Evaluation of Angiopoietin-2 Serum Level as a Marker of Cardiovascular Risk in Children with Chronic Kidney Disease


Background: Cardiovascular complications are a major clinical problem in uremic patients accounting for 44% of all deaths in this population. Angiopoietin cytokines are involved with controlling micro vascular permeability, vasodilatation and vasoconstriction by signaling smooth muscle cells surrounding vessels. Aim: To assess Angiopoietin-2 serum level as an early marker of cardiovascular risks in children with chronic kidney disease on regular hemodialysis and correlate with intimal medial thickness and echo data in those children. Patients and methods: The study included 40 children with CKD on regular hemodialysis (HD), and they were selected from the hemodialysis unit of Al-Zahraa Hospital, Al-Azhar University, during the period from December 2014 to April 2015. Another group of 40 apparently healthy children, matches age and sex with patients group as a controls. Angiopoietin-2 serum level, Doppler ultrasound (U/S) to assess: intima-media thickness (IMT) and the peak systolic velocity (PSV) of the main arteries including the (aorta, carotid and femoral) arteries, conventional echo and tissue Doppler imaging (TDI) of mitral and tricuspid annular velocities are obtained for both groups. Results: Children on regular HD have significantly higher (Angiopoietin-2) serum level compared to their controls, and it is (161.35 ± 38.30 ng/ml) and (9.25 ± 12.64 ng/ml) respectively (p, 0.000) and increases in the aorta, carotid and femoral (IMT) with significant increase in their mean systolic velocities in patients group compared to the controls. Significant increase in tricuspid valve late diastolic velocity (TVA vel m/s) and (E/e’ ratio) obtained by (TDI), its abnormalities threshold is detected in patients group than controls, with significant increase right ventricular systolic pulmonary pressure in patients compared to the controls. Conclusions: Higher prevalence of right ventricular dysfunction is detected by conventional and TDI echo in children on hemodialysis. Angiopoietin-2 can be used as an ideal biomarker which may progress to play an adjunctive role with echocardiography in assessing cardiovascular risk of children with CKD on regular hemodialysis.

Share and Cite:

Abdel-Salam, M. , EL Wakeel, A. , Ibrahim, S. , Abdel-Rahman, T. , Ezzat, H. and Sabour, R. (2015) Evaluation of Angiopoietin-2 Serum Level as a Marker of Cardiovascular Risk in Children with Chronic Kidney Disease. Open Journal of Nephrology, 5, 105-116. doi: 10.4236/ojneph.2015.54016.

Conflicts of Interest

The authors declare no conflicts of interest.


