Investigating Circulating Inflammatory Proteins in IgA Nephropathy: Implications for Disease Progression

Background: Immunoglobulin A nephropathy (IgAN), the most common primary glomerulonephritis globally, involves complex inflammatory processes contributing to kidney damage. This study aims to elucidate the relationship between circulating inflammatory proteins and the kidney disease progression of IgAN, and comparing the circulating level of proteins with other autoimmune nephritis. Methods: This cohort study included 134 Japanese patients with biopsy-proven IgAN, alongside groups with membranous nephritis (MN, n=24), minimal change disease (MCD, n=23), and lupus nephritis (LN, n=23), collected from Nihon University School of Medicine Itabashi Hospital, Tokyo, between 2009-2018. Serum samples were analyzed pre-biopsy for 10 inflammatory proteins (TNF-R1, TNF-R2, LTBR, TNF-R4, TNF-R6B, CD27, TNF-R10A, RELT, EDA2R, and IL-1RT1) that we previously identified as important biomarker for future progression to ESKD in diabetic kidney disease. Kidney function was assessed using eGFR and proteinuria levels, with histological evaluation based on the MEST score. Results: TNF-R1 and TNF-R2 showed significant increases in all patient groups compared to healthy controls, with statistical significance. For LTBR, TNF-R4, TNF-R6B, TNF-R10A, RELT, and EDA2R, the levels increased with advancing stages in the IgAN group; however, no increase was observed at the normoalbumiuric stage. Additionally, while levels rose in both the MN and Lupus groups, no increase was observed in the MCD group. On the other hand, for CD27, a significant elevation was noted as early as the normoalbumiuric stage compared to healthy controls. Multivariate logistic analysis identified CD27 as an independent predictor of tubular atrophy/interstitial fibrosis in IgAN. Furthermore, TNF-R1, TNF-R2, LTBR, CD27, and EDA2R were significantly associated with the risk of progression to the composite outcome (CKD stage 3, 30% eGFR decline, and ESKD by Cox regression analysis, emphasizing their potential as biomarkers for IgAN progression. Conclusion: Elevated levels of specific TNFR family proteins and CD27 are strongly associated with IgAN progression, underscoring their utility in predicting kidney function decline. Future studies should focus on these biomarkers for early intervention strategies. Funding: Private Foundation Support