Identification of a urine metabolomic signature in patients with advanced-stage chronic kidney disease

Abstract

The prevalence of chronic kidney disease (CKD) is increasing and frequently progresses to end-stage renal disease. There is an urgent demand to discover novel markers of disease that allow monitoring disease progression and, eventually, response to treatment. To identify such markers, and as a proof of principle, we determined if a metabolite signature corresponding to CKD can be found in urine. In the discovery stage, we analyzed the urine metabolome by NMR of 15 patients with CKD and compared that with the metabolome of 15 healthy individuals and found a classification pattern clearly indicative of CKD. A validation cohort of urine samples from an additional 16 patients with CKD and 15 controls was then analyzed by (Selected Reaction Monitoring) liquid chromatography-triple quadrupole mass spectrometry and indicated that a group of seven urinary metabolites differed between CKD and non-CKD urine samples. This profile consisted of 5-oxoproline, glutamate, guanidoacetate, α-phenylacetylglutamine, taurine, citrate, and trimethylamine N-oxide. Thus, we identified a panel of urine metabolites differentially present in urine that may help identify and monitor patients with CKD.

UPLC-based metabonomic applications for discovering biomarkers of diseases in clinical chemistry

“…Serum metabonomics indicated that specific metabolic disturbances precede β-cell autoimmunity in humans and can be used to identify T1D children [80]. These findings suggest alternative metabolism-related pathways as therapeutic targets to prevent diabetes.…”

The systemic nature of CKD

“…Changes in the levels of metabolites, such as asymmetric dimethyl arginine 255 or long-chain acylcarnitine 256 , that contribute to complications in CKD and are involved in cardiovascular complications in patients undergoing dialy sis 169,256 can be reliably measured and are providing new insights into the pathogenesis of complications associated with uraemia [255][256][257] . Studies at the metagenomic level, that is on genetic material from bacterial communities such as the gut microbiota, provide insights into the effects of CKD on the microbiome and, conversely, on the effects of changes in the microbiome on the mani festations of CKD.…”

“…In this regard, the process has started with the application of systems biology tools to simple sets of samples (which can be obtained from plasma, urine, faeces or circulating leukocytes). For example, one study performed metabo lomics analyses in a group of 41 patients with stage 3-4 CKD 255 , whereas another analysed metabolic signatures in urine samples of a small series of 13 patients with stage 4-5 CKD 257 .…”

Combination use of medicines from two classes of renin–angiotensin system blocking agents: risk of hyperkalemia, hypotension, and impaired renal function

“…As discussed below, the use of spironolactone represents a modality of dual RAAS blockade. Proteomics of urinary exosomes or urinary metabolomics may also provide molecular signatures for patient stratification [Benito-Martin et al 2013;Zubiri et al 2013;Posada-Ayala et al 2014].…”