An overview of renal metabolomics

Abstract

The high-throughput, high-resolution phenotyping enabled by metabolomics has been applied increasingly to a variety of questions in nephrology research. This article provides an overview of current metabolomics methodologies and nomenclature, citing specific considerations in sample preparation, metabolite measurement, and data analysis that investigators should understand when examining the literature or designing a study. Furthermore, we review several notable findings that have emerged in the literature that both highlight some of the limitations of current profiling approaches, as well as outline specific strengths unique to metabolomics. More specifically, we review data on the following: (i) tryptophan metabolites and chronic kidney disease onset, illustrating the interpretation of metabolite data in the context of established biochemical pathways; (ii) trimethylamine-N-oxide and cardiovascular disease in chronic kidney disease, illustrating the integration of exogenous and endogenous inputs to the blood metabolome; and (iii) renal mitochondrial function in diabetic kidney disease and acute kidney injury, illustrating the potential for rapid translation of metabolite data for diagnostic or therapeutic aims. Finally, we review future directions, including the need to better characterize interperson and intraperson variation in the metabolome, pool existing data sets to identify the most robust signals, and capitalize on the discovery potential of emerging nontargeted methods.

Keywords: acute kidney injury; chronic kidney disease; uremia; uremic toxins.

Figure 1

Overview of metabolomics methodologies. Nuclear magnetic resonance (NMR) is robust, requiring relatively little sample preparation and no chromatographic separation. However, because of limited sensitivity and high data complexity, unambiguous identification is typically limited to less than a hundred metabolites. Mass spectrometry (MS)-based approaches have higher sensitivity and rely on a combination of chromatographic separation and mass-to-charge ratio (m/z) resolution for metabolite identification. In MS-based platforms, triple quadrupole instruments are generally used for targeted analyses, in which approximately hundreds of metabolites of known identity are measured, whereas time-of-flight and ion trap instruments are often used for nontargeted analyses of approximately thousands of metabolite peaks (only a subset of which have assigned identities). Relative advantages (+) and disadvantages (−) of the different approaches are detailed in the figure.

Figure 2

Tryptophan metabolism and incident CKD. IDO1 catalyzes the first and rate-limiting step of the tryptophan catabolism via the kynurenine pathway. Alternative pathways of tryptophan metabolism result in the production of indoxyl sulfate and indole-3-propionate (via gut microbial tryptophan metabolism) or serotonin and 5-hydroxyindoleacetic acid (5-HIAA).