低葡萄糖降解产物腹膜透析液

,单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,*,低葡萄糖降解产物腹膜透析液,腹膜透析,Nat Rev Nephrol. 2010,Feb;6(2):75-82,Worldwide prevalence of peritoneal dialysis in 2006 expressed as a percentage of the total dialysis population,Other countries,17,万,China,2,万,2009,年全球腹膜透析人数分布,自,2005,年以来接受腹膜透析的病人每年以,5-10%,速度增长,与普通,HD,比较,CAPD,的优势,操作简单,无需特殊设备,对中分子物质清除更为有效,对残余肾功能保护较好,特别适合儿童、,老年人和血,透禁忌证等人群,腹膜透析的主要问题,腹膜纤维化和超滤失败成为目前腹膜透析面临的重要问题。,传统的腹膜透析液主要选择葡萄糖作为渗透性物质，在加热过程中会形成葡萄糖降解产物对腹膜间皮细胞具有明显的细胞毒性作用，是导致腹膜纤维化和超滤失败的重要原因之一,低葡萄糖降解产物腹膜透析液,一、葡萄糖降解产物产生的主要原因及其影响,二、低葡萄糖降解产物腹透液的研究进展,三、低葡萄糖降解产物腹透液的主要优势,葡萄糖,GDPs,损伤腹膜间皮细胞功能,导致大量细胞因子如,IL-6,TGF-,，,VEGF,等,腹膜超滤功能和,PD,技术的失败,限制了传统腹膜透析液的长期应用,糖基化终末产物（,AGE,）,单袋长期储存,高温灭菌,pH,值条件,(5.5,6.5),加重腹膜间皮细胞转分化和新生血管形成,结合到含有,AGE,受体（,RAGE,） 的腹膜间皮细胞层,AGE,可进入血液循环，加重 动脉粥样硬化和淀粉样变,一、葡萄糖降解产物产生的主要原因及其影响,二、,低葡萄糖降解产物腹透液的研究进展,1,、渗透剂的研究,2,、包装方式改良的双室双袋腹膜透析液的研究,1,、渗透剂的研究,氨基酸腹透液,多肽腹透液,多聚糖,(Icodextrin),腹透液,其他成分腹膜透析液,氨基酸腹透液,氨基酸腹透液,无葡萄糖，,无葡萄糖降解产物，减少腹膜与葡萄糖的接触,优点,缺点,酸碱度较高（,PH 6.7,），更接近生理状态，减少对腹膜的刺激,氨基酸腹透液中加入碳酸氢盐缓冲液使其,PH,值保持在中性,可使其生物相容性得到进一步改善,氨基酸腹透液的大量应用能抑制食欲，引起代谢性酸中毒等。因此，氨基酸腹透液不宜单独使用。,氨基酸腹透液（国外研究）,Peritoneal Dialysis International, Vol. 18, pp 210-216,Peritoneal Dialysis International, Vol. 19, pp. 462,470,American Journal of Kidney Diseases, 1998,5(32): pp 761-769,Nephrol Dial Transplant (2003) 18: 1086,1094,Clin Nephrol.,2002 Dec;58(6):445-50,1.1%,氨基酸腹膜透析液与葡萄糖腹膜透析液相比：,减少患者氨基酸和蛋白质的丢失,可显著降低患者血钾、血磷水平,改善氮平衡，增加前白蛋白、白蛋白、转铁蛋白、血红蛋白水平，改善血浆氨基酸谱,更好的保护腹膜间皮细胞结构和功能,1.1%,氨基酸腹膜透析液减少患者氨基酸和蛋白质的丢失,Peritoneal Dialysis International, Vol. 18, pp 210-216,Nephrol Dial Transplant (2003) 18: 1086,1094,1.1%,氨基酸腹膜透析液较传统的葡萄糖腹膜透析液更好的保护腹膜间皮细胞结构和功能,Nephrol Dial Transplant (2003) 18: 1086,1094,Ultrastructural study of HPMCs by scanning electron,microscopy,A,：,5 mM D-glucose,B,：,30 mM D-glucose,C,：,Dianeal,D,：,Nutrineal,24h,fixed with 2.5%glutaraldehyde,HPMCs were cultured on PET membranes,A,B,C,D,Control:,A:,5 mM D-glucose,Experimental conditions:,B:,30 mM D-glucose,C,、,E:,spent Dianeal,D,、,F:,Nutrineal,Ultrastructural study of HPMCs by transmission electron microscopy under control and experimental conditions,Nephrol Dial Transplant (2003) 18: 1086,1094,氨基酸腹透液（国内研究,-1,）,国内一医院在,2004,年观察,24,例不卧床腹膜透析,(CAPD),患者随机进入治疗组、对照组。治疗组每日使用,1,次,0.491 %,的氨基酸透析液,留腹,4,7h ,每,3,个月随访,1,次,观察期为,6,个月。,结果,:,治疗组氨基酸透析,3,个月后白蛋白、转铁蛋白、前白蛋白呈明显上升,之后保持在稳定水平,;,对照组上述指标则逐步下降。