Michael BROWNLEE, Angela Bruna MAFFİONE, Pietro FERRARA, Ida GİARDİNO, Maria DAPOLİTO, Anna Laura COLİA, Michele SACCO, Massimo PETTOELLO-MANTOVANİ

Ürenin damar toksisitesi, kronik böbrek yetmezliğine bağlı kalp ve damar hastalıklarının patogenezinde yeni bir “eski oyuncu”

Çocuklarda kronik böbrek hastalığı son dönem böbrek hastalığına yol açabilen geri dönüşümsüz bir süreçtir. Diyaliz alan son dönem böbrek hastası çocuklarda ölüm oranı son on yıl içinde dramatik olarak artmıştır ve genel çocuk nüfusu ile karşılaştırıldığında anlamlı derecede daha yüksektir. Ayrıca, çocukluk çağında son dönem böbrek hastalığı gelişmiş olan diyaliz ve nakil hastaları, yaş/ırk açısından benzer topluluklara göre çok daha kısa yaşamaktadır. Farklı çalışmalar, kalp ve damar hastalığının, son dönem böbrek hastalığı olan çocuklarda ve çocuklukta başlayan kronik böbrek hastalığı olan erişkinlerde, en önde gelen ölüm nedeni olduğunu ve kronik böbrek hastalığı olan çocukların kalp ve damar hastalığı gelişmesi açısından en yüksek risk grubunda olduğunu göstermektedir. Karaciğerde amino asitler ve diğer azotlu metabolitlerin yıkımı sırasında oluşan üre, normalde böbrekler tarafından idrara üretildiği kadar hızlı bir şekilde atılır. Böbrek işlevi bozulduğunda, kan üre yoğunluğu giderek artacaktır. Uzun bir süre, ürenin toksisitesinin ihmal edilebilir olduğu kabul edilmiştir. Ancak, plazma üresinin, kronik böbrek yetmezliği ile hızlandırılmış bir damar sertliği modelinde, aort plağı alanının tek önemli öngörücüsü olması, kronik diyaliz uygulanan hastalarda saptanan yüksek üre düzeylerinin, bu hasta grubunda, damar sertliğinin hızlanmasında önemli bir rol oynayabileceğini düşündürmektedir. Bu derlemenin amacı, böbrek yetmezliğinde hızlanan kalp ve damar hastalıklarının patogenezinde, ürenin oynadığı role yeni bir ışık tutmaktır

Vascular toxicity of urea, a new “old player” in the pathogenesis of chronic renal failure induced cardiovascular diseases

Chronic kidney disease in children is an irreversible process that may lead to end-stage renal disease. The mortality rate in children with endstage renal disease who receive dialysis increased dramatically in the last decade, and it is significantly higher compared with the general pediatric population. Furthermore, dialysis and transplant patients, who have developed end-stage renal disease during childhood, live respectively far less as compared with age/race-matched populations.Different reports show that cardiovascular disease is the leading cause of death in children with end-stage renal disease and in adults with childhood-onset chronic kidney disease, and that children with chronic kidney disease are in the highest risk group for the development of cardiovascular disease.Urea, which is generated in the liver during catabolism of amino acids and other nitrogenous metabolites, is normally excreted into the urine by the kidneys as rapidly as it is produced. When renal function is impaired, increasing concentrations of blood urea will steadily accumulate. For a long time, urea has been considered to have negligible toxicity. However, the finding that plasma urea is the only significant predictor of aortic plaque area fraction in an animal model of chronic renal failure -accelerated atherosclerosis, suggests that the high levels of urea found in chronic dialysis patients might play an important role in accelerated atherosclerosis in this group of patients. The aim of this review was to provide novel insights into the role played by urea in the pathogenesis of accelerated cardiovascular disease in renal failure

