Relationship between angiogenic growth factors and atherosclerosis in renal transplantation recipients: a cross-sectional study

Authors

Keywords:

Atherosclerosis, Angiopoietin-2, Vascular endothelial growth factors, Renal resistive index, Renal transplant recipients, Renal failure

Abstract

BACKGROUND: Accelerated development of atherosclerosis has been observed in renal transplant recipients (RTRs). Angiopoietin-2 (Ang-2) and vascular endothelial growth factor (VEGF) are vascular enzymes that play important roles in vascular development and angiogenesis.

OBJECTIVE: This study aimed to investigate the relationship between Ang-2 and VEGF and atherosclerosis in RTRs.

DESIGN AND SETTING: This study was conducted at Ankara City Hospital, Turkey.

METHODS: This cross-sectional study included 36 (37.5%) female and 60 (62.5%) male RTRs. All findings were compared with those of 70 healthy controls. Ultrasonographic measurements of the carotid artery intima-media thickness (CA-IMT) and renal resistive index (RRI) were used as indicators of atherosclerosis. RESULTS: Log10 Ang-2, log10 VEGF, CA-IMT, and RRI levels were significantly higher in patients than in healthy controls. No significant differences were detected in CA-IMT and RRI between those with log10 Ang-2 3.53 pg/mL and those with < 3.53 pg/mL. No significant differences were detected in CA-IMT and RRI between those with log10 VEGF 1.98 pg/mL and those with < 1.98 pg/mL. No correlation was detected between log10 Ang-2 and log10 VEGF, CA-IMT, or RRI.

CONCLUSIONS: Increased serum angiogenic growth factor levels and increased atherosclerosis development were detected in RTRs compared to healthy individuals. No relationship was observed between angiogenic growth factors and atherosclerosis. This may be due to the decreased synthesis and effect of angiogenic growth factor receptors synthesized from atherosclerotic plaques due to atherosclerosis, which improves after renal transplantation.

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Author Biographies

Melahat Çoban, Ankara Bilkent City Hospital, Ankara, Türkiye

PhD. Assistant Professor, Department of Nephrology, Ankara Bilkent City Hospital, Ankara, Türkiye.

Beyza Algul Durak, Ankara Bilkent City Hospital, Ankara, Türkiye

MD. Department of Nephrology, Ankara Bilkent City Hospital, Ankara, Türkiye.

Mine Sebnem Karakan, Yıldırım Beyazıt University, Ankara, Türkiye

PhD. Professor, Department of Nephrology, Yıldırım Beyazıt University, Ankara, Türkiye.

References

Sarnak MJ, Levey AS, Schoolwerth AC, et al. Kidney disease as a risk factor for development of cardiovascular disease: a statement from the American Heart Association Councils on Kidney in Cardiovascular Disease, High Blood Pressure Research, Clinical Cardiology, and Epidemiology and Prevention. Circulation. 2003;108(17):2154-69. PMID: 14581387; https://doi.org/10.1161/01.cir.0000095676.90936.80.

Recio-Mayoral A, Banerjee D, Streather C, Kaski JC. Endothelial dysfunction, inflammation and atherosclerosis in chronic kidney disease--a cross-sectional study of predialysis, dialysis and kidneytransplantation patients. Atherosclerosis. 2011;216(2):446-51. PMID: 21414625; https://doi.org/10.1016/j.atherosclerosis.2011.02.017.

Radermacher J, Mengel M, Ellis S, et al. The renal arterial resistance index and renal allograft survival. N Engl J Med. 2003;349(2):115-24. PMID: 12853584; https://doi.org/10.1056/nejmoa022602.

Chudek J, Kolonko A, Król R, et al. The intrarenal vascular resistance parameters measured by duplex Doppler ultrasound shortly after kidney transplantation in patients with immediate, slow, and delayed graft function. Transplant Proc. 2006;38(1):42-5. PMID: 16504659; https:// doi.org/10.1016/j.transproceed.2005.12.013.

Kramann R, Frank D, Brandenburg VM, et al. Prognostic impact of renal arterial resistance index upon renal allograft survival: the time point matters. Nephrol Dial Transplant. 2012;27(10):3958-63. PMID: 22247231; https://doi.org/10.1093/ndt/gfr772.

Shimizu Y, Itoh T, Hougaku H, et al. Clinical usefulness of duplex ultrasonography for the assessment of renal arteriosclerosis in essential hypertensive patients. Hypertens Res. 2001;24(1):13-7. PMID: 11213024; https://doi.org/10.1291/hypres.24.13.

