In Patients with Membranous Lupus Nephritis, Exostosin-Positivity and Exostosin-Negativity Represent Two Different Phenotypes
Authors: Aishwarya Ravindran, Marta Casal Moura, Fernando C. Fervenza, Samih H. Nasr, Mariam P. Alexander, Mary E. Fidler, Loren P. Herrera Hernandez, Pingchuan Zhang, Joseph P. Grande, Lynn D. Cornell, Lou Ann Gross, Vivian Negron, Grace E. Jenson, Benjamin J. Madden, M. Cristine Charlesworth, Sanjeev Sethi
Journal: Journal of the American Society of Nephrology (2021)

Significance Statement Approximately 20% of patients with lupus nephritis, the most common renal manifestation of systemic lupus erythematosus, show membranous lupus nephritis on kidney biopsy, and nearly 10% eventually develop ESKD. Recently, two proteins, Exostosin 1 and Exostosin 2 (EXT1/EXT2), were shown to be present in a subset of membranous lupus nephritis kidney biopsy specimens. In an examination of 374 membranous lupus nephritis kidney biopsy specimens, the authors found 32.6% to be EXT1/EXT2-positive. Kidney biopsy specimens from patients with EXT1/EXT2-positive membranous lupus nephritis showed less chronicity features (glomerulosclerosis, interstitial fibrosis, and tubular atrophy) compared with those from EXT1/EXT2-negative patients. EXT1/EXT2-negative patients were also more likely to reach ESKD than EXT1/EXT2-positive patients. These findings suggest that the presence of EXT1/EXT2 is favorable, and that EXT1/EXT2-positive patients have better renal outcomes compared with EXT1/EXT2-negative patients. Background In patients with secondary (autoimmune) membranous nephropathy, two novel proteins, Exostosin 1 and Exostosin 2 (EXT1/EXT2), are potential disease antigens, biomarkers, or both. In this study, we validate the EXT1/EXT2 findings in a large cohort of membranous lupus nephritis. Methods We conducted a retrospective cohort study of patients with membranous lupus nephritis, and performed immunohistochemistry studies on the kidney biopsy specimens against EXT1 and EXT2. Clinicopathologic features and outcomes of EXT1/EXT2-positive versus EXT1/EXT2-negative patients were compared. Results Our study cohort included 374 biopsy-proven membranous lupus nephritis cases, of which 122 (32.6%) were EXT1/EXT2-positive and 252 (67.4%) were EXT1/EXT2-negative. EXT1/EXT2-positive patients were significantly younger ( P =0.01), had significantly lower serum creatinine levels ( P =0.02), were significantly more likely to present with proteinuria ≥3.5 g/24 h ( P =0.009), and had significantly less chronicity features (glomerulosclerosis, P =0.001 or interstitial fibrosis and tubular atrophy, P &lt;0.001) on kidney biopsy. Clinical follow-up data were available for 160 patients, of which 64 (40%) biopsy results were EXT1/EXT2-positive and 96 (60%) were EXT1/EXT2-negative. The proportion of patients with class 3/4 lupus nephritis coexisting with membranous lupus nephritis was not different between the EXT1/EXT2-positive and EXT1/EXT2-negative groups (25.0% versus 32.3%; P= 0.32). The patients who were EXT1/EXT2-negative evolved to ESKD faster and more frequently compared with EXT1/EXT2-positive patients (18.8% versus 3.1%; P =0.003). Conclusions The prevalence of EXT1/EXT2 positivity was 32.6% in our cohort of membranous lupus nephritis. Compared with EXT1/EXT2-negative membranous lupus nephritis, EXT1/EXT2-positive disease appears to represent a subgroup with favorable kidney biopsy findings with respect to chronicity indices. Cases of membranous lupus nephritis that are EXT1/EXT2-negative are more likely to progress to ESKD compared with those that are EXT1/EXT2-positive.