,治疗组,nPNA,、,%LBM,（瘦体重百分比）、,MAMC,在研究期间始终稳定,对照组则随透析时间的延长降低明显。两组患者透析充分性指标在氨基酸透析期间始终保持充分状态。,J Nephrol Dialy transplant 2004,，,13,（,4,）,氨基酸腹透液（国内研究,-2,）,国内另一医院,2004,年,通过体外实验对照观察了,含氨基酸腹膜透析液（,1.1%Nutrineal,）和传统葡萄糖腹膜透析液（,1.5%Dianeal,）,对正常人腹膜间皮细胞（,HPMC,）的生物相容性及功能的影响。,结论：,与传统的葡萄糖腹膜透析液相比，氨基酸腹膜透析液能更好地维持,HPMCs,在细胞存活能力、细胞黏附功能及蛋白合成等方面的功能。,Chin J Nephrol February,，,2004,20,（,1,）,多肽腹透液,多肽腹透液,组成,优点,缺点,血清乳蛋白或纤维素水解而得到,提供氨基酸,改善腹透患者的营养状态,比氨基酸腹透液的超滤功能强,大分子多肽易导致机体过敏反应，故临床上多应用,8,10,个氨基酸的短链多肽,研究表明多肽腹透液有一定的应用前景,但其对营养状态的影响、生物相容性、临床疗效等方面尚须进一步研究。,An integrin-activating peptide, PHSRN, ameliorates inhibitory effects of conventional peritoneal dialysis fluids on peritoneal wound healing,Nephrol Dial Transplant (2010) 25: 1109,1119,Wound-healing process after peritoneal injury induced by stripping of the mesothelial cell monolayer.,Effects of PHSRN on pathological changes,多聚糖,(Icodextrin),腹透液,多聚糖腹透液,组成,优点,缺点,多聚糖是一种淀粉衍生物，分子量为,16000d,，约为葡萄糖分子量的,100,倍,超滤能力相当于,3.86%/4.25%,的葡萄糖透析液,适合于高转运和高平均转运的患者,渗透压维持时间长、透析效能好、安全性较好、,对心血管疾病相关因素有正性影响,高级糖基化终末期产物形成少,体外和体内实验都表明，多聚糖,作为渗透剂，仅,25%,可被腹膜吸收，降低血胰岛素水平，增加胰岛素敏感性,皮疹、价格昂贵、麦芽糖积聚以及低钠血症等,多聚糖腹膜透析液研究进展,多聚糖腹膜透析液通过减少糖负荷、降低体内胰岛素水平，增加血浆,adiponectin,分泌水平等，进而改善胰岛素抵抗。,Therapeutic Apheresis and Dialysis.2009 12(3):243,249,Ai Nakao,等研究证实多聚糖腹膜透析液较高糖腹膜透析液可降低,VEGF,和,bFGF,的表达、减少,AGEs,的积累、降低,AGE,受体（,RAGE),表达。且多聚糖腹膜透析液对血管生成、间皮细胞纤维化等腹膜改变减轻。进而延缓腹膜透析液引起的腹膜功能的恶化，延长腹膜透析使用的时间,Nephrol Dial Transplant(2010)25:1479-1488,对腹膜间皮细胞活性的影响,*P.0001 vs control (standard M199 medium); P.001 vs icodextrin; P.0001 vs icodextrin,3.86%,2.27% Glucose,1.36%,Icodextrin,*,*,*,*,Ito, et al. Nephron Clin Pract. 2003;93:c97-c105,多聚糖腹透液（,Icodextrin,）,Smaller increase in TGF-,1,in vitro,Ito, et al. Nephron Clin Pract. 2003;93:c97-c105,*P.0005 vs control (standard M199 medium); P.001 vs icodextrin; P.0001 vs icodextrin; P.0001 vs control,TGF-,1,(pg/mL/10,4,cells),3.86%,2.27% Glucose,1.36%,Icodextrin,*,多聚糖腹透液（,Icodextrin,）,多聚糖腹膜透析液延缓腹膜透析液引起的腹膜功能的恶化，延长腹膜透析使用的时间,Intraperitoneal injection was performed once daily with an instillation volume of 20 ml per injection during 8 weeks,(a),control Wistar rats with non-treated,(,n,= 8),(b),streptozotocin (STZ)-induced diabetic rats with 5/6 kidney,Ablation,(n= 8),(c) diabetic rats with 5/6 kidney ablation injected standard 4.25% glucose-based peritoneal dialysis fluid (PDF) for 8 weeks (,n,= 8),(d) diabetic rats with 5/6 kidney ablation injected 