The clinicopathologic spectrum of membranous nephropathy with lupus-like features

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.