l-Homoarginine and its AGXT2-metabolite GOCA in chronic kidney disease as markers for clinical status and prognosis
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.
Keywordsl-Homoarginine GOCA AGXT2 Human plasma LC–MS/MS
The present work was supported by a grant from the Else Kröner-Fresenius-Stiftung.
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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.
All participants enrolled in this study provided written informed consent according to the Declaration of Helsinki.
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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