7.5% icodextrin-based PDF for 8 weeks (,n,= 8),Histological appearance of peritoneum,Nephrol Dial Transplant(2010)25:1479-1488,Vascular endothelial growth factor (VEGF) expression was evaluated by a VEGF immunostaining of the peritoneum,Nephrol Dial Transplant(2010)25:1479-1488,Fibrosis was evaluated with fibronectin immunostaining of the peritoneum,Nephrol Dial Transplant(2010)25:1479-1488,Basic fibroblast growth factor (bFGF) expression was evaluated by a bFGF immunostaining of the peritoneum,Nephrol Dial Transplant(2010)25:1479-1488,Advanced glycation end-product (AGE) accumulation was evaluated by an AGE immunostaining of the peritoneum,Nephrol Dial Transplant(2010)25:1479-1488,(19),Schalkwijk et al.,Reduced 1,2-dicarbonyl compounds in bicarbonate/lactate-buffered peritoneal dialysis fluids based on glucose polymers or amino acids. Perit Dial Int 2000;20:796-798.,Reduces GDP compared with conventional glucose solution,3-DG,mol/L,MGO,mol/L,GO,mol/L,Methylglyoxal (,mol/L),Glyoxal (,mol/L),3-Deoxyglucosone (,mol/L),多聚糖腹透液（,Icodextrin,）,Reduced AGE FormationCML* Generation,Icodextrin vs Dextrose,CML Generation (pmol/mL),Ueda, et al. Kidney Int. 2000;58:2518-2524,.,*,N,-carboxymethyllysine;,*P =.001 vs heat-sterilized 1.5% dextrose,*,*,1.36% glucose,(filter-sterilized),1.36% glucose,(heat-sterilized),Icodextrin,多聚糖腹透液（,Icodextrin,）,With the same risk factors, patients using Extraneal (usually older),have,a 32% reduced risk of transfer to HD.,Retrospective multicenter study,1045 patients,Mean follow-up: 14,5 months,Restores fluid balance,Lower probability of transfer to HD with,Extraneal,Divino F.J.C. and the Spanish 67 hospital group. Peri Dial Intern 23 Suppl. 1 Feb. 2003:S19.,EG (Extraneal patients),GG (Glucose only patients),多聚糖腹透液（,Icodextrin,）,Patients Reporting Better Health (%),Icodextrin patients report better health after 1 year,*,Wolfson, et al. Am J Kidney Dis. 2002;40:1055-1065,30,25,20,15,10,5,0,N=25,*Patients who completed both baseline and week 52 KDQoL forms.,N=41,2.27% glucose,Icodextrin,p0.05 vs 2.27% glucose,Improvements in Quality of Life with Extraneal,Randomized, double- blind, active-controlled study,N = 66,Study duration 52 weeks,CAPD and APD,多聚糖腹透液（,Icodextrin,）,Icodextrin,优缺点总结,David W JOHNSON,et al,.,Recommendations for the use of icodextrin in peritoneal dialysis patients. NEPHROLOGY 2003; 8 , 1,7,多聚糖腹透液（,Icodextrin,）,其他成分腹膜透析液,学者们还研究了,白蛋白、代血浆类物质、合成多聚体、甘油、木糖醇、山梨醇、果糖,等作为渗透剂的可行性,但多因为价格昂贵、毒副作用大等未能得到进一步应用。