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Predictors of response to terlipressin therapy in hepatorenal syndrome: Metabolomic and proteomic analysis from the CONFIRM trial.

Andrew S Allegretti·Josh Levitsky·Pratima Sharma·Tianqi Ouyang·Khurram Jamil·Scott Silvey·Jasmohan S Bajaj
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Abstract

BACKGROUND: Terlipressin is the only FDA-approved vasoconstrictor for hepatorenal syndrome (HRS). The CONFIRM study is the largest trial of terlipressin versus placebo. Novel predictors of HRS response are required to enrich patient selection and optimize outcomes. METHODS: Samples at treatment initiation were tested using (a) liquid chromatography-mass spectrometry of 1594 plasma/1420 urine metabolites (Metabolon Inc.), (b) aptamer-based array of 7289 plasma proteins (SomaScan), and (c) 14 plasma/urine pre-specified assays. The CONFIRM trial's original definition of HRS response [2 serum creatinine (SCr) <1.5&#xa0;mg/dL separated by >2&#xa0;h] was used as the primary outcome. RESULTS: In all, 115 patients [79 terlipressin-treated (TT) and 36 placebo-treated (PT)] provided samples. Baseline characteristics, outcomes, and 2:1 TT:PT allocation were preserved from the original 300-patient trial. A total of 36 out of 116 (31.0%) patients achieved HRS reversal. HRS reversal was associated with lower SCr (p=0.001), cystatin C (p=0.005), angiopoietin-2 (p=0.04), and beta-2 microglobulin (p=0.006). In metabolite analysis, PT had the most significant differences in HRS reversal [n=26 plasma, n=50 urine, including lower urine levels of those centered on sulfated secondary bile acids (microbiome-derived), N-acetylated amino acids, catechols (both uremic toxins), and phosphocholines (cell membrane integrity)], with fewer in TT (n=1 plasma, n=2 urine), and in all patients (n=3 plasma, n=7 urine). There were no significant aptamers associated with HRS reversal after false-discovery correction. CONCLUSIONS: SCr, cystatin C, angiopoietin-2, and beta-2 microglobulin were associated with HRS reversal. Protein and metabolite signals centered on microbiome function and uremic toxins appeared more robust in PT patients, likely selecting a subgroup that may recover without terlipressin. Use of novel biomarkers may enrich for terlipressin response.

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HumansHepatorenal SyndromeTerlipressinMaleFemaleMiddle AgedVasoconstrictor AgentsProteomicsMetabolomicsTreatment OutcomeBiomarkersAgedCreatinineAdultacute kidney injuryacute on chronic liver failurecirrhosisliver failureliver transplantrenal failurevasoconstrictorJournal ArticleRandomized Controlled TrialMulticenter StudyResearch Support, Non-U.S. Gov'tResearch Support, N.I.H., Extramural

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Andrew S Allegretti, Josh Levitsky, Pratima Sharma, Tianqi Ouyang, Khurram Jamil, Scott Silvey, Jasmohan S Bajaj. 2025-07-14. Predictors of response to terlipressin therapy in hepatorenal syndrome: Metabolomic and proteomic analysis from the CONFIRM trial.. https://doi.org/10.1097/hc9.0000000000000766

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