CN114903998A - 渗透压保护防治腹膜纤维化和超滤衰竭 - Google Patents
渗透压保护防治腹膜纤维化和超滤衰竭 Download PDFInfo
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Abstract
腹膜纤维化是导致腹膜透析患者发生腹膜超滤衰竭的主要原因，从而造成腹透患者无法继续单纯依靠腹膜透析而必须转为血液透析。由于腹膜透析液必须是高渗液才能从体内透出水分，我们认为高渗所致腹膜间皮细胞损伤和死亡是腹膜纤维化的重要原因之一。正常情况下，腹膜间皮细胞不会经常暴露于高渗透压，因此可能缺乏对高渗的调节能力，容易被损伤而致死亡。我们的发明是将体内正常产生的或外源性的一种或多种晶体或胶体渗透物质如甜菜碱加入目前在临床使用的腹膜透析液中，为腹膜间皮细胞提供甜菜碱等渗透调节分子。使得细胞能够更好地适应高渗，以减轻高渗而致细胞损伤和死亡。最终达到保护腹膜间皮细胞，减少腹膜纤维化和延缓超滤衰竭的目的。
Description
技术领域
生物技术领域。
背景技术
腹膜透析(Peritoneal dialysis,PD)是尿毒症终末期肾病(End stage of renaldisease,ESRD)患者主要肾脏替代疗法之一。在PD中，使用高渗溶液通过腹膜(PM)将机体多余的水分从体内清除。目前，浓度为1.5-4.25％的晶体葡萄糖是PD溶液中最常用的渗透剂，例如来自Baxter(Deerfield，IL，USA)的Dianeal。但PD患者随着透析时间延长，低浓度葡萄糖透析液很快无法引出足够的水分，就需使用高浓度葡萄糖作为透析液，随着高浓度葡萄糖透析液使用次数的增加，通常在透析5年后出现透析效率低下，患者无法继续单纯依靠腹膜透析而必须转为血液透析。据统计，超滤衰竭的发生率随着PD年限的延长而增加，而超滤衰竭是腹膜透析患者被迫退出腹膜透析的主要原因。预防和减缓腹膜纤维化是避免腹膜透析患者出现超滤衰竭的根本方法，是保障他们长期透析成功延长寿命的关键。
腹膜组织由间皮层、基底层和间皮下支持组织三层组成。其中间皮下支持组织富含微血管，间皮细胞和间皮下微血管是完成腹膜透析的最主要的细胞和结构基础。腹膜纤维化在形态学上表现为间皮细胞减少，死亡的间皮细胞被肌成纤维细胞或成纤维细胞替代，炎症细胞浸润和细胞外基质的大量堆积并伴随血管数目增加。因此，间皮细胞的死亡和腹膜炎症是引起腹膜纤维化的根本原因。目前主流观点认为导致间皮细胞死亡和腹膜炎症的因素是高浓度葡萄糖本身，以及高浓度葡萄糖诱导的细胞代谢异常和产生的自由基。因此近年来，较多的科研和临床研究致力寻求替代高浓度葡萄糖溶液的透析液，但遗憾的是都未能达到防止腹膜纤维化的效果。
发明专利CN 109394781 A中使用葡萄糖聚合物代替葡萄糖，葡萄糖聚合物分子体积大，无法直接经由扩散作用通过腹膜壁进入腹膜内微血管并为身体所吸收，因此于腹膜腔内产生高胶体渗透压，以维持留置期的脱水及廓清效能，降低透析过程相关炎症发生，延长腹膜透析患者的透龄。以多聚葡萄糖为渗透液的艾考糊精透析液就是其中的一种。Dousdampanis等人发表的《Icodextrin and peritoneal dialysis:advantages and newapplications》(《Int Urol Nephrol》2018年第3期)一文中使用艾考糊精代替传统高浓度葡萄糖作腹膜透析液。