1、糖尿病腎病診治進展,東南大學(xué)腎臟病研究所 東南大學(xué)附屬中大醫(yī)院 劉必成,Global projections for the diabetes epidemic: 20102030,Chen L, et al. Nat Rev Endocrinol; 2012;8:228-236,中國成人糖尿病患病率調(diào)查,全國抽樣，98,658例成人，2010年 患病率11.6%, (男12.1%, 女11.0%) 調(diào)查前診斷率3.5% 治療率25.8%，血糖控制率39.7% 據(jù)此估計中國糖尿病患者人數(shù)1.139億,Xu Y .Ning G JAMA 2013; Sep. 4, 310(9):948-49,中

2、國DM患病率流行病學(xué)調(diào)查（）,Incident counts 38(suppl1):12-22,DN or DKD, Whats the difference?,腎臟肥大、高濾過 GBM增厚 系膜基質(zhì)擴張 足細胞病變,Liu BC, Act Pharmacol Sin, 2003 Liu BC, et al. Clin Chim Act, 2008 Liu BC, et al. Am J Nephrol, 2003 Dai HY, Liu BC, Am J Med Sci, 2010,糖尿病腎病早期病理特征,Diabetes,Diabetic nephropathy,ESRD,腎臟肥大、高濾過

3、 GBM增厚,系膜基質(zhì)擴張 足細胞病變,腎臟纖維化,Susztak et al. J Am Soc Nephrol 2006 Mima A, et al. Diabetes 2008 Liu BC, et al. Am J Nephrol, 2003,亞臨床期,臨床早期,晚 期,糖尿病腎病發(fā)生機制的新認識,DN病理特征,Jefferson JA, et al. Kidney Int. 2008; 74:22-36.,Jefferson JA,et al. Kidney Int. 2008; 74:22-36.,足細胞病變DN發(fā)生發(fā)展的關(guān)鍵,DN足細胞病變,足細胞數(shù)目減少 足細胞足突密度減少,S

4、hankland SJ. Kidney Int.2006; 69:2131-47. Dalla Vestra M,et al. Diabetes 2003; 52: 10311035,免疫熒光染色足細胞WT1,Controls DN DN+Irb,Dai HY, Liu BC J Am Med Sci, 2010,腎小球足細胞數(shù)量減少,足細胞脫落原因,正常時足細胞通過31整合素和dystroglycans黏附于基底膜 高糖抑制整合素3的表達導(dǎo)致黏附降低,Chen HC, et al. Life Sci 2000; 67: 23452353. Han SY, et al. Cell Tissue

5、 Res. 2006 ;323:321-32.,高糖,（）,糖尿病時足細胞EMT,Li Y, et al.Am J Pathol.2008; 172:299-308.,糖尿病,腎小球高濾過 高灌注,足細胞病變,腎小球基底膜（GBM）病變,系膜細胞病變,蛋白尿,血管病變,腎小球硬化,腎小管間質(zhì)硬化,腎功能減退,腎小球內(nèi)皮病變,生長因子、趨化因子、細胞因子,Navarro-Gonzalez JF, et al. Nat. Rev. Nephrol, 2011,Clinical Science, 2013(124):139-152,Am J Physiol Regul Integr Comp Phy

6、siol 300: R1009R1022, 2011.,0 50 100 150,肌酐清除率 ml/min,10 8 6 4 2 0,P200g/min，或尿蛋白定量0.5g/24h 腎功能開始進行性下降 出現(xiàn)高血壓、浮腫 低蛋白血癥明顯 浮腫對利尿劑反應(yīng)差,晚期DN特點,出現(xiàn)氮質(zhì)血癥、水腫及高血壓 GFR快速下降（平均每月1ml/min） 蛋白尿持續(xù)存在，低蛋白血癥不斷加重 合并型腎小管性酸中毒，較早出現(xiàn)高鉀血癥 常合并有冠心病、腦血管疾病及周圍血管病變 、神經(jīng)病變、視網(wǎng)膜病變等,DN診斷,結(jié)合病史、體征和實驗室檢查，診斷不難 需區(qū)分DN or DKD 了解各種合并癥和并發(fā)癥、危險因素 腎活

