NELL1 is a target antigen in malignancy-associated membranous nephropathy

Abstract

Patients with membranous nephropathy have an increased risk of malignancy compared to the general population, but the target antigen for malignancy-associated membranous nephropathy is unknown. To explore this, we utilized mass spectrometry for antigen discovery in malignancy-associated membranous nephropathy examining immune complexes eluted from frozen kidney biopsy tissue using protein G bead immunoglobulin capture. Antigen discovery was performed comparing cases of membranous nephropathy of unknown and known type. Mass spectrophotometric analysis revealed that nerve epidermal growth factor-like 1 (NELL1) immune complexes were uniquely present within the biopsy tissue in membranous nephropathy. Additional NELL1-positive cases were subsequently identified by immunofluorescence. In a consecutive series, 3.8% of PLA2R-and THSD7A-negative cases were NELL1-positive. These NELL1-positive cases had segmental to incomplete IgG capillary loop staining (93.4%) and dominant or codominant IgG1-subclass staining (95.5%). The mean age of patients with NELL1-positive membranous nephropathy was 66.8 years, with a slight male predominance (58.2%) and 33% had concurrent malignancy. Compared with PLA2R-and THSD7A-positive cases of membranous nephropathy, there was a greater proportion of cases with malignancies in the NELL1-associated group. Thus, NELL1associated membranous nephropathy has a unique histopathology characterized by incomplete capillary loop staining, IgG1-predominance, and is more often associated with malignancy than other known types of membranous nephropathy.

Advances in Membranous Nephropathy

“…These observations were largely confirmed by Caza et al [ 50 ] who confirmed that NELL-1 could be the first antigen in malignancy associated MN. In their series of 91 patients, they found that IgG deposits were global but incomplete or segmental in 93.4% of cases, IgG1 subclass was present in all cases while IgG4 was detected in only 54%, and a cancer was diagnosed in 33% of cases.…”

“…Caza et al [ 50 ] also analyzed the distribution of the various antigens in a cohort of 1378 biopsies of “primary” MN collected over a five-year period at Arkana laboratories.Of the 111 biopsies of cancer-associated MN, 42 were with unknown antigen, 35 were PLA2R positive, 30 were NELL1 positive, and four were THSD7A positive. When the prevalence of cancer was analyzed per subcategory of MN identified by antigen, NELL-1 came first (33%) followed by THSD7A (11%) while PLA2R-positive cases accounted for only 4%.…”

New ‘Antigens’ in Membranous Nephropathy

“…The incidence of malignancy varies from 10% to 33%, depending on demographics. 28 The MN may even precede the detection of the malignancy. Serum antibodies to NELL1 are detected in NELL1-associated MN.…”

Membranous nephropathy: current understanding of various causes in light of new target antigens

“…A recent study by Caza et al [ 17 ▪▪ ] confirmed that NELL-1 could be the first candidate antigen in malignancy-associated membranous nephropathy. They reported the largest series of NELL-1-associated membranous nephropathy including 91 patients.…”

“…Caza et al [ 17 ▪▪ ] also specified antigen prevalence in 111 cancer-associated membranous nephropathy identified among 1378 biopsies of ‘primary’ membranous nephropathy collected over a 5-year period (Fig. 2 ).…”