糖尿病肾病的重要治疗进展：从基础研究到临床应用

doi:10.20223/j.cnki.1000-8535.2025.08.001

摘要/Abstract

摘要： 糖尿病肾病（DN）是指由糖尿病所致的慢性肾脏疾病,是目前我国和全球范围内慢性肾脏疾病和终末期肾脏疾病的首位病因。DN发病率逐年攀升,且预后不良,已成为我国重大的公共卫生问题之一。DN不仅明显降低了患者的生活质量,还增加了心血管疾病的风险。随着对DN发病机制的深入研究,近十余年来在DN治疗手段方面取得了显著进展,包括新型药物的研发、生活方式的干预及各种新兴疗法的探索。本文旨在系统性综述近年来DN领域的重要治疗进展,阐明这些进展在临床应用中的有效性和适用性,并展望未来的研究方向,以期为临床实践提供参考和指导。

关键词: 糖尿病肾病, SGLT-2抑制剂, GLP-1受体激动剂, DPP-4抑制剂, 盐皮质激素受体拮抗剂

Abstract: Diabetic nephropathy（DN）is a form of chronic kidney disease（CKD）induced by diabetes．Diabetic nephropathy represents the leading cause of CKD and end-stage renal disease both in China and globally．The incidence of DN has been steadily increasing and its prognosis remains unfavorable．Diabetic nephropathy has become a major public health concern．Diabetic nephropathy not only significantly affects patients' quality of life but also increases the risk of cardiovascular diseases．Recent advancements in our understanding of the pathogenesis of DN have facilitated significant progress in treatment options over the past decade．These developments include the introduction of novel pharmacological agents,the implementation of lifestyle modifications,and the exploration of various emerging therapeutic approaches．This review aims to systematically expound the significant therapeutic advancements in the field of DN in recent years,evaluate the efficacy and applicability of these advancements in clinical practice,and explore potential future research directions,thereby providing valuable insights and guidance for clinical practice．

Key words: diabetic nephropathy, SGLT-2 inhibitors, GLP-1 receptor agonists, DPP-4 inhibitors, mineralocorticoid receptor antagonists

范李云飞, 何凤. 糖尿病肾病的重要治疗进展：从基础研究到临床应用[J]. 广州医药, 2025, 56(8): 1006-1020.

FAN Liyunfei, HE Feng. Important advances in diabetic nephropathy treatment：From basic research to clinical application[J]. Guangzhou Medical Journal, 2025, 56(8): 1006-1020.

参考文献

[1] AHMAD E,LIM S,LAMPTEY R,et al.Type 2 diabetes[J].The Lancet,2022,400(10365):1803-1820.
[2] GUTHRIE R.Canagliflozin and cardiovascular and renal events in type 2 diabetes[J].Postgraduate Medicine,2018,130(2):149-153.
[3] LI Y,NING Y,SHEN B,et al.Temporal trends in prevalence and mortality for chronic kidney disease in China from 1990 to 2019:An analysis of the Global Burden of Disease Study 2019[J].Clin Kidney J,2023,16(2):312-321.
[4] FORBES J M,FOTHERINGHAM A K.Vascular complications in diabetes:Old messages,new thoughts[J].Diabetologia,2017,60(11):2129-2138.
[5] BLANCO F J,REGO-PÉREZ I.Mitochondria and mitophagy:Biosensors for cartilage degradation and osteoarthritis[J].Osteoarthritis Cartilage,2018,26(8):989-991.
[6] GU Y Y,LU F H,HUANG X R,et al.Non-coding RNAs as biomarkers and therapeutic targets for diabetic kidney disease[J].Front Pharmacol,2021(11):583528.
[7] ZHANG X,SHI Z,LIU Q,et al.Effects of coenzyme Q10 intervention on diabetic kidney disease:A systematic review and meta-analysis[J].Medicine,2019,98(24):e15850.
[8] WANG H,KARNATI S,MADHUSUDHAN T.Regulation of the homeostatic unfolded protein response in diabetic nephropathy[J].Pharmaceuticals(Basel),2022,15(4):401.
