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

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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.

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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

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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).

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    Authors and Affiliations

    1. Pathology and Medical Biology, University Medical Center Groningen and University of Groningen, Groningen, The Netherlands

      Anne-Roos S. Frenay & Harry van Goor

    2. Centre of Pharmacology and Toxicology, Hannover Medical School, Carl-Neuberg-Str. 1, 30625, Hannover, Germany

      Arslan Arinc Kayacelebi, Bibiana Beckmann & Dimitrios Tsikas

    3. Division of Human Nutrition, Wageningen, The Netherlands

      Sabita S. Soedamah-Muhtu

    4. Nephrology, University Medical Center Groningen and University of Groningen, Groningen, The Netherlands

      Martin H. de Borst, Else van den Berg & Stephan J. L. Bakker

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    1. Anne-Roos S. Frenay
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    2. Arslan Arinc Kayacelebi
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    Correspondence to Dimitrios Tsikas.

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    Ethical statement

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

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    All authors report no conflicts of interest.

    Additional information

    A.-R. S. Frenay and A. A. Kayacelebi have contributed equally to this work and are both first authors.

    S. J. L. Bakker and D. Tsikas are both senior authors.

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    Frenay, AR.S., Kayacelebi, A.A., Beckmann, B. et al. High urinary homoarginine excretion is associated with low rates of all-cause mortality and graft failure in renal transplant recipients. Amino Acids 47, 1827–1836 (2015). https://doi.org/10.1007/s00726-015-2038-6

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