Serum Metabolomic Changes Following Bariatric Surgery Adjusted for Measured Glomerular Filtration Rate Suggest Mechanisms of Kidney Protection

BackgroundBariatric surgery reduces glomerular hyperfiltration in the short term and is associated with a reduced risk of glomerular filtration rate decline during long-term follow-up. Assessing surgery-induced changes in serum metabolites may be useful to understand the metabolic benefits to the kidney occurring after bariatric surgery. MethodsIn a prospective, single-center research cohort of 27 adults with severe obesity who underwent bariatric surgery, we measured serum metabolites using untargeted ultrahigh performance liquid chromatography-tandem mass spectrometry and measured glomerular filtration rate (mGFR) by iohexol plasma clearance 1-3 months prior and 6 months after bariatric surgery. In generalized estimating equation (GEE) models that included age, sex, mGFR, and post-surgery terms, we examined bariatric surgery-associated changes in serum metabolites as well as associations between serum metabolites and mGFR. We used MetaboAnalyst to perform pathway analyses to determine bariatric surgery-associated metabolite pathway changes. ResultsBariatric surgery was significantly associated with changes in 223 serum metabolites after adjustment for age, sex, and mGFR at a Bonferroni-corrected p-value of 4.85 x 10-5. Following bariatric surgery, there were several pathways that were downregulated (alpha-linoleic acid and linoleic acid, methionine, tyrosine-kynurenine, and alanine-glucose metabolism pathways; raw p<0.05) or upregulated (phenylacetate, bile acid biosynthesis, taurine and hypo-taurine metabolism, porphyrin metabolism pathways; raw p<0.05), though only downregulation of alpha-linoleic acid and linoleic acid metabolism pathway was significant after correcting for multiple comparisons. Creatinine also demonstrated a significant mGFR-independent decrease following surgery. Top metabolites significantly associated with mGFR included N,N,N-trimethyl-alanyl proline betaine (TMAP), followed by creatinine, N-acetylethreonine, pseudouridine, N-acetylserine, myo-inositol, 5-methylthioribose, 5,6-dihydrouridine, erythronate, and N6-succinyladenosine. ConclusionWe confirmed several mGFR-independent metabolomic changes after bariatric surgery and also identified metabolites associated with mGFR in this setting. Further studies are needed to investigate the potential mechanistic role of identified metabolites to clarify mechanisms of obesity-related kidney disease.