艾考糊精是通过α(1-4)和α(1-6)糖苷键连接的水溶性葡萄糖聚合物，平均相对分子质量为16200Da，目前市场上有百特公司生产的含7.5％的艾考糊精透析液，渗透压为285mosm/L。与人体的渗透压相等，主要是利用胶体渗透压通过腹膜上的小孔等渗地清除水分。艾考糊精分子量大，不容易被细胞吸收，艾考糊精透析液的超滤特点是留腹后腹腔中的超滤量呈缓慢持续上升，但留腹时间短，艾考糊精的超滤量并不高，需要延长留腹时间才能达到超滤的目的。常规艾考糊精透析液至少要留腹7小时以上，这与临床上持续性不卧床腹膜透析(CAPD)和自动化腹膜透析(APD)的透析要求不相符。因此，艾考糊精透析液通常必须与含葡萄糖的透析液联合使用，例如CAPD的病人一天用一次艾考糊精，三次葡萄糖。这导致临床研究评价艾考糊精对腹膜的作用很难。此外，使用艾考糊精透析液对患者血糖的检测存在影响，临床研究显示,在每天使用1袋艾考糊精后,血中的麦芽糖浓度会明显升高,并最终稳定在基线的5倍左右。这些糖类物质会使血糖检测结果高于真实值,导致临床医生误认为高血糖而过多使用胰岛素或者掩盖严重的低血糖，甚至可危及患者生命。另外有报道使用艾考糊精后出现无菌性腹膜炎,虽然并未得到前瞻RCT研究的证实,但这些因素导致人们对icodextrin透析液对腹膜安全性的担忧。因此，无论是含有葡萄糖的腹膜透析液，还是多聚糖的艾考糊精腹膜透析液等都是通过晶体或胶体渗透压进行超滤脱水，高渗透压均可能造成腹膜间皮细胞的渗透损伤或死亡，所以目前PD技术需要解决的关键问题是如何在葡萄糖或其他透析液的基础上保护腹膜，特别是腹膜间皮细胞，从而防止腹膜纤维化，不发生超滤衰竭。
发明内容
众所周知，暴露于高细胞外渗透压的哺乳动物细胞的原型反应是由于水通道蛋白的水外排而立即收缩。随后细胞通过高表达某些酶或细胞渗透调节分子的转运蛋白，例如醛糖还原酶aldose reductase(AR)，增强葡萄糖向山梨糖醇的转化，促使高渗应激的细胞内积累山梨糖醇、转运甜菜碱的GABA转运蛋白BGT1、转运肌醇的钠/肌醇共转运蛋白SMIT等来主动提高细胞内有机渗透物质的浓度，从而平衡细胞内和细胞外的渗透压。
我们的研究发现腹膜透析液必须使用的高渗透压是造成间皮细胞死亡的重要因素。当渗透压达到400mOsm以上时，即正常的2.5％葡萄糖透析液的渗透压值时，不论渗透物质是葡萄糖、氯化钠、甘露糖、葡萄糖聚合物以及细胞未能代谢的左旋葡萄糖都可以诱导腹膜间皮细胞发生死亡。我们推测是由于腹膜间皮细胞正常生理条件下并没有遇到特别高渗的情况，所以这些细胞对高渗的调节能力较弱，从而发生死亡。因此，如何提高腹膜间皮细胞调节高渗的能力可能是保护细胞的关键环节之一。
本发明研发过程中，我们惊奇地发现，当我们将体内正常产生的或外源性的一种或多种晶体或胶体渗透调节物质如甜菜碱、肌醇、山梨糖醇及甘磷酸胆碱等加入至临床常用的葡萄糖或艾考糊精腹膜透析液中，可以为腹膜间皮细胞提供高渗保护，来帮助细胞对高渗环境进行自我调节，使得腹膜间皮细胞能够更好地适应高渗环境，减少细胞死亡，从而使得腹膜纤维化减轻，并显著延缓腹膜透析超滤衰竭的发生时间。
本发明提供一种腹膜透析液，其特征在于，所述透析液包含：(a)一种或多种晶体或胶体渗透调节物质；(b)常用的腹膜透析液基质。
