TY - JOUR

T1 - Plasma metabolomics identifies markers of impaired renal function

T2 - A meta-analysis of 3089 persons with type 2 diabetes

AU - Tofte, Nete

AU - Vogelzangs, Nicole

AU - Mook-Kanamori, Dennis

AU - Brahimaj, Adela

AU - Nano, Jana

AU - Ahmadizar, Fariba

AU - van Dijk, Ko Willems

AU - Frimodt-Møller, Marie

AU - Arts, Ilja

AU - Beulens, Joline W.J.

AU - Rutters, Femke

AU - van der Heijden, Amber A.

AU - Kavousi, Maryam

AU - Stehouwer, Coen D.A.

AU - Nijpels, Giel

AU - van Greevenbroek, Marleen M.J.

AU - van der Kallen, Carla J.H.

AU - Rossing, Peter

AU - Ahluwalia, Tarunveer S.

AU - T Hart, Leen M.

PY - 2020

Y1 - 2020

N2 - 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 (PFDR = 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 (PFDR < 0.03). We observed positive associations with cholesterol and phospholipids in high-density lipoproteins (HDL) and apolipoprotein A1 (PFDR < 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 (PTyr = 0.003; PHDLrelated < 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.

AB - 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 (PFDR = 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 (PFDR < 0.03). We observed positive associations with cholesterol and phospholipids in high-density lipoproteins (HDL) and apolipoprotein A1 (PFDR < 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 (PTyr = 0.003; PHDLrelated < 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.

KW - Albuminuria

KW - Meta-analysis

KW - Metabolomics

KW - NMR

KW - Renal function

U2 - 10.1210/clinem/dgaa173

DO - 10.1210/clinem/dgaa173

M3 - Journal article

C2 - 32271379

AN - SCOPUS:85085416952

VL - 105

JO - Journal of Clinical Endocrinology and Metabolism

JF - Journal of Clinical Endocrinology and Metabolism

SN - 0021-972X

IS - 7

M1 - dgaa173

ER -