Comparison of effects of m-TOR inhibitors and calcineurin inhibitor on SUPAR and ox-LDL levels in renal transplant recipients
Keywords:
mTOR inhibitors, calcineurin inhibitor, early markers of inflammation, renal trasplant
Abstract
Introduction: We aimed to investigate the effect of different immunosuppressive regimens on SUPAR and ox-LDL levels which are early markers of inflammation in renal transplant recipients. Methods: A total number of 83 patients were enrolled in our study. While fourty-eight of those were received mTORi, thirty five patients were been receiving CNI. According to the immunosuppressive regimen patients were divided into CNI and m-TORi receving groups and serum SUPAR and ox-LDL levels were measured. Results: Log-SUPAR values were lower in the group receiving m-TORi (3.40 ± 0.1 vs 3.48 ± 0.4, p=0.010). OxLDL/LDL levels were higher (0.0168 ± 005 vs 0.0132 ± 004, p=0.009) in the CNI group. In linear regression analysis, a statistically significant relationship was detected between the use of m-TORi and log-SUPAR (β=-0.052, 95% CI [-0.224, -0.012], p = 0.041). A negative and independent relationship was found between HT and log-SUPAR (β=-0.60, 95% CI--0.112, -0.018], p=0.0024) and ox-LDL (β=-0.169 [-0.330, -0.008], p=0.040). Very strong correlation (r=1.0, p=<0.001) and independent relationship (β=.321 [0.313,0.330], p=<0.001) was detected between ox-LDL and SUPAR. Conclusion: As a result, when compared immunsuppression between m-TORi and CNI, the former was associated with lower SUPAR and oxLDL levels.
References
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23) Alachkar N, Li J, Matar D, Vujjini V, Alasfar S, Tracy M, et al. Monitoring suPAR levels in post-kidney transplant focal segmental glomerulosclerosis treated with therapeutic plasma exchange and rituximab. BMC Nephrol. 2018;19(1):361. doi: 10.1186/s12882-018-1177-x.
24) Wei C, El Hindi S, Li J, Fornoni A, Goes N, Sageshima J, et al. Circulating urokinase receptor as a cause of focal segmental glomerulosclerosis. Nat Med. 2011;17(8):952-60. doi: 10.1038/nm.2411.
25) Segarra A, Jatem E, Quiles MT, Arbós MA, Ostos H, Valtierra N, et al. Valor diagnóstico de los niveles séricos del receptor soluble de la uroquinasa en adultos con síndrome nefrótico idiopático. Nefrologia. 2014;34(1):46-52. doi: 10.3265/Nefrologia.pre2013.Oct.12256.
26) Maas RJ, Deegens JK, Wetzels JF. Serum suPAR in patients with FSGS: trash or treasure? Pediatr Nephrol. 2013;28(7):1041-8. doi: 10.1007/s00467-013-2452-5.
27) Holdaas H, Rostaing L, Serón D, Cole E, Chapman J, Fellstrøm B, et al.; ASCERTAIN Investigators. Conversion of long-term kidney transplant recipients from calcineurin inhibitor therapy to everolimus: a randomized, multicenter, 24-month study. Transplantation. 2011;92(4):410-8. doi: 10.1097/TP.0b013e318224c12d.
28) Paoletti E, Citterio F, Corsini A, Potena L, Rigotti P, Sandrini S, et al.; ENTROPIA Project. Everolimus in kidney transplant recipients at high cardiovascular risk: a narrative review. J Nephrol. 2020;33(1):69-82. doi: 10.1007/s40620-019-00609-y.
29) Kurdi A, Roth L, Van der Veken B, Van Dam D, De Deyn PP, De Doncker M, et al. Everolimus depletes plaque macrophages, abolishes intraplaque neovascularization and improves survival in mice with advanced atherosclerosis. Vascul Pharmacol. 2019;113:70-6. doi: 10.1016/j.vph.2018.12.004.
2) Hernández-Fuentes MP, Lechler RI. Chronic graft loss. Immunological and non-immunological factors. Contrib Nephrol. 2005;146:54-64. doi: 10.1159/000082065.