在一些实施例中，前述腹膜透析液的特征在于，所述常用腹膜透析液基质可以为葡萄糖溶液或艾考糊精溶液。透析液基质的差异对细胞存活度影响较小，而当加入一定浓度细胞渗透压调节分子后细胞存活度才明显提升。
在一些实施例中，前述腹膜透析液的特征在于，所述一种或多种细胞渗透压调节分子可以为甜菜碱、肌醇、山梨糖醇或甘磷酸胆碱，以及他们的组合物。令人惊讶的是，当我们往常用的4.25％PD中加入不同浓度甜菜碱时，体外试验结果显示细胞存活度随着甜菜碱剂量的增大细胞死亡呈剂量依赖性的减少。并且在动物实验中也有同样趋势，动物试验结果表明小鼠腹膜功能及腹膜纤维化的发生发展显著减轻。
在一些实施例中，增加渗透压调节分子后的腹膜透析液，透析效率并没有降低。
因此，本发明专利实际解决的问题是：提供了一种新型的腹膜透析液组成，在不改变透析效果的前提下，减少了腹膜间皮细胞在透析过程中的死亡，从根本上延缓了腹膜纤维化进程，延长了患者接受腹膜透析的时间。
为了解决上述问题，本发明所制腹膜透析液有以下几个方案：
(1)一种腹膜透析液，其特征在于，按重量百分比计，所述透析液包含：0.01mM至1000mM甜菜碱溶液。
(2)一种腹膜透析液，其特征在于，按重量百分比计，所述透析液包含：(a)1.5％至4.25％葡萄糖溶液；(b)0.01mM至1000mM甜菜碱溶液。
(3)一种腹膜透析液，其特征在于，按重量百分比计，所述透析液包含：0.01mM至1000mM甜菜碱、0.01mM至1000mM肌醇、0.01mM至1000mM山梨糖醇、0.01mM至1000mM甘磷酸胆碱溶液或这些渗透物质的两种或多种组合物。
(4)一种腹膜透析液，其特征在于，按重量百分比计，所述透析液包含：(a)1.5％至4.25％葡萄糖溶液；(b)0.01mM至1000mM甜菜碱、0.01mM至1000mM肌醇、0.01mM至1000mM山梨糖醇、0.01mM至1000mM甘磷酸胆碱溶液或这些渗透物质的两种或多种组合物。
(5)一种腹膜透析液，其特征在于，按重量百分比计，所述透析液包含：(a)7.5％艾考糊精溶液；(b)0.01mM至1000mM甜菜碱溶液。
(6)一种腹膜透析液，其特征在于，按重量百分比计，所述透析液包含：(a)7.5％艾考糊精溶液；(b)0.01mM至1000mM甜菜碱、0.01mM至1000mM肌醇、0.01mM至1000mM山梨糖醇、0.01mM至1000mM甘磷酸胆碱溶液或这些渗透物质的两种或多种组合物。
附图说明
图1甜菜碱剂量依赖改善高糖高渗引起的腹膜间皮细胞损伤及死亡。1：给予细胞不同浓度甜菜碱预处理12h后再同时高糖处理24h的光镜图,单纯给予腹膜间皮细胞4.25％的葡萄糖处理时，细胞的死亡明显增加，而同时给予不同浓度甜菜碱处理后，我们发现细胞从1mM甜菜碱开始细胞存活明显改善，而且随着剂量的增大细胞死亡逐渐减少。2：腹膜间皮细胞结晶紫染色，Betaine处理后的细胞存活情况与甜菜碱呈现出剂量依赖的增多。3：上清中LDH释放率的检测分析腹膜间皮细胞释放到上清中的乳酸脱氢酶LDH也随着甜菜碱剂量增加而逐渐降低。4：Western blot检测Betaine对高糖诱导的焦亡相关分子的影响。5：对D的蛋白结果进行定量分析，发现caspase-3的活性形式表达明显降低。(以上数据均为n≥3,*/#p<0.05,**/##p<0.01,*vs CONTROL,#vs Glu 4.25％)。