[9] ELEFTHERIADIS T,PISSAS G,TSOGKA K,et al.A unifying model of glucotoxicity in human renal proximal tubular epithelial cells and the effect of the SGLT2 inhibitor dapagliflozin[J].Int Urol Nephrol,2020,52(6):1179-1189.
[10] HAAS B,ECKSTEIN N,PFEIFER V,et al.Efficacy,safety and regulatory status of SGLT2 inhibitors:Focus on canagliflozin[J].Nutr Diabetes,2014,4(11):e143.
[11] SCHAUB J A,ALAKWAA F M,MCCOWN P J,et al.SGLT2 inhibitors mitigate kidney tubular metabolic and mTORC1 perturbations in youth-onset type 2 diabetes[J].J Clin Invest,2023,133(5):e164486.
[12] DURANTE W,BEHNAMMANESH G,PEYTON K J.Effects of sodium-glucose co-transporter 2 inhibitors on vascular cell function and arterial remodeling[J].Int J Mol Sci,2021,22(16):8786.
[13] WANG A,LI Z,ZHUO S,et al.Mechanisms of cardiorenal protection with SGLT2 inhibitors in patients with T2DM based on network pharmacology[J].Front Cardiovasc Med,2022(9):857952.
[14] PERKOVIC V,JARDINE M J,NEAL B,et al.Canagliflozin and renal outcomes in type 2 diabetes and nephropathy[J].N Engl J Med,2019,380(24):2295-2306.
[15] HEERSPINK H J L,STEFÁNSSON B V,CORREA-ROTTER R,et al.Dapagliflozin in patients with chronic kidney disease[J].N Engl J Med,2020,383(15):1436-1446.
[16] BAIGENT C,EMBERSON JONATHANR,HAYNES R,et al.Impact of diabetes on the effects of sodium glucose co-transporter-2 inhibitors on kidney outcomes:Collaborative meta-analysis of large placebo-controlled trials[J].Lancet,2022,400(10365):1788-1801.
[17] MEIER J J.GLP-1 receptor agonists for individualized treatment of type 2 diabetes mellitus[J].Nat Rev Endocrinol,2012,8(12):728-742.
[18] de GRAAF C,DONNELLY D,WOOTTEN D,et al.Glucagon-like peptide-1 and its class B G protein-coupled receptors:A long March to therapeutic successes[J].Pharmacol Rev,2016,68(4):954-1013.
[19] GALLWITZ B.Glucagon-like peptide-1 analogues for Type 2 diabetes mellitus:Current and emerging agents[J].Drugs,2011,71(13):1675-1688.
[20] MARSO S P,DANIELS G H,BROWN-FRANDSEN K,et al.Liraglutide and cardiovascular outcomes in type 2 diabetes[J].N Engl J Med,2016,375(4):311-322.
[21] TUTTLE K R,BOSCH-TRABERG H,CHERNEY D Z I,et al.Post hoc analysis of SUSTAIN 6 and PIONEER 6 trials suggests that people with type 2 diabetes at high cardiovascular risk treated with semaglutide experience more stable kidney function compared with placebo[J].Kidney Int,2023,103(4):772-781.
[22] JIANG P,ZENG Y,YANG W,et al.The effects of Fc fusion protein glucagon-like peptide-1 and glucagon dual receptor agonist with different receptor selectivity in vivo studies[J].Biomed Pharmacother,2024(174):116485.
[23] DEACON C F.Dipeptidyl peptidase 4 inhibitors in the treatment of type 2 diabetes mellitus[J].Nat Rev Endocrinol,2020,16(11):642-653.
[24] OMAR B,AHRÉN B.Pleiotropic mechanisms for the glucose-lowering action of DPP-4 inhibitors[J].Diabetes,2014,63(7):2196-2202.
[25] BAE E J.DPP-4 inhibitors in diabetic complications:Role of DPP-4 beyond glucose control[J].Arch Pharm Res,2016,39(8):1114-1128.
[26] KAWANAMI D,TAKASHI Y,TAKAHASHI H,et al.Renoprotective effects of DPP-4 inhibitors[J].Antioxidants(Basel),2021,10(2):246.
