Metabolomics Markers of Impaired Renal Function

Nete Tofte, Nicole Vogelzangs, Dennis Mook-Kanamori, Adela Brahimaj, Jana Nano, Fariba Ahmadizar, Ko Willems van Dijk, Marie Frimodt-Møller, Ilja Arts, Joline W J Beulens, Femke Rutters, Amber A van der Heijden, Maryam Kavousi, Coen D A Stehouwer, Giel Nijpels, Marleen M J van Greevenbroek, Carla J H van der Kallen, Peter Rossing, Tarunveer S Ahluwalia, Leen M’t Hart
The Journal of Clinical Endocrinology & Metabolism, Volume 105, Issue 7, July 2020, dgaa173
https://doi.org/10.1210/clinem/dgaa173

Abstract

Context

There is a need for novel biomarkers and better understanding of the pathophysiology of diabetic kidney disease.

Objective

To investigate associations between plasma metabolites and kidney function in people with type 2 diabetes (T2D).

Design

3089 samples from individuals with T2D, collected between 1999 and 2015, from 5 independent Dutch cohort studies were included. Up to 7 years follow-up was available in 1100 individuals from 2 of the cohorts.

Main outcome measures

Plasma metabolites (n = 149) were measured by nuclear magnetic resonance spectroscopy. Associations between metabolites and estimated glomerular filtration rate (eGFR), urinary albumin-to-creatinine ratio (UACR), and eGFR slopes were investigated in each study followed by random effect meta-analysis. Adjustments included traditional cardiovascular risk factors and correction for multiple testing.

Results

In total, 125 metabolites were significantly associated (P_{FDR =} 1.5×10^–32 − 0.046; β = −11.98-2.17) with eGFR. Inverse associations with eGFR were demonstrated for branched-chain and aromatic amino acids (AAAs), glycoprotein acetyls, triglycerides (TGs), lipids in very low-density lipoproteins (VLDL) subclasses, and fatty acids (P_FDR < 0.03). We observed positive associations with cholesterol and phospholipids in high-density lipoproteins (HDL) and apolipoprotein A1 (P_FDR < 0.05). Albeit some metabolites were associated with UACR levels (P < 0.05), significance was lost after correction for multiple testing. Tyrosine and HDL-related metabolites were positively associated with eGFR slopes before adjustment for multiple testing (P_Tyr = 0.003; P_HDLrelated < 0.05), but not after.

Conclusions

This study identified metabolites associated with impaired kidney function in T2D, implying involvement of lipid and amino acid metabolism in the pathogenesis. Whether these processes precede or are consequences of renal impairment needs further investigation.

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