Neural Epidermal Growth Factor–Like 1 Protein–Positive Membranous Nephropathy in Chinese Patients

Abstract

Background and objectivesThe neural EGF-like 1 (NELL-1) protein is a novel antigen in primary membranous nephropathy. The prevalence and clinical characteristics of NELL-1–positive membranous nephropathy in Chinese individuals with primary membranous nephropathy are unclear.Design, setting, participants, & measurementsA total of 832 consecutive patients with biopsy-proven primary membranous nephropathy were enrolled. The glomerular expression of phospholipase A2 receptor (PLA2R) and thrombospondin type 1 domain-containing 7A (THSD7A) was screened. Glomerular immunohistochemistry staining for NELL-1 was performed in 43 patients with PLA2R- and THSD7A-negative membranous nephropathy, 31 patients with PLA2R-positive membranous nephropathy, and two patients with PLA2R and THSD7A double positivity. The NELL-1 antibody was also detected in the sera of patients with NELL-1–positive membranous nephropathy by western blot. Clinical and pathologic features were comparable between patients with isolated NELL-1–positive, isolated PLA2R/THSD7A-positive, and triple antigen–negative membranous nephropathy.ResultsAmong the 832 patients with primary membranous nephropathy, 11 of 54 (20%) patients with PLA2R-negative membranous nephropathy had THSD7A-positive membranous nephropathy. NELL-1–positive membranous nephropathy accounted for 35% (15 of 43) of all patients with PLA2R- and THSD7A-negative membranous nephropathy. One patient was double positive for NELL-1 and PLA2R in glomerular deposits and positive for only the PLA2R antibody in the serum. Most patients with NELL-1–positive membranous nephropathy were women. No tumors were found. There were significant differences in the prevalence of IgG subtypes between patients with different antigen positivity. Among patients with isolated NELL-1–positive membranous nephropathy, although 80% (12 of 15) were IgG4 staining positive, the proportion of IgG4 dominance was only 67% (ten of 15).ConclusionsAbout one third of patients who were PLA2R and THSD7A negative were NELL-1 positive in Chinese patients with primary membranous nephropathy. NELL-1–positive membranous nephropathy was more common than THSD7A-positive membranous nephropathy in PLA2R-negative membranous nephropathy.

B Cells in Primary Membranous Nephropathy: Escape from Immune Tolerance and Implications for Patient Management

“…Thrombospondin type-1 domain-containing 7A (THSD7A) is another target antigen implicated in about 5% of cases, and is likewise associated with circulating antibodies [39,40]. Other novel antigens identified include neural epidermal growth factor-1 (NELL1), exostosin 1/exostosin 2 (EXT1/EXT2), semaphorin 3B (Sema3B), and protocadherin-7 (PCDH7); circulating antibodies to some of these antigens have been isolated from the sera of patients with MN [41][42][43][44][45][46]. A growing number of studies suggest that these antibodies may be directly pathogenic in MN, and carry diagnostic, prognostic and therapeutic significance.…”

Traditional indigenous medicines are an etiologic consideration for NELL1-positive membranous nephropathy

“…Given the retrospective observational design, serum samples for mercury analysis were not available for most patients and would be false negative if measured at the time of follow-up due to TIM discontinuation. We also are unable to exclude the possibility of spontaneous J o u r n a l P r e -p r o o f remission, as MN is known to spontaneously remit in 32% of patients 5 , which may be even higher in NELL1-positive patients 6 .…”

How Times Have Changed! A Cornucopia of Antigens for Membranous Nephropathy

“…NELL1-associated MN has unique histopathologic features, including a segmental or incomplete global pattern of immune complex deposition (71) and IgG1 subclass predominance (22,68,71). The presence of NELL1 autoantibodies in the circulation was demonstrated by seroreactivity against recombinant protein under non-reducing conditions and has been independently confirmed by three groups (22,68,70,72). In a single patient where serial serum samples were available, immunological remission (i.e., disappearance of anti-NELL1 antibodies) preceded clinical remission (22), consistent with what is seen in PLA2R-associated MN (19).…”

“…Unlike the case for the target antigens in PLA2R and THSD7A-positive MN, NELL1 is not routinely expressed by podocytes under normal conditions. NELL1 associated MN comprises 3.8-16% of all PLA2R-negative MN cases in the United States and may be more frequent among Chinese patients, making up 35% of PLA2R-negative MN cases in these cohorts (22,68,70). NELL1-associated MN has unique histopathologic features, including a segmental or incomplete global pattern of immune complex deposition (71) and IgG1 subclass predominance (22,68,71).…”