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Low plasma homoarginine concentration is associated with high rates of all-cause mortality in renal transplant recipients

Low plasma homoarginine concentration is associated with high rates of all-cause mortality in renal transplant recipients
Low plasma homoarginine concentration is associated with high rates of all-cause mortality in renal transplant recipients

In renal transplant recipients (RTR), we recently found that low urinary excretion of homoarginine (hArg) is associated with mortality and graft failure. However, it is not known whether such prospective associations also hold true for plasma concentrations of hArg. In the present study, we therefore determined plasma concentrations of hArg in the same cohort, i.e. in 687 RTR (functioning graft ≥1 year), and in 140 healthy donors, before and after kidney donation. Plasma hArg concentrations were significantly lower in RTR compared to healthy controls [1.24 (0.95-1.63) µM vs. 1.58 (1.31-2.03) µM, P < 0.001], and kidney donation resulted in a decrease in plasma hArg concentration to 1.41 (1.10-1.81) µM (P < 0.001). In RTR, multivariable linear regression analysis revealed BMI (β = 0.124), heart rate (β = -0.091), pre-emptive transplantation (β = 0.078), antidiabetic medication (β = -0.091), eGFR (β = 0.272), plasma PTH (β = -0.098), uric acid (β = 0.137), alkaline phosphatase (β = -0.100), HDL (β = -0.111), NT-pro-BNP (β = -0.166), and urinary urea excretion (β = 0.139) as main determinants of plasma hArg (all P < 0.05). In RTR, plasma hArg concentration was inversely associated with all-cause [hazard ratio (HR) 0.59 (95% CI 0.50-0.70), P < 0.001] and cardiovascular mortality [HR 0.50 (0.39-0.66), P < 0.001], both expressed per standard deviation change in log-transformed hArg, independent of potential confounders. To conclude, our results suggest that the kidney is a major hArg production site and an important modulator of hArg homeostasis in the renal and cardiovascular systems. Moreover, low plasma hArg is independently associated with increased risk of cardiovascular mortality in RTR, which corroborates the cardiovascular importance of preserving kidney function after transplantation.

Journal Article
0939-4451
1193-1202
Kayacelebi, Arslan Arinc
a604b415-f02a-46ac-be52-2bc4f2e938a9
Minović, Isidor
fab227c4-c980-4e12-91b1-b5d18b7094de
Hanff, Erik
8befb29e-999b-40cd-925e-70f476589531
Frenay, Anne-Roos S.
314506f7-a54f-4950-88fa-d22db328ab1d
de Borst, Martin H.
6353763c-cd68-40ba-8b6d-516578574096
Feelisch, Martin
8c1b9965-8614-4e85-b2c6-458a2e17eafd
van Goor, Harry
6e4f96a5-c749-43b6-a488-6af71f932dc3
Bakker, Stephan J.L.
48ec36f5-acbd-4cc3-82dd-3a8b7cb038f0
Tsikas, Dimitrios
396ecdca-73a0-4fc3-ac8b-e13daf17075d
Kayacelebi, Arslan Arinc
a604b415-f02a-46ac-be52-2bc4f2e938a9
Minović, Isidor
fab227c4-c980-4e12-91b1-b5d18b7094de
Hanff, Erik
8befb29e-999b-40cd-925e-70f476589531
Frenay, Anne-Roos S.
314506f7-a54f-4950-88fa-d22db328ab1d
de Borst, Martin H.
6353763c-cd68-40ba-8b6d-516578574096
Feelisch, Martin
8c1b9965-8614-4e85-b2c6-458a2e17eafd
van Goor, Harry
6e4f96a5-c749-43b6-a488-6af71f932dc3
Bakker, Stephan J.L.
48ec36f5-acbd-4cc3-82dd-3a8b7cb038f0
Tsikas, Dimitrios
396ecdca-73a0-4fc3-ac8b-e13daf17075d

Kayacelebi, Arslan Arinc, Minović, Isidor, Hanff, Erik, Frenay, Anne-Roos S., de Borst, Martin H., Feelisch, Martin, van Goor, Harry, Bakker, Stephan J.L. and Tsikas, Dimitrios (2017) Low plasma homoarginine concentration is associated with high rates of all-cause mortality in renal transplant recipients. Amino Acids, 49 (7), 1193-1202. (doi:10.1007/s00726-017-2420-7).

Record type: Article

Abstract

In renal transplant recipients (RTR), we recently found that low urinary excretion of homoarginine (hArg) is associated with mortality and graft failure. However, it is not known whether such prospective associations also hold true for plasma concentrations of hArg. In the present study, we therefore determined plasma concentrations of hArg in the same cohort, i.e. in 687 RTR (functioning graft ≥1 year), and in 140 healthy donors, before and after kidney donation. Plasma hArg concentrations were significantly lower in RTR compared to healthy controls [1.24 (0.95-1.63) µM vs. 1.58 (1.31-2.03) µM, P < 0.001], and kidney donation resulted in a decrease in plasma hArg concentration to 1.41 (1.10-1.81) µM (P < 0.001). In RTR, multivariable linear regression analysis revealed BMI (β = 0.124), heart rate (β = -0.091), pre-emptive transplantation (β = 0.078), antidiabetic medication (β = -0.091), eGFR (β = 0.272), plasma PTH (β = -0.098), uric acid (β = 0.137), alkaline phosphatase (β = -0.100), HDL (β = -0.111), NT-pro-BNP (β = -0.166), and urinary urea excretion (β = 0.139) as main determinants of plasma hArg (all P < 0.05). In RTR, plasma hArg concentration was inversely associated with all-cause [hazard ratio (HR) 0.59 (95% CI 0.50-0.70), P < 0.001] and cardiovascular mortality [HR 0.50 (0.39-0.66), P < 0.001], both expressed per standard deviation change in log-transformed hArg, independent of potential confounders. To conclude, our results suggest that the kidney is a major hArg production site and an important modulator of hArg homeostasis in the renal and cardiovascular systems. Moreover, low plasma hArg is independently associated with increased risk of cardiovascular mortality in RTR, which corroborates the cardiovascular importance of preserving kidney function after transplantation.

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More information

Accepted/In Press date: 10 April 2017
e-pub ahead of print date: 20 April 2017
Published date: July 2017
Keywords: Journal Article

Identifiers

Local EPrints ID: 413734
URI: https://eprints.soton.ac.uk/id/eprint/413734
ISSN: 0939-4451
PURE UUID: fe71a18c-a82c-44f9-b663-a9df9639ab90
ORCID for Martin Feelisch: ORCID iD orcid.org/0000-0003-2320-1158

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Date deposited: 01 Sep 2017 16:31
Last modified: 10 Dec 2019 01:37

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Contributors

Author: Arslan Arinc Kayacelebi
Author: Isidor Minović
Author: Erik Hanff
Author: Anne-Roos S. Frenay
Author: Martin H. de Borst
Author: Martin Feelisch ORCID iD
Author: Harry van Goor
Author: Stephan J.L. Bakker
Author: Dimitrios Tsikas

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