Central European Journal of Medicine

, Volume 8, Issue 3, pp 346–353 | Cite as

ADMA and C-reactive protein as mortality predictors in dialysis patients

  • Aleksandra M. Ignjatović
  • Tatjana P. Cvetković
  • Radmila M. Pavlović
  • Vidojko M. Đorđević
  • Zoran G. Milošević
  • Vidosava B. Đorđević
  • Dušica D. Pavlović
  • Ivana R. Stojanović
  • Slavoljub C. Živanović
Research Article


There is a higher mortality between patients with end-stage renal disease than patients in the general population. These circumstances have led to a search for risk factors as predictors of mortality in dialysis patients. Amongst those, inhibitors of the nitric-oxide (NO) synthesis deserve special attention, since patients with end-stage renal disease are also characterized by accelerated atherosclerosis. Asymmetric-dimethylarginine (ADMA) and symmetric-dimethylarginine (SDMA), as well as C-reactive protein (CRP), have also been recognized as predictors of mortality in patients on dialysis. The aim of our study was to compare the prediction power of ADMA, SDMA and CRP for all-cause mortality in patients with end stage renal disease during the fourteen month follow-up. In total 162 patients on hemodialysis were included. ADMA and SDMA were measured by the high-performance liquid chromatography (HPLC); CRP was measured using immunonephelometric assays. During the 14-month period 28 patients (34.1%) died from all-cause mortality. Using univariate analysis, hazard ratios (HR) of the potential independent predictors of mortality in hemodialysis patients were ADMA (HR 1.39 (1.01–1.91) p=0.043) and CRP (HR 1.024 (1.009–1.1.040) p=0.001). Further, multivariate analysis (MVA), however, showed that ADMA is the only predictor of all-cause mortality (HR 1.76 (1.002–3.11) P=0.049), while SDMA failed to predict death in this population. Therefore, our data shows that ADMA is an independent and better marker of all-cause mortality compared with CRP.


Asymmetric-dimethylarginine Symmetric-dimethylarginine C-reactive protein Dialysis Mortality prediction 


