Background EXT1/2 and NCAM1 associated membranous lupus nephritis (MLN) may represent distinct disease phenotypes with prognostic significance. Methods We searched our archives for patients with systemic lupus erythematous (SLE) and at least two kidney biopsies demonstrating MLN. Each biopsy was stained for EXT1 and NCAM1 and scored as positive or negative. Histopathologic and clinical data were reviewed. Results We identified 31 patients with a clinical diagnosis of SLE and at least two kidney biopsies with MLN. 28 patients (90%) showed concordant staining for EXT1 and NCAM1 in both biopsies; 8 (26%) patients were EXT1-positive and NCAM1-negative, 18 (58%) patients were EXT1-negative and NCAM1-negative, and 2 (7%) patients were EXT1-negative and NCAM1-positive. Three patients (10%) had discordant EXT1 staining between their first and last biopsies; two patients (7%) were EXT1-positive in their first biopsy and EXT1-negative in their last biopsy and one patient (3%) was EXT1-negative in their first biopsy and EXT1-positive in their last biopsy. Compared to the EXT1-negative cohort at the time of first biopsy, the EXT1-positive cohort had a higher average eGFR (141 v. 111 ml/min/1.73m^2; p = 0.04), lower average % global glomerulosclerosis (0.5 v. 12%; p = 0.05), lower average interstitial fibrosis and tubular atrophy (2.5 v. 11.7%; p = 0.06), and lower average total NIH chronicity scores (0.75 v. 2.33, p = 0.05). On long-term follow-up, the rate of change in eGFR did not significantly differ between the two groups (p = 0.24). One EXT1-positive patient (12.5%) developed stage 4 CKD or ESKD compared to four patients (20%) in the EXT-negative group and two of the three EXT1-discordant patients (p = 0.38). Conclusions We performed the largest retrospective repeat-biopsy study to evaluate EXT1 and NCAM1 autoantigens in MLN. Our data demonstrate that EXT1-positivity is associated with better kidney function at the time of diagnosis and raises the possibility that EXT1 status may change throughout the disease course of MLN.
Background Membranous nephropathy is an uncommon cause of nephrotic syndrome in pediatrics. Methods We reviewed our kidney biopsy records for patients ≤ 20 years of age with membranous nephropathy without evidence of systemic lupus erythematosus within 6 months of biopsy (January 1995-September 2020). Staining for PLA2R, NELL1, THSD7A, SEMA3B, EXT2 (3 biopsies), and IgG-subclass were performed. Results Sixteen children (≤ 12 years) and 25 adolescents (13-20 years) were identified. Four children and 15 adolescents showed autoantigen positivity: PLA2R+/SEMA3B-( 13), SEMA3B+/PLA2R+ (2), SEMA3B+/PLA2R− (1), NELL1 (1), EXT2+ (2), and THSD7A (0). Co-morbidities associated with PLA2R positivity included IPEX syndrome, active hepatitis B, Von Hippel Lindau syndrome, solitary kidney, type 1 diabetes, hyperuricemia, pregnancy (1), obesity (3), type II diabetes, H. pylori, viral prodrome, and nephrolithiasis. The SEMA3B+/PLA2R− adolescent was pregnant, the NELL1+ adolescent was obese, and the two EXT2+ adolescents eventually met the clinical criteria for lupus (4, 9 years post-biopsy). Co-morbidities among the remaining 24 patients included remote hepatitis B (2), Down's syndrome, lysinuric protein intolerance, recurrent UTIs, hypothyroidism, pregnancy (3), and obesity (2). Follow-up data was available for 12 children and 16 adolescents. Of the 12 children, 6 achieved complete remission, 4 achieved partial remission, and 2 had no response to treatment (1 transplant). Of the 16 adolescents, 4 achieved complete remission, 4 achieved partial remission, and 8 had no response to treatment (3 transplants). A child with "full-house" immunofluorescence staining achieved spontaneous disease remission. Conclusion Our non-lupus membranous nephropathy cohort represents one of the largest pediatric studies to date.
Purpose of reviewMultiple antigenic targets were discovered in membranous nephropathy, representing distinct autoimmune diseases with a similar morphologic pattern of injury. An overview of recent developments, including antigen types, clinical associations, serologic monitoring, and advancements in understanding disease pathogenesis are provided. Recent findingsSeveral new antigenic targets have defined subtypes of membranous nephropathy, including Neural epidermal growth factor-like 1, protocadherin 7, HTRA1, FAT1, SEMA3B, NTNG1, NCAM1, exostosin 1/2, transforming growth factor beta receptor 3, CNTN1, proprotein convertase subtilisin/kexin type 6, and neuron-derived neurotrophic factor. Autoantigens in membranous nephropathy may demonstrate unique clinical associations, assisting the nephrologist to identify potential disease etiologies and triggers, such as autoimmune disease, cancer, medications, and infections.
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