修回日期: 2002-07-21
接受日期: 2002-08-02
在线出版日期: 2003-03-15
肝肾综合征(HRS)是继发于肝硬化、重型肝炎等严重肝病肝功能失代偿情况下的肾功能衰竭综合征, 其死亡率很高, 目前仍缺乏确切有效的治疗方法, 除对基础肝病的积极治疗外, 肝移植对HRS有明确疗效, TIPS、MARS、血管活性药物等治疗可暂时改善肾功能, 也可作为肝移植的辅助治疗措施. 本文就HRS治疗方面的进展情况进行综述.
引文著录: 张斌, 万谟彬, 王灵台. 肝肾综合征的治疗进展. 世界华人消化杂志 2003; 11(3): 330-333
Revised: July 21, 2002
Accepted: August 2, 2002
Published online: March 15, 2003
N/A
- Citation: N/A. N/A. Shijie Huaren Xiaohua Zazhi 2003; 11(3): 330-333
- URL: https://www.wjgnet.com/1009-3079/full/v11/i3/330.htm
- DOI: https://dx.doi.org/10.11569/wcjd.v11.i3.330
肝肾综合征(hepatorenal syndrome, HRS)是继发于肝硬化、重型肝炎等严重肝病肝功能失代偿的肾功能衰竭综合征, 其肾脏的损害为功能性改变, 是可逆的[1-11]. HRS的发病机制还不十分清楚, 可能与门脉高压后全身小动脉扩张有关, 造成体循环血管总阻力的下降和动脉低血压, 使动脉有效循环量相对不足, 导致肾脏血管收缩, 使肾灌注不足, 最终导致肾衰的发生[12-22]. HRS的死亡率很高, 在一项肝硬化合并腹水患者的大样本随访研究中, 1、5年后发生HRS的比例分别为18%和39%, 患者平均生存时间仅为1.7 wk, 或10 wk的死亡率高达90%[23]. 目前仍缺乏确切有效治疗HRS的方法, 肝移植被认为是治疗HRS有明确疗效的方法, 但是其远期疗效不够理想[24,25], 经颈静脉肝内门体分流术(transjugular intrahepatic portasystemic shunt, TIPS)、分子黏附再循环系统(molecular abosorbent recirculating system, MARS)及血管活性药物等治疗可暂时改善肾功能, 也可作为肝移植的辅助措施[26-31], 以下就这方面的进展情况进行综述.
从血流动力学角度分析, HRS主要有二种类型, 一种为低排高阻型, 与短期内大量体液丢失有关, 在HRS中较少见, 这种类型经扩容治疗后肾功能改善较为显著; 另一种为高排低阻型, 相对多见, 可能与肝病患者病情发展过程中体内假性神经递质增加有关, 可导致中枢及交感神经系统功能紊乱, 并导致血管扩张, 使全身有效循环量相对不足, 这种类型对扩容治疗的疗效不明显. 因而目前对扩容的治疗效果仍有争议, 虽部分患者在扩容后可出现肾功能的改善, 但如果尿量未增加而导致容量负荷增加, 则有出现肺水肿的可能, 并可能加重稀释性低钠血症, 导致血浆渗透压下降, 细胞外水分向细胞内转移, 并渗入浆膜腔, 肾组织细胞内水分增加, 影响肾小球循环血供, 进一步加重HRS. 另外需要高度重视低钠血症的纠正, 采用高渗盐水对HRS可能有一定的改善作用, 但目前对此仍有争议.
2.1.1 多巴胺及多巴酚丁胺: 可以扩张肾血管并增加心排血量, 改善肾血流量及滤过率, 建议采用小剂量多巴胺(<5 ug. kg-1.min-1)进行治疗; 后者为β受体兴奋剂, 也有增加肾血流量及尿量的作用. 二者联合使用较好, 但疗效报道不一.
2.1.2 前列腺素类: Bataller et al[32]认为肝功能紊乱可影响到肾脏中前列腺素的合成和释放, 导致HRS患者肾脏产生前列腺素E2(PGE2)和6-oxo-PGF1α减少. 另外, 肝硬化腹水患者使用可以抑制环氧合酶的非类固醇类消炎药, 可以促进HRS的发生. 但也有学者提出相反意见, 如Clewell et al[33]研究表明, 静脉内给予PGs或口服米索前列醇, 对改善HRS患者的肾功能没有确切的疗效.
