Improved Renal Preservation

描述（由申请人提供）：拟议研究的最终目的是通过延长安全储存时间和改善任何给定储存期后的结果，在移植前大幅度改善人体肾脏的保存。该提案将建立在现有结果的基础上，表明21世纪医学公司开发的一种新的肾脏保存液（Renasol）在犬和麻素肾移植模型中都优于行业标准UW溶液。该提案将探索Renasol和一种特殊的新配方蛋白质因子（“营养因子”）的组合，这种组合可以显着改善狗肾脏的低温储存。利用兔肾移植模型，将获得更多关于营养因子适宜浓度的信息。还将评估一种有潜在价值的Renasol添加剂，该添加剂可能有助于保护人类肾脏免受急性低血压的影响。犬肾移植也将使用单纯冷藏保存4天的肾，并使用Renasol和Renasol +营养因子。为了预期临床应用，以及由此产生的稳定性要求，将使用犬和麻素模型进行测试，以显示Renasol在4℃下预先储存数月后仍保持其有效性。这些研究将产生最终配方，将在II期进行人体临床试验，并在i期上市。在拟议的研究过程中，尿液样本将被常规收集，并使用内部蛋白质组学工作站进行蛋白质分析。这些观察结果将确定观察到的低温损伤程度是否与尿蛋白浓度的可定义的相对或绝对变化相关。这可能为肾保存性损伤提供一种新的预测诊断指标。在移植前保留肾脏损伤较小的能力将显著降低移植后透析的成本和风险，减少排斥事件，并增加净器官供应。

DESCRIPTION (provided by applicant): The ultimate aim of the proposed research is to enable a substantial improvement in human kidney preservation prior to transplantation by extending the safe storage time and improving outcomes after any given period of storage. This proposal will build upon existing results indicating that a new renal preservation solution developed at 21st Century Medicine (Renasol) is superior to the industry standard, UW solution, in both canine and leporine renal transplant models. The proposal will explore a combination of Renasol and a specific new formulation of protein factors ("trophic factors") that dramatically improve hypothermic storage of dog kidneys. More information will be obtained on the appropriate concentration of trophic factors using the rabbit renal transplant model. A potentially valuable additive for Renasol that may help protect human kidneys from the effects of agonal hypotension will also be evaluated. Canine renal transplants will also be performed using kidneys preserved by simple cold storage for 4 days with Renasol and with Renasol + trophic factors. In anticipation of clinical application, and resulting stability requirements, tests will be conducted, using both the canine and leporine models, to show Renasol retains its effectiveness after months of prior storage at 4 deg. C. These studies will result in a final formulation that will be taken into human clinical trials in Phase II and marketed in Phase Ill. During the course of the proposed studies, urine samples will be collected on a routine basis and subjected to protein profiling using an in-house proteomics workstation. These observations will determine whether the degree of hypothermic injury observed is correlated with definable relative or absolute changes in urinary protein concentrations. This may provide a new predictive diagnostic marker of renal preservation injury. The ability to preserve kidneys with less damage prior to transplantation will significantly reduce the costs and risks of post-transplant dialysis, reduce rejection episodes, and increase the net organ supply.