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保存时间和在任何给定的保存时间后改善结果，使移植前的人类肾脏保存得到实质性的改善。这项建议将建立在现有结果的基础上，这些结果表明，21世纪医学公司(Renasol)开发的一种新的肾脏保存溶液在犬和Leporine肾移植模型中都优于行业标准UW溶液。该提案将探索雷纳索和一种特定的新蛋白质因子(“营养因子”)的组合，这种新配方可以显著改善狗肾脏的低温储存。使用兔肾移植模型，将获得更多关于营养因子的适当浓度的信息。雷纳索尔的一种潜在的有价值的添加剂也将被评估，该添加剂可能有助于保护人类肾脏免受过敏性低血压的影响。犬肾移植也将使用简单的冷冻保存4天的肾脏与Renasol和Renasol营养因子一起进行。根据临床应用的预期和由此产生的稳定性要求，将使用犬和Leporine模型进行测试，以证明雷纳索在先前4℃储存数月后仍具有有效性。C.这些研究将产生最终配方，该配方将在第二阶段进入人体临床试验，并在第三阶段上市。在拟议的研究过程中，将常规收集尿样，并使用内部蛋白质组学工作站进行蛋白质图谱分析。这些观察将确定所观察到的低温损伤的程度是否与尿蛋白浓度的可确定的相对或绝对变化相关。这可能为肾脏保存损伤的诊断提供一种新的预测指标。在移植前以较少的损伤保存肾脏的能力将显著降低移植后透析的成本和风险，减少排斥反应，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.