[27] ROSENSTOCK J,PERKOVIC V,JOHANSEN O E,et al.Effect of linagliptin vs placebo on major cardiovascular events in adults with type 2 diabetes and high cardiovascular and renal risk:The CARMELINA randomized clinical trial[J].JAMA,2019,321(1):69-79.
[28] GREEN J B,BETHEL M A,ARMSTRONG P W,et al.Effect of sitagliptin on cardiovascular outcomes in type 2 diabetes[J].N Engl J Med,2015,373(3):232-242.
[29] ROSCIONI S S,de ZEEUW D,BAKKER S J L,et al.Management of hyperkalaemia consequent to mineralocorticoid-receptor antagonist therapy[J].Nat Rev Nephrol,2012,8(12):691-699.
[30] van den BERG T N A,RONGEN G A,FRÖHLICH G M,et al.The cardioprotective effects of mineralocorticoid receptor antagonists[J].Pharmacol Ther,2014,142(1):72-87.
[31] ALICIC R Z,ROONEY M T,TUTTLE K R.Diabetic kidney disease:Challenges,progress,and possibilities[J].Clin J Am Soc Nephrol,2017,12(12):2032-2045.
[32] FILIPPATOS G,ANKER S D,PITT B,et al.Finerenone and heart failure outcomes by kidney function/albuminuria in chronic kidney disease and diabetes[J].JACC Heart Fail,2022,10(11):860-870.
[33] GEORGIANOS P I,VAIOS V,ELEFTHERIADIS T,et al.Therapeutic advances in diabetic kidney disease[J].Int J Mol Sci,2023,24(3):2803.
[34] UCHIDA H A,NAKAJIMA H,HASHIMOTO M,et al.Efficacy and safety of esaxerenone in hypertensive patients with diabetic kidney disease:A multicenter,open-label,prospective study[J].Adv Ther,2022,39(11):5158-5175.
[35] DHAUN N,WEBB D J.Endothelins in cardiovascular biology and therapeutics[J].Nat Rev Cardiol,2019,16(8):491-502.[PubMed]
[36] HOU J,LIU S,ZHANG X,et al.Structural basis of antagonist selectivity in endothelin receptors[J].Cell Discov,2024(10):79.
[37] LIU C,CHEN J,GAO Y,et al.Endothelin receptor antagonists for pulmonary arterial hypertension[J].Cochrane Database Syst Rev,2021,3(3):CD004434.
[38] CHORRO F J,DEL CANTO I,BRINES L,et al.Experimental study of the effects of EIPA,losartan,and BQ-123 on electrophysiological changes induced by myocardial stretch[J].Rev Esp Cardiol(Engl Ed),2015,68(12):1101-1110.
[39] ZHOU Y,CHI J,HUANG Y,et al.Efficacy and safety of endothelin receptor antagonists in type 2 diabetic kidney disease:A systematic review and meta-analysis of randomized controlled trials[J].Diabet Med,2021,38(1):e14411.
[40] HOEKMAN J,LAMBERS HEERSPINK H J,VIBERTI G,et al.Predictors of congestive heart failure after treatment with an endothelin receptor antagonist[J].Clin J Am Soc Nephrol,2014,9(3):490-498.
[41] EGIDO J,ROJAS-RIVERA J,MAS S,et al.Atrasentan for the treatment of diabetic nephropathy[J].Expert Opin Investig Drugs,2017,26(6):741-750.
[42] HEERSPINK H J L,PARVING H H,ANDRESS D L,et al.Atrasentan and renal events in patients with type 2 diabetes and chronic kidney disease(SONAR):A double-blind,randomised,placebo-controlled trial[J].Lancet,2019,393(10184):1937-1947.
[43] ZHU Z,LUAN G,PENG S,et al.Huangkui capsule attenuates diabetic kidney disease through the induction of mitophagy mediated by STING1/PINK1 signaling in tubular cells[J].Phytomedicine,2023(119):154975.
[44] KUMAR S,MITTAL A,BABU D,et al.Herbal medicines for diabetes management and its secondary complications[J].Curr Diabetes Rev,2021,17(4):437-456.
[45] KUMAR A,MAZUMDER R,RANI A,et al.Novel approaches for the management of type 2 diabetes mellitus:An update[J].Curr Diabetes Rev,2024,20(4):e051023221768.
