POS1509-HPR EXPLORING GENETIC EVIDENCE FOR THE CAUSAL RELATIONSHIP BETWEEN AUTOIMMUNE DISEASES AND KIDNEY INJURY: INSIGHTS FROM A MENDELIAN RANDOMIZATION STUDY

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Background: The kidney plays a central role in maintaining electrolyte balance and removing toxins from the body. It is particularly vulnerable to damage caused by autoimmune responses, either localized to the kidneys or resulting from systemic autoimmunity targeting renal autoantigens [1]. As a result, patients with autoimmune diseases (ADs) are at an increased risk of kidney complications. For instance, individuals with rheumatoid arthritis (RA) are more likely to experience a decline in kidney function over time [2]. However, the exact nature and direction of the causal relationship between ADs and kidney injury remain unclear. While observational studies suggest a strong association between ADs and kidney damage, confounding factors and the possibility of reverse causality complicate the interpretation of these findings [3]. To address these challenges, Mendelian randomization (MR) offers a robust approach for exploring the potential causal links between ADs and kidney injury, minimizing biases such as confounding and reverse causality. Objectives: In this study, we aimed to explore the causal relationship between ADs and kidney damage through MR analysis. Methods: We utilized genome-wide association study (GWAS) summary statistics from the most comprehensive and up-to-date datasets of European ancestry. These datasets included data on estimated glomerular filtration rate (eGFR) and six major autoimmune diseases (ADs): rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), type 1 diabetes (T1D), Crohn's disease (CD), ulcerative colitis (UC), and primary sclerosing cholangitis (PSC). To thoroughly assess the potential causal relationships between autoimmune diseases and kidney injure, we applied the Latent Heritable Confounder Mendelian Randomization (LHC-MR) method. This approach incorporates latent heritable confounders, modeling their contribution to both exposure and outcome, while simultaneously estimating the bidirectional effects of the traits involved. Unlike traditional Mendelian randomization methods, LHC-MR leverages genome-wide genetic markers to estimate not only the direct heritability and bidirectional causal effects, but also any confounding effects, while appropriately accounting for sample overlap. These features make LHC-MR particularly suitable for our analysis. The results from the LHC-MR method are presented as odds ratios (ORs) with corresponding 95% confidence intervals (CIs). We used a Bonferroni-corrected significance threshold of 4.17×10-3 for causal inference. A one-way causal relationship was suggested when the P value in one direction fell below this threshold (P < 4.17×10-3), and the P value in the other direction exceeded 0.05, indicating no significant reverse effect. Bidirectional causality was inferred when the P value in both directions was below the significance threshold (P < 4.17×10-3). Results: In the forward Mendelian randomization (MR) analysis of autoimmune diseases (ADs) and estimated glomerular filtration rate (eGFR), we found significant positive causal associations between eGFR and Crohn's disease (CD) (OR: 1.076; 95% CI: 1.054-1.098) and ulcerative colitis (UC) (OR: 1.093; 95% CI: 1.050-1.136). These findings suggest that a higher risk of CD and UC, which primarily affect the digestive system, is associated with increased eGFR levels, implying that kidney function may be less impacted in these patients. In contrast, rheumatoid arthritis (RA) (OR: 0.911; 95% CI: 0.872-0.950) and type 1 diabetes (T1D) (OR: 0.822; 95% CI: 0.753-0.891) exhibited negative causal associations with eGFR. This indicates that a higher risk of these immune diseases is linked to a faster decline in eGFR and an increased risk of kidney injury. These findings align with previous studies, such as those by Sho Fukuisho Fukui et al., which demonstrated that a higher risk of RA is associated with decreased eGFR levels and kidney damage [4]. However, the reverse MR analysis did not find causal effects of kidney damage on RA, T1D, CD, or UC. This suggests that kidney damage does not appear to cause these autoimmune diseases directly. Interestingly, LHC-MR analysis revealed a bidirectional causal relationship between primary sclerosing cholangitis (PSC) and eGFR, suggesting that kidney damage may influence the development of PSC and vice versa. Notably, we found no causal relationship between systemic lupus erythematosus (SLE) and eGFR, warranting caution in interpreting this result. Conclusion: Our findings suggest that the presence of rheumatoid arthritis (RA), type 1 diabetes (T1D), and primary sclerosing cholangitis (PSC) may accelerate the decline in estimated glomerular filtration rate (eGFR) and increase the risk of kidney injury, highlighting the critical role that immune mechanisms play in kidney damage. These results emphasize the importance of immune-related processes in kidney function and provide a foundation for future research. REFERENCES: [1] Messerer DAC, Halbgebauer R, Nilsson B, Pavenstädt H, Radermacher P, Huber-Lang M. Immunopathophysiology of trauma-related acute kidney injury. Nat Rev Nephrol. 2021 Feb;17(2):91-111. [2] Hickson, LaTonya J et al. "Development of reduced kidney function in rheumatoid arthritis." American journal of kidney diseases: the official journal of the National Kidney Foundation vol. 63,2 (2014): 206-13. [3] Rovin BH. Systemic autoimmune diseases and the kidney. Kidney Int. 2020 Feb;97(2):222-225. [4] Fukui S, Winkelmayer WC, Tedeschi SK, Marrugo J, Guan H, Harrold L, Litman HJ, Shinozaki T, Solomon DH. Disease activity of rheumatoid arthritis and kidney function decline: a large prospective registry study. Ann Rheum Dis. 2024 Aug 21:ard-2024-226156. Acknowledgements: This work was financially supported by the National innovation and EntrepreneurshipTraining Program for College Students, China (20240439). Disclosure of Interests: None declared . © The Authors 2025. This abstract is an open access article published in Annals of Rheumatic Diseases under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). Neither EULAR nor the publisher make any representation as to the accuracy of the content. The authors are solely responsible for the content in their abstract including accuracy of the facts, statements, results, conclusion, citing resources etc.

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