[1] Scavarda, V.T., Pinheiro, A.C., Costa, S.D., Andrade, Z.M., Carvalhaes, J.T.A., Campos, O., Carvalho, A.C. and Moises, V.A. (2014) Children with Chronic Renal Disease Undergoing Dialysis or Conservative Treatment—Differences in Structural and Functional Echocardiographic Parameters. Echocardiography. 31, 1131-1137.
[2] Covic, A., Mardare, N., Gusbeth-Tatomir, P., Brumaru, O., Gavrilovici, C., et al. (2006) Increased Arterial Stiffness in Children on Haemodialysis. Nephrology Dialysis Transplantation, 21, 729-735.
[3] Shroff, R.C., McNair, R., Figg, N., Skepper, J.N., Schurgers, L., et al. (2008) Dialysis Accelerates Medial Vascular Calcification in Part by Triggering Smooth Muscle Cell Apoptosis. Circulation, 118, 1748-1757.
[4] Dursun, I., Poyrazoglu, H.M., Gunduz, Z., Ulger, H., Yykylmaz, A., et al. (2009) The Relationship between Endothelial Microparticles and Arterial Stiffness and Atherosclerosis in Children with Chronic Kidney Disease. Nephrology Dialysis Transplantation, 24, 2511-2518.
[5] Mitsnefes, M.M., Barletta, G.M., Dresner, I.G., Chand, D.H., Geary, D., et al. (2006) Severe Cardiac Hypertrophy and Long-Term Dialysis: The Midwest Pediatric Nephrology Consortium Study. Pediatric Nephrology, 21, 1167-1170.
[6] McDonald, S.P. and Craig, J.C., Australian and New Zealand Paediatric Nephrology Association (2004) Long-Term Survival of Children with End-Stage Renal Disease. New England Journal of Medicine, 350, 2654-2662.
[7] Oh, J., Wunsch, R., Turzer, M., Bahner, M., Raggi, P., et al. (2002) Advanced Coronary and Carotid Arteriopathy in Young Adults with Childhood-Onset Chronic Renal Failure. Circulation, 106, 100-105.
[8] Davis, S., Aldrich, T.H., Jones, P.F., et al. (1996) Isolation of Angiopoietin-1, a Ligand for the Tie 2 Receptor, by Secretion-Trap Expression Cloning. Cell, 87, 1161-1169.
[9] Fam, N.P., Verma, S., Kutryk, M., et al. (2003) Clinician Guide to Angiogenesis. Circulation, 108, 2613-2618.
[10] Brindle, N.P., Saharinen, P. and Alitalo, K. (2006) Signaling and Functions of Angiopoietin-1 in Vascular Protection. Circulation Research, 98, 1014-1023.
[11] Fiedler, U. and Augustin, H.G. (2006) Angiopoietins: A Link between Angiogenesis and Inflammation. Trends in Immunology, 27, 552-558.
[12] Fiedler, U., Scharpfenecker, M., Koidl, S., Hegen, A., Grunow, V., et al. (2004) The Tie-2 Ligand Angiopoietin-2 Is Stored and Rapidly Released upon Stimulation from Endothelial Cell Weibel-Palade Bodies. Blood, 103, 4150-4156.
[13] Kuo, M.C., Patschan, D., Patschan, S., Cohen-Gould, L., Park, H.C., et al. (2008) Ischemia-Induced Exocytosis of Weibel-Palade Bodies Mobilizes Stem Cells. Journal of the American Society of Nephrology, 19, 2321-2330.
[14] David, S., Kumpers, P., Lukasz, A., Fliser, D., Martens-Lobenhoffer, J., et al. (2010) Circulating Angiopoietin-2 Levels Increase with Progress of Chronic Kidney Disease. Nephrology Dialysis Transplantation, 25, 2571-2576.
[15] David, S., Kümpers, P., Hellpap, J., Horn, R., Leitolf, H., et al. (2009) Angiopoietin-2 and Cardiovascular Disease in Dialysis and Kidney Transplantation. American Journal of Kidney Diseases, 53, 770-778.
[16] David, S., John, S.G., Jefferies, H.J., Sigrist, M.K., Kümpers, P., et al. (2012) Angiopoietin-2 Levels Predict Mortality in CKD Patients. Nephrology Dialysis Transplantation, 27, 1867-1872.
[17] Gillard, B.K., Chen, Y.S., Gaubatz, J.W., et al. (2005) Plasma Factors Required for Human Apolipoprotein A-II Dimerization. Biochemistry, 44, 471-479.
[18] Sahn, D.J., DeMaria, A., Kisslo, J., et al. (1978) Recommendations regarding Quantitation in M-Mode Echocardiography: Results of a Survey of Echocardiographic Measurements. Circulation, 58, 1072-1083.
[19] Giusca, S., Dambrauskaite, V., Scheurwegs, C., D’Hooge, J., Claus, P., Herbots, L., et al. (2010) Deformation Imaging Describes Right Ventricular Function Better than Longitudinal Displacement of the Tricuspid Ring. Heart, 96, 281-288.
[20] Lang, R.M., Badano, L.P., Mor-Avi, V., Afilalo, J., Armstrong, A., Ernande, L., Flachskampf, F.A., Foster, E., Goldstein, S.A., Kuznetsova, T., Lancellotti, P., Muraru, D., Picard, M.H., Rietzschel, E.R., Rudski, L., Spencer, K.T., Tsang, W. and Voigt, J.U. (2015) Recommendations for Cardiac Chamber Quantification by Echocardiography in Adults: An Update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging. Journal of the American Society of Echocardiography, 28, 1-39.
[21] Chavhan, G.B., Parra, D.A., Andrea, M. and Oscar, M.N. (2008) Normal Doppler Spectral Waveforms of Major Pediatric Vessels: Specific Patterns. Radiographics, 28, 691-706.
[22] Parekh, R.S., Carroll, C.E., Wolfe, R.A. and Port, F.K. (2002) Cardiovascular Mortality in Children and Young Adults with End-Stage Kidney Disease. Journal of Pediatrics, 141, 191-197.
[23] Groothoff, J.W., Gruppen, M.P., Offringa, M., Hutten, J., Lilien, M.R., Van De Kar, N.J., Wolff, E.D., Davin, J.C. and Heymans, H.S. (2002) Mortality and Causes of Death of End-Stage Renal Disease in Children: A Dutch Cohort Study. Kidney International, 61, 621-629.