[46] ZHANG H W,LIN Z X,TUNG Y S,et al.Cordyceps sinensis(a traditional Chinese medicine)for treating chronic kidney disease[J].Cochrane Database Syst Rev,2014,2014(12):CD008353.
[47] WANG K,CHEN Q,SHAO Y,et al.Anticancer activities of TCM and their active components against tumor metastasis[J].Biomed Pharmacother,2021(133):111044.
[48] DAHLÉN A D,DASHI G,MASLOV I,et al.Trends in antidiabetic drug discovery:FDA approved drugs,new drugs in clinical trials and global sales[J].Front Pharmacol,2021(12):807548.
[49] STOTTLEMYER B A,MCDERMOTT M C,MINOGUE M R,et al.Assessing adverse drug reaction reports for antidiabetic medications approved by the food and drug administration between2012 and 2017:A pharmacovigilance study[J].Ther Adv Drug Saf,2023(14):20420986231181334.
[50] FRÍAS J P,DAVIES M J,ROSENSTOCK J,et al.Tirzepatide versus semaglutide once weekly in patients with type 2 diabetes[J].N Engl J Med,2021,385(6):503-515.
[51] ZHAO F,ZHOU Q,CONG Z,et al.Structural insights into multiplexed pharmacological actions of tirzepatide and peptide 20 at the GIP,GLP-1 or glucagon receptors[J].Nat Commun,2022,13(1):1057.
[52] LI W,ZHOU Q,CONG Z,et al.Structural insights into the triple agonism at GLP-1R,GIPR and GCGR manifested by retatrutide[J].Cell Discov,2024,10(1):77.
[53] CHO Y M,MERCHANT C E,KIEFFER T J.Targeting the glucagon receptor family for diabetes and obesity therapy[J].Pharmacol Ther,2012,135(3):247-278.
[54] LEAN M E J.Low-calorie diets in the management of type 2 diabetes mellitus[J].Nat Rev Endocrinol,2019,15(5):251-252.
[55] JINNOUCHI H,YOSHIDA A,TANIGUCHI M,et al.Efficacy of self-review of lifestyle behaviors with once-weekly glycated albumin measurement in people with type 2 diabetes:A randomized pilot study[J].Diabetes Ther,2024,15(7):1561-1575.
[56] TENG H L,YEN M,FETZER S,et al.Tailoring health-promoting programs for patients with chronic kidney disease:Randomized controlled trial[J].West J Nurs Res,2021,43(2):138-150.
[57] MERLI M,BERZIGOTTI A,ZELBER-SAGI S,et al.EASL Clinical Practice Guidelines on nutrition in chronic liver disease[J].J Hepatol,2019,70(1):172-193.
[58] PAWAR K,THOMPKINSON D K.Multiple functional ingredient approach in formulating dietary supplement for management of diabetes:A review[J].Crit Rev Food Sci Nutr,2014,54(7):957-973.
[59] GOSMANOV A R,UMPIERREZ G E.Medical nutrition therapy in hospitalized patients with diabetes[J].Curr Diab Rep,2012,12(1):93-100.
[60] BÖHM M,SCHUMACHER H,WERNER C,et al.Association between exercise frequency with renal and cardiovascular outcomes in diabetic and non-diabetic individuals at high cardiovascular risk[J].Cardiovasc Diabetol,2022,21(1):12.
[61] KANBAY M,COPUR S,YILDIZ A B,et al.Physical exercise in kidney disease:A commonly undervalued treatment modality[J].Eur J Clin Invest,2024,54(2):e14105.
[62] LEEHEY D J,COLLINS E,KRAMER H J,et al.Structured exercise in obese diabetic patients with chronic kidney disease:A randomized controlled trial[J].Am J Nephrol,2016,44(1):54-62.
[63] ZHOU Z,YING C,ZHOU X,et al.Aerobic exercise training alleviates renal injury in db/db mice through inhibiting Nox4-mediated NLRP3 inflammasome activation[J].Exp Gerontol,2022(168):111934.
[64] FORMIGARI G P,DÁTILO M N,VAREDA B,et al.Renal protection induced by physical exercise may be mediated by the irisin/AMPK axis in diabetic nephropathy[J].Sci Rep,2022,12(1):9062.
