Amino Acids

, Volume 51, Issue 3, pp 565–575 | Cite as

Effect of renal function on homeostasis of asymmetric dimethylarginine (ADMA): studies in donors and recipients of renal transplants

  • M. Yusof SaidEmail author
  • Rianne M. Douwes
  • Marco van Londen
  • Isidor Minović
  • Anne-Roos Frenay
  • Martin H. de Borst
  • Else van den Berg
  • M. Rebecca Heiner-Fokkema
  • Arslan Arinc Kayacelebi
  • Alexander Bollenbach
  • Harry van Goor
  • Gerjan Navis
  • Dimitrios Tsikas
  • Stephan J. L. Bakker
Original Article


Asymmetric dimethylarginine (ADMA) is a methylated form of arginine and an endogenous nitric oxide synthase inhibitor. Renal function decline is associated with increase of plasma ADMA in chronic kidney disease populations. It is yet unknown how isolated renal function impairment affects ADMA homeostasis in healthy humans. Here, we measured plasma concentrations and urinary excretion of ADMA using GC–MS/MS in 130 living kidney donors before and at 1.6 (1.6–1.9) months after donation. We additionally analyzed 201 stable renal transplant recipients (RTR) that were included > 1 year after transplantation, as a model for kidney disease in the context of single kidney state. We measured true glomerular filtration rate (mGFR) using 125I-iothalamate. To study enzymatic metabolism of ADMA, we also measured l-citrulline as primary metabolite. Mean age was 52 ± 10 years in donors and 54 ± 12 years in RTR. Renal function was significantly reduced from pre- to post-donation (mGFR: 104 ± 17 vs. 66 ± 10 ml/min per 1.73 m2 BSA, − 36 ± 7%, P < 0.001). Urinary ADMA excretion strongly and significantly decreased from pre- to post-donation (60.6 ± 16.0 vs. 40.5 ± 11.5 µmol/24 h, − 31.5 ± 21.5%, P < 0.001), while plasma ADMA increased only slightly (0.53 ± 0.08 vs. 0.58 ± 0.09 µM, 11.1 ± 20.1%, P < 0.001). Compared to donors post-donation, RTR had significantly worse renal function (mGFR: 49 ± 18 ml/min/1.73 m2, − 25 ± 2%, P < 0.001) and lower urinary ADMA excretion (30.9 ± 12.4 µmol/24 h, − 23.9 ± 3.4%, P < 0.001). Plasma ADMA in RTR (0.60 ± 0.11 µM) did not significantly differ from donors post-donation (2.9 ± 1.9%, P = 0.13). Plasma citrulline was inversely associated with mGFR (st. β: − 0.23, P < 0.001), consistent with increased ADMA metabolism to citrulline with lower GFR. In both groups, the response of urinary ADMA excretion to renal function loss was much larger than that of plasma ADMA. As citrulline was associated with GFR, our data indicate that with renal function impairment, a decrease in urinary ADMA excretion does not lead to a corresponding increase in plasma ADMA, likely due to enhanced metabolism, thus allowing for lower renal excretion of ADMA.


ADMA homeostasis ADMA metabolism Kidney transplantation Kidney donation 



Asymmetric dimethylarginine


Alanine-glyoxylate aminotransferase 2


Body mass index


Body surface area


Chronic kidney disease


Chronic Kidney Disease Epidemiology Collaboration


Diastolic blood pressure


Dimethylarginine dimethylaminohydrolase




Estimated glomerular filtration rate


Fractional excretion


Gas chromatography–tandem mass spectrometry


Glomerular filtration rate


Measured glomerular filtration rate


Nitric oxide


Protein arginine methyltransferase


Renal transplant recipient


Systolic blood pressure


Standard deviation


Symmetric dimethylarginine


Ultra-high performance liquid chromatography–tandem mass spectrometry



N. de Ruiter, E. Jonkers, P de Blaauw, and J. van der Krogt, technicians of the laboratory of metabolic diseases, are gratefully acknowledged for citrulline and arginine analyses. Funding was provided by Stichting voor de Technische Wetenschappen (NL) & DSM Animal Nutrition and Health (14939).

Compliance with ethical standards

Conflict of interest

R. M. Douwes is supported by the applied science division of the Dutch Technology Foundation (Stichting voor Technische Wetenschappen-Nederlandse Organisatie voor Wetenschappelijk Onderzoek; STW-NWO) in a partnership program with DSM Animal Nutrition and Health, a manufacturer of animal nutrition and nutritional products; project number: 14939.

Informed consent and ethical approval

All procedures performed in this study were in accordance with the ethical standards of the institutional and national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. This article does not contain any studies with animals performed by any of the authors. Informed consent was obtained from all individual participants included in the study.


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Copyright information

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

Authors and Affiliations

  • M. Yusof Said
    • 1
    Email author
  • Rianne M. Douwes
    • 1
  • Marco van Londen
    • 1
  • Isidor Minović
    • 2
  • Anne-Roos Frenay
    • 3
  • Martin H. de Borst
    • 1
    • 6
  • Else van den Berg
    • 1
  • M. Rebecca Heiner-Fokkema
    • 2
  • Arslan Arinc Kayacelebi
    • 4
  • Alexander Bollenbach
    • 4
  • Harry van Goor
    • 5
    • 6
  • Gerjan Navis
    • 1
    • 6
  • Dimitrios Tsikas
    • 4
  • Stephan J. L. Bakker
    • 1
    • 6
  1. 1.Division of Nephrology, Department of Internal MedicineUniversity Medical Center Groningen, Sector A, University of GroningenGroningenThe Netherlands
  2. 2.Department of Laboratory MedicineUniversity Medical Center Groningen, University of GroningenGroningenThe Netherlands
  3. 3.Department of Gynecology and ObstetricsAmsterdam University Medical Center, University of AmsterdamAmsterdamThe Netherlands
  4. 4.Institute of Toxicology, Core Unit ProteomicsHannover Medical SchoolHannoverGermany
  5. 5.Department of Pathology and Medical BiologyUniversity Medical Center Groningen, University of GroningenGroningenThe Netherlands
  6. 6.Groningen Kidney CenterGroningenThe Netherlands

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