The Korean journal of internal medicine

The Korean Association of Internal Medicine (대한내과학회)
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Circulating renalase predicts all-cause mortality and renal outcomes in patients with advanced chronic kidney disease

  • Baek, Seon Ha (Department of Internal Medicine, Seoul National University Bundang Hospital) ;
  • Cha, Ran-hui (National Medical Center) ;
  • Kang, Shin Wook (Yonsei University College of Medicine) ;
  • Park, Cheol Whee (College of Medicine, Seoul St. Mary's Hospital, The Catholic University of Korea) ;
  • Cha, Dae Ryong (Korea University Ansan Hospital) ;
  • Kim, Sung Gyun (Hallym University Sacred Heart Hospital) ;
  • Yoon, Sun Ae (College of Medicine, Uijeongbu St. Mary's Hospital, The Catholic University of Korea) ;
  • Kim, Sejoong (Department of Internal Medicine, Seoul National University Bundang Hospital) ;
  • Han, Sang-Youb (Inje University Ilsan Paik Hospital) ;
  • Park, Jung Hwan (Konkuk University Medical Center) ;
  • Chang, Jae Hyun (Gachon University Gil Medical Center) ;
  • Lim, Chun Soo (Seoul National University College of Medicine) ;
  • Kim, Yon Su (Seoul National University College of Medicine) ;
  • Na, Ki Young (Department of Internal Medicine, Seoul National University Bundang Hospital)
  • Received : 2017.02.11
  • Accepted : 2017.05.21
  • Published : 2019.07.01
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Abstract

Background/Aims: Patients with chronic kidney disease (CKD) have been found to show markedly increased rates of end-stage renal disease, major adverse cardiovascular and cerebrovascular events (MACCEs), and mortality. Therefore, new biomarkers are required for the early detection of such clinical outcomes in patients with CKD. We aimed to determine whether the level of circulating renalase was associated with CKD progression, MACCEs, and all-cause mortality, using data from a prospective randomized controlled study, Kremezin STudy Against Renal disease progression in Korea (K-STAR; NCT 00860431). Methods: A retrospective analysis of the K-STAR data was performed including 383 patients with CKD (mean age, 56.4 years; male/female, 252/131). We measured circulating renalase levels and examined the effects of these levels on clinical outcomes. Results: The mean level of serum renalase was 75.8 ± 34.8 ㎍/mL. In the multi-variable analysis, lower hemoglobin levels, higher serum creatinine levels, and diabetes mellitus were significantly associated with a higher renalase levels. Over the course of a mean follow-up period of 56 months, 25 deaths and 61 MACCEs occurred. Among 322 patients in whom these outcomes were assessed, 137 adverse renal outcomes occurred after a mean follow-up period of 27.8 months. Each 10-㎍/mL increase in serum renalase was associated with significantly greater hazards of all-cause mortality and adverse renal outcomes (hazard ratio [HR] = 1.112, p = 0.049; HR = 1.052, p = 0.045). However, serum renalase level was not associated with the rate of MACCEs in patients with CKD. Conclusions: Our results indicated that circulating renalase might be a predictor of mortality and adverse renal outcomes in patients with CKD.

Keywords

Acknowledgement

The authors would like to thank Soyeon Ahn, PhD (Medical Research Collaborating Center, Seoul National University Bundang Hospital) for valuable comments of statistical methods without compensation.