3) Baran DA, Galin ID, Gass AL. Calcineurin inhibitor-associated early renal insufficiency in cardiac transplant recipients: risk factors and strategies for prevention and treatment. Am J Cardiovasc Drugs. 2004;4(1):21-9. doi: 10.2165/00129784-200404010-00003.
4) Guerra G, Srinivas TR, Meier-Kriesche HU. Calcineurin inhibitor-free immunosuppression in kidney transplantation. Transpl Int. 2007;20(10):813-27. doi: 10.1111/j.1432-2277.2007.00528.x.
5) Kajiwara M, Masuda S. Role of mTOR inhibitors in kidney disease. Int J Mol Sci. 2016;17(6):975. doi: 10.3390/ijms17060975.
6) Baboolal K. A phase III prospective, randomized study to evaluate concentration-controlled sirolimus (rapamune) with cyclosporine dose minimization or elimination at six months in de novo renal allograft recipients. Transplantation. 2003;75(8):1404-8. doi: 10.1097/01.TP.0000063703.32564.3B.
7) Budde K, Becker T, Arns W, Sommerer C, Reinke P, Eisenberger U, Kramer S, et al.; ZEUS Study Investigators. Everolimus-based, calcineurin-inhibitor-free regimen in recipients of de-novo kidney transplants: an open-label, randomised, controlled trial. Lancet. 2011;377(9768):837-47. doi: 10.1016/S0140-6736(10)62318-5.
8) Eisen HJ, Tuzcu EM, Dorent R, Kobashigawa J, Mancini D, Valantine-von Kaeppler HA, et al.; RAD B253 Study Group. Everolimus for the prevention of allograft rejection and vasculopathy in cardiac-transplant recipients. N Engl J Med. 2003;349(9):847-58. doi: 10.1056/NEJMoa022171.
9) Eisen H. Long-term cardiovascular risk in transplantation: insights from the use of everolimus in heart transplantation. Nephrol Dial Transplant. 2006;21(Suppl 3):iii9-13. doi: 10.1093/ndt/gfl295.
10) Desmedt S, Desmedt V, Delanghe JR, Speeckaert R, Speeckaert MM. The intriguing role of soluble urokinase receptor in inflammatory diseases. Crit Rev Clin Lab Sci. 2017;54(2):117-33. doi: 10.1080/10408363.2016.1269310.
11) Eapen DJ, Manocha P, Ghasemzadeh N, Patel RS, Al Kassem H, Hammadah M, et al. Soluble urokinase plasminogen activator receptor level is an independent predictor of the presence and severity of coronary artery disease and of future adverse events. J Am Heart Assoc. 2014;3(5):e001118. doi: 10.1161/JAHA.114.001118.
12) Lyngbæk S, Marott JL, Sehestedt T, Hansen TW, Olsen MH, Andersen O, et al. Cardiovascular risk prediction in the general population with use of suPAR, CRP, and Framingham Risk Score. Int J Cardiol. 2013;167(6):2904-11. doi: 10.1016/j.ijcard.2012.07.018.
13) Vela CG, Cristol JP, Descomps B, Mourad G. Prospective study of lipid disorders in FK506-versus cyclosporine-treated renal transplant patients. Transplant Proc. 2000;32(2):398. doi: 10.1016/s0041-1345(99)00993-8.
14) Kobashigawa JA, Kasiske BL. Hyperlipidemia in solid organ transplantation. Transplantation. 1997;63(3):331-8. doi: 10.1097/00007890-199702150-00001.
15) Shihab FS, Bennett WM, Tanner AM, Andoh TF. Mechanism of fibrosis in experimental tacrolimus nephrotoxicity. Transplantation. 1997;64(12):1829-37. doi: 10.1097/00007890-199712270-00034.
16) Khanna AK, Pieper GM. NADPH oxidase subunits (NOX-1, p22phox, Rac-1) and tacrolimus-induced nephrotoxicity in a rat renal transplant model. Nephrol Dial Transplant. 2007;22(2):376-85. doi: 10.1093/ndt/gfl608.
17) Kurdi A, De Meyer GR, Martinet W. Potential therapeutic effects of mTOR inhibition in atherosclerosis. Br J Clin Pharmacol. 2016;82(5):1267-79. doi: 10.1111/bcp.12820.
