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Amino Acids

, Volume 49, Issue 7, pp 1193–1202 | Cite as

Low plasma homoarginine concentration is associated with high rates of all-cause mortality in renal transplant recipients

  • Arslan Arinc Kayacelebi
  • Isidor Minović
  • Erik Hanff
  • Anne-Roos S. Frenay
  • Martin H. de Borst
  • Martin Feelisch
  • Harry van Goor
  • Stephan J. L. Bakker
  • Dimitrios TsikasEmail author
Original Article

Abstract

In renal transplant recipients (RTR), we recently found that low urinary excretion of homoarginine (hArg) is associated with mortality and graft failure. However, it is not known whether such prospective associations also hold true for plasma concentrations of hArg. In the present study, we therefore determined plasma concentrations of hArg in the same cohort, i.e. in 687 RTR (functioning graft ≥1 year), and in 140 healthy donors, before and after kidney donation. Plasma hArg concentrations were significantly lower in RTR compared to healthy controls [1.24 (0.95–1.63) µM vs. 1.58 (1.31–2.03) µM, P < 0.001], and kidney donation resulted in a decrease in plasma hArg concentration to 1.41 (1.10–1.81) µM (P < 0.001). In RTR, multivariable linear regression analysis revealed BMI (β = 0.124), heart rate (β = −0.091), pre-emptive transplantation (β = 0.078), antidiabetic medication (β = −0.091), eGFR (β = 0.272), plasma PTH (β = −0.098), uric acid (β = 0.137), alkaline phosphatase (β = −0.100), HDL (β = −0.111), NT-pro-BNP (β = −0.166), and urinary urea excretion (β = 0.139) as main determinants of plasma hArg (all P < 0.05). In RTR, plasma hArg concentration was inversely associated with all-cause [hazard ratio (HR) 0.59 (95% CI 0.50–0.70), P < 0.001] and cardiovascular mortality [HR 0.50 (0.39–0.66), P < 0.001], both expressed per standard deviation change in log-transformed hArg, independent of potential confounders. To conclude, our results suggest that the kidney is a major hArg production site and an important modulator of hArg homeostasis in the renal and cardiovascular systems. Moreover, low plasma hArg is independently associated with increased risk of cardiovascular mortality in RTR, which corroborates the cardiovascular importance of preserving kidney function after transplantation.

Keywords

Cardiovascular risk Transplantation Graft survival Kidney 

Abbreviations

ADMA

Asymmetric dimethylarginine

AGAT

l-Arginine:l-glycine amidinotransferase

BSA

Body surface area

BMI

Body mass index

CI

Confidence interval

eGFR

Estimated glomerular filtration rate

GATM

Glycine amidinotransferase

hArg

Homoarginine

HR

Hazard ratio

IQR

Interquartile range

KTx

Kidney transplantation

NO

Nitric oxide

NOS

Nitric oxide synthase

NT-pro-BNP

N-terminal pro-hormone of brain natriuretic peptide

PTH

Parathyroid hormone

QC

Quality control

RTR

Renal transplant recipients

Notes

Acknowledgements

This work was supported by Grants from the Dutch Kidney Foundation (NSN C08-2254, P13-114), by COST Action BM1005: ENOG: European Network on Gasotransmitters (http://www.gasotransmitters.eu), and by the Top Institute Food and Nutrition (A-1003).

Compliance with ethical standards

Ethical statement

The Institutional Review Board approved the study protocol (METc 2008/186), which was in adherence to the Declaration of Helsinki.

Conflict of interest

All authors report no conflicts of interest.

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Copyright information

© Springer-Verlag Wien 2017

Authors and Affiliations

  • Arslan Arinc Kayacelebi
    • 1
  • Isidor Minović
    • 2
  • Erik Hanff
    • 1
  • Anne-Roos S. Frenay
    • 3
  • Martin H. de Borst
    • 2
  • Martin Feelisch
    • 4
  • Harry van Goor
    • 3
  • Stephan J. L. Bakker
    • 2
  • Dimitrios Tsikas
    • 1
    Email author
  1. 1.Centre of Pharmacology and ToxicologyHannover Medical SchoolHannoverGermany
  2. 2.NephrologyUniversity Medical Center Groningen and University of GroningenGroningenThe Netherlands
  3. 3.Pathology and Medical BiologyUniversity Medical Center Groningen and University of GroningenGroningenThe Netherlands
  4. 4.Clinical and Experimental Sciences, Faculty of Medicine, NIHR Southampton Biomedical Research CentreUniversity of Southampton and University Hospital Southampton NHS Foundation TrustSouthamptonUK

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