李雯静,杨小娟

• 1:延安大学附属医院肾内科

摘要(Abstract)：

糖尿病肾病（DKD）是糖尿病的严重并发症，心血管事件和终末期肾脏病（ESRD）是DKD患者死亡的主要原因。近20年来，降糖、降脂和阻断肾素-血管紧张素-醛固酮系统（RAAS）治疗虽然可以降低DKD患者尿蛋白，抑制其肾脏纤维化，但对肾脏和心血管结局的改善作用有限。研究表明，盐皮质激素受体（MR）过度活化可触发炎症和肾脏纤维化，导致DKD进展。非奈利酮是一种新型非甾体类盐皮质激素受体拮抗剂（MRA），其可以使DKD患者心肾双重获益。本研究主要综述了MRA治疗DKD的机制及非奈利酮治疗DKD的有效性、安全性，以期为非奈利酮治疗DKD提供证据支持。

关键词(KeyWords)： 糖尿病肾病;盐皮质激素受体拮抗剂;非奈利酮;综述

Abstract:

Keywords:

基金项目(Foundation):

作者(Author): 李雯静,杨小娟

参考文献(References)：

• [1]FILIPPATOS G,ANKER S D,AGARWAL R,et al.Finerenone and cardiovascular outcomes in patients with chronic kidney disease and type 2 diabetes[J].Circulation,2021,143(6):540-552.DOI:10.1161/CIRCULATIONAHA.120.051898.
• [2]Kidney Disease:Improving Global Outcomes (KDIGO) Diabetes Work Group.KDIGO 2020 clinical practice guideline for diabetes management in chronic kidney disease[J].Kidney Int,2020,98(4S):S1-115.DOI:10.1016/j.kint.2020.06.019.
• [3]BOMBACK A S,KLEMMER P J.The incidence and implications of aldosterone breakthrough[J].Nat Clin Pract Nephrol,2007,3(9):486-492.DOI:10.1038/ncpneph0575.
• [4]AL DHAYBI O,BAKRIS G L.Non-steroidal mineralocorticoid antagonists:prospects for renoprotection in diabetic kidney disease[J].Diabetes Obes Metab,2020,22(Suppl 1):69-76.DOI:10.1111/dom.13983.
• [5]中华医学会肾脏病学分会专家组.糖尿病肾脏疾病临床诊疗中国指南[J].中华肾脏病杂志，2021,37(3):255-304.DOI:10.3760/cma.j.cn441217-20201125-00041.
• [6]KOLKHOF P,B?RFACKER L.30 years of the mineralocorticoid receptor:mineralocorticoid receptor antagonists:60 years of research and development[J].J Endocrinol,2017,234(1):T125-140.DOI:10.1530/JOE-16-0600.
• [7]PITT B,KOBER L,PONIKOWSKI P,et al.Safety and tolerability of the novel non-steroidal mineralocorticoid receptor antagonist BAY94-8862 in patients with chronic heart failure and mild or moderate chronic kidney disease:a randomized,double-blind trial[J].Eur Heart J,2013,34(31):2453-2463.DOI:10.1093/eurheartj/eht187.
• [8]LIAN M,HEWITSON T D,WIGG B,et al.Long-term mineralocorticoid receptor blockade ameliorates progression of experimental diabetic renal disease[J].Nephrol Dial Transplant,2012,27(3):906-912.DOI:10.1093/ndt/gfr495.
• [9]LIU G,MIYATA K,HITOMI H,et al.Involvement of mineralocorticoid receptor in high glucose-induced big mitogenactivated protein kinase 1 activation and mesangial cell proliferation[J].J Hypertens,2010,28(3):536-542.DOI:10.1097/HJH.0b013e3283346b62.
• [10]GERISCH M,HEINIG R,ENGELEN A,et al.Biotransformation of finerenone,a novel nonsteroidal mineralocorticoid receptor antagonist,in dogs,rats,and humans,in vivo and in vitro[J].Drug Metab Dispos,2018,46(11):1546-1555.DOI:10.1124/dmd.118.083337.
• [11]HEINIG R,GERISCH M,ENGELEN A,et al.Pharmacokinetics of the novel,selective,non-steroidal mineralocorticoid receptor antagonist finerenone in healthy volunteers:results from an absolute bioavailability study and drug-drug interaction studies in vitro and in vivo[J].Eur J Drug Metab Pharmacokinet,2018,43(6):715-727.DOI:10.1007/s13318-018-0483-9.
• [12]KOLKHOF P,DELBECK M,KRETSCHMER A,et al.Finerenone,a novel selective nonsteroidal mineralocorticoid receptor antagonist protects from rat cardiorenal injury[J].JCardiovasc Pharmacol,2014,64(1):69-78.DOI:10.1097/FJC.0000000000000091.
• [13]AGARWAL R,KOLKHOF P,BAKRIS G,et al.Steroidal and non-steroidal mineralocorticoid receptor antagonists in cardiorenal medicine[J].Eur Heart J,2021,42(2):152-161.DOI:10.1093/eurheartj/ehaa736.
• [14]ZHANG M Z,BAO W,ZHENG Q Y,et al.Efficacy and safety of finerenone in chronic kidney disease:a systematic review and meta-analysis of randomized clinical trials[J].Front Pharmacol,2022,13:819327.DOI:10.3389/fphar.2022.819327.
