Transplantation of an organ harvested from another person is one of the methods of treatment of end-stage failure of vascularised organs (kidneys, heart, liver). Good results obtained with this method derive from advances in the graft rejection prevention treatment. The use of immunosuppressants is associated with numerous complications, such as increased frequency of infections, increased incidence of cancer, bone marrow damage or cardiovascular complications. Normal haemostasis is a result of equilibrium between coagulation factors and their inhibitors. Imbalance in this equilibrium leads to life-threatening bleeding or thrombosis, which is why its maintenance is very important. Studies suggest the presence of hypercoagulability in renal transplant recipients (1, 2). Haemostasis disturbances are inherently correlated with endothelial dysfunction. Early descriptions of endothelial dysfunction focused on structural changes or on the loss of anatomical integrity of this organ. It is currently known that endothelial cells are characterised by highly variable biological activity performing an extremely important role in functioning of the whole body. Małyszko et al. demonstrated impaired haemostasis and endothelial function in dialysed patients and in patients with chronic kidney disease (3, 4). Epithelial damage may contribute to accelerated atherosclerosis development in the group of transplant recipients.
Vascular Adhesion Protein-1 (VAP-1) is a multi-function protein, which mediates lymphocyte adhesion to the vascular endothelium (5-9). Biochemically, VAP-1 is a homodimeric transmembrane glycoprotein with a molecular mass of 170-180 kDa, made of 764 amino acids, with a short N-terminal cytoplasmic part, a single transmembrane domain and a large extracellular C-terminal domain (5-9). Each subunit has six N-glycosylation sites (10). N-glycoside chains of VAP-1, ended with sialic acid, differ depending on the tissue in which they occur. This differentiation suggests their functional differences (11). The structure of DNA coding the VAP-1 molecule displays high homology with enzymes of the semicarbazide-sensitive amine oxidase (SSAO) class (12). VAP-1 also displays enzymatic activity of a semicarbazide-sensitive amine oxidase. Its active centre contains a copper atom (9, 13). SSAO/VAP-1 catalyses a reaction of two-stage deamination of primary amine groups (methylamine, aminoacetone, benzylamine) leading to the formation of aldehydes and additionally hydrogen peroxide and ammonia (14). On one hand, the activity of VAP-1 provides protection from amines of endo- and exogenous origins, and on the other hand, high concentration of the products formed increases the quantity of other adhesion molecules, leading to escalation of the inflammatory process. Increased concentration of toxic aldehydes and oxygen radicals, which are the source of oxidative stress, in the endothelial environment may result in endothelial damage and may contribute to the development of atherosclerosis and vascular damage in diabetic patients (15-17). Elevated activity of SSAO is observed in atherosclerosis, diabetes and obesity (18-20). VAP-1 concentration, SSAO activity and SSAO activity products are elevated in congestive heart failure and hepatitis (21). Elevated VAP-1 levels were found in persons with chronic kidney disease, which suggests that it may be excreted via the kidneys (22). Moreover, recently Li et al. have demonstrated that VAP-1 may be a good predictor of cardiovascular death in persons with type 2 diabetes (21). Constant expression of VAP-1 is observed in high endothelial venules (HEV), which physiologically are present in lymphoid organs, in the liver and in dendritic cells of lymph node proliferation centres (6). VAP-1 is also present in vascular smooth muscle cells and in adipocytes. Physiologically, soluble VAP-1 (sVAP-1) is present in the serum of healthy persons. It is probably released as a result of enzymatic proteolysis or is formed directly on messenger RNA devoid of the membrane region-coding fragment (12). Metalloproteinases may release VAP-1 from adipocytes and this process is intensified in hyperglycaemia (23). sVAP possesses immunomodulatory function causing much stronger binding of T-cells to endothelial cells, which may play an important role in the graft rejection process (24). In the case of kidney transplant, in which rejection signs were found, high expression of VAP-1 was detected in the endothelium of peritubular vessels that became morphologically similar to HEV (25). SSAO oxidates dopamine and, to a lower extent, norepinephrine, and does not oxidate epinephrine. SSAO/VAP-1 is insensitive to MAO inhibitors (26). In view of its monoamine oxidase activity, like renalase, VAP-1 may be a factor regulating blood pressure.
1. Małyszko J, Małyszko JS, Pawlak K et al.: Coagulo-lytic system and endothelial function in cyclosporine-treated kidney allograft recipients. Transplantation 1996; 62: 828-830.
2. Vanrenterghem Y, Roels L, Lerut T et al.: Thromboembolic complications and haemostatic changes in cyclosporine treated cadaveric kidney allograft recipients. Lancet 1985; 1: 999-1002.
