 domain-containing 7A (THSD7A)-negative cases. Clinicopathological data and long-term outcomes were collected. NELL-1 deposition patterns were classified as diffuse or segmental.

Of 556 PLA2R- and THSD7A-negative MN cases, 12.2% (n = 68) were NELL-1 positive. The median age was 46 (interquartile range [IQR]: 38-66) years, with female predominance (M/F sex ratio, 0.7:1). Secondary causes were identified in 20.6% of cases; all 7 malignancies occurred in elderly men (aged ≥ 60 years). Elderly patients had higher serum creatinine (0.89 vs. 0.64 mg/dl, P < 0.01), heavier proteinuria (7.4 ± 4.0 vs. 4.6 ± 2.8 g/24 h, P < 0.01), and lower albumin (22.9 ± 6.4 vs. 27.3 ± 7.9 g/l, P = 0.014). Diffuse NELL-1 deposition was associated with greater proteinuria and lower albumin. After excluding malignancy, outcome analysis of 51 patients (median follow-up 48 months) showed a high remission rate (49/51, 96.1%) and 33.3% spontaneous remission (SR). In contrast, malignancy-associated cases had poor outcomes, with 57.1% mortality within 1 year after the MN diagnosis.

NELL-1-associated MN occurs at a relatively younger age in women, whereas malignancy predominantly occurred in elderly men in Han Chinese population. Diffuse deposition was associated with higher proteinuria. Overall prognosis was favorable, except in malignancy-associated cases, suggesting malignancy screening at diagnosis, particularly in elderly men.