免疫抑制剂对肾移植术后肝纤维化影响的研究进展

丁鹏; 李皓; 庄权; 明英姿

doi:10.3969/j.issn.1674-7445.2019.05.023

免疫抑制剂对肾移植术后肝纤维化影响的研究进展

doi: 10.3969/j.issn.1674-7445.2019.05.023

410013 长沙，中南大学湘雅三医院器官移植中心

基金项目:

国家自然科学基金 81771722

国家自然科学基金 81700658

详细信息

作者简介:
丁鹏，男，1991年生，硕士，研究方向为肾移植与肝纤维化，Email：dingpeng_china@126.com

通讯作者:
明英姿，女，博士，教授，研究方向为器官移植与移植免疫，Email：myz_china@aliyun.com

中图分类号: R617, R575
计量
- 文章访问数: 253
- HTML全文浏览量: 107
- PDF下载量: 22
- 被引次数: 0
出版历程
- 收稿日期: 2019-05-08
- 网络出版日期: 2021-01-19
- 刊出日期: 2019-09-15

Research progress in the effect of immunosuppressive agents on liver fibrosis after renal transplantation

摘要

摘要: 肾移植已成为治疗终末期肾病的有效手段，但是肾移植术后受者的并发症仍较多。其中，肝损伤是其严重并发症之一。目前认为导致这一并发症的主要原因与肾移植受者长期服用免疫抑制剂有关。既往研究认为使用免疫抑制剂可引起移植后代谢综合征、病毒感染及药物性肝损伤，从而导致肝纤维化，但近来的一些研究文献却提示免疫抑制剂对肾移植术后肝纤维化具有改善作用。本文从免疫抑制剂导致肾移植术后肝纤维化的病因及其相关机制、免疫抑制剂对肾移植术后肝纤维化所起作用的新观点等方面进行阐述及总结，希望为临床肾移植术后肝纤维化的防治提供正确的思路，从而提高肾移植术后受者及移植物的存活率。
- 肾移植 /
- 免疫抑制剂 /
- 肝纤维化 /
- 实体器官移植 /
- 移植后代谢综合征 /
- 感染 /
- 巨细胞病毒 /
- 非酒精性脂肪肝 /
- 乙型肝炎病毒

HTML全文

图 1 肝纤维化形成大致流程图

Figure 1. Approximate flowchart of hepatic fibrosis formation

下载: 全尺寸图片幻灯片

图 2 免疫抑制剂抑制肝纤维化进展的位点

Figure 2. The site of immunosuppressive agents inhibiting hepatic fibrosis progression

下载: 全尺寸图片幻灯片

参考文献(38)