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  1. [1]
    Foley RN, Parfrey PS Sarnak MJ. Epidemiology of cardiovascular disease in chronic renal disease. J Am Soc Nephrol. 1998,9(12 Suppl),S16–23PubMedGoogle Scholar
  2. [2]
    Vanholder R, Massy Z, Argiles A, Spasovski G, Verbeke F Lameire N. Chronic kidney disease as cause of cardiovascular morbidity and mortality. Nephrol Dial Transplant. 2005,20(6),1048–1056PubMedCrossRefGoogle Scholar
  3. [3]
    Lindner A, Charra B, Sherrard DJ Scribner BH. Accelerated atherosclerosis in prolonged maintenance hemodialysis. N Engl J Med. 1974,290(13),697–701PubMedCrossRefGoogle Scholar
  4. [4]
    Cighetti G, Fermo I, Aman CS, Ferraroni M, Secchi A, Fiorina P, et al. Dimethylarginines in complicated type 1 diabetes: roles of insulin, glucose, and oxidative stress. Free Radic Biol Med. 2009,47(3),307–311PubMedCrossRefGoogle Scholar
  5. [5]
    Vallance P, Leone A, Calver A, Collier J Moncada S. Accumulation of an endogenous inhibitor of nitric oxide synthesis in chronic renal failure. Lancet. 1992,339(8793),572–575PubMedCrossRefGoogle Scholar
  6. [6]
    Oner-Iyidogan Y, Oner P, Kocak H, Gurdol F, Bekpinar S, Unlucerci Y, et al. Dimethylarginines and inflammation markers in patients with chronic kidney disease undergoing dialysis. Clin Exp Med. 2009,9(3),235–241PubMedCrossRefGoogle Scholar
  7. [7]
    Zoccali C Kielstein JT. Asymmetric dimethylarginine: a new player in the pathogenesis of renal disease? Curr Opin Nephrol Hypertens. 2006,15(3),314–320PubMedCrossRefGoogle Scholar
  8. [8]
    Zoccali C, Benedetto FA, Maas R, Mallamaci F, Tripepi G, Malatino LS, et al. Asymmetric dimethylarginine, C-reactive protein, and carotid intima-media thickness in end-stage renal disease. J Am Soc Nephrol. 2002,13(2),490–496PubMedGoogle Scholar
  9. [9]
    Furuki K, Adachi H, Matsuoka H, Enomoto M, Satoh A, Hino A, et al. Plasma levels of asymmetric dimethylarginine (ADMA) are related to intima-media thickness of the carotid artery: an epidemiological study. Atherosclerosis. 2007,191(1),206–210PubMedCrossRefGoogle Scholar
  10. [10]
    Zeller M, Korandji C, Guilland JC, Sicard P, Vergely C, Lorgis L, et al. Impact of asymmetric dimethylarginine on mortality after acute myocardial infarction. Arterioscler Thromb Vasc Biol. 2008,28(5),954–960PubMedCrossRefGoogle Scholar
  11. [11]
    Aucella F, Maas R, Vigilante M, Tripepi G, Schwedhelm E, Margaglione M, et al. Methylarginines and mortality in patients with end stage renal disease: a prospective cohort study. Atherosclerosis. 2009,207(2),541–545PubMedCrossRefGoogle Scholar
  12. [12]
    Boger RH, Endres HG, Schwedhelm E, Darius H, Atzler D, Luneburg N, et al. Asymmetric dimethylarginine as an independent risk marker for mortality in ambulatory patients with peripheral arterial disease. J Intern Med. 2011,269(3),349–361PubMedCrossRefGoogle Scholar
  13. [13]
    Wilson AM, Shin DS, Weatherby C, Harada RK, Ng MK, Nair N, et al. Asymmetric dimethylarginine correlates with measures of disease severity, major adverse cardiovascular events and all-cause mortality in patients with peripheral arterial disease. Vasc Med. 2010,15(4),267–274PubMedCrossRefGoogle Scholar
  14. [14]
    Iapichino G, Albicini M, Umbrello M, Sacconi F, Fermo I, Pavlovich R, et al. Tight glycemic control does not affect asymmetric-dimethylarginine in septic patients. Intensive Care Med. 2008, 34(10),1843–50PubMedCrossRefGoogle Scholar
  15. [15]
    Fliser D, Kronenberg F, Kielstein JT, Morath C, Bode-Boger SM, Haller H, et al. Asymmetric dimethylarginine and progression of chronic kidney disease: the mild to moderate kidney disease study. J Am Soc Nephrol. 2005,16(8),2456–2461PubMedCrossRefGoogle Scholar
