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Development of bio-artificial kidney

生物人工肾的研制

基本信息

批准号：
16591270
负责人：
FUJIMURA Akio
金额：
$ 1.98万
依托单位：
JICHI MEDICAL UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2004
资助国家：
日本
起止时间：
2004 至 2006
项目状态：
已结题

项目摘要

Anionic middle molecule uremic toxins, which can not be removed by conventional hemodialysis, play major role for progress of arteriosclerosis in patients with chronic renal failure. Most of the toxins, such as indoxyl sulfate, is secreted via organic anion transporter-3 (OAT-3) in proximal tubule cells in healthy subjects. To develop a novel hybrid artificial kidney, where the proximal tubular cells over-expressing OAT-3 are cultured on hollow fibers, we performed following experiments.1) We established cultured proximal tubule cells over-expressing OAT-3. We confirmed higher transport of indoxyl sulfate in the cells and also higher expression of the protein by Western blot and immuno-histochemistry.2) We succeeded to seed the cells onto hollowfiber modules, which we previously reported.3) We found higher selective removal of indoxyl sulfate by the system in vitro. The clearance of indoxyl sulfate was 38 ml/min/m2, which was 8-times higher than that with control cells.4) We also applied this system to dogs with or without renal failure. We found high removal capacity of indoxyl sulfate from circulating blood of renal failure dog with a few adverse reactions.Thus, we succeeded to develop a novel hybrid artificial kidney with proximal tubular cells over-expressing OAT-3. This system may be useful to remove uremic toxins which can not be removed by conventional hemodialysis.

阴离子中分子尿毒症毒素在慢性肾功能衰竭患者动脉硬化的发展中起着重要作用，而传统血液透析无法清除这种毒素。大多数毒素，如硫酸吲哚酚，是通过有机阴离子转运蛋白-3 （OAT-3）在健康人体近端小管细胞分泌的。为了开发一种新型杂交人工肾脏，我们在中空纤维上培养过表达OAT-3的近端小管细胞，进行了以下实验。1)建立过表达OAT-3的近端小管细胞。Western blot和免疫组化分析证实，硫酸吲哚酚在细胞内的转运量增加，表达量增加。2)我们成功地将细胞植入中空纤维模块，这是我们之前报道过的。3)该体系对硫酸吲哚酚具有较高的体外选择性去除效果。对硫酸吲哚酚的清除率为38 ml/min/m2，是对照细胞的8倍。4)我们还将该系统应用于有或没有肾衰竭的狗。我们发现，在肾功能衰竭犬的循环血液中，吲哚酚硫酸盐有很高的去除能力，而且不良反应少。因此，我们成功地开发了一种具有近端小管细胞过表达OAT-3的新型杂交人工肾。该系统可用于去除常规血液透析不能去除的尿毒症毒素。