2.1.3 内皮素拮抗剂: 内皮素具有收缩肾血管的作用, 使用内皮素拮抗剂可以达到扩张肾脏血管的目的. Soper et al[34]用内皮素A-受体拮抗剂BQ-123治疗3例酒精性肝硬化合并HRS 的患者, 取得了一定疗效, 但由于病例数较少, 还不能肯定其疗效.
2.1.4 抗氧化剂: Holt et al[35]对12例HRS患者给予一种抗氧化剂N-乙酰半胱氨酸进行静注治疗, 疗程5 d, 尽管肝功能或全身血液动力学没有变化, 但是肌酐清除率从(24±3) ml/min改善为(43±4) ml/min, 提示其具有减轻氧化剂损害的作用, 对肾功能也有一定的改善作用. 但这些也是初步的研究结果, 还需要进一步临床对照研究来证实.
2.1.5 其他: 如654-2 具有扩张肾血管的作用, 患者狂躁时可改用东莨菪碱治疗.
2.2.1 抗利尿类药物: 抗利尿类药物有血管收缩作用, 对于肝硬化合并肾功能损害的患者可以增加内脏和全身血管的阻力, 从而使全身循环血容量进行重新分布. 通过静脉注射抗利尿激素-1受体激活剂8-鸟氨酸抗利尿激素或鸟氨酸加压素后, 仅4 h后就可以改善全身血压及肾脏的灌注压, 并进一步增加了肾脏血流量和肾小球滤过率[36], 注射超过48 h后可以进一步改善肾功能, 对肾素-血管紧张素系统和交感神经系统的活性均有显著的抑制作用, 有利于改善肾血流和肾小球滤过率. 在配合使用白蛋白进行扩充血容量治疗的基础上, 注射鸟氨酸加压素(ornipressin)治疗至第15天时, 肾功能的改善会更加显著, 但是由于全身血管收缩可以出现局部组织的缺血性萎缩, 如肌肉坏死性肠炎、萎缩性心脏病及口咽部溃疡等, 因而限制了这种治疗的进一步推广. 但是, 注射另一种抗利尿类药物特利加压素(terlipressi) 48 h后, 可以改善肾功能, 但没有以上的严重副作用[37], 值的进一步推广使用. 另外特利加压素联合应用白蛋白或其他有扩张肾脏血管作用的药物, 如低剂量的多巴胺, 其效果会更好[38].
2.2.2 α-肾上腺素兴奋剂: 米多君(midodrine)是一种α-肾上腺素兴奋剂, 可以改善肝硬化患者的全身和肾脏血液动力学, 但是对于HRS患者没有这样的效果[39], 但当米多君与扩容药物及奥曲肽(Octreotide, 一种生长抑素类似物)进行联合治疗时, 对全身和肾脏的血液动力学和尿钠排泄等均有显著的改善作用, Angeli et al[40]联合使用奥曲肽、米多君和白蛋白治疗5例HRS, 疗程为20 d, 结果发现, 患者尿量、肾血流量及肾小球滤过率(GFR)等均有明显改善, 且在提高生存率方面优于用小剂量多巴胺和扩容治疗.
TIPS插入治疗可以降低门脉压力, 使一部分内脏血容量直接回到体循环中, 从而可以在一定程度上限制血液中具有血管活性作用的神经体液因子对内脏的作用, 因而对肾脏血流动力学也有一定的改善作用[41-52]. 然而TIPS不是对每一个HRS患者的肾功能均有改善作用, 而仅仅是对于部分敏感者有效, 目前对于适合TIPS治疗的适应证还不确定, 也许与肾脏损害程度和黄疸水平有一定关系, 这些还需要进行进一步的临床研究, 而且他也不能将患者肾功能恢复到完全正常的水平, 这可能与TIPS导致的急性高动力循环有关[53].
