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


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.


Cardiovascular risk Transplantation Graft survival Kidney 



Asymmetric dimethylarginine


Body surface area


Confidence interval


Diastolic blood pressure


Estimated glomerular filtration rate


Food frequency questionnaire




Glycated hemoglobin


High-density lipoprotein


Human leukocyte antigen


Hazard risk


High-sensitivity C-reactive protein


Interquartile range


Kidney transplantation


Low-density lipoprotein


Lower limit of detection


Nitric oxide


Nitric oxide synthase


N-terminal pro-hormone of brain natriuretic peptide


Parathyroid hormone


Quality control


Renal transplant recipients


Symmetric dimethylarginine


Urinary homoarginine



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 (, 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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