Publication

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

Hanff, E., Said, M. Y., Kayacelebi, A. A., Post, A., Minovic, I., van den Berg, E., de Borst, M. H., van Goor, H., Bakker, S. J. L. & Tsikas, D., Nov-2019, In : Amino Acids. 51, 10-12, p. 1485-1499 15 p.

Research output: Contribution to journalArticleAcademicpeer-review

APA

Hanff, E., Said, M. Y., Kayacelebi, A. A., Post, A., Minovic, I., van den Berg, E., ... Tsikas, D. (2019). High plasma guanidinoacetate-to-homoarginine ratio is associated with high all-cause and cardiovascular mortality rate in adult renal transplant recipients. Amino Acids, 51(10-12), 1485-1499. https://doi.org/10.1007/s00726-019-02783-6

Author

Hanff, Erik ; Said, Mohammad Yusof ; Kayacelebi, Arslan Arinc ; Post, Adrian ; Minovic, Isidor ; van den Berg, Else ; de Borst, Martin H ; van Goor, Harry ; Bakker, Stephan J L ; Tsikas, Dimitrios. / High plasma guanidinoacetate-to-homoarginine ratio is associated with high all-cause and cardiovascular mortality rate in adult renal transplant recipients. In: Amino Acids. 2019 ; Vol. 51, No. 10-12. pp. 1485-1499.

Harvard

Hanff, E, Said, MY, Kayacelebi, AA, Post, A, Minovic, I, van den Berg, E, de Borst, MH, van Goor, H, Bakker, SJL & Tsikas, D 2019, 'High plasma guanidinoacetate-to-homoarginine ratio is associated with high all-cause and cardiovascular mortality rate in adult renal transplant recipients', Amino Acids, vol. 51, no. 10-12, pp. 1485-1499. https://doi.org/10.1007/s00726-019-02783-6

Standard

High plasma guanidinoacetate-to-homoarginine ratio is associated with high all-cause and cardiovascular mortality rate in adult renal transplant recipients. / Hanff, Erik; Said, Mohammad Yusof; Kayacelebi, Arslan Arinc; Post, Adrian; Minovic, Isidor; van den Berg, Else; de Borst, Martin H; van Goor, Harry; Bakker, Stephan J L; Tsikas, Dimitrios.

In: Amino Acids, Vol. 51, No. 10-12, 11.2019, p. 1485-1499.

Research output: Contribution to journalArticleAcademicpeer-review

Vancouver

Hanff E, Said MY, Kayacelebi AA, Post A, Minovic I, van den Berg E 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. 2019 Nov;51(10-12):1485-1499. https://doi.org/10.1007/s00726-019-02783-6


BibTeX

@article{45666c0272754b9ebf307468e204c7a3,
title = "High plasma guanidinoacetate-to-homoarginine ratio is associated with high all-cause and cardiovascular mortality rate in adult renal transplant recipients",
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] mu M vs. 2.78 [2.89-3.35] mu M (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, ARGININE-CREATINE PATHWAY, RISK-FACTOR HOMOARGININE, ASYMMETRIC DIMETHYLARGININE, GLYCINE AMIDINOTRANSFERASE, GC-MS, SUBSTRATE-SPECIFICITY, BLOOD-PRESSURE, INBORN ERROR, METABOLISM, DEFICIENCY",
author = "Erik Hanff and Said, {Mohammad Yusof} and Kayacelebi, {Arslan Arinc} and Adrian Post and Isidor Minovic and {van den Berg}, Else and {de Borst}, {Martin H} and {van Goor}, Harry and Bakker, {Stephan J L} and Dimitrios Tsikas",
year = "2019",
month = "11",
doi = "10.1007/s00726-019-02783-6",
language = "English",
volume = "51",
pages = "1485--1499",
journal = "Amino Acids",
issn = "0939-4451",
publisher = "SPRINGER WIEN",
number = "10-12",

}

RIS

TY - JOUR

T1 - High plasma guanidinoacetate-to-homoarginine ratio is associated with high all-cause and cardiovascular mortality rate in adult renal transplant recipients

AU - Hanff, Erik

AU - Said, Mohammad Yusof

AU - Kayacelebi, Arslan Arinc

AU - Post, Adrian

AU - Minovic, Isidor

AU - van den Berg, Else

AU - de Borst, Martin H

AU - van Goor, Harry

AU - Bakker, Stephan J L

AU - Tsikas, Dimitrios

PY - 2019/11

Y1 - 2019/11

N2 - 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] mu M vs. 2.78 [2.89-3.35] mu M (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.

AB - 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] mu M vs. 2.78 [2.89-3.35] mu M (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.

KW - Arginine

KW - Cardiovascular risk

KW - Graft survival

KW - Kidney

KW - Transplantation

KW - ARGININE-CREATINE PATHWAY

KW - RISK-FACTOR HOMOARGININE

KW - ASYMMETRIC DIMETHYLARGININE

KW - GLYCINE AMIDINOTRANSFERASE

KW - GC-MS

KW - SUBSTRATE-SPECIFICITY

KW - BLOOD-PRESSURE

KW - INBORN ERROR

KW - METABOLISM

KW - DEFICIENCY

U2 - 10.1007/s00726-019-02783-6

DO - 10.1007/s00726-019-02783-6

M3 - Article

C2 - 31535220

VL - 51

SP - 1485

EP - 1499

JO - Amino Acids

JF - Amino Acids

SN - 0939-4451

IS - 10-12

ER -

ID: 97267764