Advertisement

Amino Acids

pp 1–11 | Cite as

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

  • M. Yusof Said
  • 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
  • 43 Downloads

Abstract

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.

Keywords

ADMA homeostasis ADMA metabolism Kidney transplantation Kidney donation 

Abbreviations

ADMA

Asymmetric dimethylarginine

AGXT2

Alanine-glyoxylate aminotransferase 2

BMI

Body mass index

BSA

Body surface area

CKD

Chronic kidney disease

CKD-EPI

Chronic Kidney Disease Epidemiology Collaboration

DBP

Diastolic blood pressure

DDAH

Dimethylarginine dimethylaminohydrolase

DMA

Dimethylamine

eGFR

Estimated glomerular filtration rate

FE

Fractional excretion

GC–MS/MS

Gas chromatography–tandem mass spectrometry

GFR

Glomerular filtration rate

mGFR

Measured glomerular filtration rate

NO

Nitric oxide

PRMT

Protein arginine methyltransferase

RTR

Renal transplant recipient

SBP

Systolic blood pressure

SD

Standard deviation

SDMA

Symmetric dimethylarginine

UHPLC–MS/MS

Ultra-high performance liquid chromatography–tandem mass spectrometry

Notes

Acknowledgements

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.

References

  1. Achan V, Broadhead M, Malaki M et al (2003) Asymmetric dimethylarginine causes hypertension and cardiac dysfunction in humans and is actively metabolized by dimethylarginine dimethylaminohydrolase. Arterioscler Thromb Vasc Biol 23:1455–1459.  https://doi.org/10.1161/01.ATV.0000081742.92006.59 CrossRefGoogle Scholar
  2. American Diabetes Association (2008) Diagnosis and classification of diabetes mellitus. Diabetes Care 31(Suppl 1):S55–S60.  https://doi.org/10.2337/dc08-S055 CrossRefGoogle Scholar
  3. Apperloo AJ, de Zeeuw D, Donker AJ, de Jong PE (1996) Precision of glomerular filtration rate determinations for long-term slope calculations is improved by simultaneous infusion of 125I-iothalamate and 131I-hippuran. J Am Soc Nephrol 7:567–572Google Scholar
  4. Böger RH, Bode-Böger SM, Szuba A et al (1998) Asymmetric dimethylarginine (ADMA): a novel risk factor for endothelial dysfunction: its role in hypercholesterolemia. Circulation 98:1842–1847.  https://doi.org/10.1161/01.CIR.98.18.1842 CrossRefGoogle Scholar
  5. Du Bois D, Du Bois EF (1916) A formula to estimate the approximate surface area if height and weight be known. Nutrition 5:303–311; discussion 312–3. https://doi.org/10.1001/archinte.1916.00080130010002 Google Scholar
  6. Caplin B, Wang Z, Slaviero A et al (2012) Alanine-glyoxylate aminotransferase-2 metabolizes endogenous methylarginines, regulates NO, and controls blood pressure. Arterioscler Thromb Vasc Biol 32:2892–2900.  https://doi.org/10.1161/ATVBAHA.112.254078 CrossRefGoogle Scholar
  7. Chen KW, Wu MWF, Chen Z et al (2016) Compensatory hypertrophy after living donor nephrectomy. Transplant Proc 48:716–719.  https://doi.org/10.1016/j.transproceed.2015.12.082du CrossRefGoogle Scholar
  8. Engeli S, Tsikas D, Lehmann AC et al (2012) Influence of dietary fat ingestion on asymmetrical dimethylarginine in lean and obese human subjects. Nutr Metab Cardiovasc Dis 22:720–726.  https://doi.org/10.1016/j.numecd.2011.01.002 CrossRefGoogle Scholar
  9. Fliser D, Kronenberg F, Kielstein JT et al (2005) Asymmetric dimethylarginine and progression of chronic kidney disease: the mild to moderate kidney disease study. J Am Soc Nephrol 16:2456–2461.  https://doi.org/10.1681/ASN.2005020179 CrossRefGoogle Scholar
  10. Frenay A-RS, van den Berg E, de Borst MH et al (2015) Plasma ADMA associates with all-cause mortality in renal transplant recipients. Amino Acids 47:1941–1949.  https://doi.org/10.1007/s00726-015-2023-0 CrossRefGoogle Scholar
