Advertisement

Clinical Research in Cardiology

, Volume 107, Issue 3, pp 201–213 | Cite as

Symmetric dimethylarginine (SDMA) outperforms asymmetric dimethylarginine (ADMA) and other methylarginines as predictor of renal and cardiovascular outcome in non-dialysis chronic kidney disease

  • Insa E. Emrich
  • Adam M. Zawada
  • Jens Martens-Lobenhoffer
  • Danilo Fliser
  • Stefan Wagenpfeil
  • Gunnar H. Heine
  • Stefanie M. Bode-Böger
Original Paper

Abstract

Background

Chronic kidney disease (CKD) is associated with increased risk of renal and cardiovascular events. It has been claimed that endogenous methylarginines, asymmetric dimethylarginine (ADMA) and symmetric dimethylarginine (SDMA), are contributing factors. However, earlier studies were partly contradictory and mainly focused on prevalent dialysis patients. Moreover, the potential contribution of degradation products, such as acetylated ADMA and SDMA (AcADMA and AcSDMA) and other methylarginines including L-NG-monomethylarginine (LNMMA) remains unknown. To better understand their potential pathophysiological contribution to renal and cardiovascular events, we aimed to provide a comprehensive analysis of methylarginines in a cohort of patients with non-dialysis CKD.

Methods

Blood samples of 528 patients with CKD KDIGO G2 to G4 were obtained from the CARE FOR HOMe study. Baseline plasma levels of ADMA, SDMA, AcADMA, AcSDMA, and LNMMA were measured by liquid chromatography—tandem mass spectrometry. All patients were followed annually for CKD progression and for incident atherosclerotic cardiovascular events.

Results

During 5.1 ± 2.1 years follow-up, 80 patients displayed CKD progression and 145 patients developed incident atherosclerotic cardiovascular events. In univariate Cox regression analyses, elevated plasma levels of all five metabolites were associated with both CKD progression and atherosclerotic cardiovascular disease. However, adjustment for confounders attenuated the prognostic implications of ADMA, LNMMA, AcADMA and AcSDMA. In contrast, patients in the highest tertile of plasma SDMA remained at highest risk for CKD progression and incident atherosclerotic cardiovascular events in fully adjusted Cox regression analyses.

Conclusion

Our results underline a potential pathophysiological role of SDMA in CKD progression and atherosclerotic cardiovascular disease among non-dialysis CKD patients. SDMA predicts CKD progression and future atherosclerotic cardiovascular events more consistently than other methylarginines. Future experimental and clinical studies should therefore focus upon SDMA rather than upon ADMA.

Keywords

Chronic kidney disease Non-traditional cardiovascular risk factors Renal progression Methylarginines 

Notes

Acknowledgements

The present work was supported by a grant from the Else Kröner-Fresenius-Stiftung. The results presented in this paper have not been published previously in whole or part, except in abstract form.

Author contributions

IEE, AMZ, JML, GHH, DF and SMBB designed research, JML, SMBB, AMZ and IEE conducted research, IEE, GHH and SW analyzed data and performed statistical analysis, IEE, GHH and SMBB wrote the paper. All authors read and approved the final manuscript. The authors have no conflicts of interest.

Compliance with ethical standards

Financial disclosure.

None.

Supplementary material

392_2017_1172_MOESM1_ESM.docx (562 kb)
Supplementary material 1 (DOCX 561 KB)

