Dataset Information

Metabolomic Profiling in Individuals with a Failing Kidney Allograft.

ABSTRACT:

Background

Alteration of certain metabolites may play a role in the pathophysiology of renal allograft disease.

Methods

To explore metabolomic abnormalities in individuals with a failing kidney allograft, we analyzed by liquid chromatography-mass spectrometry (LC-MS/MS; for ex vivo profiling of serum and urine) and two dimensional correlated spectroscopy (2D COSY; for in vivo study of the kidney graft) 40 subjects with varying degrees of chronic allograft dysfunction stratified by tertiles of glomerular filtration rate (GFR; T1, T2, T3). Ten healthy non-allograft individuals were chosen as controls.

Results

LC-MS/MS analysis revealed a dose-response association between GFR and serum concentration of tryptophan, glutamine, dimethylarginine isomers (asymmetric [A]DMA and symmetric [S]DMA) and short-chain acylcarnitines (C4 and C12), (test for trend: T1-T3 = p<0.05; p = 0.01; p<0.001; p = 0.01; p = 0.01; p<0.05, respectively). The same association was found between GFR and urinary levels of histidine, DOPA, dopamine, carnosine, SDMA and ADMA (test for trend: T1-T3 = p<0.05; p<0.01; p = 0.001; p<0.05; p = 0.001; p<0.001; p<0.01, respectively). In vivo 2D COSY of the kidney allograft revealed significant reduction in the parenchymal content of choline, creatine, taurine and threonine (all: p<0.05) in individuals with lower GFR levels.

Conclusions

We report an association between renal function and altered metabolomic profile in renal transplant individuals with different degrees of kidney graft function.

SUBMITTER: Bassi R

PROVIDER: S-EPMC5214547 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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Publications

Metabolomic Profiling in Individuals with a Failing Kidney Allograft.

Bassi Roberto R Niewczas Monika A MA Biancone Luigi L Bussolino Stefania S Merugumala Sai S Tezza Sara S D'Addio Francesca F Ben Nasr Moufida M Valderrama-Vasquez Alessandro A Usuelli Vera V De Zan Valentina V El Essawy Basset B Venturini Massimo M Secchi Antonio A De Cobelli Francesco F Lin Alexander A Chandraker Anil A Fiorina Paolo P

PloS one 20170104 1

<h4>Background</h4>Alteration of certain metabolites may play a role in the pathophysiology of renal allograft disease.<h4>Methods</h4>To explore metabolomic abnormalities in individuals with a failing kidney allograft, we analyzed by liquid chromatography-mass spectrometry (LC-MS/MS; for ex vivo profiling of serum and urine) and two dimensional correlated spectroscopy (2D COSY; for in vivo study of the kidney graft) 40 subjects with varying degrees of chronic allograft dysfunction stratified by ...[more]

PMID: 28052095

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Project description:Heat stroke can induce a systemic inflammatory response, which may lead to multi‑organ dysfunction including acute kidney injury (AKI) and electrolyte disturbances. To investigate the pathogenesis of heat stroke (HS)‑related AKI, a mouse model of HS was induced by increasing the animal's core temperature to 41˚C. Blood samples obtained from the tail vein were used to measure plasma glucose and creatinine levels. Micro‑positron emission tomography‑computed tomography (micro‑PET/CT), H&E staining and transmission electron microscopy were conducted to examine metabolic and morphological changes in the mouse kidneys. Immunohistochemistry (IHC) and western blot analyses were performed to investigate the expression of apoptosis‑inducing factor mitochondria‑associated 2 (Aifm2), high‑mobility group box 1 (HMGB1) and receptor for advanced glycosylation end products (RAGE). Liquid chromatography‑mass spectrometry analysis was conducted to find differential metabolites and signaling pathways. The HS mouse model was built successfully, with significantly increased creatinine levels detected in the serum of HS mice compared with controls, whereas micro‑PET/CT revealed active metabolism in the whole body of HS mice. H&E and TUNEL staining revealed that the kidneys of HS mice exhibited signs of hemorrhage and apoptosis. IHC and western blotting demonstrated significant upregulation of Aifm2, HMGB1 and RAGE in response to HS. Finally, 136 differential metabolites were screened out, and enrichment of the 'biosynthesis of unsaturated fatty acids' pathway was detected. HS‑associated AKI is the renal manifestation of systemic inflammatory response syndrome, and may be triggered by the HMGB1/RAGE pathway. Metabolomics indicated increased adrenic acid, docosahexaenoic acid and eicosapentaenoic acid may serve as metabolic biomarkers for AKI in HS. The findings suggested that a correlation between the HMGB1/RAGE pathway and biosynthesis of unsaturated fatty acids may contribute to the progression of HS‑related AKI.

Project description:Background and objectivesPatients with CKD display altered plasma amino acid profiles. This study estimated the association between the estimated GFR and urinary and plasma amino acid profiles in CKD patients.Design, setting, participants, & measurementsUrine and plasma samples were taken from 52 patients with different stages of CKD, and plasma samples only were taken from 25 patients on maintenance hemodialysis. Metabolic profiling was performed by liquid chromatography coupled with tandem mass spectrometry after phenylisothiocyanate derivatization.ResultsMost plasma amino acid concentrations were decreased in hemodialysis patients, whereas proline, citrulline, asparagine, asymmetric dimethylarginine, and hydroxykynurenine levels were increased (P<0.05). Both plasma levels and urinary excretion of citrulline were higher in the group of patients with advanced CKD (CKD stages 2 and 3 versus CKD stages 4 and 5; in plasma: 35.9±16.3 versus 61.8±23.6 µmol/L, P<0.01; in urine: 1.0±1.2 versus 7.1±14.3 µmol/mol creatinine, P<0.001). Plasma asymmetric dimethylarginine levels were higher in advanced CKD (CKD stages 2 and 3, 0.57±0.29; CKD stages 4 and 5, 1.02±0.48, P<0.001), whereas urinary excretion was lower (2.37±0.93 versus 1.51±1.43, P<0.001). Multivariate analyses adjusting on estimated GFR, serum albumin, proteinuria, and other covariates revealed associations between diabetes and plasma citrulline (P=0.02) and between serum sodium and plasma asymmetric dimethylarginine (P=0.03). Plasma tyrosine to phenylalanine and valine to glycine ratios were lower in advanced CKD stages (P<0.01).ConclusionCKD patients have altered plasma and urinary amino acid profiles that are not corrected by dialysis. Depending on solutes, elevated plasma levels were associated with increased or decreased urinary excretion, depicting situations of uremic retention (asymmetric dimethylarginine) or systemic overproduction (citrulline). These results give some insight in the CKD-associated modifications of amino acid metabolism, which may help improve their handling.

Dataset Information

Metabolomic Profiling in Individuals with a Failing Kidney Allograft.

Background

Methods

Results

Conclusions

Publications

Metabolomic Profiling in Individuals with a Failing Kidney Allograft.

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