The Clinicopathologic Spectrum of Membranous Nephropathy with Lupus-Like Features

Abstract

Introduction: The pathologic features of membranous lupus nephritis (MLN) are occasionally encountered in secondary membranous nephropathy (sMN) without overt clinical evidence of SLE. Moreover, some sMN with lupus-like features (LL-MN) have a clinical presentation more typical of primary membranous nephropathy (pMN). Based on the confounding clinical and pathologic presentation, it is unclear how to categorize and treat these patients. Methods: We performed immunohistochemical staining for recently discovered target antigens associated with MN -NELL-1, THSD7A, and EXT1/2, and compared the clinicopathologic presentation of patients with LL-MN to those with pMN and MLN. Results: From 2015-2020, there were 21 patients with MLN and 99 with MN, of which 59% were diagnosed pMN and 41% sMN. 44% of sMN showed lupus-like features (LL-fx). All LL-MN were negative for PLA2R and NELL1, but 12% were positive for EXT1/2. 50% of LL-MN had an identifiable systemic disease, of which 56% were autoimmune disease (AD) and 44% infection. Compared to pMN, LL-MN had higher incidence of underlying AD (p=0.02). Within pMN, 24% also had LL-fx (LL-pMN), and all but 1 were PLA2R-(78%) or NELL1-positive (15%). Only 5% of pMN had an AD, 66% of which showed LL-fx. Most idiopathic LL-MN were treated and behaved clinically similarly to pMN. There were no differences in outcome in terms of progression towards ESRD or mortality between LL-MN versus pMN and MLN. Conclusion: LL-MN appears to have a significant association with underlying AD and has a subset showing EXT1/2 positivity, whereas most LL-pMN and idiopathic LL-MN likely represent an atypical pathologic presentation of pMN.

Clinical significance of exostosin 1 in confirmed and suspected lupus membranous nephropathy

“…Choung et al reported that some cases with lupus-like features were positive for EXT1. 28 They speculated that lupus-like MN might be significantly associated with an underlying autoimmune disease. In our study, we observed similar clinicopathological differences, particularly in renal outcomes, between EXT1-positive and EXT1-negative cases in both confirmed and suspected LMN.…”

Membranous nephropathy: pathogenesis and treatments

“… 145 Novel target antigens and autoantibodies identified in PMN have also appeared in SMN caused by malignant tumors or autoimmune disease. 146 , 147 , 148 Meanwhile, due to the unique clinical and pathological phenotypes of many forms of MN associated with novel MN target antigens, Mayo Clinic suggests that a new classification of MN could be proposed based on novel target antigens. 60 , 61 Whether the new classification could improve the specificity and sensitivity of target antigen detection and guide treatment more effectively requires further investigation.…”

“…However, whether PLA2R can replace renal biopsy as preferred diagnostic standard remains questionable 145 . Novel target antigens and autoantibodies identified in PMN have also appeared in SMN caused by malignant tumors or autoimmune disease 146–148 . Meanwhile, due to the unique clinical and pathological phenotypes of many forms of MN associated with novel MN target antigens, Mayo Clinic suggests that a new classification of MN could be proposed based on novel target antigens 60,61 .…”