O4 Development and validation of dimethylarginines (DAS) as a novel biomarker to identify pre-ACLF and predict outcomes following acute decompensation of cirrhosis in two prospective multicentre European cohorts

<h3>Background and Aims</h3> Asymmetric dimethylarginine (ADMA) and its stereoisomer symmetric dimethylarginine (SDMA) reduce nitric oxide generation, cause endothelial cell dysfunction and play a role in driving portal hypertension and liver-related mortality. This study aimed to develop and validate a new scoring system termed DAS, combining these 2 biomarkers, in predicting liver-related events following AD. <h3>Method</h3> The derivation cohort encompassed patients from the DASIMAR study (n=271), a prospective, observational, UK study recruiting patients admitted non-electively with AD cirrhosis. The validation cohort was from the PREDICT study (n=409) which was a multicentre European trial with a similar design. ADMA and SDMA analysis were performed by liquid chromatography- tandem mass spectrometry at baseline (T0) and a second time point within 7 days (T1). <h3>Results</h3> With regards to inpatient transplant-free mortality in the DASIMAR cohort, T0 DAS was significantly higher in those who died (13%) compared to survivors (6.2 vs 4.1 umol/L, p&lt;0.001). Indeed, T0 DAS remained a predictor of inpatient mortality in multivariable analysis (OR 1.19 [95% CI 1.03–1.38], p=0.017) and was superior to the baseline CLIF-C AD score. When assessing 90-day mortality, T0 DAS was also significantly higher in those who died (n=63) compared to survivors (5.4 vs 4.1 umol/L, p&lt;0.001). T0 DAS also remained significant in multivariable analysis (OR 1.27 [95% CI 1.08–1.48], p=0.003) and was again superior to the baseline CLIF-C AD score. When assessing 90-day mortality in the PREDICT cohort a similar signal was demonstrated with significantly higher T0 DAS scores in those who died (5.5 vs 4.2 umol/L, p=0.033). Significantly higher T0 DAS scores were noted in the DASIMAR cohort in the pre-ACLF patients (5.4 vs 3.7 umol/L, p=0.002). This was confirmed in the PREDICT cohort where T0 DAS was an independent predictor of ACLF development in multivariable analysis (OR 1.13 [95% CI 1.01–1.25], p=0.027). T0 DAS scores were also significantly higher in those who developed acute kidney injury (AKI) during admission compared to those who did not in the DASIMAR cohort (5.0 vs 3.5 umol/L, p&lt;0.001). This was shown in multivariable analysis (OR 1.24 [1.03 – 1.49], p=0.021) and replicated in the PREDICT cohort where T0 DAS also predicted renal failure in multivariable analysis (OR 1.15 [1.02–1.32], p=0.025). <h3>Conclusion</h3> This study demonstrates that the novel DAS score can predict liver-related events including mortality, ACLF development and renal dysfunction. With further validation, DAS could be translated for clinical use in identifying patients at risk of liver-related events.