Identifying Plasma and Urine Metabolite Biomarkers of Salt Sensitivity of Blood Pressure from the DASH-Sodium Trial

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Introduction: Hypertension is the leading preventable cause of premature death worldwide and high sodium (HS) intake is the strongest dietary risk factor for hypertension. Salt sensitivity of blood pressure (SSBP), defined as an increase in blood pressure in parallel to an increase in salt intake, affects ~50% of hypertensive patients but is not routinely examined in clinical settings due to the complexity of current testing procedures. Previously, we sought to identify unique plasma biomarkers for SSBP to differentiate salt-sensitive (SS) versus salt-resistant (SR) participants using metabolomics and lipidomic profiling of plasma samples from the Dietary Approaches to Stop Hypertension-Sodium (DASH-Sodium) Trial. We identified that a HS diet was associated with changes in three plasma metabolites, an increase in citramalic acid and decreases in 2-ketoisocaproic acid and tocopherol alpha compared to low sodium (LS) diet, in SS but not SR participants. Here, we sought to validate these findings using additional plasma and urine samples from DASH-Sodium Trial and to identify novel biomarkers for SSBP by directly comparing plasma and urine metabolomic profiles between SS and SR participants after HS diet. We hypothesized that: 1). SS and SR participants would exhibit different alterations in the plasma and urine metabolomic profiles after LS or HS diets. 2). SS participants would exhibit different metabolomic profiles compared to SR participants after HS diet. METHOD: Theplasma and urine samples from 59 SS and 44 SR participants (total of 103 participants) from the DASH-Sodium Trial were sent to the West Coast Metabolomics Center at University of California at Davis for an untargeted metabolomic screening. Then, metabolomics data were provided to GeneVia Technologies (Tampere, Western Finland, Finland) for analysis. Result: For hypothesis 1, plasma metabolomic profiles showed that HS diet consumption was associated with changes in 11 metabolites in SS participants and 10 metabolites in SR participants compared to LS diet (p<0.05). There was no difference in urine metabolites after LS or HS diets in SS and SR participants (P>0.05). For hypothesis 2, metabolomic profiles showed that SR participants had differences in 11 plasma metabolites and 12 urine metabolites compared to SS participants after HS diet (p<0.05). Discussion: In this study, we observed a decrease in plasma 2-ketoisocaproic acid after a HS diet in SS participants, which validates the finding from our previous study, but we did not see any changes in plasma tocopherol alpha and citramalic acid. We also observed that nine plasma metabolites differed similarly between LS and HS diets in those participants regardless of being SS or SR and changes in some of those metabolites are associated with hypertension such as increases in cholesterone, glutamyl-valine, methionine sulfoxide and a decrease in a glutamine. Importantly, only SR participants showed increased plasma glutamic acid, a BP-lowering compound, and only SS participants showed an increased plasma anthranilic acid, which is observed in hypertensive patients. When directly comparing metabolites from SS and SR participants after a HS diet, SR participants exhibited a higher plasma level of 3-aminoisobutyric acid, which has been shown to attenuate SSBP in rats. Furthermore, 2-picolinic acid levels were higher in plasma and lower in urine of SR compared to SS participants, which may suggest its protective role against the SSBP in SR participants. In summary, these findings provide the preliminary evidence for the use of identified metabolites as novel biomarkers for SSBP to advance the testing procedures of SSBP in clinical settings. This study was funded by the National Institutes of Health (R01 AG075963 & R01 AG062515) and by Hevolution Foundation Grant (HF-GRO-23–1199246-43). This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.

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