References

  1. 1.
    Go AS, Chertow GM, Fan D et al (2004) Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization. N Engl J Med 351(13):1296–1305CrossRefPubMedGoogle Scholar
  2. 2.
    Gansevoort RT, Correa-Rotter R, Hemmelgarn BR et al (2013) Chronic kidney disease and cardiovascular risk: epidemiology, mechanisms, and prevention. Lancet 382(9889):339–352CrossRefPubMedGoogle Scholar
  3. 3.
    Hallan SI, Coresh J, Astor BC et al (2006) International comparison of the relationship of chronic kidney disease prevalence and ESRD risk. J Am Soc Nephrol 17(8):2275–2284CrossRefPubMedGoogle Scholar
  4. 4.
    Stahli BE, Gebhard C, Gick M et al. (2017) Outcomes of patients with periprocedural atrial fibrillation undergoing percutaneous coronary intervention for chronic total occlusion. Clin Res Cardiol. https://doi.org/10.1007/s00392-017-1148-4 Google Scholar
  5. 5.
    Fu M, Ahrenmark U, Berglund S et al. (2017) Adherence to optimal heart rate control in heart failure with reduced ejection fraction: insight from a survey of heart rate in heart failure in Sweden (HR-HF study). Clin Res Cardiol. https://doi.org/10.1007/s00392-017-1146-6 PubMedPubMedCentralGoogle Scholar
  6. 6.
    O’Neal WT, Efird JT, Kamel H et al (2015) The association of the QT interval with atrial fibrillation and stroke: the Multi-Ethnic Study of Atherosclerosis. Clin Res Cardiol 104(9):743–750CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Laursen PN, Holmvang L, Kelbaek H et al (2017) Drop-out from cardiovascular magnetic resonance in a randomized controlled trial of ST-elevation myocardial infarction does not cause selection bias on endpoints. Clin Res Cardiol 106(7):525–532CrossRefPubMedGoogle Scholar
  8. 8.
    Lee SY, Hong MK, Shin DH et al (2017) Clinical outcomes of dual antiplatelet therapy after implantation of drug-eluting stents in patients with different cardiovascular risk factors. Clin Res Cardiol 106(3):165–173CrossRefPubMedGoogle Scholar
  9. 9.
    Custodis F, Roggenbuck U, Lehmann N et al (2016) Resting heart rate is an independent predictor of all-cause mortality in the middle aged general population. Clin Res Cardiol 105(7):601–612CrossRefPubMedGoogle Scholar
  10. 10.
    Zeus T, Ketterer U, Leuf D et al (2016) Safety of percutaneous coronary intervention in patients with acute ischemic stroke/transient ischemic attack and acute coronary syndrome. Clin Res Cardiol 105(4):356–363CrossRefPubMedGoogle Scholar
  11. 11.
    Meyer T, Herrrmann-Lingen C, Chavanon ML et al (2015) Higher plasma levels of MR-pro-atrial natriuretic peptide are linked to less anxiety: results from the observational DIAST-CHF study. Clin Res Cardiol 104(7):574–581CrossRefPubMedGoogle Scholar
  12. 12.
    Levey AS, Atkins R, Coresh J et al (2007) Chronic kidney disease as a global public health problem: approaches and initiatives—a position statement from Kidney Disease Improving Global Outcomes. Kidney Int 72(3):247–259CrossRefPubMedGoogle Scholar
  13. 13.
    Kielstein JT, Zoccali C (2005) Asymmetric dimethylarginine: a cardiovascular risk factor and a uremic toxin coming of age? Am J Kidney Dis 46(2):186–202CrossRefPubMedGoogle Scholar
  14. 14.
    Schepers E, Speer T, Bode-Boger SM et al (2014) Dimethylarginines ADMA and SDMA: the real water-soluble small toxins? Semin Nephrol 34(2):97–105CrossRefPubMedGoogle Scholar
  15. 15.
    Willeit P, Freitag DF, Laukkanen JA et al (2015) Asymmetric dimethylarginine and cardiovascular risk: systematic review and meta-analysis of 22 prospective studies. J Am Heart Assoc 4(6):e001833CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Vallance P, Leone A, Calver A et al (1992) Accumulation of an endogenous inhibitor of nitric oxide synthesis in chronic renal failure. The Lancet 339(8793):572–575CrossRefGoogle Scholar
  17. 17.
    Yilmaz MI, Saglam M, Caglar K et al (2006) The determinants of endothelial dysfunction in CKD: oxidative stress and asymmetric dimethylarginine. Am J Kidney Dis 47(1):42–50CrossRefPubMedGoogle Scholar
  18. 18.
    Boger RH, Bode-Boger SM, Thiele W et al (1997) Biochemical evidence for impaired nitric oxide synthesis in patients with peripheral arterial occlusive disease. Circulation 95(8):2068–2074CrossRefPubMedGoogle Scholar
  19. 19.
    Bode-Boger SM, Scalera F, Kielstein JT et al (2006) Symmetrical dimethylarginine: a new combined parameter for renal function and extent of coronary artery disease. J Am Soc Nephrol 17(4):1128–1134CrossRefPubMedGoogle Scholar
  20. 20.