  16. [16]
    Bode-Boger SM, Scalera F, Kielstein JT, Martens-Lobenhoffer J, Breithardt G, Fobker M, et al. Symmetrical dimethylarginine: a new combined parameter for renal function and extent of coronary artery disease. J Am Soc Nephrol. 2006,17(4), 1128–1134PubMedCrossRefGoogle Scholar
  17. [17]
    Schindler R, Boenisch O, Fischer C, Frei U. Effect of the hemodialysis membrane on the inflammatory reaction in vivo. Clin Nephrol. 2000,53(6),452–459PubMedGoogle Scholar
  18. [18]
    Zoccali C, Mallamaci F Tripepi G. Inflammation and atherosclerosis in end-stage renal disease. Blood Purif. 2003,21(1),29–36PubMedCrossRefGoogle Scholar
  19. [19]
    Wanner C, Zimmermann J, Schwedler S, Metzger T. Inflammation and cardiovascular risk in dialysis patients. Kidney Int Suppl. 2002, (80), 99–102Google Scholar
  20. [20]
    Pecoits-Filho R, Barany P, Lindholm B, Heimburger O Stenvinkel P. Interleukin-6 is an independent predictor of mortality in patients starting dialysis treatment. Nephrol Dial Transplant. 2002,17(9),1684–1648PubMedCrossRefGoogle Scholar
  21. [21]
    Panichi V, Maggiore U, Taccola D, Migliori M, Rizza GM, Consani C, et al. Interleukin-6 is a stronger predictor of total and cardiovascular mortality than C-reactive protein in haemodialysis patients. Nephrol Dial Transplant. 2004,19(5),1154–1160PubMedCrossRefGoogle Scholar
  22. [22]
    Paroni R, Fermo I, Fiorina P Cighetti G. Determination of asymmetric and symmetric dimethylarginines in plasma of hyperhomocysteinemic subjects. Amino Acids. 2005,28(4),389–394PubMedCrossRefGoogle Scholar
  23. [23]
    Teerlink T, Nijveldt RJ, de Jong S van Leeuwen PA. Determination of arginine, asymmetric dimethylarginine, and symmetric dimethylarginine in human plasma and other biological samples by high-performance liquid chromatography. Anal Biochem. 2002,303(2),131–137PubMedCrossRefGoogle Scholar
  24. [24]
    Zoccali C, Bode-Boger S, Mallamaci F, Benedetto F, Tripepi G, Malatino L, et al. Plasma concentration of asymmetrical dimethylarginine and mortality in patients with end-stage renal disease: a prospective study. Lancet. 2001,358(9299),2113–2117PubMedCrossRefGoogle Scholar
  25. [25]
    Ravani P, Tripepi G, Malberti F, Testa S, Mallamaci F Zoccali C. Asymmetrical dimethylarginine predicts progression to dialysis and death in patients with chronic kidney disease: a competing risks modeling approach. J Am Soc Nephrol. 2005,16(8),2449–2455PubMedCrossRefGoogle Scholar
  26. [26]
    Kumagai H, Sakurai M, Takita T, Maruyama Y, Uno S, Ikegaya N, et al. Association of homocysteine and asymmetric dimethylarginine with atherosclerosis and cardiovascular events in maintenance hemodialysis patients. Am J Kidney Dis. 2006,48(5),797–805PubMedCrossRefGoogle Scholar
  27. [27]
    Busch M, Fleck C, Wolf G Stein G. 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. 2006,30(3),225–232PubMedCrossRefGoogle Scholar
  28. [28]
    Lee JH, Cook JR, Yang ZH, Mirochnitchenko O, Gunderson SI, Felix AM, et al. PRMT7, a new protein arginine methyltransferase that synthesizes symmetric dimethylarginine. J Biol Chem. 2005, 280(5),3656–3664PubMedCrossRefGoogle Scholar
  29. [29]
    Richard S, Morel M Cleroux P. Arginine methylation regulates IL-2 gene expression: a role for protein arginine methyltransferase 5 (PRMT5). Biochem J. 2005,388(Pt 1),379–386PubMedGoogle Scholar
  30. [30]
    Boger RH, Sydow K, Borlak J, Thum T, Lenzen H, Schubert B, et al. LDL cholesterol upregulates synthesis of asymmetrical dimethylarginine in human endothelial cells: involvement of S-adenosylmethionine-dependent methyltransferases. Circ Res. 2000, 87(2),99–105PubMedCrossRefGoogle Scholar
