Advertisement

Amino Acids

pp 1–10 | Cite as

l-Homoarginine and its AGXT2-metabolite GOCA in chronic kidney disease as markers for clinical status and prognosis

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

Abstract

Plasma concentrations of l-homoarginine (hArg) are an emerging marker for clinical status and prognosis in renal and cardiovascular disease. Lowered hArg concentrations are associated with higher risk for these conditions, although a clear pathophysiological explanation for this association has not been established. Baseline plasma samples of patients with different stages of chronic kidney disease (CKD) (n = 527) were obtained from the CARE FOR HOMe study and were analyzed for hArg and, for the first time, its metabolite 6-guanidino-2-oxocaproic acid (GOCA) by isotope dilution LC–MS/MS methods. GOCA is converted from hArg by the enzyme alanine:glyoxylate aminotransferase 2 (AGXT2), which is also in the focus of current cardiovascular research. hArg levels ranged from 0.20–4.01 µmol/L with a median of 1.42 µmol/L, whereas GOCA levels were 0.08–25.82 nmol/L with a median of 1.45 nmol/L. hArg levels in the highest tertile (≥ 1.71 µmol/L) were associated with significantly lower risk for reaching the renal (hazard ratio 0.369, 95% confidence interval 0.028–0.655) or cardiovascular (HR 0.458, CI 0.295–0.712) endpoints in univariate Cox regression analysis. Inversely, GOCA levels in the highest tertile (≥ 2.13 nmol/L) were associated with increased renal (HR 3.807, CI 1.963–7.381) and cardiovascular (HR 1.611, CI 1.041–2.495) risk. A decreased ratio between hArg and GOCA predicted even more pronounced the risks for renal (HR 0.178, CI 0.087–0.363) and cardiovascular (HR 0.447, CI 0.281–0.709) events. However, adjustment for the confounders eGFR and albuminuria attenuated these findings. A pathophysiological role of an increased activity of AGXT2 in CKD should be evaluated in future clinical studies.

Keywords

l-Homoarginine GOCA AGXT2 Human plasma LC–MS/MS 

Notes

Acknowledgement

The present work was supported by a grant from the Else Kröner-Fresenius-Stiftung.

Compliance with ethical standards

Conflict of interest

The authors declare that they do not have any conflict of interest.

Research involving human participants and/or animals

This study involved human participants. It was approved by the local Ethics Committee and was conducted according to the Declaration of Helsinki.

Informed consent

All participants enrolled in this study provided written informed consent according to the Declaration of Helsinki.

