Key Points
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The human metabolome reflects genetic variability, intrinsic biochemical processes, environmental challenges and complex interactions of all these factors
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Metabolomics is instrumental in discovering specific biomarkers in diseases with systemic effects such as chronic kidney disease (CKD)
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Metabolomics analysis can detect CKD-relevant biomarkers in tissues, plasma, serum and urine samples
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Most metabolite biomarkers of CKD are markers of glomerular filtration, markers of tubular function or metabolites that reflect a decline in mitochondrial function, alterations in the urea cycle or amino acid metabolism
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As CKD stage increases, the metabolic biomarker signatures of different renal diseases tends to become more similar and less dependent on the underlying renal disease
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Metabolic biomarkers seen in the later stages of CKD reflect a loss of glomerular filtration, tubular function and a decline in kidney metabolism and endocrine function
Abstract
Chronic kidney disease (CKD) has a high prevalence in the general population and is associated with high mortality; a need therefore exists for better biomarkers for diagnosis, monitoring of disease progression and therapy stratification. Moreover, very sensitive biomarkers are needed in drug development and clinical research to increase understanding of the efficacy and safety of potential and existing therapies. Metabolomics analyses can identify and quantify all metabolites present in a given sample, covering hundreds to thousands of metabolites. Sample preparation for metabolomics requires a very fast arrest of biochemical processes. Present key technologies for metabolomics are mass spectrometry and proton nuclear magnetic resonance spectroscopy, which require sophisticated biostatistic and bioinformatic data analyses. The use of metabolomics has been instrumental in identifying new biomarkers of CKD such as acylcarnitines, glycerolipids, dimethylarginines and metabolites of tryptophan, the citric acid cycle and the urea cycle. Biomarkers such as c-mannosyl tryptophan and pseudouridine have better performance in CKD stratification than does creatinine. Future challenges in metabolomics analyses are prospective studies and deconvolution of CKD biomarkers from those of other diseases such as metabolic syndrome, diabetes mellitus, inflammatory conditions, stress and cancer.
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Acknowledgements
The authors' work is supported by Innovative Medicines Initiative Joint Undertaking under Grant agreement number 115439 (StemBANCC), and number 115317 (DIRECT), the German Federal Ministry of Education and Research (BMBF) to the German Center Diabetes Research (DZD e.V.) grant to J.A. and the Deutsche Forschungsgemeinschaft (DFG) number Ho 1665/5-1, Ho 1665/5-2 and Ho 1665/5-3 to B.H. The authors would like to express their gratitude for critical reading of the manuscript to Dr. Cornelia Prehn and Dr. Alexander Cecil at Helmholtz Zentrum München, Genome Analysis Center, Neuherberg, Germany.
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Supplementary information
Supplementary information S1 (figure)
Overview of the most important metabolites and pathways that are altered in CKD. (PDF 1558 kb)
Supplementary information S2 (table)
Molecules, pathways and their relevance in chronic kidney disease (PDF 165 kb)
PowerPoint slides
Glossary
- Uraemic toxins
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Solutes that are excreted by the healthy kidney but accumulate and contribute to uraemia in patients with CKD.
- Metabolic fingerprint
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A snapshot of the metabolites present in sample under specific conditions.
- Mass spectrometry
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An analytical method by which ionised molecules are detected according to their mass-to-charge ratio.
- Proton nuclear magnetic resonance spectroscopy
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An analytical method that analyses the absorption and re-emission of energy of proton nuclei in a strong magnetic field.
- Tandem mass spectrometers
-
A mass spectrometer apparatus consisting of two quadrupole mass spectrometers connected by a single quadrupole.
- Quadrupole linear ion trap (Q-TRAP)–MS
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A mass spectrometer equipped with a quadrupole that is used to trap charged molecules.
- Quadrupole time-of-flight (Q-TOF)–MS
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A mass spectrometer that determines the mass-to-charge ratio of molecules based on their flight time in the apparatus.
- Orbitrap
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A mass analyser that converts frequency signals from trapped ions to mass spectrum using the Fourier transform.
- Derivatization steps
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Chemical modification of molecules to increases their ability to ionize before mass analyses.
- Isotope dilution
-
An approach to determine the concentration of substances by comparison with a stable isotope-labelled added internal standard.
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Hocher, B., Adamski, J. Metabolomics for clinical use and research in chronic kidney disease. Nat Rev Nephrol 13, 269–284 (2017). https://doi.org/10.1038/nrneph.2017.30
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DOI: https://doi.org/10.1038/nrneph.2017.30
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