• [15]DEFRONZO R A,BAKRIS G L.Modifying chronic kidney disease progression with the mineralocorticoid receptor antagonist finerenone in patients with type 2 diabetes[J].Diabetes Obes Metab,2022,24(7):1197-1205.DOI:10.1111/dom.14696.
• [16]AGARWAL R,ANKER S D,BAKRIS G,et al.Investigating new treatment opportunities for patients with chronic kidney disease in type 2 diabetes:the role of finerenone[J].Nephrol Dial Transplant,2022,37(6):1014-1023.DOI:10.1093/ndt/gfaa294.
• [17]BUONAFINE M,BONNARD B,JAISSER F.Mineralocorticoid receptor and cardiovascular disease[J].Am J Hypertens,2018,31(11):1165-1174.DOI:10.1093/ajh/hpy120.
• [18]中华内科杂志编辑委员会，盐皮质激素受体拮抗剂临床应用共识专家组.盐皮质激素受体拮抗剂临床应用多学科中国专家共识（2022)[J].中华内科杂志，2022,61(9):981-999.
• [19]BARRERA-CHIMAL J,LIMA-POSADA I,BAKRIS G L,et al.Mineralocorticoid receptor antagonists in diabetic kidney disease-mechanistic and therapeutic effects[J].Nat Rev Nephrol,2022,18(1):56-70.DOI:10.1038/s41581-021-00490-8.
• [20]HUANG L L,NIKOLIC-PATERSON D J,MA F Y,et al.Aldosterone induces kidney fibroblast proliferation via activation of growth factor receptors and PI3K/MAPK signalling[J].Nephron Exp Nephrol,2012,120(4):e115-122.DOI:10.1159/000339500.
• [21]ZHANG A H,JIA Z J,GUO X H,et al.Aldosterone induces epithelial-mesenchymal transition via ROS of mitochondrial origin[J].Am J Physiol Renal Physiol,2007,293(3):F723-731.DOI:10.1152/ajprenal.00480.2006.
• [22]GONZáLEZ-BLáZQUEZ R,SOMOZA B,GIL-ORTEGA M,et al.Finerenone attenuates endothelial dysfunction and albuminuria in a chronic kidney disease model by a reduction in oxidative stress[J].Front Pharmacol,2018,9:1131.DOI:10.3389/fphar.2018.01131.
• [23]GRUNE J,BEYHOFF N,SMEIR E,et al.Selective mineralocorticoid receptor cofactor modulation as molecular basis for finerenone's antifibrotic activity[J].Hypertension,2018,71(4):599-608.DOI:10.1161/HYPERTENSIONAHA.117.10360.
• [24]BAKRIS G L,AGARWAL R,CHAN J C,et al.Effect of finerenone on albuminuria in patients with diabetic nephropathy:a randomized clinical trial[J].JAMA,2015,314(9):884-894.DOI:10.1001/jama.2015.10081.
• [25]HOLTKAMP F A,DE ZEEUW D,DE GRAEFF P A,et al.Albuminuria and blood pressure,independent targets for cardioprotective therapy in patients with diabetes and nephropathy:a post hoc analysis of the combined RENAAL and IDNT trials[J].Eur Heart J,2011,32(12):1493-1499.DOI:10.1093/eurheartj/ehr017.
• [26]YAMOUT H,LAZICH I,BAKRIS G L.Blood pressure,hypertension,RAAS blockade,and drug therapy in diabetic kidney disease[J].Adv Chronic Kidney Dis,2014,21(3):281-286.DOI:10.1053/j.ackd.2014.03.005.
• [27]BAKRIS G L,AGARWAL R,ANKER S D,et al.Effect of finerenone on chronic kidney disease outcomes in type 2 diabetes[J].N Engl J Med,2020,383(23):2219-2229.DOI:10.1056/NEJMoa2025845.
• [28]PITT B,FILIPPATOS G,AGARWAL R,et al.Cardiovascular events with finerenone in kidney disease and type 2 diabetes[J].N Engl J Med,2021,385(24):2252-2263.DOI:10.1056/NEJMoa2110956.
• [29]AGARWAL R,FILIPPATOS G,PITT B,et al.Cardiovascular and kidney outcomes with finerenone in patients with type 2 diabetes and chronic kidney disease:the FIDELITY pooled analysis[J].Eur Heart J,2022,43(6):474-484.DOI:10.1093/eurheartj/ehab777.
• [30]VUKADINOVI?D,LAVALL D,VUKADINOVI?A N,et al.True rate of mineralocorticoid receptor antagonists-related hyperkalemia in placebo-controlled trials:a meta-analysis[J].Am Heart J,2017,188:99-108.DOI:10.1016/j.ahj.2017.03.011.
• [31]RUILOPE L M,AGARWAL R,ANKER S D,et al.Design and baseline characteristics of the finerenone in reducing cardiovascular mortality and morbidity in diabetic kidney disease trial[J].Am JNephrol,2019,50(5):345-356.DOI:10.1159/000503712.
• [32]AGARWAL R,JOSEPH A,ANKER S D,et al.Hyperkalemia risk with finerenone:results from the FIDELIO-DKD trial[J].J Am Soc Nephrol,2022,33(1):225-237.DOI:10.1681/ASN.2021070942.

文章评论(Comment)：