  11. Heymsfield SB, Arteaga C, McManus C et al (1983) Measurement of muscle mass in humans: validity of the 24-hour urinary creatinine method. Am J Clin Nutr 37:478–494.  https://doi.org/10.1093/ajcn/37.3.478 CrossRefGoogle Scholar
  12. Inker LA, Schmid CH, Tighiouart H et al (2012) Estimating glomerular filtration rate from serum creatinine and cystatin C. N Engl J Med 367:20–29.  https://doi.org/10.1056/NEJMoa1114248 CrossRefGoogle Scholar
  13. Jha V, Garcia-Garcia G, Iseki K et al (2013) Chronic kidney disease: global dimension and perspectives. Lancet (London, England) 382:260–272.  https://doi.org/10.1016/S0140-6736(13)60687-X CrossRefGoogle Scholar
  14. Kakimoto Y, Akazawa S (1970) Isolation and identification of N-G, N-G- and N-G, N′-G-dimethyl-arginine, N-epsilon-mono-, di-, and trimethyllysine, and glucosylgalactosyl- and galactosyl-delta-hydroxylysine from human urine. J Biol Chem 245:5751–5758Google Scholar
  15. Kayacelebi AA, Langen J, Weigt-Usinger K et al (2015) Biosynthesis of homoarginine (hArg) and asymmetric dimethylarginine (ADMA) from acutely and chronically administered free l-arginine in humans. Amino Acids 47:1893–1908.  https://doi.org/10.1007/s00726-015-2012-3 CrossRefGoogle Scholar
  16. Kielstein JT, Zoccali C (2005) Asymmetric dimethylarginine: a cardiovascular risk factor and a uremic toxin coming of age? Am J Kidney Dis 46:186–202.  https://doi.org/10.1053/j.ajkd.2005.05.009lin CrossRefGoogle Scholar
  17. Kielstein JT, Impraim B, Simmel S et al (2004) Cardiovascular effects of systemic nitric oxide synthase inhibition with asymmetrical dimethylarginine in humans. Circulation 109:172–177.  https://doi.org/10.1161/01.cir.0000105764.22626.b1 CrossRefGoogle Scholar
  18. Lin KY, Ito A, Asagami T et al (2002) Impaired nitric oxide synthase pathway in diabetes mellitus: role of asymmetric dimethylarginine and dimethylarginine dimethylaminohydrolase. Circulation 106:987–992.  https://doi.org/10.1161/01.cir.0000027109.14149.67 CrossRefGoogle Scholar
  19. Martens-Lobenhoffer J, Rodionov RN, Drust A, Bode-Böger SM (2011) Detection and quantification of α-keto-δ-(NG, NG-dimethylguanidino)valeric acid: a metabolite of asymmetric dimethylarginine. Anal Biochem 419:234–240.  https://doi.org/10.1016/j.ab.2011.08.044 CrossRefGoogle Scholar
  20. Matsuguma K, Ueda S, Yamagishi S-I et al (2006) Molecular mechanism for elevation of asymmetric dimethylarginine and its role for hypertension in chronic kidney disease. J Am Soc Nephrol 17:2176–2183.  https://doi.org/10.1681/asn.2005121379 CrossRefGoogle Scholar
  21. Morris SM (2016) Arginine metabolism revisited. J Nutr 146:2579S–2586S.  https://doi.org/10.3945/jn.115.226621 CrossRefGoogle Scholar
  22. Nijveldt RJ, Van Leeuwen PAM, Van Guldener C et al (2002) Net renal extraction of asymmetrical (ADMA) and symmetrical (SDMA) dimethylarginine in fasting humans. Nephrol Dial Transplant 17:1999–2002CrossRefGoogle Scholar
  23. Ogawa T, Kimoto M, Watanabe H, Sasaoka K (1987) Metabolism of NG, NG- and NG, NG-dimethylarginine in rats. Arch Biochem Biophys 252:526–537.  https://doi.org/10.1016/0003-9861(87)90060-9 CrossRefGoogle Scholar
  24. Rodionov RN, Murry DJ, Vaulman SF et al (2010) Human alanine-glyoxylate aminotransferase 2 lowers asymmetric dimethylarginine and protects from inhibition of nitric oxide production. J Biol Chem 285:5385–5391.  https://doi.org/10.1074/jbc.M109.091280 CrossRefGoogle Scholar
