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Uremic solutes and risk of end-stage renal disease in type 2 diabetes: metabolomic study.

ABSTRACT: Here we studied plasma metabolomic profiles as determinants of progression to end-stage renal disease (ESRD) in patients with type 2 diabetes (T2D). This nested case-control study evaluated 40 cases who progressed to ESRD during 8-12 years of follow-up and 40 controls who remained alive without ESRD from the Joslin Kidney Study cohort. Controls were matched with cases for baseline clinical characteristics, although controls had slightly higher eGFR and lower levels of urinary albumin excretion than cases. Plasma metabolites at baseline were measured by mass spectrometry-based global metabolomic profiling. Of the named metabolites in the library, 262 were detected in at least 80% of the study patients. The metabolomic platform recognized 78 metabolites previously reported to be elevated in ESRD (uremic solutes). Sixteen were already elevated in the baseline plasma of our cases years before ESRD developed. Other uremic solutes were either not different or not commonly detectable. Essential amino acids and their derivatives were significantly depleted in the cases, whereas certain amino acid-derived acylcarnitines were increased. All findings remained statistically significant after adjustment for differences between study groups in albumin excretion rate, eGFR, or HbA1c. Uremic solute differences were confirmed by quantitative measurements. Thus, abnormal plasma concentrations of putative uremic solutes and essential amino acids either contribute to progression to ESRD or are a manifestation of an early stage(s) of the disease process that leads to ESRD in T2D.

SUBMITTER: Niewczas MA

PROVIDER: S-EPMC4072128 | biostudies-literature | 2014 May

REPOSITORIES: biostudies-literature

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Uremic solutes and risk of end-stage renal disease in type 2 diabetes: metabolomic study.

Niewczas Monika A MA Sirich Tammy L TL Mathew Anna V AV Skupien Jan J Mohney Robert P RP Warram James H JH Smiles Adam A Huang Xiaoping X Walker Walker W Byun Jaeman J Karoly Edward D ED Kensicki Elizabeth M EM Berry Gerard T GT Bonventre Joseph V JV Pennathur Subramaniam S Meyer Timothy W TW Krolewski Andrzej S AS

Kidney international 20140115 5

Here we studied plasma metabolomic profiles as determinants of progression to end-stage renal disease (ESRD) in patients with type 2 diabetes (T2D). This nested case-control study evaluated 40 cases who progressed to ESRD during 8-12 years of follow-up and 40 controls who remained alive without ESRD from the Joslin Kidney Study cohort. Controls were matched with cases for baseline clinical characteristics, although controls had slightly higher eGFR and lower levels of urinary albumin excretion t ...[more]

PMID: 24429397

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Project description:BACKGROUND: Chronic kidney disease (CKD) is characterized by the progressive accumulation of various potential toxic solutes. Furthermore, uremic plasma is a complex mixture hampering accurate determination of uremic toxin levels and the identification of novel uremic solutes. METHODS: In this study, we applied (1)H-nuclear magnetic resonance (NMR) spectroscopy, following three distinct deproteinization strategies, to determine differences in the plasma metabolic status of stage 3-4 CKD patients and healthy controls. Moreover, the human renal proximal tubule cell line (ciPTEC) was used to study the influence of newly indentified uremic solutes on renal phenotype and functionality. RESULTS: Protein removal via ultrafiltration and acetonitrile precipitation are complementary techniques and both are required to obtain a clear metabolome profile. This new approach, revealed that a total of 14 metabolites were elevated in uremic plasma. In addition to confirming the retention of several previously identified uremic toxins, including p-cresyl sulphate, two novel uremic retentions solutes were detected, namely dimethyl sulphone (DMSO2) and 2-hydroxyisobutyric acid (2-HIBA). Our results show that these metabolites accumulate in non-dialysis CKD patients from 9±7 µM (control) to 51±29 µM and from 7 (0-9) µM (control) to 32±15 µM, respectively. Furthermore, exposure of ciPTEC to clinically relevant concentrations of both solutes resulted in an increased protein expression of the mesenchymal marker vimentin with more than 10% (p<0.05). Moreover, the loss of epithelial characteristics significantly correlated with a loss of glucuronidation activity (Pearson r?=?-0.63; p<0.05). In addition, both solutes did not affect cell viability nor mitochondrial activity. CONCLUSIONS: This study demonstrates the importance of sample preparation techniques in the identification of uremic retention solutes using (1)H-NMR spectroscopy, and provide insight into the negative impact of DMSO2 and 2-HIBA on ciPTEC, which could aid in understanding the progressive nature of renal disease.

Dataset Information

Uremic solutes and risk of end-stage renal disease in type 2 diabetes: metabolomic study.

Publications

Uremic solutes and risk of end-stage renal disease in type 2 diabetes: metabolomic study.

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