References

  1. Spasovski G, Ortiz A, Vanholder R, El Nahas M. Proteomics in chronic kidney disease: the issues clinical nephrologists need an answer for. Proteomics Clin Appl 2011;5:233-240. https://doi.org/10.1002/prca.201000150
  2. Barsoum RS. Chronic kidney disease in the developing world. N Engl J Med 2006;354:997-999. https://doi.org/10.1056/NEJMp058318
  3. Maciorkowska D, Zbroch E, Malyszko J. Circulating renalase, catecholamines, and vascular adhesion protein 1 in hypertensive patients. J Am Soc Hypertens 2015;9:855-864. https://doi.org/10.1016/j.jash.2015.08.002
  4. Desir GV, Wang L, Peixoto AJ. Human renalase: a review of its biology, function, and implications for hypertension. J Am Soc Hypertens 2012;6:417-426. https://doi.org/10.1016/j.jash.2012.09.002
  5. 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. https://doi.org/10.1172/JCI24066
  6. Li G, Xu J, Wang P, et al. Catecholamines regulate the activity, secretion, and synthesis of renalase. Circulation 2008;117:1277-1282. https://doi.org/10.1161/CIRCULATIONAHA.107.732032
  7. Guo X, Wang L, Velazquez H, Safirstein R, Desir GV. Renalase: its role as a cytokine, and an update on its association with type 1 diabetes and ischemic stroke. Curr Opin Nephrol Hypertens 2014;23:513-518. https://doi.org/10.1097/MNH.0000000000000044
  8. Zbroch E, Koc-Zorawska E, Malyszko J, Malyszko J, Mysliwiec M. Circulating levels of renalase, norepinephrine, and dopamine in dialysis patients. Ren Fail 2013;35:673-679. https://doi.org/10.3109/0886022X.2013.778754
  9. Wang F, Li J, Xing T, Xie Y, Wang N. Serum renalase is related to catecholamine levels and renal function. Clin Exp Nephrol 2015;19:92-98. https://doi.org/10.1007/s10157-014-0951-8
  10. Przybylowski P, Malyszko J, Kozlowska S, Malyszko J, Koc-Zorawska E, Mysliwiec M. Serum renalase depends on kidney function but not on blood pressure in heart transplant recipients. Transplant Proc 2011;43:3888-3891. https://doi.org/10.1016/j.transproceed.2011.08.075
  11. Malyszko J, Zbroch E, Malyszko JS, Koc-Zorawska E, Mysliwiec M. Renalase, a novel regulator of blood pressure, is predicted by kidney function in renal transplant recipients. Transplant Proc 2011;43:3004-3007. https://doi.org/10.1016/j.transproceed.2011.08.032
  12. Gluba-Brzozka A, Michalska-Kasiczak M, Franczyk-Skora B, Nocun M, Banach M, Rysz J. Markers of increased cardiovascular risk in patients with chronic kidney disease. Lipids Health Dis 2014;13:135. https://doi.org/10.1186/1476-511X-13-135
  13. Desir GV, Tang L, Wang P, et al. Renalase lowers ambulatory blood pressure by metabolizing circulating adrenaline. J Am Heart Assoc 2012;1:e002634.
  14. Desir GV. Role of renalase in the regulation of blood pressure and the renal dopamine system. Curr Opin Nephrol Hypertens 2011;20:31-36. https://doi.org/10.1097/MNH.0b013e3283412721
  15. Wang F, Huang B, Li J, Liu L, Wang N. Renalase might be associated with hypertension and insulin resistance in type 2 diabetes. Ren Fail 2014;36:552-556. https://doi.org/10.3109/0886022X.2013.876352
  16. Ghosh SS, Krieg RJ, Sica DA, Wang R, Fakhry I, Gehr T. Cardiac hypertrophy in neonatal nephrectomized rats: the role of the sympathetic nervous system. Pediatr Nephrol 2009;24:367-377. https://doi.org/10.1007/s00467-008-0978-8
  17. Baraka A, El Ghotny S. Cardioprotective effect of renalase in 5/6 nephrectomized rats. J Cardiovasc Pharmacol Ther 2012;17:412-416. https://doi.org/10.1177/1074248412446977
  18. Cha RH, Kang SW, Park CW, et al. A randomized, controlled trial of oral intestinal sorbent AST-120 on renal function deterioration in patients with advanced renal dysfunction. Clin J Am Soc Nephrol 2016;11:559-567. https://doi.org/10.2215/CJN.12011214