[65] MI L,HU J,LI N,et al.The mechanism of stem cell aging[J].Stem Cell Rev Rep,2022,18(4):1281-1293.
[66] CHEN S,DU K,ZOU C.Current progress in stem cell therapy for type 1 diabetes mellitus[J].Stem Cell Res Ther,2020,11(1):275.
[67] WEIR G C,CAVELTI-WEDER C,BONNER-WEIR S.Stem cell approaches for diabetes:Towards beta cell replacement[J].Genome Med,2011,3(9):61.
[68] MILLMAN J R,PAGLIUCA F W.Autologous pluripotent stem cell-derived β-like cells for diabetes cellular therapy[J].Diabetes,2017,66(5):1111-1120.
[69] KIEFFER T J,HOESLI C A,JAMES SHAPIRO A M.Advances in islet transplantation and the future of stem cell-derived islets to treat diabetes[J].Cold Spring Harb Perspect Med,2025,15(5):a041624.
[70] LIU X,WANG Y,LI Y,et al.Research status and prospect of stem cells in the treatment of diabetes mellitus[J].Sci China Life Sci,2013,56(4):306-312.
[71] STANEKZAI J,ISENOVIC E R,MOUSA S A.Treatment options for diabetes:Potential role of stem cells[J].Diabetes Res Clin Pract,2012,98(3):361-368.
[72] GRIFFIN T P,MARTIN W P,ISLAM N,et al.The promise of mesenchymal stem cell therapy for diabetic kidney disease[J].Curr Diab Rep,2016,16(5):42.
[73] HABIBA U E,KHAN N,GREENE D L,et al.The therapeutic effect of mesenchymal stem cells in diabetic kidney disease[J].J Mol Med(Berl),2024,102(4):537-570.
[74] SUN Y,SHI H,YIN S,et al.Human mesenchymal stem cell derived exosomes alleviate type 2 diabetes mellitus by reversing peripheral insulin resistance and relieving β-cell destruction[J].ACS Nano,2018,12(8):7613-7628.
[75] ZHANG K,CHENG K.Stem cell-derived exosome versus stem cell therapy[J].Nat Rev Bioeng,2023:1-2.
[76] BONNET C,GONZALEZ S,DENG S X.Limbal stem cell therapy[J].Curr Opin Ophthalmol,2024,35(4):309-314.
[77] TANG W.Challenges and advances in stem cell therapy[J].Biosci Trends,2019,13(4):286.
[78] DU S,LI Y,GENG Z,et al.Engineering islets from stem cells:The optimal solution for the treatment of diabetes?[J].Front Immunol,2022(13):869514.
[79] WANG J,XIANG H,LU Y,et al.New progress in drugs treatment of diabetic kidney disease[J].Biomed Pharmacother,2021(141):111918.
[80] ZHANG B.CRISPR/Cas gene therapy[J].J Cell Physiol,2021,236(4):2459-2481.
[81] WADDINGTON S N,PERANTEAU W H,RAHIM A A,et al.Fetal gene therapy[J].J Inherit Metab Dis,2024,47(1):192-210.
[82] APARICIO-TREJO O E,ARANDA-RIVERA A K,OSORIO-ALONSO H,et al.Extracellular vesicles in redox signaling and metabolic regulation in chronic kidney disease[J].Antioxidants(Basel),2022,11(2):356.
[83] WALDRON-LYNCH F,HEROLD K C.Immunomodulatory therapy to preserve pancreatic β-cell function in type 1 diabetes[J].Nat Rev Drug Discov,2011,10(6):439-452.
[84] FANG Y,YU A,YE L,et al.Research progress in tumor targeted immunotherapy[J].Expert Opin Drug Deliv,2021,18(8):1067-1090.
[85] NI Q,PHAM N B,MENG W S,et al.Advances in immunotherapy of type I diabetes[J].Adv Drug Deliv Rev,2019(139):83-91.
[86] QUATTRIN T,MASTRANDREA L D,WALKER L S K.Type 1 diabetes[J].Lancet,2023,401(10394):2149-2162.
[87] YANG L,NING Q,TANG S S.Recent advances and next breakthrough in immunotherapy for cancer treatment[J].J Immunol Res,2022(2022):8052212.
