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

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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.

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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

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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.

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Authors and Affiliations

  1. Core Unit Proteomics, Institute of Toxicology, Hannover Medical School, Carl-Neuberg-Str. 1, 30625, Hannover, Germany

    Erik Hanff, Arslan Arinc Kayacelebi & Dimitrios Tsikas

  2. Division of Nephrology, Department of Internal Medicine, University Medical Center Groningen and University of Groningen, Groningen, The Netherlands

    Mohammad Yusof Said, Adrian Post, Isidor Minovic, Martin H. de Borst & Stephan J. L. Bakker

  3. Division of Acute Medicine, Department of Internal Medicine, University Medical Center Groningen and University of Groningen, Groningen, The Netherlands

    Else van den Berg

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

    Harry van Goor

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  1. Erik Hanff
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Hanff, E., Said, M.Y., Kayacelebi, A.A. et al. High plasma guanidinoacetate-to-homoarginine ratio is associated with high all-cause and cardiovascular mortality rate in adult renal transplant recipients. Amino Acids 51, 1485–1499 (2019). https://doi.org/10.1007/s00726-019-02783-6

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