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Amino Acids

, Volume 47, Issue 9, pp 1827–1836 | Cite as

High urinary homoarginine excretion is associated with low rates of all-cause mortality and graft failure in renal transplant recipients

  • Anne-Roos S. Frenay
  • Arslan Arinc Kayacelebi
  • Bibiana Beckmann
  • Sabita S. Soedamah-Muhtu
  • Martin H. de Borst
  • Else van den Berg
  • Harry van Goor
  • Stephan J. L. Bakker
  • Dimitrios TsikasEmail author
Original Article
Part of the following topical collections:
  1. Homoarginine, Arginine and Relatives

Abstract

Renal transplant recipients (RTR) have an increased cardiovascular risk profile. Low levels of circulating homoarginine (hArg) are a novel risk factor for mortality and the progression of atherosclerosis. The kidney is known as a major source of hArg, suggesting that urinary excretion of hArg (UhArg) might be associated with mortality and graft failure in RTR. hArg was quantified by mass spectrometry in 24-h urine samples of 704 RTR (functioning graft ≥1 year) and 103 healthy subjects. UhArg determinants were identified with multivariable linear regression models. Associations of UhArg with all-cause mortality and graft failure were assessed using multivariable Cox regression analyses. UhArg excretion was significantly lower in RTR compared to healthy controls [1.62 (1.09–2.61) vs. 2.46 (1.65–4.06) µmol/24 h, P < 0.001]. In multivariable linear regression models, body surface area, diastolic blood pressure, eGFR, pre-emptive transplantation, serum albumin, albuminuria, urinary excretion of urea and uric acid and use of sirolimus were positively associated with UhArg, while donor age and serum phosphate were inversely associated (model R 2 = 0.43). During follow-up for 3.1 (2.7–3.9) years, 83 (12 %) patients died and 45 (7 %) developed graft failure. UhArg was inversely associated with all-cause mortality [hazard risk (HR) 0.52 (95 % CI 0.40–0.66), P < 0.001] and graft failure [HR 0.58 (0.42–0.81), P = 0.001]. These associations remained independent of potential confounders. High UhArg levels are associated with reduced all-cause mortality and graft failure in RTR. Kidney-derived hArg is likely to be of particular importance for proper maintenance of cardiovascular and renal systems.

Keywords

Cardiovascular risk Transplantation Graft survival Kidney 

Abbreviations

ADMA

Asymmetric dimethylarginine

BSA

Body surface area

CI

Confidence interval

DBP

Diastolic blood pressure

eGFR

Estimated glomerular filtration rate

FFQ

Food frequency questionnaire

hArg

Homoarginine

HbA1c

Glycated hemoglobin

HDL

High-density lipoprotein

HLA

Human leukocyte antigen

HR

Hazard risk

hsCRP

High-sensitivity C-reactive protein

IQR

Interquartile range

KTx

Kidney transplantation

LDL

Low-density lipoprotein

LOD

Lower limit of detection

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

SDMA

Symmetric dimethylarginine

UhArg

Urinary homoarginine

Notes

Acknowledgments

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 (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 2015

Authors and Affiliations

  • Anne-Roos S. Frenay
    • 1
  • Arslan Arinc Kayacelebi
    • 2
  • Bibiana Beckmann
    • 2
  • Sabita S. Soedamah-Muhtu
    • 3
  • Martin H. de Borst
    • 4
  • Else van den Berg
    • 4
  • Harry van Goor
    • 1
  • Stephan J. L. Bakker
    • 4
  • Dimitrios Tsikas
    • 2
    Email author
  1. 1.Pathology and Medical BiologyUniversity Medical Center Groningen and University of GroningenGroningenThe Netherlands
  2. 2.Centre of Pharmacology and ToxicologyHannover Medical SchoolHannoverGermany
  3. 3.Division of Human NutritionWageningenThe Netherlands
  4. 4.NephrologyUniversity Medical Center Groningen and University of GroningenGroningenThe Netherlands

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