PDF

___

1. Wong CJ, Moxey-Mims M, Jerry-Fluker J, Warady BA, Furth SL. CKiD (CKD in Children) Prospective Cohort Study: a review of current findings. Am J Kidney Dis 2012; 60: 1002-11. [CrossRef ]
2. Warady BA, Chadha V. Chronic kidney disease in children: the global perspective. Pediatr Nephrol 2007; 22: 1999-2009. [CrossRef ]
3. US Renal Data System. USRDS 2011 Annual Data Report: Atlas of Chronic Kidney Disease and End-Stage Renal Disease in the United States, Bethesda, MD, National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, 2011.
4. Mitsnefes MM. Cardiovascular disease in children with chronic kidney disease. J Am Soc Nephrol 2012; 23: 578- 85. [CrossRef ]
5. Schiffri EL, Lipman ML, Mann JF. Chronic kidney disease: effects on the cardiovascular system. Circulation 2007; 116: 85-97. [CrossRef ]
6. Kavey RE, Allada V, Daniels SR, et al. Cardiovascular risk reduction in high-risk pediatric patients: a scientific statement from the American Heart Association Expert Panel on Population and Prevention Science; the Councils on Cardiovascular Disease in the Young, Epidemiology and Prevention, Nutrition, Physical Activity and Metabolism, High Blood Pressure Research, Cardiovascular Nursing, and the Kidney in Heart Disease; and the Interdisciplinary Working Group on Quality of Care and Outcomes Research, endorsed by the American Academy of Pediatrics. Circulation 2006; 114: 2710-38. [CrossRef ]
7. Chade AR, Lerman A, Lerman LO. Kidney in early atherosclerosis. Hypertension 2005; 45: 1042-9. [CrossRef ]
8. Vanholder R, Baurmeister U, Brunet P, et al. A bench to bedside view of uremic toxins. J Am oc Nephrol 2008; 19: 863-70. [CrossRef ]
9. Massy ZA, Pietrement C, Touré F. Reconsidering the lack of urea toxicity in dialysis patnts. Semin Dial 2016; 29: 333-7. [CrossRef ]
10. Johnson WJ, Hagge WW, Wagoner RD, Dinapoli RP, Rosevear JW. Effects of urea loading in patients with faradvanced renal failure. Mayo Clin Proc 1972; 47: 21-9.
11. Eknoyan G, Beck GJ, Cheung AK, et al. Effect of dialysis dose and membrane flux in maintenance hemodialysis. N Engl J Med 2002; 347: 2010-9. [CrossRef ]
12. Ivanovski O, Szumilak D, Nguyen-Khoa T, et al. The antioxidant N-acetylcysteine prevents accelerated atherosclerosis in uremic apolipoprotein E knockout mice. Kidney Int 2005; 67: 2288-94 [CrossRef ]
13. Apostolov OE, Ray D, Savenka AV, Shah SV, Basnakian AG. Chronic uremia stimulates LDL carbamylation and atherosclerosis. J Am Soc Nephrol 2010; 21: 1852-7. [CrossRef ]
14. Vanholder R, Massy Z, Argiles A, et al. Chronic kidney disease as a cause of cardiovascular morbidity and mortality. Nephrol Dial Transpl 2005; 20: 1048-56. [CrossRef ]
15. Davignon J, Ganz P. Role of endothelial dysfunction in atherosclerosis. Circulation 2004; 109: 27-32. [CrossRef ]
16. Lilien MR, Groothoff JW. Cardiovascular disease in children with CKD or ESRD. Nat Rev Nephrol 2009; 5: 229-35. [CrossRef ]
17. Jofre R, Rodriguez-Benitez P, Lopez-Gomez JM, PerezGarcia R. Inflammatory syndrome in patients on hemodialysis. J Am Soc Nephrol 2006; 17: 274-80. [CrossRef ]
18. Ross R. Atherosclerosis. An inflammatory disease. N Engl J Med 1999; 340: 115-26. [CrossRef ]
19. D’Apolito M, Du X, Pisanelli D, et al. Urea-induced ROS cause endothelial dysfunction in chronic renal failure. Atherosclerosis 2015; 239: 393-400. [CrossRef ]
20. Zou MH, Shi C, Cohen RA. High glucose via peroxynitrite causes tyrosine nitration and inactivation of prostacyclin synthase that is associated with Thromboxane/ Prostaglandin H2 Receptor–Mediated Apoptosis and Adhesion Molecule Expression in Cultured Human Aortic Endothelial Cells. Diabetes 2002; 51: 198-203. [CrossRef ]
21. Marchetti V, Menghini R, Rizza S, et al. Benfotiamine counteracts glucose toxicity effects on endothelial progenitor cell differentiation via Akt/FoxO signaling. Diabetes 2006; 55: 2231-7. [CrossRef ]
22. Asahara T, Takahashi T, Masuda H, et al. VEGF contributes to postnatal neovascularization by mobilizing bone marrow-derived endothelial progenitor cells. EMBO J 1999; 18: 3964-72. [CrossRef ]
23. Yuen DA, Connelly KA, Advani A, et al. Culture modified bone marrow cells attenuate cardiac and renal injury in a chronic kidney disease rat model via a novel antifibrotic mechanism. PLoS One 2010; 5: e9543. [CrossRef ]
24. Tepper OM, Galiano RD, Capla JM, et al. Human endothelial progenitor cells from type II diabetics exhibit impaired proliferation, adhesion, and incorporation into vascular structures. Circulation 2002; 106: 2781-6. [CrossRef ]