  19. Cheng JM, Akkerhuis KM, Meilhac O, et al. Circulating osteoglycin and NGAL/MMP9 complex concentrations predict 1-year major adverse cardiovascular events after coronary angiography. Arterioscler Thromb Vasc Biol 2014;34:1078-1084. https://doi.org/10.1161/ATVBAHA.114.303486
  20. Muhlestein JB, Lappe DL, Lima JA, et al. Effect of screening for coronary artery disease using CT angiography on mortality and cardiac events in high-risk patients with diabetes: the FACTOR-64 randomized clinical trial. JAMA 2014;312:2234-2243. https://doi.org/10.1001/jama.2014.15825
  21. Ho KK, Pinsky JL, Kannel WB, Levy D. The epidemiology of heart failure: the Framingham Study. J Am Coll Cardiol 1993;22(4 Suppl A):6A-13A. https://doi.org/10.1016/0735-1097(93)90455-A
  22. Westin GG, Armstrong EJ, Bang H, et al. Association between statin medications and mortality, major adverse cardiovascular event, and amputation-free survival in patients with critical limb ischemia. J Am Coll Cardiol 2014;63:682-690. https://doi.org/10.1016/j.jacc.2013.09.073
  23. Wang L, Velazquez H, Moeckel G, et al. Renalase prevents AKI independent of amine oxidase activity. J Am Soc Nephrol 2014;25:1226-1235. https://doi.org/10.1681/ASN.2013060665
  24. Milani M, Ciriello F, Baroni S, et al. FAD-binding site and NADP reactivity in human renalase: a new enzyme involved in blood pressure regulation. J Mol Biol 2011;411:463-473. https://doi.org/10.1016/j.jmb.2011.06.010
  25. Boomsma F, Tipton KF. Renalase, a catecholamine-metabolising enzyme? J Neural Transm (Vienna) 2007;114:775-776. https://doi.org/10.1007/s00702-007-0672-1
  26. Malyszko J, Koc-Zorawska E, Zorawski M, et al. Renalase is removed by kidneys and during dialysis: excess related to CKD complications? Curr Vasc Pharmacol 2015;13:134-140. https://doi.org/10.2174/1570161113666141217141805
  27. Koc-Zorawska E, Malyszko J, Malyszko JS, Mysliwiec M. VAP-1, a novel molecule linked to endothelial damage and kidney function in kidney allograft recipients. Kidney Blood Press Res 2012;36:242-247. https://doi.org/10.1159/000343413
  28. Wybraniec MT, Mizia-Stec K, Trojnarska O, et al. Low plasma renalase concentration in hypertensive patients after surgical repair of coarctation of aorta. J Am Soc Hypertens 2014;8:464-474. https://doi.org/10.1016/j.jash.2014.04.009
  29. Zbroch E, Malyszko J, Malyszko JS, Koc-Zorawska E, Mysliwiec M. Renalase, a novel enzyme involved in blood pressure regulation, is related to kidney function but not to blood pressure in hemodialysis patients. Kidney Blood Press Res 2012;35:395-399. https://doi.org/10.1159/000338178
  30. Gu R, Lu W, Xie J, Bai J, Xu B. Renalase deficiency in heart failure model of rats: a potential mechanism underlying circulating norepinephrine accumulation. PLoS One 2011;6:e14633. https://doi.org/10.1371/journal.pone.0014633
  31. Dziedzic M, Petkowicz B, Bednarek-Skublewska A, Solski J, Buczaj A, Choina P. Relationship between renalase and N-terminal pro-B-type natriuretic peptide (NT pro-BNP) in haemodialysis patients. Ann Agric Environ Med 2014;21:132-135.
  32. Malyszko J, Malyszko JS, Mikhailidis DP, Rysz J, Zorawski M, Banach M. Hypertension and kidney disease: is renalase a new player or an innocent bystander? J Hypertens 2012;30:457-462. https://doi.org/10.1097/HJH.0b013e32834f0bb7
  33. Eisenhofer G, Rundquist B, Aneman A, et al. Regional release and removal of catecholamines and extraneuronal metabolism to metanephrines. J Clin Endocrinol Metab 1995;80:3009-3017.
  34. Schlaich MP, Socratous F, Hennebry S, et al. Sympathetic activation in chronic renal failure. J Am Soc Nephrol 2009;20:933-939. https://doi.org/10.1681/ASN.2008040402

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