Calabia J, Torguet P, Garcia I, et al. The relationship between renal resistive index, arterial stiffness, and atherosclerotic burden: the link between macrocirculation and microcirculation. J Clin Hypertens. 2014;16(3):186-91. PMID: 24548343; https://doi.org/10.1111/jch.12248.

Barr MP, Bouchier-Hayes DJ, Harmey JJ. Vascular endothelial growth factor is an autocrine survival factor for breast tumour cells under hypoxia. Int J Oncol. 2008;32(1):41-8. PMID: 18097541.

Shibuya M. Vascular endothelial growth factor and its receptor system: physiological functions in angiogenesis and pathological roles in various diseases. J Biochem. 2013;153(1):13-9. PMID: 23172303; https://doi. org/10.1093/jb/mvs136.

Yilmaz MI, Sonmez A, Saglam M, et al. A longitudinal study of inflammation, CKD-mineral bone disorder, and carotid atherosclerosis after renal transplantation. Clin J Am Soc Nephrol. 2015;10(3):471-9. PMID: 25542907; https://doi.org/10.2215/cjn.07860814.

Nafar M, Khatami F, Kardavani B, et al. Atherosclerosis after kidney transplantation: changes of intima-media thickness of carotids during early posttransplant period. Urol J. 2007;4(2):105-10. PMID: 17701931.

Pinho A, Sampaio S, Pestana M. Accelerated atherosclerosis after renal transplantation: an unsuspected cause of uncontrolled hypertension.

Int J Nephrol Renovasc Dis. 2014;7:295-6. PMID: 25053893; https://doi. org/10.2147/IJNRD.S69358

Junarta J, Hojs N, Ramphul R, et al. Progression of endothelial dysfunction, atherosclerosis, and arterial stiffness in stable kidney transplant patients: a pilot study. BMC Cardiovasc Disord. 2020;20(1):6. PMID: 31914943; https://doi.org/10.1186/s12872-019-01309-y.

Basiratnia M, Fazel M, Lotfi M, et al. Subclinical atherosclerosis and related risk factors in renal transplant recipients. Pediatr Nephrol. 2010;25(2):343-

PMID: 19911201; https://doi.org/10.1007/s00467-009-1345-0.

Kasiske BL. Risk factors for accelerated atherosclerosis in renal transplant recipients. Am J Med. 1988;84(6):985-92. PMID: 3287917; https://doi. org/10.1016/0002-9343(88)90302-6.

Lindholm A, Albrechtsen D, Frödin L, et al. Ischemic heart disease-major cause of death and graft loss after renal transplantation in Scandinavia. Transplantation. 1995;60(5):451-7. PMID: 7676492; https:// doi.org/10.1097/00007890-199509000-00008.

Turkmen K, Tonbul HZ, Toker A, et al. The relationship between oxidative stress, inflammation, and atherosclerosis in renal transplant and endstage renal disease patients. Ren Fail. 2012;34(10):1229-37. PMID: 23025491; https://doi.org/10.3109/0886022x.2012.723580.

Heine GH, Gerhart MK, Ulrich C, Köhler H, Girndt M. Renal Doppler resistance indices are associated with systemic atherosclerosis in kidney transplant recipients. Kidney Int. 2005;68(2):878-85. PMID: 16014069; https://doi.org/10.1111/j.1523-1755.2005.00470.x.

Akgul A, Sasak G, Basaran C, et al. Relationship of renal resistive index and cardiovascular disease in renal transplant recipients. Transplant Proc. 2009;41(7):2835-37. PMID: 19765450; https://doi.org/10.1016/j. transproceed.2009.07.023.

Brennan DC, Lentine KL. Is there a correlation between atherosclerosis and renal resistive indices in kidney transplant recipients? Nat Clin Pract Nephrol. 2006;2(2):64-5. PMID: 16932391; https://doi.org/10.1038/ncpneph0090.

Köger P, Engelberger S, Thalhammer C, et al. Association of intrarenal resistance index and systemic atherosclerosis after kidney transplantation. In Vivo. 2021;35(6):3369-75. PMID: 34697171; https:// doi.org/10.21873/invivo.12635.

David S, Kümpers P, Lukasz A, et al. Circulating angiopoietin-2 levels increase with progress of chronic kidney disease. Nephrol Dial Transplant. 2010;25(8):2571-6. PMID: 20179005; https://doi.org/10.1093/ndt/gfq060.

