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Development and validation of GC–MS methods for the comprehensive analysis of amino acids in plasma and urine and applications to the HELLP syndrome and pediatric kidney transplantation: evidence of altered methylation, transamidination, and arginase activity

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Abstract

We developed and validated gas chromatography–mass spectrometry (GC–MS) methods for the simultaneous measurement of amino acids and their metabolites in 10-µL aliquots of human plasma and urine. De novo synthesized trideutero-methyl esters were used as internal standards. Plasma proteins were precipitated by acidified methanol and removed by centrifugation. Supernatants and native urine were evaporated to dryness. Amino acids were first esterified using 2 M HCl in methanol and then amidated using pentafluoropropionic anhydride for electron-capture negative-ion chemical ionization. Time programmes were used for the gas chromatograph oven and the selected-ion monitoring of specific anions. The GC–MS methods were applied in clinical studies on the HELLP syndrome and pediatric kidney transplantation (KTx) focusing on l-arginine-related pathways. We found lower sarcosine (N-methylglycine) and higher asymmetric dimethylarginine (ADMA) plasma concentrations in HELLP syndrome women (n = 7) compared to healthy pregnant women (n = 5) indicating altered methylation. In plasma of pediatric KTx patients, lower guanidinoacetate and homoarginine concentrations were found in plasma but not in urine samples of patients treated with standard mycophenolate mofetil-based immunosuppression (MMF; n = 22) in comparison to matched patients treated with MMF-free immunosuppression (n = 22). On average, the global arginine bioavailability ratio was by about 40% lower in the MMF group compared to the EVR group (P = 0.004). Mycophenolate, the major pharmacologically active metabolite of MMF, is likely to inhibit the arginine:glycine amidinotransferase (AGAT), and to enhance arginase activity in leukocytes and other types of cell of MMF-treated children.

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Abbreviations

AA:

Amino acid

ADMA:

Asymmetric dimethylarginine

AGAT:

Arginine:glycine amidinotransferase

CKD:

Chronic kidney disease

CNI:

Calcineurin inhibitor

DDAH:

Dimethylarginine dimethylaminohydrolase

DMA:

Dimethylamine

ECNICI:

Electron-capture negative-ion chemical ionization

EVR:

Everolimus

GAA:

Guanidinoacetate

GABR:

Global arginine bioavailability ratio

GAMT:

Guanidinoacetate N-methyltransferase

GATM:

Glycine:arginine transamidinase

GC–MS:

Gas chromatography–mass spectrometry

GNMT:

Glycine N-methyltransferase

hArg:

Homoarginine

HELLP:

Hemolysis, elevated liver enzymes, low platelet

IQR:

Interquartile range

IS:

Internal standard

KTx:

Kidney transplantation

LOD:

Limit of detection

LOQ:

Limit of quantification

Me:

Methyl

MeOH:

Methanol

MMF:

Mycophenolate mofetil

MPA:

Mycophenolic acid

m/z :

Mass-to-charge ratio

NMDAR:

N-Methyl-d-aspartate glutamate receptor

NO:

Nitric oxide

NOS:

Nitric oxide synthase

OH-Pro:

Hydroxyproline

PFP:

Pentafluoropropionyl

PFPA:

Pentafluoropropionic anhydride

PRMT:

Protein-arginine methyltransferase

QC:

Quality control

rLLOQ:

Relative low limit of quantification

Sar:

Sarcosine

SDMA:

Symmetric dimethylarginine

SIM:

Selected-ion monitoring

S/N or SN:

Signal-to-noise ratio

TIC:

Total ion current

UNOxR:

Urinary nitrate-to-nitrite molar ratio

WoG:

Week of gestation

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Authors and Affiliations

  1. Core Unit Proteomics, Hannover Medical School, Institute of Toxicology, Carl-Neuberg-Strasse 1, 30625, Hannover, Germany

    Erik Hanff, Alexander Bollenbach, Arslan Arinc Kayacelebi & Dimitrios Tsikas

  2. Department of Pediatric Kidney, Liver and Metabolic Diseases, Hannover Medical School, Hannover, Germany

    Stephan Ruben, Martin Kreuzer & Dieter Haffner

  3. Department of Pediatrics, Hannover Medical School, Hannover, Germany

    Anibh Martin Das

  4. Department of Obstetrics and Gynecology, Hannover Medical School, Hannover, Germany

    Frauke von Versen-Höynck & Constantin von Kaisenberg

  5. Department of Urology and Urological Oncology, Hannover Medical School, Hannover, Germany

    Stefan Ückert

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  1. Erik Hanff
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  2. Stephan Ruben
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Hanff, E., Ruben, S., Kreuzer, M. et al. Development and validation of GC–MS methods for the comprehensive analysis of amino acids in plasma and urine and applications to the HELLP syndrome and pediatric kidney transplantation: evidence of altered methylation, transamidination, and arginase activity. Amino Acids 51, 529–547 (2019). https://doi.org/10.1007/s00726-018-02688-w

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