[1]	CRENESSE D, LAURENS M, HEURTEAUX C, et al. Rat liver ischemia-reperfusion-induced apoptosis and necrosis are decreased by FK506 pretreatment[J]. Eur J Pharmacol, 2003, 473(2-3):177-184. doi: 10.1016/S0014-2999(03)01977-0
[2]	GUNDERSON A, SAID A. Liver disease in kidney transplant recipients[J]. Transplant Rev (Orlando), 2015, 29(1):1-7. DOI: 10.1016/j.trre.2014.08.002.
[3]	CONTE C, SECCHI A. Post-transplantation diabetes in kidney transplant recipients: an update on management and prevention[J]. Acta Diabetol, 2018, 55(8):763-779. DOI: 10.1007/S00592-018-1137-8.
[4]	ANDRADE AR, BITTENCOURT PL, CODES L, et al. New onset diabetes and non-alcoholic fatty liver disease after liver transplantation[J]. Ann Hepatol, 2017, 16(6):932-940. DOI: 10.5604/01.3001.0010.5285.
[5]	MIKOLASEVIC I, ORLIC L, HRSTIC I, et al. Metabolic syndrome and non-alcoholic fatty liver disease after liver or kidney transplantation[J]. Hepatol Res, 2016, 46(9):841-852. DOI: 10.1111/hepr.12642.
[6]	FELIPE C, FERREIRA AN, DE PAULA M, et al. Incidence and risk factors associated with cytomegalovirus infection after thetreatment of acute rejection during the first year in kidney transplant recipients receiving preemptive therapy[J]. Transpl Infect Dis, 2019:e13106. DOI: 10.1111/tid.13106.
[7]	KESIRAJU S, SRIKANTI P, SAHARIAH S. Hepatitis C infection in renal transplantation: pathogenesis, current impact and emerging trends[J]. Virusdisease, 2017, 28(3):233-241. DOI: 10.1007/s13337-017-0393-5.
[8]	POL S, PARLATI L, JADOUL M. Hepatitis C virus and the kidney[J]. Nat Rev Nephrol, 2019, 15(2):73-86. DOI: 10.1038/s41581-018-0081-8.
[9]	ILIESCU L, MERCAN-STANCIU A, TOMA L, et al. A severe case of hyperglycemia in a kidney transplant recipient undergoing interferon-free therapy for chronic hepatitis C[J]. Acta Endocrinol (Buchar), 2018, 14(4):533-538. DOI: 10.4183/aeb.2018.533.
[10]	MORI UBALDINI F, STRATTA RJ, NUNEZ M. Delayed spontaneous hepatitis C virus elimination in a renal transplant patient following graft rejection[J]. Transpl Infect Dis, 2019, 21(3):e13079. DOI: 10.1111/tid.13079.
[11]	DIZDAR OS, ERSOY A, AKSOY S, et al. Analysis of liver function test abnormalities in kidney transplant recipients: 7 year experience[J]. Pak J Med Sci, 2016, 32(6):1330-1335. DOI: 10.12669/pjms.326.10725.
[12]	LACKNER C, TINIAKOS D. Fibrosis and alcohol-related liver disease[J]. J Hepatol, 2019, 70(2):294-304. DOI: 10.1016/j.jhep.2018.12.003.
[13]	ALEGRE F, PELEGRIN P, FELDSTEIN AE. Inflammasomes in liver fibrosis[J]. Semin Liver Dis, 2017, 37(2):119-127. DOI: 10.1055/s-0037-1601350.
[14]	LAI M, AFDHAL NH. Liver fibrosis determination[J]. Gastroenterol Clin North Am, 2019, 48(2):281-289. DOI: 10.1016/j.gtc.2019.02.002.
[15]	ALTAMIRANO-BARRERA A, BARRANCO-FRAGOSO B, MÉNDEZ-SÁNCHEZ N. Management strategies for liver fibrosis[J]. Ann Hepatol, 2017, 16(1):48-56. DOI: 10.5604/16652681.1226814.
[16]	BANSAL MB, CHAMROONKUL N. Antifibrotics in liver disease: are we getting closer to clinical use?[J]. Hepatol Int, 2019, 13(1):25-39. DOI: 10.1007/s12072-018-9897-3.
[17]	LEI XF, FU W, KIM-KANEYAMA JR, et al. Hic-5 deficiency attenuates the activation of hepatic stellate cells and liver fibrosis through upregulation of Smad7 in mice[J]. J Hepatol, 2016, 64(1):110-117. DOI: 10.1016/j.jhep.2015.08.026.
[18]	BARCENA-VARELA M, COLYN L, FERNANDEZ-BARRENA MG. Epigenetic mechanisms in hepatic stellate cell activation during liver fibrosis and carcinogenesis[J]. Int J Mol Sci, 2019, 20(10): E2507. DOI: 10.3390/ijms20102507.
[19]	ALRIC L, DI-MARTINO V, SELVES J, et al. Long-term impact of renal transplantation on liver fibrosis during hepatitis C virus infection[J]. Gastroenterology, 2002, 123(5):1494-1499. doi: 10.1053/gast.2002.36610
[20]	ROTH D, GAYNOR JJ, REDDY KR, et al. Effect of kidney transplantation on outcomes among patients with hepatitis C[J]. J Am Soc Nephrol, 2011, 22(6):1152-1160. DOI: 10.1681/ASN.2010060668.