  25. Rodionov RN, Martens-Lobenhoffer J, Brilloff S et al (2014) Role of alanine: glyoxylate aminotransferase 2 in metabolism of asymmetric dimethylarginine in the settings of asymmetric dimethylarginine overload and bilateral nephrectomy. Nephrol Dial Transplant 29:2035–2042.  https://doi.org/10.1093/ndt/gfu236 CrossRefGoogle Scholar
  26. Servillo L, Giovane A, Cautela D et al (2013) The methylarginines NMMA, ADMA, and SDMA are ubiquitous constituents of the main vegetables of human nutrition. Nitric Oxide Biol Chem 30:43–48.  https://doi.org/10.1016/j.niox.2013.02.080 CrossRefGoogle Scholar
  27. Siroen MPC, Van Der Sijp JRM, Teerlink T et al (2005) The human liver clears both asymmetric and symmetric dimethylarginine. Hepatology 41:559–565.  https://doi.org/10.1002/hep.20579 CrossRefGoogle Scholar
  28. Taner T, Iqbal CW, Textor SC et al (2015) Compensatory hypertrophy of the remaining kidney in medically complex living kidney donors over the long term. Transplantation 99:555–559.  https://doi.org/10.1097/tp.0000000000000356 CrossRefGoogle Scholar
  29. Teerlink T (2005) ADMA metabolism and clearance. Vasc Med 10(Suppl 1):S73–S81.  https://doi.org/10.1191/1358863x05vm597oa CrossRefGoogle Scholar
  30. Tojo A, Welch WJ, Bremer V et al (1997) Colocalization of demethylating enzymes and NOS and functional effects of methylarginines in rat kidney. Kidney Int 52:1593–1601CrossRefGoogle Scholar
  31. Tomlinson JAP, Caplin B, Boruc O et al (2015) Reduced renal methylarginine metabolism protects against progressive kidney damage. J Am Soc Nephrol 26:3045–3059.  https://doi.org/10.1681/ASN.2014030280 CrossRefGoogle Scholar
  32. Tsikas D, Schubert B, Gutzki FM et al (2003) Quantitative determination of circulating and urinary asymmetric dimethylarginine (ADMA) in humans by gas chromatography-tandem mass spectrometry as methyl ester tri(N-pentafluoropropionyl) derivative. J Chromatogr B Anal Technol Biomed Life Sci 798:87–99.  https://doi.org/10.1016/j.jchromb.2003.09.001 CrossRefGoogle Scholar
  33. van den Berg E, Engberink MF, Brink EJ et al (2012) Dietary acid load and metabolic acidosis in renal transplant recipients. Clin J Am Soc Nephrol 7:1811–1818.  https://doi.org/10.2215/CJN.04590512 CrossRefGoogle Scholar
  34. van den Berg E, Engberink MF, Brink EJ et al (2013) Dietary protein, blood pressure and renal function in renal transplant recipients. Br J Nutr 109:1463–1470.  https://doi.org/10.1017/S0007114512003455 CrossRefGoogle Scholar
  35. van Londen M, Wijninga AB, de Vries J et al (2018) Estimated glomerular filtration rate for longitudinal follow-up of living kidney donors. Nephrol Dial Transplant 33:1054–1064.  https://doi.org/10.1093/ndt/gfx370 CrossRefGoogle Scholar
  36. Weiner ID, Mitch WE, Sands JM (2015) Urea and ammonia metabolism and the control of renal nitrogen excretion. Clin J Am Soc Nephrol 10:1444–1458.  https://doi.org/10.2215/CJN.10311013 CrossRefGoogle Scholar
  37. Wolf C, Lorenzen JM, Stein S et al (2012) Urinary asymmetric dimethylarginine (ADMA) is a predictor of mortality risk in patients with coronary artery disease. Int J Cardiol 156:289–294.  https://doi.org/10.1016/j.ijcard.2010.11.003 CrossRefGoogle Scholar
  38. Wyss M, Kaddurah-Daouk R (2000) Creatine and creatinine metabolism. Physiol Rev 80:1107–1213.  https://doi.org/10.1152/physrev.2000.80.3.1107 CrossRefGoogle Scholar
  39. Zoccali C, Benedetto FA, Maas R et al (2002) Asymmetric dimethylarginine, C-reactive protein, and carotid intima-media thickness in end-stage renal disease. J Am Soc Nephrol 13:490–496CrossRefGoogle Scholar

Copyright information

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

Authors and Affiliations

  • M. Yusof Said
    • 1
  • 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

Personalised recommendations