Serum metabolites associated with dietary protein intake: results from the Modification of Diet in Renal Disease (MDRD) randomized clinical trial

Casey Rebholz, Zihe Zheng, Morgan Grams, Lawrence Appel, Mark J. Sarnak, Lesley A. Inker, Andrew S. Levey, Josef Coresh

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BACKGROUND: Accurate assessment of dietary intake is essential, but self-report of dietary intake is prone to measurement error and bias. Discovering metabolic consequences of diets with lower compared with higher protein intake could elucidate new, objective biomarkers of protein intake. OBJECTIVES: The goal of this study was to identify serum metabolites associated with dietary protein intake. METHODS: Metabolites were measured with the use of untargeted, reverse-phase ultra-performance liquid chromatography-tandem mass spectrometry quantification in serum specimens collected at the 12-mo follow-up visit in the Modification of Diet in Renal Disease (MDRD) Study from 482 participants in study A (glomerular filtration rate: 25-55 mL · min-1 · 1.73 m-2) and 192 participants in study B (glomerular filtration rate: 13-24 mL · min-1 · 1.73 m-2). We used multivariable linear regression to test for differences in log-transformed metabolites (outcome) according to randomly assigned dietary protein intervention groups (exposure). Statistical significance was assessed at the Bonferroni-corrected threshold: 0.05/1193 = 4.2 × 10-5. RESULTS: In study A, 130 metabolites (83 known from 28 distinct pathways, including 7 amino acid pathways; 47 unknown) were significantly different between participants randomly assigned to the low-protein diet compared with the moderate-protein diet. In study B, 32 metabolites (22 known from 8 distinct pathways, including 4 amino acid pathways; 10 unknown) were significantly different between participants randomly assigned to the very-low-protein diet compared with the low-protein diet. A total of 11 known metabolites were significantly associated with protein intake in the same direction in both studies A and B: 3-methylhistidine, N-acetyl-3-methylhistidine, xanthurenate, isovalerylcarnitine, creatine, kynurenate, 1-(1-enyl-palmitoyl)-2-arachidonoyl-GPE (P-16:0/20:4), 1-(1-enyl-stearoyl)-2-arachidonoyl-GPE (P-18:0/20:4), 1-(1-enyl-palmitoyl)-2-arachidonoyl-GPC (P-16:0/20:4), sulfate, and γ-glutamylalanine. CONCLUSIONS: Among patients with chronic kidney disease, an untargeted serum metabolomics platform identified multiple pathways and metabolites associated with dietary protein intake. Further research is necessary to characterize unknown compounds and to examine these metabolites in association with dietary protein intake among individuals without kidney disease.This trial was registered at as NCT03202914.

Original languageEnglish (US)
Pages (from-to)517-525
Number of pages9
JournalThe American journal of clinical nutrition
Issue number3
StatePublished - Mar 1 2019



  • chronic kidney disease
  • diet modification
  • metabolic pathways
  • metabolites
  • protein

ASJC Scopus subject areas

  • Medicine (miscellaneous)
  • Nutrition and Dietetics

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