Low plasma homoarginine concentration is associated with high rates of all-cause mortality in renal transplant recipients
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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.
KeywordsCardiovascular risk Transplantation Graft survival Kidney
Body surface area
Body mass index
Estimated glomerular filtration rate
Nitric oxide synthase
N-terminal pro-hormone of brain natriuretic peptide
Renal transplant recipients
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 (http://www.gasotransmitters.eu), and by the Top Institute Food and Nutrition (A-1003).
Compliance with ethical standards
The Institutional Review Board approved the study protocol (METc 2008/186), which was in adherence to the Declaration of Helsinki.
Conflict of interest
All authors report no conflicts of interest.
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