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Amino Acids

, Volume 51, Issue 10–12, pp 1485–1499 | Cite as

High plasma guanidinoacetate-to-homoarginine ratio is associated with high all-cause and cardiovascular mortality rate in adult renal transplant recipients

  • Erik HanffEmail author
  • Mohammad Yusof Said
  • Arslan Arinc Kayacelebi
  • Adrian Post
  • Isidor Minovic
  • Else van den Berg
  • Martin H. de Borst
  • Harry van Goor
  • Stephan J. L. Bakker
  • Dimitrios Tsikas
Original Article

Abstract

l-Arginine:glycine amidinotransferase (AGAT) is the main producer of the creatine precursor, guanidinoacetate (GAA), and l-homoarginine (hArg). We and others previously reported lower levels of circulating and urinary hArg in renal transplant recipients (RTR) compared to healthy subjects. In adults, hArg emerged as a novel risk factor for renal and cardiovascular adverse outcome. Urinary GAA was found to be lower in children and adolescents with kidney transplants compared to healthy controls. Whether GAA is also a risk factor in the renal and cardiovascular systems of adults, is not yet known. In the present study, we aimed to investigate the significance of circulating GAA and the GAA-to-hArg molar ratio (GAA/hArg) in adult RTR. We hypothesized that GAA/hArg represents a measure of the balanced state of the AGAT activity in the kidneys, and would prospectively allow assessing a potential association between GAA/hArg and long-term outcome in RTR. The median follow-up period was 5.4 years. Confounders and potential mediators of GAA/hArg associations were evaluated with multivariate linear regression analyses, and the association with all-cause and cardiovascular mortality or death-censored graft loss was studied with Cox regression analyses. The study cohort consisted of 686 stable RTR and 140 healthy kidney donors. Median plasma GAA concentration was significantly lower in the RTR compared to the kidney donors before kidney donation: 2.19 [1.77–2.70] µM vs. 2.78 [2.89–3.35] µM (P < 0.001). In cross-sectional multivariable analyses in RTR, HDL cholesterol showed the strongest association with GAA/hArg. In prospective analyses in RTR, GAA/hArg was associated with a higher risk for all-cause mortality (hazard ratio (HR): 1.35 [95% CI 1.19–1.53]) and cardiovascular mortality (HR: 1.46 [95% CI 1.24–1.73]), independent of potential confounders. GAA but not GAA/hArg was associated with death-censored graft loss in crude survival and Cox regression analyses. The association of GAA and death-censored graft loss was lost after adjustment for eGFR. Our study suggests that in the kidneys of RTR, the AGAT-catalyzed biosynthesis of GAA is decreased. That high GAA/hArg is associated with a higher risk for all-cause and cardiovascular mortality may suggest that low plasma hArg is a stronger contributor to these adverse outcomes in RTR than GAA.

Keywords

Arginine Cardiovascular risk Graft survival Kidney Transplantation 

Abbreviations

ADMA

Asymmetric dimethylarginine

AGAT

Arginine:glycine amidinotransferase

BSA

Body surface area

BMI

Body mass index

CI

Confidence interval

CKD

Chronic kidney disease

eGFR

Estimated glomerular filtration rate

GAA

Guanidinoacetate

hArg

Homoarginine

HR

Hazard ratio

IQR

Interquartile range

MMF

Mycophenolate mofetil

NO

Nitric oxide

NOS

Nitric oxide synthase

eNOS

Endothelial 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 (www.gasotransmitters.eu) and by the Top Institute Food and Nutrition (A-1003). This study was based on the TransplantLines Food and Nutrition Biobank and Cohort Study (TxL-FN), which was funded by the Top Institute Food and Nutrition of the Netherlands (Grant A-1003). The study is registered at clinicaltrials.gov under number NCT02811835.

Compliance with ethical standards

Conflict of interest

All authors report no conflict of interest.

Ethical approval

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

Supplementary material

726_2019_2783_MOESM1_ESM.docx (43 kb)
Supplementary material 1 (DOCX 42 kb)

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Copyright information

© Springer-Verlag GmbH Austria, part of Springer Nature 2019

Authors and Affiliations

  • Erik Hanff
    • 1
    Email author
  • Mohammad Yusof Said
    • 2
  • Arslan Arinc Kayacelebi
    • 1
  • Adrian Post
    • 2
  • Isidor Minovic
    • 2
  • Else van den Berg
    • 3
  • Martin H. de Borst
    • 2
  • Harry van Goor
    • 4
  • Stephan J. L. Bakker
    • 2
  • Dimitrios Tsikas
    • 1
  1. 1.Core Unit Proteomics, Institute of ToxicologyHannover Medical SchoolHannoverGermany
  2. 2.Division of Nephrology, Department of Internal MedicineUniversity Medical Center Groningen and University of GroningenGroningenThe Netherlands
  3. 3.Division of Acute Medicine, Department of Internal MedicineUniversity Medical Center Groningen and University of GroningenGroningenThe Netherlands
  4. 4.Department of Pathology and Medical BiologyUniversity Medical Center Groningen and University of GroningenGroningenThe Netherlands

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