Causal Associations Between Autoimmune Diseases and Renal Failure: A Two-Sample Mendelian Randomization Study with Mediation Analysis of Rheumatoid Arthritis and Glomerulonephritis

Background/Aims: Autoimmune diseases are frequently associated with renal involvement; however, their causal relationships with renal failure remain unclear. This study aimed to investigate the causal effects of multiple autoimmune diseases on renal failure and explore the mediating role of glomerulonephritis using Mendelian randomization (MR).

Materials and Methods: Summary statistics for systemic lupus erythematosus, Sjögren syndrome, rheumatoid arthritis, and systemic sclerosis were retrieved from the IEU Open genome wide association studies project. Renal failure was defined as the study outcome. A two-sample MR framework was applied using the inverse variance weighted (IVW), weighted median, and MR-Egger methods, with additional sensitivity analyses performed to assess heterogeneity and horizontal pleiotropy. Furthermore, a mediation MR model was implemented in which rheumatoid arthritis was treated as the exposure, glomerulonephritis as the mediator, and renal failure as the outcome.

Results: No significant causal associations with renal failure were observed for systemic lupus erythematosus, Sjögren syndrome, or systemic sclerosis. In contrast, genetically predicted rheumatoid arthritis was associated with an increased risk of renal failure (OR = 1.11, 95% CI: 1.05–1.18, P = 0.0005). Mediation analysis revealed a significant indirect effect of glomerulonephritis on the pathway from rheumatoid arthritis to renal failure (P = 3.07 × 10-7).

Conclusion: This study provides genetic evidence supporting a causal link between rheumatoid arthritis and renal failure, with glomerulonephritis serving as an important potential genetic mediator of this association. These findings underscore the importance of early renal monitoring and management in patients with rheumatoid arthritis.

Cite this article as: Zhuang X, Zheng J, Xin L, Yu L. Causal Associations Between Autoimmune Diseases and Renal Failure: A Two-Sample Mendelian Randomization Study with Mediation Analysis of Rheumatoid Arthritis and Glomerulonephritis. ArchRheumatol. Published online September 08, 2026. doi: 10.5152/ArchRheumatol.2026.26382.