[88] FISEHA T.Urinary biomarkers for early diabetic nephropathy in type 2 diabetic patients[J].Biomark Res,2015(3):16.
[89] ZÜRBIG P,JERUMS G,HOVIND P,et al.Urinary proteomics for early diagnosis in diabetic nephropathy[J].Diabetes,2012,61(12):3304-3313.
[90] HUANG Q,FEI X,ZHAN H,et al.Urinary N-acetyl-β-d-glucosaminidase-creatine ratio is a valuable predictor for advanced diabetic kidney disease[J].J Clin Lab Anal,2023,37(1):e24769.
[91] DU S,ZHAI L,YE S,et al.In-depth urinary and exosome proteome profiling analysis identifies novel biomarkers for diabetic kidney disease[J].Sci China Life Sci,2023,66(11):2587-2603.
[92] MCBRIDE W T,KURTH M J,DOMANSKA A,et al.Blood and urinary cytokine balance and renal outcomes at cardiac surgery[J].BMC Nephrol,2021,22(1):406.
[93] MISE K,HOSHINO J,UENO T,et al.Prognostic value of tubulointerstitial lesions,urinary N-acetyl-β-d-glucosaminidase,and urinary β2-microglobulin in patients with type 2 diabetes and biopsy-proven diabetic nephropathy[J].Clin J Am Soc Nephrol,2016,11(4):593-601.
[94] PAN H C,YANG S Y,CHIOU T T,et al.Comparative accuracy of biomarkers for the prediction of hospital-acquired acute kidney injury:A systematic review and meta-analysis[J].Crit Care,2022,26(1):349.
[95] FRIED J G,MORGAN M A.Renal imaging:Core curriculum 2019[J].Am J Kidney Dis,2019,73(4):552-565.
[96] OLSON M C,NAVIN P J,WELLE C L,et al.Small bowel radiology[J].Curr Opin Gastroenterol,2021,37(3):267-274.
[97] MARTÍN NOGUEROL T,LUNA ALCALÁ A,BELTRÁN L S,et al.Advanced MR imaging techniques for differentiation of neuropathic arthropathy and osteomyelitis in the diabetic foot[J].Radiographics,2017,37(4):1161-1180.
[98] VEETURI S S,HALL S,FUJIMURA S,et al.Imaging of intracranial aneurysms:A review of standard and advanced imaging techniques[J].Transl Stroke Res,2025,16(3):1016-1027.
[99] NISHIZAKI Y,UEDA R,NOJIRI S,et al.Clinical research support activities in core clinical research hospitals throughout Japan[J].Juntendo Iji Zasshi,2022,68(4):413-415.
[100] HOLLIDAY E G,WEAVER N,BARKER D,et al.Adapting clinical trials in health research:A guide for clinical researchers[J].Med J Aust,2023,218(10):451-454.
[101] ZIMMET P Z,ALBERTI K G M M.Epidemiology of diabetes-status of a pandemic and issues around metabolic surgery[J].Diabetes Care,2016,39(6):878-883.
[102] BOUGHTON C K,HOVORKA R.Advances in artificial pancreas systems[J].Sci Transl Med,2019,11(484):eaaw4949.
[103] WATSON C J E.The current challenges for pancreas transplantation for diabetes mellitus[J].Pharmacol Res,2015(98):45-51.
[104] AYADA G,EDEL Y,BURG A,et al.Multidisciplinary team led by internists improves diabetic foot ulceration outcomes a before-after retrospective study[J].Eur J Intern Med,2021(94):64-68.
[105] SAINT-PIERRE C,PRIETO F,HERSKOVIC V,et al.Team collaboration networks and multidisciplinarity in diabetes care:Implications for patient outcomes[J].IEEE J Biomed Health Inform,2019,24(1):319-329.
[106] MARTÍNEZ-RAMÍREZ H R.Multidisciplinary strategies in the management of early chronic kidney disease[J].2013,44(8):611-615.
[107] QUIRCE S,COSÍO B G,ESPAÑA A,et al.Management of eosinophil-associated inflammatory diseases:The importance of a multidisciplinary approach[J].Front Immunol,2023(14):1192284.