    Kielstein JT, Bode-Boger SM, Frolich JC et al (2003) Asymmetric dimethylarginine, blood pressure, and renal perfusion in elderly subjects. Circulation 107(14):1891–1895CrossRefPubMedGoogle Scholar
  21. 21.
    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(8):2456–2461CrossRefPubMedGoogle Scholar
  22. 22.
    Ravani P, Tripepi G, Malberti F et al (2005) Asymmetrical dimethylarginine predicts progression to dialysis and death in patients with chronic kidney disease: a competing risks modeling approach. J Am Soc Nephrol 16(8):2449–2455CrossRefPubMedGoogle Scholar
  23. 23.
    Hanai K, Babazono T, Nyumura I et al (2009) Asymmetric dimethylarginine is closely associated with the development and progression of nephropathy in patients with type 2 diabetes. Nephrol Dial Transpl 24(6):1884–1888CrossRefGoogle Scholar
  24. 24.
    Kielstein JT, Boger RH, Bode-Boger SM et al (2002) Marked increase of asymmetric dimethylarginine in patients with incipient primary chronic renal disease. J Am Soc Nephrol 13(1):170–176PubMedGoogle Scholar
  25. 25.
    Zoccali C, Bode-Boger S, Mallamaci F et al (2001) Plasma concentration of asymmetrical dimethylarginine and mortality in patients with end-stage renal disease: a prospective study. Lancet 358(9299):2113–2117CrossRefPubMedGoogle Scholar
  26. 26.
    Shafi T, Hostetter TH, Meyer TW et al. Serum asymmetric and symmetric dimethylarginine and morbidity and mortality in hemodialysis patients. Am J Kidney Dis 2017Google Scholar
  27. 27.
    Schlesinger S, Sonntag SR, Lieb W et al (2016) Asymmetric and symmetric dimethylarginine as risk markers for total mortality and cardiovascular outcomes: a systematic review and meta-analysis of prospective studies. PLoS One 11(11):e0165811CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Busch M, Fleck C, Wolf G et al (2006) Asymmetrical (ADMA) and symmetrical dimethylarginine (SDMA) as potential risk factors for cardiovascular and renal outcome in chronic kidney disease—possible candidates for paradoxical epidemiology? Amino Acids 30(3):225–232CrossRefPubMedGoogle Scholar
  29. 29.
    Tripepi G, Mattace Raso F, Sijbrands E et al (2011) Inflammation and asymmetric dimethylarginine for predicting death and cardiovascular events in ESRD patients. Clin J Am Soc Nephrol 6(7):1714–1721CrossRefPubMedGoogle Scholar
  30. 30.
    Drew DA, Tighiouart H, Scott T et al (2014) Asymmetric dimethylarginine, race, and mortality in hemodialysis patients. Clin J Am Soc Nephrol 9(8):1426–1433CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Aucella F, Maas R, Vigilante M et al (2009) Methylarginines and mortality in patients with end stage renal disease: a prospective cohort study. Atherosclerosis 207(2):541–545CrossRefPubMedGoogle Scholar
  32. 32.
    Mendes Ribeiro AC, Roberts NB, Lane C et al (1996) Accumulation of the endogenous l-arginine analogue NG-monomethyl-l-arginine in human end-stage renal failure patients on regular haemodialysis. Exp Physiol 81(3):475–481CrossRefPubMedGoogle Scholar
  33. 33.
    Torremans A, Marescau B, Vanholder R et al (2003) The low nanomolar levels of N G-monomethylarginine in serum and urine of patients with chronic renal insufficiency are not significantly different from control levels. Amino Acids 24(4):375–381CrossRefPubMedGoogle Scholar
  34. 34.
    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(12):2892–2900CrossRefPubMedGoogle Scholar
  35. 35.
    Martens-Lobenhoffer J, Bode-Boger SM (2015) Amino acid N-acetylation: metabolic elimination of symmetric dimethylarginine as symmetric N(alpha)-acetyldimethylarginine, determined in human plasma and urine by LC-MS/MS. J Chromatogr B Analyt Technol Biomed Life Sci 975:59–64CrossRefPubMedGoogle Scholar
  36. 36.
    Martens-Lobenhoffer J, Rodionov RN, Bode-Boger SM (2014) Determination of asymmetric Nalpha-acetyldimethylarginine in humans: a phase II metabolite of asymmetric dimethylarginine. Anal Biochem 452:25–30CrossRefPubMedGoogle Scholar
  37. 37.
    Rodionov RN, Martens-Lobenhoffer J, Brilloff S et al (2016) Acetylation of asymmetric and symmetric dimethylarginine: an undercharacterized pathway of metabolism of endogenous methylarginines. Nephrol Dial Transpl 31(1):57–63CrossRefGoogle Scholar
  38. 38.
    Grun OS, Herath E, Weihrauch A et al (2012) Does the measurement of the difference of resistive indexes in spleen and kidney allow a selective assessment of chronic kidney injury? Radiology 264(3):894–902CrossRefPubMedGoogle Scholar
  39. 39.
    Wolf A, Zalpour C, Theilmeier G et al (1997) Dietary l-arginine supplementation normalizes platelet aggregation in hypercholesterolemic humans. J Am Coll Cardiol 29(3):479–485CrossRefPubMedGoogle Scholar