18) Baetta R, Granata A, Canavesi M, Ferri N, Arnaboldi L, Bellosta S, Pfister P, Corsini A. Everolimus inhibits monocyte/macrophage migration in vitro and their accumulation in carotid lesions of cholesterol-fed rabbits. J Pharmacol Exp Ther. 2009;328(2):419-25. doi: 10.1124/jpet.108.144147.
19) Andreassen AK, Andersson B, Gustafsson F, Eiskjaer H, Rådegran G, Gude E, et al.; SCHEDULE investigators. Everolimus initiation with early calcineurin inhibitor withdrawal in de novo heart transplant recipients: three-year results from the randomized SCHEDULE Study. Am J Transplant. 2016;16(4):1238-47. doi: 10.1111/ajt.13588.
20) Masetti M, Potena L, Nardozza M, Prestinenzi P, Taglieri N, Saia F, et al. Differential effect of everolimus on progression of early and late cardiac allograft vasculopathy in current clinical practice. Am J Transplant. 2013;13(5):1217-26. doi: 10.1111/ajt.12208.
21) Cakir U, Alis G, Erturk T, Karayagiz AH, Karabulut U, Berber I. Role of Everolimus on cardiac functions in kidney transplant recipients. Transplant Proc. 2017;49(3):497-500. doi: 10.1016/j.transproceed.2017.02.007.
22) Lim LM, Kung LF, Kuo MC, Kuo HT. The risk factors of mTORi-associated posttransplant proteinuria. Transplant Proc. 2018;50(8):2535-8. doi: 10.1016/j.transproceed.2018.03.090.
23) Alachkar N, Li J, Matar D, Vujjini V, Alasfar S, Tracy M, et al. Monitoring suPAR levels in post-kidney transplant focal segmental glomerulosclerosis treated with therapeutic plasma exchange and rituximab. BMC Nephrol. 2018;19(1):361. doi: 10.1186/s12882-018-1177-x.
24) Wei C, El Hindi S, Li J, Fornoni A, Goes N, Sageshima J, et al. Circulating urokinase receptor as a cause of focal segmental glomerulosclerosis. Nat Med. 2011;17(8):952-60. doi: 10.1038/nm.2411.
25) Segarra A, Jatem E, Quiles MT, Arbós MA, Ostos H, Valtierra N, et al. Valor diagnóstico de los niveles séricos del receptor soluble de la uroquinasa en adultos con síndrome nefrótico idiopático. Nefrologia. 2014;34(1):46-52. doi: 10.3265/Nefrologia.pre2013.Oct.12256.
26) Maas RJ, Deegens JK, Wetzels JF. Serum suPAR in patients with FSGS: trash or treasure? Pediatr Nephrol. 2013;28(7):1041-8. doi: 10.1007/s00467-013-2452-5.
27) Holdaas H, Rostaing L, Serón D, Cole E, Chapman J, Fellstrøm B, et al.; ASCERTAIN Investigators. Conversion of long-term kidney transplant recipients from calcineurin inhibitor therapy to everolimus: a randomized, multicenter, 24-month study. Transplantation. 2011;92(4):410-8. doi: 10.1097/TP.0b013e318224c12d.
28) Paoletti E, Citterio F, Corsini A, Potena L, Rigotti P, Sandrini S, et al.; ENTROPIA Project. Everolimus in kidney transplant recipients at high cardiovascular risk: a narrative review. J Nephrol. 2020;33(1):69-82. doi: 10.1007/s40620-019-00609-y.
29) Kurdi A, Roth L, Van der Veken B, Van Dam D, De Deyn PP, De Doncker M, et al. Everolimus depletes plaque macrophages, abolishes intraplaque neovascularization and improves survival in mice with advanced atherosclerosis. Vascul Pharmacol. 2019;113:70-6. doi: 10.1016/j.vph.2018.12.004.
Published
2022-03-15
How to Cite
1.
Yılmaz B, Yılmaz A, Fatma DA, Ersan S, Tanrısev M, Çolak H. Comparison of effects of m-TOR inhibitors and calcineurin inhibitor on SUPAR and ox-LDL levels in renal transplant recipients. Rev Nefrol Dial Traspl. [Internet]. 2022Mar.15 [cited 2024Sep.1];42(1):48-5. Available from: http://revistarenal.org.ar/index.php/rndt/article/view/756
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