TIPS对于患者的生存是否有改善, 目前结论报道不一, 如Rossle et al[54]认为HRS合并难治性腹水患者接受TIPS治疗的生存情况可以得到改善, 要显著好于接受腹腔穿刺放腹水治疗的患者; Spahr et al[55]报道1例肝硬化合并HRS的患者接受TIPS治疗后尿量增多, 肾功能明显改善, 而Lebrec et al[56]研究认为TIPS治疗远期疗效不理想, 他们对25例难治性腹水的患者进行TIPS治疗, 其中8例为合并黄疸且肝功能为child C级, 接受TIPS的患者2 a死亡率为56%, 显著高于接受重复大量穿刺放腹水的患者(29%). 最近, Brensing et al[57]在一项大样本TIPS治疗HRS的研究中, 2年生存率为35%, 并按HRSⅠ、Ⅱ型进行进一步研究, Ⅱ型患者的1年生存为70%, 显著高于Ⅰ型的20%, Cox 回归分析结果发现, HRS类型和血胆红素水平是TIPS治疗后生存的独立因素.
分子黏附再循环系统(MARS)是一种改良的透析治疗方法, 他应用含白蛋白的透析液, 可以选择性地清除与白蛋白结合的物质, 他采用一个透析设备, 含有通透性不均匀的聚合树脂透析膜(聚砜类渗透膜), 在患者血液和膜的透析液侧均用人血白蛋白. 在透析过程中, 一个密闭的透析环路可以将与白蛋白结合的毒素从血浆中黏附在膜上, 与白蛋白结合的毒素与透析膜黏附后经过持续不断的解离而得以清除. 水溶性的毒素也可以被活性炭柱和离子交换树脂黏附后进行清除, 这个系统与一个连续的静脉血液滤过系统连接, 以利于清除分子量<50 kd的物质[58-61].
Mitzner et al[62]比较了MARS透析和传统血液透析方法在HRS治疗中的疗效, 结果发现MARS显著好于传统透析方法, 其中MARS透析治疗组可以较显著的减少血清胆红素水平和肌酐水平[从(3.8 ±1.6) mg/dL到(2.3±1.5) mg/dL], 因而延长了生存时间, 但是, 2 wk生存率仍然低于40%. MARS还有许多其他优点, 如接受治疗的患者在治疗过程中可以保持平均动脉压的稳定, 还可清除许多细胞因子, 如TNF和IL-6, 这些物质与引起血管扩张物质的产生有关, 因而对HRS的改善有好处[63]. 目前MARS是一种暂时性的支持治疗, 可作为拟行肝移植的HRS过渡性治疗.
目前认为肝移植是治疗HRS具有明确疗效的方法[64-69], 但是患者接受肝脏移植后, 生存率要显著低于肾功能正常的移植患者, 而且他们肾功能恢复正常的时间要慢数月或数年, 因而疗效并不十分理想, 而且肝移植不容易被每一个患者乐意接受, 因而对合并HRS患者采用肝移植并不十分适合[70-71], 该方法还在进一步的完善中.
总之, HRS仍然是医学的难题, 目前尚缺乏疗效理想的治疗手段, 本文中的许多治疗措施有助于延长患者的生命, 尤其是肝移植已经显示出良好的运用前景, 随着临床的进一步完善, 其疗效还将进一步提高. 但是, 这些治疗方法需要有所选择的运用, 个体的疗效差异较大, 目前还没有一个明确的使用标准, 因而需要在临床中进行不断的研究. HRS是一个综合性的治疗, 上述方法仅仅是治疗中的一个部分, 而常规性治疗和良好的护理在治疗中具有基础性的作用, 不能被忽视. 由于HRS可因过度利尿、大量放腹水、出血、感染及肾脏损害药物的使用等因素诱发, 因而尽可能地避免诱发和加重HRS的各种因素在总体治疗中具有十分重要的作用. 目前肝移植尽管技术日趋成熟, 但是受到器官供体、费用及手术并发症等多种因素的限制, 因而不能很好的推广, 而且HRS患者经过长期的慢性疾病过程, 最后发展到肝肾功能衰竭期, 即使肝移植手术十分成功, 但其疗效仍要大打折扣. TIPS、MRAS及血管活性药物的使用等可以一定程度上改善HRS的肾功能, 也可以作为肝移植的辅助治疗措施, 为肝移植的成功开展创造条件, 但是这些治疗手段与肝移植技术一样, 仍然在不断的发展和完善中, 相信随着医学技术水平的不断提高, HRS的治疗效果还会有更大的提高.
编辑: N/A
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