References

  1. Atzler D, Schwedhelm E, Choe Cu (2015) l-Homoarginine and cardiovascular disease. Curr Opin Clin Nutr Metab Care 18:83–88CrossRefPubMedGoogle Scholar
  2. Atzler D, Cracowski JL, Cordts K, Boger RH, Humbert M, Schwedhelm E (2016) Homoarginine predicts mortality in treatment-naive patients with pulmonary arterial hypertension. Int J Cardiol 217:12–15CrossRefPubMedGoogle Scholar
  3. Choe CU, Atzler D, Wild PS, Carter AM, Boger RH, Ojeda F, Simova O, Stockebrand M, Lackner K, Nabuurs C, Marescau B, Streichert T, Muller C, Luneburg N, de Deyn PP, Benndorf RA, Baldus S, Gerloff C, Blankenberg S, Heerschap A, Grant PJ, Magnus T, Zeller T, Isbrandt D, Schwedhelm E (2013) Homoarginine levels are regulated by l-arginine: glycine amidinotransferase and affect stroke outcome: results from human and murine studies. Circulation 128:1451–1461CrossRefPubMedGoogle Scholar
  4. Cooke JP (2004) Asymmetrical dimethylarginine: the Über marker? Circulation 109:1813–1818CrossRefPubMedGoogle Scholar
  5. Cullen ME, Yuen AHY, Felkin LE, Smolenski RT, Hall JL, Grindle S, Miller LW, Birks EJ, Yacoub MH, Barton PJR (2006) Myocardial expression of the arginine: glycine amidinotransferase gene is elevated in heart failure and normalized after recovery: potential implications for local creatine synthesis. Circulation 114:I-16–I-20.  https://doi.org/10.1161/circulationaha.105.000448 CrossRefGoogle Scholar
  6. Davids M, Ndika JDT, Salomons GS, Blom HJ, Teerlink T (2012) Promiscuous activity of arginine:glycine amidinotransferase is responsible for the synthesis of the novel cardiovascular risk factor homoarginine. FEBS Lett 586:3653–3657CrossRefPubMedGoogle Scholar
  7. Drechsler C, Kollerits B, Meinitzer A, März W, Ritz E, König P, Neyer U, Pilz S, Wanner C, Kronenberg F (2013) Homoarginine and progression of chronic kidney disease: results from the mild to moderate kidney disease study. PLoS One 8:e63560.  https://doi.org/10.1371/journal.pone.0063560 CrossRefPubMedPubMedCentralGoogle Scholar
  8. Drechsler C, Pihlstrøm H, Meinitzer A, Pilz S, Tomaschitz A, Abedini S, Fellstrom B, Jardine AG, Wanner C, März W, Holdaas H (2015) Homoarginine and clinical outcomes in renal transplant recipients: results from the assessment of lescol in renal transplantation study. Transplantation 99:1470–1476.  https://doi.org/10.1097/TP.0000000000000568 CrossRefPubMedGoogle Scholar
  9. Emrich IE, Zawada AM, Martens-Lobenhoffer J, Fliser D, Wagenpfeil S, Heine GH, Bode-Böger SM (2018) Symmetric dimethylarginine (SDMA) outperforms asymmetric dimethylarginine (ADMA) and other methylarginines as predictor of renal and cardiovascular outcome in non-dialysis chronic kidney disease. Clin Res Cardiol 107:201–213.  https://doi.org/10.1007/s00392-017-1172-4 CrossRefPubMedGoogle Scholar
  10. Frenay A-RS, Kayacelebi AA, Beckmann B, Soedamah-Muhtu SS, de Borst MH, van den Berg E, van Goor H, Bakker SJL, Tsikas D (2015) High urinary homoarginine excretion is associated with low rates of all-cause mortality and graft failure in renal transplant recipients. Amino Acids 47:1827–1836.  https://doi.org/10.1007/s00726-015-2038-6 CrossRefPubMedGoogle Scholar
  11. Günes DN, Kayacelebi AA, Hanff E, Lundgren J, Redfors B, Tsikas D (2017) Metabolism and distribution of pharmacological homoarginine in plasma and main organs of the anesthetized rat. Amino Acids 49:2033–2044.  https://doi.org/10.1007/s00726-017-2465-7 CrossRefPubMedGoogle Scholar
  12. Hrabak A, Bajor T, Temesi A (1994) Comparison of substrate and inhibitor specificity of arginase and nitric oxide (NO) synthase for arginine analogues and related compounds in murine and rat macrophages. Biochem Biophys Res Commun 198:206–212CrossRefPubMedGoogle Scholar
  13. Hu X-L, Li M-P, Song P-Y, Tang J, Chen X-P (2017) AGXT2: an unnegligible aminotransferase in cardiovascular and urinary systems. J Mol Cell Cardiol 113:33–38.  https://doi.org/10.1016/j.yjmcc.2017.09.010 CrossRefPubMedGoogle Scholar
  14. Kayacelebi AA, Minović I, Hanff E, Frenay A-RS, de Borst MH, Feelisch M, van Goor H, Bakker SJL, Tsikas D (2017) Low plasma homoarginine concentration is associated with high rates of all-cause mortality in renal transplant recipients. Amino Acids 49:1193–1202.  https://doi.org/10.1007/s00726-017-2420-7 CrossRefPubMedGoogle Scholar
  15. Kielstein JT, Salpeter SR, Bode-Böger SM, Cooke JP, Fliser D (2006) Symmetric dimethylarginine (SDMA) as endogenous marker of renal function–a meta-analysis. Nephrol Dial Transplant 21:2446–2451CrossRefPubMedGoogle Scholar