Schmidt RJ, Baylis C. Total nitric oxide production is low in patients with chronic renal disease. Kidney Int. 2000;58(3):1261-6. PMID: 10972689; https://doi.org/10.1046/j.1523-1755.2000.00281.x.

Yang X, Zhang H, Shi Y, et al. Association of serum angiopoietin-2 with malnutrition, inflammation, atherosclerosis and valvular calcification syndrome and outcome in peritoneal dialysis patients: a prospective cohort study. J Transl Med. 2018;16(1):312. PMID: 30445969; https:// doi.org/10.1186/s12967-018-1687-0.

Tsai YC, Lee CS, Chiu YW, et al. Angiopoietin-2 as a prognostic biomarker of major adverse cardiovascular events and all-cause mortality in chronic kidney disease. PLoS One. 2015;10(8):e0135181. PMID: 26274392; https:// doi.org/10.1371/journal.pone.0135181.

David S, John SG, Jefferies HJ, et al. Angiopoietin-2 levels predict mortality in CKD patients. Nephrol Dial Transplant. 2012;27(5):1867-72. PMID: 21976741; https://doi.org/10.1093/ndt/gfr551.

Iribarren C, Phelps BH, Darbinian JA, et al. Circulating angiopoietins-1 and -2, angiopoietin receptor Tie-2 and vascular endothelial growth factor-A as biomarkers of acute myocardial infarction: a prospective nested case-control study. BMC Cardiovasc Disord. 2011;11:31. PMID: 21672190; https://doi.org/10.1186/1471-2261-11-31.

Le Dall J, Ho-Tin-Noé B, Louedec L, et al. Immaturity of microvessels in haemorrhagic plaques is associated with proteolytic degradation of angiogenic factors. Cardiovasc Res. 2010;85(1):184-93. PMID: 19620132; https://doi.org/10.1093/cvr/cvp253.

El-Asrar MA, Elbarbary NS, Ismail EA, Bakr AA. Circulating angiopoietin-2 levels in children and adolescents with type 1 diabetes mellitus: relation to carotid and aortic intima-media thickness. Angiogenesis. 2016;19(3):421-31. PMID: 27236773; https://doi.org/10.1007/s10456016-9517-6.

Shroff RC, Price KL, Kolatsi-Joannou M, et al. Circulating angiopoietin-2 is a marker for early cardiovascular disease in children on chronic dialysis. PLoS One. 2013;8(2):e56273. PMID: 23409162; https://doi.org/10.1371/ journal.pone.0056273.

Mayer G. Capillary rarefaction, hypoxia, VEGF and angiogenesis in chronic renal disease. Nephrol Dial Transplant 2011;26(4):1132-7. PMID: 21330358; https://doi.org/10.1093/ndt/gfq832.

Ahmed A, Fujisawa T. Multiple roles of angiopoietins in atherogenesis.

Curr Opin Lipidol. 2011;22(5):380-5. PMID: 21881497; https://doi. org/10.1097/mol.0b013e32834b26b3.

David S, Kümpers P, Hellpap J, et al. Angiopoietin 2 and cardiovascular disease in dialysis and kidney transplantation. Am J Kidney Dis.

;53(5):770-8. PMID: 19268412; https://doi.org/10.1053/j. ajkd.2008.11.030.

Blann AD, Belgore FM, McCollum CN, et al. Vascular endothelial growth factor and its receptor, Flt-1, in the plasma of patients with coronary or peripheral atherosclerosis, or Type II diabetes. Clin Sci. 2002;102(2):187-94. PMID: 11834138.

Liu Y, Hong K, Weng W, et al. Association of vascular endothelial growth factor (VEGF) protein levels and gene polymorphism with the risk of chronic kidney disease. Libyan J Med. 2023;18(1):2156675.

Nguyen TTU, Kim H, Chae YJ, Jung JH, Kim W. Serum VEGF-D level is correlated with renal dysfunction and proteinuria in patients with diabetic chronic kidney disease. Medicine. 2022;101(7):e28804. PMID: 35363168; https://doi.org/10.1097/md.0000000000028804.

Pilmore HL, Eris JM, Painter DM, et al. Vascular endothelial growth factor expression in human chronic renal allograft rejection. Transplantation. 1999;67(6):929-33. PMID: 10199746; https://doi.org/10.1097/00007890199903270-00024.