,近来学者们致力于渗透剂的混合应用研究，临床研究表明,0.6%,的氨基酸和,1.4%,的甘油腹透液,混合使用可达到,2.27%,葡萄糖腹透液的超滤率，是安全的、病人可以耐受，相对于葡萄糖腹透液来说，患者糖负荷明显下降，腹透液中,CA125,水平显著升高，其远期临床效果尚须进一步大样本的临床观察。,2,、包装方式改良的双室双袋腹膜透析液的研究,定义：,基于传统腹膜透析液进行改良的双室双袋腹膜透析液由于其显著降低了腹膜透析液中,GDPs,的含量,又称之为,低葡萄糖降解产物腹膜透析液,:,双室双袋腹膜透析液优势,双室双袋腹膜透析液将缓冲剂和葡萄糖分别消毒,并分隔包装,使高浓度葡萄糖处于低,pH,值环境,(2.8,3.2) ,从而最大限度降低了,GDPs,的产生。,双室双袋腹膜透析液的包装方式使透析液混合后的,pH,值在,7.0,7.4,之间,使其较传统腹膜透析液更符合人体生理状态。,由于碳酸氢根在加热过程中可与钙、镁等反应产生沉淀，因此传统腹膜透析液使用乳酸盐作为缓冲剂,而双室双袋腹膜透析液的分隔包装使碳酸氢盐作为缓冲剂成为可能。,目前临床上可供使用的双室双袋腹膜透析液就有以乳酸盐、碳酸氢盐、或碳酸氢盐,-,乳酸盐混合为缓冲剂。,三、低葡萄糖降解产物腹透液的主要优势,1,、改善生物相容性,2,、减少腹膜炎,3,、提高透析效能,1,、改善生物相容性,研究表明长期使用低,GDPs,腹膜透析液较传统腹膜透析液患者，腹膜间皮细胞完整性指标,CA125,水平较高，即低,GDPs,腹膜透析液能更好地保护腹膜间皮细胞的生物学活性,Perit Dial Int 2008; 28:174,182,近年研究显示,低糖基化降解产物腹膜透析液可通过降低腹膜间皮细胞转化生长因,-,的分泌，降低腹膜上,AGE,的沉积等延缓腹膜纤维化的发生。,PeritDial Int, 2006, 26 (6) : 664-670,临床观察发现使用双室、低,GDP,透析液患者血,AGE,水平明显低于单室、高,GDP,患者。但目前关于低,GDPs,腹膜透析液临床应用有待进一步研究。,Nephrol Dial Transplant,，,2007,，,22: 2038,2044,低,GDPs,腹膜透析液,-,腹膜间皮细胞完整性指标,CA125,水平较高,Perit Dial Int, 2008; 28:174,182,低,GDPs,腹膜透析液较传统腹膜透析液明显降低患者血,AGE,水平,Nephrol Dial Transplant,，,2007,，,22: 2038,2044,2,、减少腹膜炎,研究显示使用,Physioneal,腹膜透析液（低葡萄糖降解产物腹膜透析液）的患者腹膜炎发生率明显低于使用传统腹膜透析液患者,。,Perit Dial Int, 2002, 22: 148,研究表明,与传统,PDF,相比,低,GDPs,腹膜透析液可通过减少趋化因子含量、降低血清,C,反应蛋白水平、降低白介素,-6,的产生，进而可显著减轻患者的微炎症状态,PeritDial Int,2004, 24 (1) : 48257.,Nephrol Dial Transp lant, 2007, 22 (2) : 52-59,PeritDial Int, 2001,21 ( Supp l 3) : S102-S107.,3,、提高透析效能,大量研究发现低葡萄糖腹膜透析液较传统腹膜透析液可增加溶质清除、改善腹膜超滤功能、保护残余肾功能等作用。,Perit Dial Int 2008; 28(S3):S117,S122,Nephrol Dial Transplant (2009) 24: 2899,2908,低,GDPs,腹膜透析液与传统腹膜透析液对残余肾功能的比较（,1,）,Perit Dial Int 2008; 28(S3):S117,S122,低,GDPs,腹膜透析液与传统腹膜透析液对残余肾功能的比较（,2,）,Nephrol Dial Transplant(2009) 24:2899,2908,Effects of LF on residual renal function in the total population,(A) Intention-to-treat analysis and (B) per-protocol analysis,Effects of LF on dialysate-to-plasma ratios for creatinine at 4 h (D/PCr) (A) and ultrafiltration capacity (B) LF,Levels of effluent cancer antigen 125 (A) and interleukin-6 (B) for the LF and CF groups,(A) cancer antigen 125 (B) interleukin-6,小结,葡萄糖降解产物可导致腹膜超滤功能和,PD,技术的失败。,低葡萄糖降解产物腹透液的研究进展：渗透剂的研究、包装方式改良的双室双袋腹膜透析液的研究 。,低葡萄糖降解产物腹透液的主要优势：改善生物相容性、减少腹膜炎、提高透析效能。,将来腹膜透析液的研究将致力于维护腹膜功能、提高腹透效能，改善腹透患者的生活质量、减少腹透相关并发症。,