  16. Kittel A, Müller F, König J, Mieth M, Sticht H, Zolk O, Kralj A, Heinrich MR, Fromm MF, Maas R (2014) Alanine-glyoxylate aminotransferase 2 (AGXT2) polymorphisms have considerable impact on methylarginine and beta-aminoisobutyrate metabolism in healthy volunteers. PLoS One 9:e88544CrossRefPubMedPubMedCentralGoogle Scholar
  17. Krisko I, Walker JB (1966) Influence of sex hormones on amidinotransferase levels. Metabolic Control of creatinine biosynthesis. Acta Endocrinol 53:655–662.  https://doi.org/10.1530/acta.0.0530655 PubMedGoogle Scholar
  18. Martens-Lobenhoffer J, Rodionov RN, Drust A, Bode-Böger SM (2011) Detection and quantification of alpha-keto-delta-(N(G), N(G)-dimethylguanidino)valeric acid: a metabolite of asymmetric dimethylarginine. Anal Biochem 419:234–240CrossRefPubMedGoogle Scholar
  19. Martens-Lobenhoffer J, Surdacki A, Bode-Böger S (2013) Fast and precise quantification of l-homoarginine in human plasma by HILIC-isotope dilution-MS/MS. Chromatographia 76:1755–1759CrossRefGoogle Scholar
  20. März W, Meinitzer A, Drechsler C, Pilz S, Krane V, Kleber ME, Fischer J, Winkelmann BR, Böhm BO, Ritz E, Wanner C (2010) Homoarginine, cardiovascular risk, and mortality. Circulation 122:967–975CrossRefPubMedGoogle Scholar
  21. Raedle-Hurst T, Mueller M, Meinitzer A, Maerz W, Dschietzig T (2017) Homoarginine-A prognostic indicator in adolescents and adults with complex congenital heart disease? PLoS One 12:e0184333.  https://doi.org/10.1371/journal.pone.0184333 CrossRefPubMedPubMedCentralGoogle Scholar
  22. Ravani P, Maas R, Malberti F, Pecchini P, Mieth M, Quinn R, Tripepi G, Mallamaci F, Zoccali C (2013) Homoarginine and mortality in pre-dialysis chronic kidney disease (CKD) patients. PLoS One 8:e72694.  https://doi.org/10.1371/journal.pone.0072694 CrossRefPubMedPubMedCentralGoogle Scholar
  23. Reczkowski RS, Ash DE (1994) Rat liver arginase: kinetic mechanism, alternate substrates, and inhibitors. Arch Biochem Biophys 312:31–37.  https://doi.org/10.1006/abbi.1994.1276 CrossRefPubMedGoogle Scholar
  24. Rhee EP, Ho JE, Chen M-H, Shen D, Cheng S, Larson MG, Ghorbani A, Shi X, Helenius IT, O’Donnell CJ, Souza AL, Deik A, Pierce KA, Bullock K, Walford GA, Vasan RS, Florez JC, Clish C, Yeh J-RJ, Wang TJ, Gerszten RE (2013) A genome-wide association study of the human metabolome in a community-based cohort. Cell Metab 18:130–143.  https://doi.org/10.1016/j.cmet.2013.06.013 CrossRefPubMedPubMedCentralGoogle Scholar
  25. Rodionov RN, Martens-Lobenhoffer J, Brilloff S, Hohenstein B, Jarzebska N, Jabs N, Kittel A, Maas R, Weiss N, Bode-Boger SM (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 29:2035–2042CrossRefPubMedGoogle Scholar
  26. Rodionov RN, Oppici E, Martens-Lobenhoffer J, Jarzebska N, Brilloff S, Burdin D, Demyanov A, Kolouschek A, Leiper J, Maas R, Cellini B, Weiss N, Bode-Boger SM (2016) A novel pathway for metabolism of the cardiovascular risk factor homoarginine by alanine:glyoxylate aminotransferase 2. Sci Rep 6:35277CrossRefPubMedPubMedCentralGoogle Scholar
  27. Seppälä I, Kleber ME, Lyytikäinen L-P, Hernesniemi JA, Mäkelä K-M, Oksala N, Laaksonen R, Pilz S, Tomaschitz A, Silbernagel G, Boehm BO, Grammer TB, Koskinen T, Juonala M, Hutri-Kähönen N, Alfthan G, Viikari JSA, Kähonen M, Raitakari OT, März W, Meinitzer A, Lehtimäki T (2014) Genome-wide association study on dimethylarginines reveals novel AGXT2 variants associated with heart rate variability but not with overall mortality. Eur Heart J 35:524–531.  https://doi.org/10.1093/eurheartj/eht447 CrossRefPubMedGoogle Scholar
  28. Tommasi S, Elliot DJ, Da Boit M, Gray SR, Lewis BC, Mangoni AA (2018) Homoarginine and inhibition of human arginase activity: kinetic characterization and biological relevance. Sci Rep 8:3697.  https://doi.org/10.1038/s41598-018-22099-x CrossRefPubMedPubMedCentralGoogle Scholar
  29. Worthmann H, Chen S, Martens-Lobenhoffer J, Li N, Deb M, Tryc AB, Goldbecker A, Dong Q, Kielstein JT, Bode-Böger SM, Weissenborn K (2011) High plasma dimethylarginine levels are associated with adverse clinical outcome after stroke. J Atheroscler Thromb 18:753–761CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag GmbH Austria, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Institute of Clinical PharmacologyOtto-von-Guericke UniversityMagdeburgGermany
  2. 2.Internal Medicine IV, Nephrology and HypertensionSaarland University Medical CenterHomburgGermany
  3. 3.Institute for Medical Biometry, Epidemiology and Medical Informatics, Faculty of MedicineSaarland UniversityHomburgGermany

Personalised recommendations