3. Małyszko J, Małyszko JS, Myśliwiec M: Comparison of hemostatic disturbances between patients on CAPD and HD. Perit Dial Int 2001; 21: 158-165.
4. Małyszko J, Małyszko JS, Myśliwiec M: Endothelial cell injury markers in chronic renal failure on conservative treatment and continuous ambulatory peritoneal dialysis (CAPD). Kidney Blood Press Res 2004; 27: 71-77.
5. Butcher EC, Picker LJ: Lymphocyte homing and homeostasis. Science 1996; 272: 60-66.
6. Salmi M, Jalkanen S: VAP-1: an adhesin and an enzyme. Trends Immunol 2001; 22: 211-216.
7. Salmi M, Tohka S, Jalkanen S: Human vascular adhesion protein-1 (VAP 1) plays critical role in lymphocyte-endothelial cell adhesion cascade under shear. Circ Res 2000; 86: 1245-1251.
8. Salmi M, Yegutkin GG, Lehvonen R et al.: a cell surface amine oxidase directly controls lymphocyte migration. Immunity 2001; 14: 265-276.
9. Smith DJ, Salmi M, Bono P et al.: Cloning of vascular adhesion protein-1 reveals a novel multifunctional adhesion molecule. J Exp Med 1998; 188: 17-27.
10. Salminen TA, Smith DJ, Jalkanen S et al.: Structural model of the catalytic domain of an enzyme with cell adhesion activity: human vascular adhesion protein-1 (HVAP-1) D4 domain is an amine oxidase. Protein Eng 1998; 11: 1195-1204.
11. Jaakkola K, Kaunismaki K, Tohka S et al.: Human vascular adhesion protein-1 in smooth muscle cells. Am J Pathol 1999; 155: 1953-1965.
12. Madej A, Reich A, Szepietowski JC: Naczyniowa proteina adhezyjna-1 – unikatowa cząsteczka adhezyjna. Postepy Hig Med Dosw 2005; 59: 172-179.
13. Janes SM, Mu D, Wemmer D et al.: a new redox cofactor in eukaryotic enzymes: 6-hydroxydopa at the active site of bovine serum amine oxidase. Science 1990; 248: 981-987.
14. Lyles GA, Chalmers J: The metabolism of aminoacethone to methylglyoxal by semicarbazide-sensitive amine oxides in human umbilical artery. Biochem Pharmacol 1992; 43: 1409-1414.
15. Klinman JP, Mu D: Quinoenzymes in biology. Annu Rev Biochem 1994; 63: 299-344.
16. Lyles GA: Mammalian plasma and tissue-bound semicarbazide-sensitive amine oxidases: biochemical, pharmacological and toxicological aspects. Int J Biochem Cell Biol 1996; 28: 259-274.
17. Patel KD, Zimmermann GA, Prescott SM et al.: Oxygen radicals induce human endothelial cells to express GMP-140 and bind neutrophils. J Cell Biol 1991; 112: 749-759.
18. Noda K, Nakao S, Zandi S et al.: Vascular adhesion protein-l regulates leukocyte transmigration rate in the retina during diabetes. Exp Eye Res 2009; 89: 774-781.
19. Stolen CM, Madanat R, Marti L et al.: Semicarbazide sensitive amine oxidase overexpression has dual consequences: insulin mimicry and diabetes-like complications. F ASEB J 2004; 18(6): 702-704.
20. Mercader J, Iffiń-Soltesz Z, Brenachot X et al.: SSAO substrates exhibiting insulin-like effects in adi-pocytes as a promising treatment option for metabolic disorders. Future Med Chem 2010; 2: 1735-1749.
21. Li HY, Jiang YD, Chang TJ et al.: Serum vascular adhesion protein-1 predicts 10-year cardiovascular and cancer mortality in individuals with type 2 diabetes. Diabetes 2011; 60: 993-999.
22. Lin MS, Li HY, Wei JN et al.: Serum vascular adhesion protein-1 is higher in subjects with early stages of chronic kidney disease. Clin Biochem 2008; 41: 1362-1367.
23. Li HY, Wei JN, Lin MS et al.: Serum vascular adhesion protein-1 is increased in acute and chronic hyperglycemia. Clin Chim Acta 2009; 404: 149-153.
24. Kurkijarvi R, Adams DH, Leino R et al.: Circulating form of human vascular adhesion protein-1 (VAP-1): increased serum levels in inflammatory liver diseases. J Immunol 1998; 161: 1549-1557.
25. Kurkijarvi R, Jalkanen S, Isoniemi H, Salmi M: Vascular adhesion protein-1 (VAP-1) mediates lym-phocyte-endothelial interactions in chronic kidney rejection. Eur J Immunol 2001; 31: 2876-2884.