图2甜菜碱改善腹膜透析后小鼠腹膜功能及腹膜纤维化1：腹透超滤量UF的测定结果，模型组与对照组相比，腹膜超滤量UF减少，而甜菜碱治疗组则能很好的改善腹膜功能，腹膜超滤明显增加；2-3：腹膜透析后腹透液中LDH含量的测定，模型组中LDH释放明显增多，而甜菜碱治疗组LDH的释放显著减少(n＝5,**p<0.01,***/###p<0.001，其中*表示vs对照组，#表示vs模型组)；4：Masson染色，蓝色为胶原纤维，肌纤维呈红色，正常对照组腹膜组织薄而且连续，模型组相对于正常组在间皮下可见明显的胶原沉积，腹膜增厚。甜菜碱治疗组较正常组腹膜轻微增厚，但相比模型组更薄。Scale bar＝100μm。
具体实施方式
实施例1
结果显示，对照组1和对照组2中细胞存活度相当，常用的两种透析液基质对细胞存活度几乎没有影响；而当加入1mM甜菜碱后，两个实验组的细胞存活度都显著提高。说明在透析液中添加细胞渗透压调节分子，有助于提高细胞活度。
实施例2
给予腹膜间皮细胞不同浓度的甜菜碱(0.5mM,1mM,5mM,10mM)预处理细胞12小时后再给予细胞高糖(GLU 4.25％)处理24小时，观察到细胞在单纯给予不同甜菜碱处理后细胞生长状况良好，同时给予4.25％的葡萄糖处理时，发现细胞从1mM甜菜碱开始细胞存活明显改善，而且随着剂量的增大细胞死亡逐渐减少,结晶紫染色结果提示甜菜碱处理后的细胞存活剂量依赖的增多，同时，caspase-3的活性被抑制，细胞释放到上清中的LDH液随着甜菜碱剂量增加而降低，由此证明甜菜碱可能在腹膜间皮细胞应对高糖高渗环境发挥保护作用。
实施例3
我们进一步利用向小鼠腹膜腔内注射高渗性腹膜透析液(4.25％PD)构建小鼠腹膜纤维化模型，16只C57WT小鼠分为三组，对照组n＝4：每日腹腔内注射0.9％NS按体重120ml/kg+治疗药物等体积的无菌生理盐水+治疗药物等体积的4.25％的腹膜透析液。模型组n＝6：每日腹腔内按体重120ml/kg注射4.25％的腹膜透析液+治疗药物等体积的4.25％的腹膜透析液。甜菜碱治疗组(n＝6)：每日腹腔内注射按体重120ml/kg的4.25％腹膜透析液+甜菜碱100mM。每周监测各组小鼠体重，甜菜碱治疗与高糖腹透液同时进行腹腔注射，一共持续6周，最后有2只小鼠退出实验。模型组1只、甜菜碱治疗组1只，均为体重不明原因的大幅度下降，并且在6周时打开腹腔后发现腹水浑浊。其余小鼠饮食活动均正常，精神状态较好，体重较开始时增加。实验开始时各组小鼠体重无明显差异，从第一天起，每天监测小鼠体重并记录。实验结束后统计体重可见，模型组体重均低于正常组，而甜菜碱治疗组的体重稍高于模型组，但是仍然比正常对照组低。但统计学分析均无明显的统计学差异。
动物样本取材及标本处理、保存
实验第6周做腹膜平衡实验，监测腹膜功能，并对小鼠组织样本进行取材。小鼠停止腹膜透析48h后，即可进行2h的腹膜平衡试验。小鼠腹肌肉注射1％戊巴比妥钠进行麻醉，按0.07ml/10g注射。