[24] Expert Panel on Integrated Guidelines for Cardiovascular Health and Risk Reduction in Children and Adolescents National Heart, Lung, and Blood Institute (2011) Expert Panel on Integrated Guidelines for Cardiovascular Health and Risk Reduction in Children and Adolescents: Summary Report. Pediatrics, 128, S213-S256.
[25] Litwin, M., Wühl, E., Jourdan, C., Trelewicz, J., Niemirska, A., Fahr, K., Jobs, K., Grenda, R., Wawer, Z.T., Rajszys, P., Tröger, J., Mehls, O. and Schaefer, F. (2005) Altered Morphologic Properties of Large Arteries in Children with Chronic Renal Failure and after Renal Transplantation. Journal of the American Society of Nephrology, 16, 1494-1500.
[26] Mitsnefes, M.M., Kimball, T.R., Kartal, J., Witt, S.A., Glascock, B.J., Khoury, P.R. and Daniels, S.R. (2005) Cardiac and Vascular Adaptation in Pediatric Patients. Journal of the American Society of Nephrology, 16, 2796-2803.
[27] Mitsnefes, M.M., Kimball, T.R., Witt, S.A., Glascock, B.J., Khoury, P.R. and Daniels, S.R. (2004) Abnormal Carotid Artery Structure and Function in Children and Adolescents with Successful Renal Transplantation. Circulation, 110, 97-101.
[28] Jourdan, C., Wuhl, E., Litwin, M., Fahr, K., Trelewicz, J., Jobs, K., Schenk, J.P., Grenda, R., Mehls, O., Troger, J. and Schaefer, F. (2005) Normative Values for Intima-Media Thickness and Distensibility of Large Arteries in Healthy Adolescents. Journal of Hypertension, 23, 1707-1715.
[29] Poyrazoglu, H.M., Düsünsel, R., Yikilmaz, A., Narin, N., Anarat, R., Gündüz, Z., Coskun, A., Baykan, A. and Öztürk, A. (2007) Carotid Artery Thickness in Children and Young Adults with End Stage Renal Disease. Paediatric Nephrology, 22, 109-116.
[30] Civilibal, M., Caliskan, S., Oflaz, H., Sever, L., Candan, C., Canpolat, N., Kasapcopur, O., Bugra, Z. and Arisoy, N. (2007) Traditional and “New” Cardiovascular Risk Markers and Factors in Pediatric Dialysis Patients. Paediatric Nephrology, 22, 1021-1029.
[31] Peco-Antic, A. and Paripovic, D. (2014) Renal Hypertension and Cardiovascular Disorder in Children with Chronic Kidney Disease Faculty of Medicine, University of Belgrade, Belgrade, Serbia. Srpski arhiv za celokupno lekarstvo, 142, 113-117.
[32] Drozdzz, D., Kordon, Z., Kwinta, P., Drozdz, M., Miklaszewska, M., Zachwieja, K., Rudzinski, A. and Pietrzyk, J.A. (2014) Left Ventricular Hypertrophy at Different Stages of Chronic Kidney Disease in Children and Adolescents. Experimental & Clinical Cardiology, 20, 4111-4116.
[33] Adiele, D.K., Okafor, H.U., Ojinnaka, N.C., Onwubere, B.J.C., Odetunde, O.I. and Uwaezuoke, S.N. (2014) Echocardiographic Findings in Children with Chronic Kidney Disease as Seen in the Resource-Limited Setting. Journal of Nephrology & Therapeutics, 4, 158.
[34] Rudhani, I.D., Bajraktari, G., Kryziu, E., Zylfiu, B., Sadiku, S., Elezi, Y., Rexhepaj, N., Vitia, A., Emini, M., Abazi, M., Berbatovci-Ukimeraj, M., Kryeziu, K., Hsanagjekaj, V., Korca, H. and Ukimeri, A. (2010) Left and Right Ventricular Diastolic Function in Hemodialysis Patients. Saudi Journal of Kidney Diseases and Transplantation, 21, 1053-1057.
[35] Virtanen, V.K., Saha, H.S.T., Groundstroem, K.W.E., et al. (1998) Calcium Infusion and Left Ventricular Diastolic Function in Patients with Chronic Renal Failure. Nephrology Dialysis Transplantation, 13, 384-388.
[36] London, G.M., Marchais, S.J., Guerin, A.P., et al. (1993) Cardiac Hypertrophy and Arterial Alteration in End-Stage Renal Disease: Hemodynamic Factors. Kidney International, 41, S42-S49.
[37] Bolignano, D., Rastelli, S., Agarwal, R., Fliser, D., Massy, Z., Ortiz, A., Wiecek, A., et al. (2013) Pulmonary Hypertension in CKD. American Journal of Kidney Diseases, 61, 612-622.
[38] Shroff, R.C., Price, K.L., Kolatsi-Joannou, M., Todd, A.F., Wells, D., Deanfield, J., Johnson, R.J., Rees, L., Woolf, A.S. and Long, D.A. (2013) Circulating Angiopoietin-2 Is a Marker for Early Cardiovascular Disease in Children on Chronic Dialysis. PLoS ONE, 8, e56273.
[39] Korff, T., Ernst, E., Nobiling, R., Feldner, A., Reiss, Y., et al. (2012) Angiopoietin-1 Mediates Inhibition of Hypertension-Induced Release of Angiopoietin-2 from Endothelial Cells. Cardiovascular Research, 94, 510-518.
[40] Otani, A., Takagi, H., Oh, H., Koyama, S. and Honda, Y. (2001) Angiotensin II Induces Expression of the Tie2 Receptor Ligand, Angiopoietin-2, in Bovine Retinal Endothelial Cells. Diabetes, 50, 867-875.
[41] Nakayama, T., Sato, W., Yoshimura, A., Zhang, L., Kosugi, T., et al. (2010) Endothelial von Willebrand Factor Release Due to eNOS Deficiency Predisposes to Thrombotic Microangiopathy in Mouse Aging Kidney. American Journal of Pathology, 176, 2198-2208.

Copyright © 2022 by authors and Scientific Research Publishing Inc.

Creative Commons License

This work and the related PDF file are licensed under a Creative Commons Attribution 4.0 International License.