Capillary electrophoresis–mass spectrometry as a powerful tool in biomarker discovery and clinical diagnosis: An update of recent developments

Mischak, Harald; Coon, Joshua J.; Novák, Jan; Weissinger, Eva M.; Schanstra, Joost P.; Dominiczak, Anna F.

doi:10.1002/mas.20205

Cited by 176 publications

(142 citation statements)

References 97 publications

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“…Third, it was questioned whether the greater importance of proteinuria in severe CKD could have influenced the results of urinary AA excretion. Although urine contains protease activity, proteolysis is essentially completed after voiding (31). Unspecific proteolytic cleavage of urinary proteins in vivo may have induced unspecific free AA production.…”

Section: Discussionmentioning

confidence: 99%

Plasma and Urinary Amino Acid Metabolomic Profiling in Patients with Different Levels of Kidney Function

Duranton¹,

Lundin²,

Gayrard³

et al. 2014

Clinical Journal of the American Society of Nephrology

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169

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SummaryBackground and objectives Patients 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, & measurements Urine 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.Results Most 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: 35.9616.3 versus 61.8623.6 mmol/L, P,0.01; in urine: 1.061.2 versus 7.1614.3 mmol/mol creatinine, P,0.001). Plasma asymmetric dimethylarginine levels were higher in advanced CKD (CKD stages 2 and 3, 0.5760.29; CKD stages 4 and 5, 1.0260.48, P,0.001), whereas urinary excretion was lower (2.3760.93 versus 1.5161.43, 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).Conclusion CKD 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.

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Section: Discussionmentioning

confidence: 99%

Plasma and Urinary Amino Acid Metabolomic Profiling in Patients with Different Levels of Kidney Function

Duranton¹,

Lundin²,

Gayrard³

et al. 2014

Clinical Journal of the American Society of Nephrology

Self Cite

169

124

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“…For example, the simultaneous testing of 1000 potential biomarkers at a level of P = 0.05 will yield the erroneous identification of approximately 50 spurious biomarkers by chance. Adjustments for multiple testing correct for this fact (33). There are many approaches that can properly account for multiplicity, including not only frequentist methods, but also false-discovery and Bayesian approaches.…”

Section: Sufficient Information About the Sampling Methodologymentioning

confidence: 99%

Recommendations for Biomarker Identification and Qualification in Clinical Proteomics

Mischak¹,

Allmaier²,

Apweiler³

et al. 2010

Sci. Transl. Med.

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“…[10][11][12] Urinary proteome analysis by capillary electrophoresis (CE) coupled to mass spectrometry (MS) has shown high reproducibility allowing the comparison of the protein and peptide content of thousands of samples. 13 Hence, CE-MS has been used to analyze urine samples from patients with various renal and nonrenal diseases. 14 CE-MS was used for the identification of a panel of 273 urinary peptide biomarkers of CKD (CKD273 classifier) by comparison of the urinary proteome of 379 healthy participants and 230 participants with CKD originating from a variety of renal diseases 15,16 followed by the validation of these findings in independent cohorts.…”

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confidence: 99%

Diagnosis and Prediction of CKD Progression by Assessment of Urinary Peptides

Schanstra

Zürbig

Alkhalaf

et al. 2015

Journal of the American Society of Nephrology

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Progressive CKD is generally detected at a late stage by a sustained decline in eGFR and/or the presence of significant albuminuria. With the aim of early and improved risk stratification of patients with CKD, we studied urinary peptides in a large cross-sectional multicenter cohort of 1990 individuals, including 522 with follow-up data, using proteome analysis. We validated that a previously established multipeptide urinary biomarker classifier performed significantly better in detecting and predicting progression of CKD than the current clinical standard, urinary albumin. The classifier was also more sensitive for identifying patients with rapidly progressing CKD. Compared with the combination of baseline eGFR and albuminuria (area under the curve [AUC]=0.758), the addition of the multipeptide biomarker classifier significantly improved CKD risk prediction (AUC=0.831) as assessed by the net reclassification index (0.303620.065; P,0.001) and integrated discrimination improvement (0.05860.014; P,0.001). Correlation of individual urinary peptides with CKD stage and progression showed that the peptides that associated with CKD, irrespective of CKD stage or CKD progression, were either fragments of the major circulating proteins, suggesting failure of the glomerular filtration barrier sieving properties, or different collagen fragments, suggesting accumulation of intrarenal extracellular matrix. Furthermore, protein fragments associated with progression of CKD originated mostly from proteins related to inflammation and tissue repair. Results of this study suggest that urinary proteome analysis might significantly improve the current state of the art of CKD detection and outcome prediction and that identification of the urinary peptides allows insight into various ongoing pathophysiologic processes in CKD.

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Capillary electrophoresis–mass spectrometry as a powerful tool in biomarker discovery and clinical diagnosis: An update of recent developments

Cited by 176 publications

References 97 publications

Plasma and Urinary Amino Acid Metabolomic Profiling in Patients with Different Levels of Kidney Function

Plasma and Urinary Amino Acid Metabolomic Profiling in Patients with Different Levels of Kidney Function

Recommendations for Biomarker Identification and Qualification in Clinical Proteomics

Diagnosis and Prediction of CKD Progression by Assessment of Urinary Peptides

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