26. Bonaiuto E, Lunelli M, Scarpa M et al.: A structure-activity study to identify novel and efficient substrates of the human semicarbazide-sensitive amine oxidase VAP-l enzyme. Biochimie 2010; 92: 858-863.
27. Boomsma F, Tipton KF: Renalase, a catecholamine-metabolising enzyme? J Neural Transm 2007; 114: 775-777.
28. Desir GV: Role of renalase in the regulation of blood pressure and the renal dopamine system. Curr Opin Nephrol Hypertens 2010; 20: 31-36.
29. Hennebry SC, Eikelis N, Socratous F et al.: Renalase, a novel soluble FAD-dependent protein, is synthesized in the brain and peripheral nerves. Mol Psychiatry 2010; 15: 234-236.
30. Xu J, Li G, Wang P et al.: Renalase is a novel, soluble monoamine oxidase that regulates cardiac function and blood pressure. J Clin Invest 2005; 115: 1275-1280.
31. Ghosh SS, Gehr TWB, Sica DA et al.: Effect of renalase inhibition on blood pressure. J Am Soc Nephrol 2006; 17: 208A.
32. Zhao Q, Fan Z, He J et al.: Renalase gene is anovel susceptibility gene for essential hypertension: a two-stage association study in northern Han Chinese population. J Mol Med (BerI) 2007; 85: 877-885.
33. Stec A, Semczuk A, Furmaga J et al.: Polymorphism of the renalase gene in end-stage renal disease patients affected by hypertension. Nephrol Dial Transplant 2012; 27: 4162-4166.
34. Przybyłowski P, Małyszko J, Małyszko JS: Prevalence of chronic kidney disease is extremely high in heart transplant recipients. Transplant Proc 2009; 41: 3239-3241.
35. Przybyłowski P, Małyszko J, Małyszko JS: Immunosuppressive regimen and prevalence of chronic kidney disease in orthotopic heart transplant recipients. Med Sci Monit 2010; 16: CR563-566.
36. National Kidney Foundation K/DOQI: Clinical Practice Guidelines for chronic kidney disease: Evaluation, classification, and stratification. Am J Kidney Dis 2002; 39: S1-S266.
37. Herlitz H, Lindelow B: Renal failure following cardiac transplantation. Nephrol Dial Transplant 2000; 15: 311-314.
38. Lindelow B, Bergh CH, Herlitz H, Waagstein F: Predictors and evolution of renal function during 9 years following heart transplantation. J Am Soc Nephrol 2000; 11: 951-957.
39. Ishani A, Erturk S, Hertz MI et al.: Predictors of renal function following lung or heart-lung transplantation. Kidney Int 2002; 61: 2228-2234.
40. Canales M, Youssef P, Spong R et al.: Predictors of chronic kidney disease in long-term survivors of lung and heart-lung transplantation. Am J Transplant 2006; 6: 2157-2163.
41. Przybyłowski P, Małyszko J, Małyszko JS: Chronic kidney disease in prevalent orthotopic heart transplant recipients using new CKD-EPI formula in regard to immunosuppression. Ann Transplant 2010; 15: 32-35.
42. Koc-Żórawska E, Małyszko J, Małyszko JS, Myśliwiec M: VAP-1, a nover molecule linked to endothelial damage and kidney function in kidney allograft recipients. Kidney Blood Press Res 2012; 36: 242-247.
43. Koc-Żórawska E, Małyszko J, Zbroch E et al.: Vascular adhesion protein-1 and renalase in regard to diabetes in hemodialysis patients. Arch Med Sci 2012; 8: 1048-1052.
44. Małyszko J: Mechanism of endothelial dysfunction in chronic kidney disease. Clin Chim Acta 2010; 411: 1412-1420.
45. Zbroch E, Małyszko J, Małyszko J et al.: Renalase, kidney function, and markers of endothelial dysfunction in renal transplant recipients. Pol Arch Med Wewn 2012; 122: 40-44.
46. Przybyłowski P, Koc-Żórawska E, Małyszko JS et al.: Renalase and endothelial dysfunction in heart transplant recipients. Transplant Proc 2013; 45: 394-396.
47. Małyszko J, Zbroch E, Małyszko J et al.: Renalase, a novel regulator of blood pressure, is predicted by kidney function in renal transplant recipients. Transplant Proc 2011; 43: 3004-3007.
48. Przybyłowski P, Małyszko J, Małyszko JS et al.: Blood pressure control in orthotopic heart transplant and kidney allograft recipients is far from satisfactory. Transplant Proc 2010; 42: 4263-4266.