  40. 40.
    Boger RH, Bode-Boger SM, Tsao PS et al (2000) An endogenous inhibitor of nitric oxide synthase regulates endothelial adhesiveness for monocytes. J Am Coll Cardiol 36(7):2287–2295CrossRefPubMedGoogle Scholar
  41. 41.
    Boger RH, Bode-Boger SM, Kienke S et al (1998) Dietary l-arginine decreases myointimal cell proliferation and vascular monocyte accumulation in cholesterol-fed rabbits. Atherosclerosis 136(1):67–77CrossRefPubMedGoogle Scholar
  42. 42.
    Zhou YM, Lan X, Guo HB et al (2014) Rho/ROCK signal cascade mediates asymmetric dimethylarginine-induced vascular smooth muscle cells migration and phenotype change. Biomed Res Int 2014:683707PubMedPubMedCentralGoogle Scholar
  43. 43.
    Boger RH, Bode-Boger SM, Mugge A et al (1995) Supplementation of hypercholesterolaemic rabbits with l-arginine reduces the vascular release of superoxide anions and restores NO production. Atherosclerosis 117(2):273–284CrossRefPubMedGoogle Scholar
  44. 44.
    Hogg N, Kalyanaraman B, Joseph J et al (1993) Inhibition of low-density lipoprotein oxidation by nitric oxide. Potential role in atherogenesis. FEBS Lett 334(2):170–174CrossRefPubMedGoogle Scholar
  45. 45.
    Closs EI, Basha FZ, Habermeier A et al (1997) Interference of l-arginine analogues with l-arginine transport mediated by the y + carrier hCAT-2B. Nitric Oxide 1(1):65–73CrossRefPubMedGoogle Scholar
  46. 46.
    Zewinger S, Kleber ME, Rohrer L et al. (2017) Symmetric dimethylarginine, high-density lipoproteins and cardiovascular disease. Eur Heart J 38(20):1597–1607CrossRefPubMedGoogle Scholar
  47. 47.
    Speer T, Rohrer L, Blyszczuk P et al (2013) Abnormal high-density lipoprotein induces endothelial dysfunction via activation of Toll-like receptor-2. Immunity 38(4):754–768CrossRefPubMedGoogle Scholar
  48. 48.
    Schwedhelm E, Boger RH (2011) The role of asymmetric and symmetric dimethylarginines in renal disease. Nat Rev Nephrol 7(5):275–285CrossRefPubMedGoogle Scholar
  49. 49.
    Kielstein JT, Salpeter SR, Bode-Boeger SM et al (2006) Symmetric dimethylarginine (SDMA) as endogenous marker of renal function–a meta-analysis. Nephrol Dial Transpl 21(9):2446–2451CrossRefGoogle Scholar
  50. 50.
    Lu TM, Chung MY, Lin CC et al (2011) Asymmetric dimethylarginine and clinical outcomes in chronic kidney disease. Clin J Am Soc Nephrol 6(7):1566–1572CrossRefPubMedGoogle Scholar
  51. 51.
    Young JM, Terrin N, Wang X et al (2009) Asymmetric dimethylarginine and mortality in stages 3 to 4 chronic kidney disease. Clin J Am Soc Nephrol 4(6):1115–1120CrossRefPubMedPubMedCentralGoogle Scholar
  52. 52.
    Hov GG, Aasarod KI, Sagen E et al (2015) Arginine, dimethylated arginine and homoarginine in relation to cardiovascular risk in patients with moderate chronic kidney disease. Clin Biochem 48(10–11):646–651CrossRefPubMedGoogle Scholar
  53. 53.
    Frenay AR, van den Berg E, de Borst MH et al (2015) Plasma ADMA associates with all-cause mortality in renal transplant recipients. Amino Acids 47(9):1941–1949CrossRefPubMedPubMedCentralGoogle Scholar
  54. 54.
    Abedini S, Meinitzer A, Holme I et al (2010) Asymmetrical dimethylarginine is associated with renal and cardiovascular outcomes and all-cause mortality in renal transplant recipients. Kidney Int 77(1):44–50CrossRefPubMedGoogle Scholar
  55. 55.
    Kidney Disease: Improving Global Outcomes (KDIGO) CKD Work Group. KDIGO clinical practice guideline for the evaluation and management of chronic kidney disease. Kidney Int Suppl 2013;3:1–150Google Scholar
  56. 56.
    Siegerink B, Maas R, Vossen CY et al (2013) Asymmetric and symmetric dimethylarginine and risk of secondary cardiovascular disease events and mortality in patients with stable coronary heart disease: the KAROLA follow-up study. Clin Res Cardiol 102(3):193–202CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany 2017

Authors and Affiliations

  • Insa E. Emrich
    • 1
  • Adam M. Zawada
    • 1
  • Jens Martens-Lobenhoffer
    • 2
  • Danilo Fliser
    • 1
  • Stefan Wagenpfeil
    • 3
  • Gunnar H. Heine
    • 1
  • Stefanie M. Bode-Böger
    • 2
  1. 1.Internal Medicine IV, Nephrology and HypertensionSaarland University Medical CenterHomburgGermany
  2. 2.Institute of Clinical PharmacologyOtto-von-Guericke UniversityMagdeburgGermany
  3. 3.Institute for Medical Biometry, Epidemiology and Medical InformaticsSaarland University Faculty of MedicineHomburgGermany

Personalised recommendations