Rintala SE, Savikko J, Rintala JM, von Willebrand E. Vascular endothelial growth factor (VEGF) ligand and receptor induction in rat renal allograft rejection. Transplant Proc. 2006;38(10):3236-8. PMID: 17175233; https:// doi.org/10.1016/j.transproceed.2006.10.049.

Felmeden DC, Spencer CG, Belgore FM, et al. Endothelial damage and angiogenesis in hypertensive patients: relationship to cardiovascular risk factors and risk factor management. Am J Hypertens. 2003;16(1):11-20. PMID: 12517677; https://doi.org/10.1016/s0895-7061(02)03149-7.

Celletti FL, Waugh JM, Amabile PG, et al. Vascular endothelial growth factor enhances atherosclerotic plaque progression. Nat Med. 2001;7(4):425-9. PMID: 11283668; https://doi.org/10.1038/86490.

Inoue M, Itoh H, Ueda M, et al. Vascular endothelial growth factor (VEGF) expression in human coronary atherosclerotic lesions: possible pathophysiological significance of VEGF in progression of atherosclerosis. Circulation. 1998;98(20):2108-16. PMID: 9815864; https:// doi.org/10.1161/01.cir.98.20.2108.

Ohtani K, Egashira K, Hiasa K, et al. Blockade of vascular endothelial growth factor suppresses experimental restenosis after intraluminal injury by inhibiting recruitment of monocyte lineage cells. Circulation.

;110(16):2444-52. PMID: 15477409; https://doi.org/10.1161/01. cir.0000145123.85083.66.

Yu ZM, Deng XT, Qi RM, et al. Mechanism of chronic stress-induced reduced atherosclerotic medial area and increased plaque instability in rabbit models of chronic stress. Chin Med J. 2018;131(2):161-70. PMID: 29336364; https://doi.org/10.4103/0366-6999.222322.

Kimura K, Hashiguchi T, Deguchi T, et al. Serum VEGF--as a prognostic factor of atherosclerosis. Atherosclerosis. 2007;194(1):182-8. PMID: 17141247; https://doi.org/10.1016/j.atherosclerosis.2006.07.025.

Milasan A, Smaani A, Martel C. Early rescue of lymphatic function limits atherosclerosis progression in Ldlr-/- mice. Atherosclerosis.

;283:106-19. PMID: 30851674; https://doi.org/10.1016/j. atherosclerosis.2019.01.031.

Heinonen SE, Kivelä AM, Huusko J, et al. The effects of VEGF-A on atherosclerosis, lipoprotein profile, and lipoprotein lipase in hyperlipidaemic mouse models. Cardiovasc Res. 2013;99(4):716-23. PMID: 23756254; https://doi.org/10.1093/cvr/cvt148.

Lim HS, Lip GY, Blann AD. Angiopoietin-1 and angiopoietin-2 in diabetes mellitus: relationship to VEGF, glycaemic control, endothelial damage/ dysfunction and atherosclerosis. Atherosclerosis. 2005;180(1):113-8. PMID: 15823283; https://doi.org/10.1016/j.atherosclerosis.2004.11.004.

Sánchez-Escuredo A, Pastor MC, Bayés B, et al. Inflammation, metalloproteinases, and growth factors in the development of carotid atherosclerosis in renal transplant patients. Transplant Proc. 2010;42(8):2905-7. PMID: 20970566; https://doi.org/10.1016/j. transproceed.2010.07.076.

Yilmaz MI, Sonmez A, Saglam M, et al. A longitudinal study of inflammation, CKD-mineral bone disorder, and carotid atherosclerosis after renal transplantation. Clin J Am Soc Nephrol. 2015;10(3):471-9. PMID: 25542907; https://doi.org/10.2215/cjn.07860814.

Fiedler U, Reiss Y, Scharpfenecker M, et al. Angiopoietin-2 sensitizes endothelial cells to TNF-alpha and has a crucial role in the induction of inflammation. Nat Med. 2006;12(2):235-9. PMID: 16462802; https:// doi.org/10.1038/nm1351.

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Published

2025-06-06

How to Cite

1.
Çoban M, Durak BA, Karakan MS. Relationship between angiogenic growth factors and atherosclerosis in renal transplantation recipients: a cross-sectional study. Sao Paulo Med J [Internet]. 2025 Jun. 6 [cited 2025 Jun. 15];142(6):1-10. Available from: https://periodicosapm.emnuvens.com.br/spmj/article/view/3233

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