待小鼠麻倒后，将小鼠仰卧位固定于手术台上，常规腹部消毒，铺无菌手术洞巾，操作者穿无菌手术衣，带口罩以及无菌手套。随即沿着腹白线位置用消毒的镊子剪开一小口皮肤。每只小鼠腹腔注射4.25％腹膜透析液3mL，计时器计时，透析过程中需轻柔晃动腹部。在腹腔保留1h后回抽100ul透析液于干净的600ulEP管中，置于冰上，再尾静脉取血100ul于EP管中，做好标记。在腹腔保留2h后，无菌的注射器回抽腹腔内部透析液，直到抽尽为止，读取注射器内腹膜透析液的体积，装入5ml离心管中，做好标记。同时尾静脉取血100ul。再用手术刀沿着腹白线位置打开腹腔，逐层钝性分类筋膜及肌肉，避免损伤小血管或着把由小血管破裂后渗出的血擦拭干，避免血液流入腹腔内从而影响腹透液超滤量值的计算。超滤量：无菌的纱布轻柔的蘸取腹腔内液体，并计算纱布净增加的体积。超滤量(UF)＝注射器内透析液的体积+纱布净增加的体积-3ml。
取材：充分暴露腹壁，取腹部切口两侧壁层腹膜，放入预冷的PBS中清洗多次后，剪成小块，分别放入4％PFA中固定(PFA的体积是组织体积的10倍以上)、OCT中包埋且迅速放入液氮、1.5mlEP管放入液氮用做蛋白和RNA检测。观察肠系膜以及其他脏层腹膜外观，取部分脏层腹膜分装放入EP管中，做好标记，立即液氮速冻，随后尽快将液氮内的样本放入-80℃冻存。装有组织及4％PFA的管子放于4度保存。
分离透析液：将装有1h、2h腹透液样本的600ul离心管，置于4度离心机中，3500r，4度，10min。离心后仔细转移上清至新的600ul EP管中，立即进行指标检测或者暂时放于-20度保存。
分离腹透液中细胞：将回收后的腹透液放置冰上，3500rpm，4度，10分钟，转移腹透液上清，管底沉淀若有红细胞则需要破除红细胞，最后用预冷的PBS清洗细胞3次，再次低温离心，弃掉上清回收cell，并根据细胞量加入适量的蛋白提取液，提取蛋白。
对壁层腹膜进行石蜡包埋切片，并将组织固定于OCT中进行冰冻切片的制备。
动物实验样本检测结果
模型组与对照组相比，超滤量减少，而甜菜碱治疗组则能很好的改善腹膜功能，显著增加超滤量；提示向腹透液中加入渗透调节物质甜菜碱后，腹膜的超滤功能明显增加，增强了腹膜透析的超滤效果。同时透析液中的LDH含量模型组明显增多，但甜菜碱治疗组却能很好的减轻LDH的释放，提示细胞死亡参与到腹膜功能改变过程，且甜菜碱能有效抵抗腹膜功能改变。组织Masson染色可见：正常对照组，腹膜组织薄而且连续，模型组相对于正常组在间皮下可见明显的胶原沉积，腹膜增厚。甜菜碱治疗组较正常组腹膜轻微增厚，但相比模型组更薄。
Claims (8)
1.一种腹膜透析液，其特征在于：所述腹膜透析液包含：(a)一种或多种晶体或胶体渗透调节物质；(b)常用的腹膜透析液基质。
2.权利要求1所述的腹膜透析液，其特征在于，所述一种或多种晶体或胶体渗透调节物质为甜菜碱、肌醇、山梨糖醇或甘磷酸胆碱。
3.权利要求2所述的腹膜透析液，其特征在于，所述的渗透调节物质中甜菜碱浓度为0.01mM至1000mM。
4.权利要求1-3所述的腹膜透析液，其特征在于，所述常用的腹膜透析液基质为葡萄糖溶液或其他腹膜透析溶液。
5.权利要求4所述的腹膜透析液，其特征在于，所述的腹膜透析液基质中葡萄糖溶液的浓度为1.5％～4.25％。
6.权利要求4所述的腹膜透析液，其特征在于，所述的腹膜透析液基质中艾考糊精溶液的浓度为7.5％。
7.权利要求5所述的腹膜透析液，其配制方法如下(以葡萄糖作基质的)：
含1.5％葡萄糖
含2.5％葡萄糖
含4.25％葡萄糖
8.权利要求6所述的腹膜透析液，其配制方法如下(以艾考糊精作基质的)：
含7.5％的艾考糊精
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