25. Hill JM, Zalos G, Halcox JP, et al. Circulating endothelial progenitor cells, vascular function, and cardiovascular risk. N Engl J Med 2003; 348: 593-600. [CrossRef ]
26. de Groot K, Bahlmann FK, Sowa J, et al. Uremia causes endothelial progenitor cell deficiency. Kidney Int 2004; 66: 641-6. [CrossRef ]+
27. Jie KE, Lilien MR, Goossens MH, Westerweel PE, Klein MK, Verhaar MC. Reduced endothelial progenitor cells in children with hemodialysis but not predialysis chronic kidney disease. Pediatrics 2010; 126: e990-3. [CrossRef ]
28. D’Apolito M, Colia AL, Lasalvia M, et al. Urea-induced ROS accelerate senescence in endothelial progenitor cells. Atherosclerosis 2017; 263: 127-36. [CrossRef ]
29. Padfield GJ, Short A, Mills NL, et al. The constituents and mechanisms of generation of ‘endothelial cellcolony forming units’. Cardiovasc Res 2013; 100: 288- 96. [CrossRef ]
30. Kuilman T, Peeper DS. Senescence-messaging secretome: SMS-ing cellular stress. Nat Rev Cancer 2009; 9: 81- 94. [CrossRef ]
31. Goligorsky MS, Yasuda K, Ratliff B. Dysfunctional endothelial progenitor cells in chronic kidney disease. Am Soc Nephrol 2010; 21: 911-9. [CrossRef ]
32. Bennett MR, Sinha S, Owens GK. Vascular smooth muscle cells in atherosclerosis. Circ Res 2016; 118: 692-702. [CrossRef ]
33. Madsen M, Aarup A, Albinsson S, et al. Uremia modulates the phenotype of aortic smooth muscle cells. Atherosclerosis 2017; 257: 64-70. [CrossRef ]
34. Trecherel E, Godin C, Louandre C, et al. Upregulation of BAD, a pro-apoptotic protein of the BCL2family, in vascular smooth muscle cells exposed to uremic conditions. Biochem Biophys Res Commun 2012; 417: 479-83. [CrossRef ]
35. Shroff RC, McNair R, Figg N, et al. Dialysis accelerates medial vascular calcification in part by triggering smooth muscle cell apoptosis. Circulation 2008; 118: 1748- 57. [CrossRef ]
36. Mather KJ, Steinberg HO, Baron AD. Insulin resistance in the vasculature. J Clin Invest 2013; 123: 1003-4. [CrossRef ]
37. Lteif A, Vaishnava P, Baron AD, Mather KJ. Endothelin limits insulin action in obese/insulin-resistant humans. Diabetes 2007; 56: 728-34. [CrossRef ]
38. Hanley AJ, Williams K, Stern MP, Haffner SM. Homeostasis model assessment of IR in relation to the incidence of cardiovascular disease: The San Antonio Heart Study. Diabetes Care 2002; 25: 1177-84. [CrossRef ]
39. Bodlaj G, Ber J, Pichler R, Biesenbach G. Prevalence, severity and predictors of HOMA-estimated insulin resistance in diabetic and nondiabetic patients with end-stage renal disease. J Nephrol 2006; 19: 607-12.
40. Lorenzo C, Nath SD, Hanley AJ, Abboud HE, Haffner SM. Relation of low glomerula filtrationrate to metabolic disorders in individuals without diabetes and with normoal albiminuria. Clin J Am Soc Nephrol 2008; 3: 783-9. [CrossRef ]
41. Takenaka T, Kanno Y, Ohno Y, Suzuki H. Key role of insulin resistance in vascular injury among hemodialysis patients. Metabolism 2007; 56: 153-9. [CrossRef ]
42. D’Apolito M, Du X, Zong H, et al. Urea induced ROS generation causes insulin resistance in mice with chronic renal failure. J Clin Investig 2010; 120: 203-13. [CrossRef ]
43. Fadda GZ, Hajjar SM, Perna AF, Zhou XJ, Lipson LG, Massry SG. On the mechanism of impaired insulin secretion in chronic renal failure. J Clin Invest 1991; 87: 255- 61. [CrossRef ]
44. Koppe L, Nyam E, Vivot K, et al. Urea impairs β cell glycolysis and insulin secretion in chronic kidney disease. J Clin Invest 2016; 126: 3598-612. [CrossRef ]
45. Dounousi E, Papavasiliou E, Areti Makedou M, et al. Oxidative stress is progressively enhanced with advancing stages of CKD. Am J Kidney Dis 2006; 48: 752-60. [CrossRef ]
46. Menini S, Amadio L, Oddi G, et al. Deletion of p66Shc longevity gene protects against experimental diabetic glomerulopathy by preventing diabetes-induced oxidative stress. Diabetes 2006; 55: 1642-50. [CrossRef ]
47. Dikalov S. Crosstalk between mitochondria and NADPH oxidases. Free Radic Biol Med 2011; 51: 1289-301. [CrossRef]
48. Ok E, Basnakian AG, Apostolov EO, Barri YM, Shah SV. Carbamylated low-density lipoprotein induces death of endothelial cells: a link to atherosclerosis in patients with kidney disease. Kidney Int 2005; 68: 173-8. [CrossRef ]
49. Holzer M, Gauster M, Pfeifer T, et al. Protein carbamylation renders high-density lipoprotein dysfunctional. Antioxid Redox Signal 2011; 14: 2337-46. [CrossRef ]
50. Berg AH, Drechsler C, Wenger J, et al. Carbamylation of serum albumin as a risk factor for mortality in patients with kidney failure. Sci Transl Med 2013; 5: 175ra29. [CrossRef ]