{"doi":"10.1016/j.kint.2020.07.039","title":"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 co-dominant 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, NELL1-associated 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. 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 co-dominant 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, NELL1-associated 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. Membranous nephropathy (MN) is the most common cause of idiopathic nephrotic syndrome in adults. It is a disease caused by the deposition of immune complexes in a glomerular distribution. It can be caused by antibodies directed against podocyte antigens (primary MN) or through secondary deposition of circulating immune complexes (or alternatively in situ immune complex formation) in glomeruli. The most common causes of secondary MN are autoimmune diseases, of which systemic lupus erythematosus accounts for the majority of cases (membranous lupus nephritis). The second most common secondary etiology is malignancy. Other causes include infections (such as viral hepatitis), graft-versus-host disease, allergic responses (such as against bovine serum albumin), and drug reactions. MN is the most common glomerul","journal":"Kidney International","year":2020,"id":50200,"datarank":0.7991814253184373,"base_score":5.327876168789581,"endowment":5.327876168789581,"self_citation_contribution":0.7991814253184373,"citation_network_contribution":0.0,"self_endowment_contribution":0.7991814253184373,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":205,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9594,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":248439,"name":"Samar Hassen","orcid":null,"position":1,"is_corresponding":false},{"id":248440,"name":"Zeljko Dvanajscak","orcid":null,"position":2,"is_corresponding":false},{"id":248441,"name":"Michael Kuperman","orcid":null,"position":3,"is_corresponding":false},{"id":248442,"name":"Rick Edmondson","orcid":null,"position":4,"is_corresponding":false},{"id":245936,"name":"Christian Herzog","orcid":"0000-0001-6024-3491","position":5,"is_corresponding":false},{"id":245937,"name":"Aaron J. Storey","orcid":"0000-0003-4089-5008","position":6,"is_corresponding":false},{"id":245938,"name":"John M. Arthur","orcid":"0000-0003-4342-4762","position":7,"is_corresponding":false},{"id":245939,"name":"L. Nicholas Cossey","orcid":"0000-0002-1043-3796","position":8,"is_corresponding":false},{"id":248443,"name":"Shree Sharma","orcid":null,"position":9,"is_corresponding":false},{"id":245940,"name":"Daniel J. Kenan","orcid":"0000-0002-5284-7284","position":10,"is_corresponding":false},{"id":245941,"name":"Christopher P. Larsen","orcid":"0000-0002-7175-0242","position":11,"is_corresponding":false},{"id":245935,"name":"Tiffany Caza","orcid":"0000-0001-8988-8998","position":0,"is_corresponding":true}],"reference_count":18,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-18T20:38:25.860949Z","pmid":"32828756","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}