7、檢,1、糖尿病病史短，合并大量蛋白尿 2、合并血尿 3、腎功能進行性下降，原因不明 4、有其他系統(tǒng)受累，不能用DN解釋,糖尿病腎病進展為ESRD,高血糖,高血壓,高血脂,高AGEs,高胰島素血癥,高BMI,蛋白尿,DN治療原則,控制血糖 控制血壓 糾正心血管疾病及其他危險因素 延緩腎衰進展 抗炎癥和抗纖維化治療,飲食治療,保證熱卡 合理蛋白質(zhì)飲食 充足維生素,降糖治療,口服藥物 胰島素 有明顯DN者，最好能用胰島素治療，血糖控制比較理想而又不增加肝、腎負擔(dān) 胰島素強化治療是目前DN治療新進展之一 胰島素強化治療可有效的抑制或延緩糖尿病腎病等微血管并發(fā)癥的發(fā)生發(fā)展,降壓治療,強調(diào)達標(biāo)（3mg/d

8、l者應(yīng)用RAS阻斷劑要謹慎 密切觀察尿量、腎功能和血鉀,Early stage Late stage Terminal stage,Severity of renal disease,IRMA 2 MARVAL,IDNT RENAAL DETAIL AMADEO,Microalbuminuria Macroalbuminuria ESRD,Prevention,Protection,Benedict Study Trendy,Normoalbuminuria,RAS阻斷劑延緩DN進展的循證醫(yī)學(xué)證據(jù),RAS阻斷劑在DN中的應(yīng)用,降低蛋白尿（白蛋白尿） 降低血壓 抑制腎臟肥大 抑制腎臟纖維化 抑制

9、胰島素抵抗,早期治療療效更顯著,RAS阻斷劑在DN中的應(yīng)用,注意事項,應(yīng)用前應(yīng)評估病人心、腎功能，了解水電解質(zhì)平衡、腎動脈狹窄等情況 治療開始后8周內(nèi)應(yīng)密切觀察腎功能和電解質(zhì) 腎病綜合癥者療效較差，且容易造成高鉀和腎功能可逆性下降 Scr大于265umol/L時更應(yīng)謹慎使用,Therapeutics in the treatment of diabetic nephropathy,Declves AE, Sharma K. Nat Rev Nephrol .2010, 6(6):371-80,Pirfenidone,Pirfenidone is a drug developed by Inte

10、rMune Inc. for the treatment of idiopathic pulmonary fibrosis (IPF). In 2011 it was approved for use in Europe for IPF under the trade name Esbriet Pirfenidone has well-established antifibrotic and anti-inflammatory properties in various in vitro systems and animal models of fibrosis,Sharma K, Ix JH

11、, Mathew AV et al. J Am Soc Nephrol. 2011, 22(6): 1144-51,RamachandraRao SP, et al. J Am Soc Nephrol, 2009, 20: 1765-1775.,吡非尼酮可以降低殘腎大鼠蛋白尿和NAG水平，改善腎功能,Chen JF et al. Am J Physiol Renal Physiol 2012 Nov 14.,吡非尼酮可以抑制殘腎大鼠腎間質(zhì)炎性細胞浸潤和纖維化程度,Chen JF et al. Am J Physiol Renal Physiol 2012 Nov 14.,Sham SNx SN

12、x+PFD,Sham SNx SNx+PFD,吡非尼酮可以抑制M1和M2巨噬細胞在大鼠殘腎中的浸潤,Chen JF et al. Am J Physiol Renal Physiol 2012 Nov 14.,Sham SNx SNx+PFD,Sham SNx SNx+PFD,Barragn JM, Rodrguez As, Partida1 JN, et al. Fibrogenesis 365:327-36,Bardoxolone Methyl and Kidney Function in CKD with Type 2 Diabetes,Bardoxolone methyl,Bardox

13、olone methyl is currently being developed by Reata Pharmaceuticals for the treatment of advanced chronic kidney disease (CKD) in type 2 diabetes mellitus patients Bardoxolone methyl is an inducer of the KEAP1-Nrf2 pathway, which can suppress oxidative stress and inflammation,Pergola PE, et al. N Eng

14、l J Med 2011;365:327-36,Bardoxolone Methyl and Kidney Function in CKD with Type 2 Diabetes,Pergola PE, et al. N Engl J Med 2011;365:327-36,Future potential drugs for DN,Islet Cell Transplant Aldose Reductase Inhibitors Sulodexide (GAG) Protein Kinase C (PKC) Inhibitors CTGF Inhibitors TGF- Inhibitors Anti-Inflammatory