[21]	TUÑÓN MJ, SÁNCHEZ-CAMPOS S, GUTIÉRREZ B, et al. Effects of FK506 and rapamycin on generation of reactive oxygen species, nitric oxide production and nuclear factor kappa B activation in rat hepatocytes[J]. Biochem Pharmacol, 2003, 66(3):439-445. doi: 10.1016/S0006-2952(03)00288-0
[22]	MANOJLOVIC Z, BLACKMON J, STEFANOVIC B. Tacrolimus (FK506) prevents early stages of ethanol induced hepatic fibrosis by targeting LARP6 dependent mechanism of collagen synthesis[J]. PLoS One, 2013, 8(6):e65897. DOI: 10.1371/journal.pone.0065897.
[23]	FU J, BECKER C, CAO L, et al. Development of a cyclosporin A derivative with excellent anti-hepatitis C virus potency[J]. Bioorg Med Chem, 2018, 26(4):957-969. DOI: 10.1016/j.bmc.2017.09.008.
[24]	ALBEKAIRY AM, ABDEL-RAZAQ WS, ALKATHERI AM, et al. The impact of immunosuppressant therapy on the recurrence of hepatitis C post-liver transplantation[J]. Int J Health Sci (Qassim), 2018, 12(4):78-87.
[25]	ISHⅡ N, WATASHI K, HISHIKI T, et al. Diverse effects of cyclosporine on hepatitis C virus strain replication[J]. J Virol, 2006, 80(9):4510-4520. doi: 10.1128/JVI.80.9.4510-4520.2006
[26]	NAKAGAWA M, SAKAMOTO N, TANABE Y, et al. Suppression of hepatitis C virus replication by cyclosporin a is mediated by blockade of cyclophilins[J]. Gastroenterology, 2005, 129(3):1031-1041. doi: 10.1053/j.gastro.2005.06.031
[27]	FIRPI RJ, ZHU H, MORELLI G, et al. Cyclosporine suppresses hepatitis C virus in vitro and increases the chance of a sustained virological response after liver transplantation[J]. Liver Transpl, 2006, 12(1):51-57. doi: 10.1002/lt.20532
[28]	DONG S, GENG L, SHEN MD, et al. Natural killer cell activating receptor NKG2D is involved in the immunosuppressive effects of mycophenolate mofetil and hepatitis B virus infection[J]. Am J Med Sci, 2015, 349(5):432-437. DOI: 10.1097/MAJ.0000000000000442.
[29]	YE L, LI J, ZHANG T, et al. Mycophenolate mofetil inhibits hepatitis C virus replication in human hepatic cells[J]. Virus Res, 2012, 168(1/2):33-40. DOI: 10.1016/j.virusres.2012.06.009.
[30]	MORATH C, SCHWENGER V, BEIMLER J, et al. Antifibrotic actions of mycophenolic acid[J]. Clin Transplant, 2006, 20 (Suppl 17):25-29.
[31]	CHANG HW, WU VC, WU KD, et al. In rat renal fibroblasts, mycophenolic acid inhibits proliferation and production of the chemokine CCL2, stimulated by tumour necrosis factor-alpha[J]. Br J Pharmacol, 2010, 160(7):1611-1620. DOI: 10.1111/j.1476-5381.2010.00837.x.
[32]	GUO H, LEUNG JC, CHAN LY, et al. Modulation of intra-pulmonary TGF-beta expression by mycophenolate mofetil in lupus prone MRL/lpr mice[J]. Lupus, 2005, 14(8):583-592. doi: 10.1191/0961203305lu2170oa
[33]	NAKA K, IKEDA M, ABE K, et al. Mizoribine inhibits hepatitis C virus RNA replication: effect of combination with interferon-alpha[J]. Biochem Biophys Res Commun, 2005, 330(3):871-879. doi: 10.1016/j.bbrc.2005.03.062
[34]	PATSENKER E, SCHNEIDER V, LEDERMANN M, et al. Potent antifibrotic activity of mTOR inhibitors sirolimus and everolimus but not of cyclosporine A and tacrolimus in experimental liver fibrosis[J]. J Hepatol, 2011, 55(2):388-398. DOI: 10.1016/j.jhep.2010.10.044.
[35]	BIECKER E, DE GOTTARDI A, NEEF M, et al. Long-term treatment of bile duct-ligated rats with rapamycin (sirolimus) significantly attenuates liver fibrosis: analysis of the underlying mechanisms[J]. J Pharmacol Exp Ther, 2005, 313(3):952-961. doi: 10.1124/jpet.104.079616
[36]	CZAJA AJ, CARPENTER HA. Progressive fibrosis during corticosteroid therapy of autoimmune hepatitis[J]. Hepatology, 2004, 39(6):1631-1638. doi: 10.1002/hep.20235
[37]	KNIGHT SR. Routine adherence monitoring after renal transplantation[J]. Transpl Int, 2019, 32(6):600-602. DOI: 10.1111/tri.13422.
[38]	KASISKE BL, ZEIER MG, CHAPMAN JR, et al. KDIGO clinical practice guideline for the care of kidney transplant recipients: a summary[J]. Kidney Int, 2010, 77(4):299-311. DOI: 10.1038/ki.2009.377.