  31. [31]
    Tran CT, Leipe JM Vallance P. The DDAH/ADMA/NOS pathway. Atheroscler Suppl. 2003,4(4),33–40PubMedCrossRefGoogle Scholar
  32. [32]
    Ito A, Tsao PS, Adimoolam S, Kimoto M, Ogawa T, Cooke JP. Novel mechanism for endothelial dysfunction: dysregulation of dimethylarginine dimethylaminohydrolase. Circulation. 1999,99(24), 3092–3095PubMedCrossRefGoogle Scholar
  33. [33]
    Stuhlinger MC, Tsao PS, Her JH, Kimoto M, Balint RF, Cooke JP. Homocysteine impairs the nitric oxide synthase pathway: role of asymmetric dimethylarginine. Circulation 2001,104(21), 2569–2575PubMedCrossRefGoogle Scholar
  34. [34]
    Lin KY, Ito A, Asagami T, Tsao PS, Adimoolam S, Kimoto M, et al. Impaired nitric oxide synthase pathway in diabetes mellitus: role of asymmetric dimethylarginine and dimethylarginine dimethylaminohydrolase. Circulation 2002,106(8), 987–992PubMedCrossRefGoogle Scholar
  35. [35]
    Weis M, Kledal TN, Lin KY, Panchal SN, Gao SZ, Valantine HA, et al. Cytomegalovirus infection impairs the nitric oxide synthase pathway: role of asymmetric dimethylarginine in transplant arteriosclerosis. Circulation. 2004,109(4),500–505PubMedCrossRefGoogle Scholar
  36. [36]
    Tripepi G, Mallamaci F, Zoccali C. Inflammation markers, adhesion molecules, and all-cause and cardiovascular mortality in patients with ESRD: searching for the best risk marker by multivariate modeling. J Am Soc Nephrol. 2005,16 Suppl 1,S83–88PubMedCrossRefGoogle Scholar
  37. [37]
    Zimmermann J, Herrlinger S, Pruy A, Metzger T, Wanner C. Inflammation enhances cardiovascular risk and mortality in hemodialysis patients. Kidney Int. 1999,55(2),648–658PubMedCrossRefGoogle Scholar
  38. [38]
    Kato A, Takita T, Furuhashi M, Maruyama Y, Hishida A. Comparison of serum albumin, C-reactive protein and carotid atherosclerosis as predictors of 10-year mortality in hemodialysis patients. Hemodial Int. 2010,14(2),226–232PubMedCrossRefGoogle Scholar
  39. [39]
    Mallamaci F, Tripepi G, Cutrupi S, Malatino LS, Zoccali C. Prognostic value of combined use of biomarkers of inflammation, endothelial dysfunction, and myocardiopathy in patients with ESRD. Kidney Int. 2005,67(6),2330–2337PubMedCrossRefGoogle Scholar
  40. [40]
    Tripepi G, Mattace Raso F, Sijbrands E, Seck MS, Maas R, Boger R, et al. Inflammation and asymmetric dimethylarginine for predicting death and cardiovascular events in ESRD patients. Clin J Am Soc Nephrol. 2011,6(7),1714–1721PubMedCrossRefGoogle Scholar
  41. [41]
    Danesh J, Wheeler JG, Hirschfield GM, Eda S, Eiriksdottir G, Rumley A, et al. C-reactive protein and other circulating markers of inflammation in the prediction of coronary heart disease. N Engl J Med. 2004,350(14),1387–1397PubMedCrossRefGoogle Scholar

Copyright information

© Versita Warsaw and Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  • Aleksandra M. Ignjatović
    • 1
    • 2
  • Tatjana P. Cvetković
    • 3
    • 4
  • Radmila M. Pavlović
    • 1
  • Vidojko M. Đorđević
    • 4
  • Zoran G. Milošević
    • 2
  • Vidosava B. Đorđević
    • 3
  • Dušica D. Pavlović
    • 3
  • Ivana R. Stojanović
    • 3
  • Slavoljub C. Živanović
    • 1
  1. 1.Faculty of Medicine Niš, Research Centre for BiomedicineUniversity of NišNisSerbia
  2. 2.Faculty of Medicine Niš, Department of Medical StatisticsUniversity of NišNisSerbia
  3. 3.Faculty of Medicine Niš, Institute of BiochemistryUniversity of NišNisSerbia
  4. 4.Clinical Centre NišClinic of nephrologyNisSerbia

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