Using minimal Factor H therapy and normothermic conditions to prepare kidneys for transplantation

肾移植是治疗肾衰竭的金标准。然而，器官的供应在数量和质量上都是有限的。这就需要在供者死亡后或与风险增加有关的非最佳供者捐献的肾脏进行移植。这些肾脏与移植后长时间无足够的氧气供应和细胞损伤增加有关，导致器官损伤立即增加。这可能会缩短肾脏的长期存活期，并导致患者需要再次移植，从而加剧器官短缺危机。我们已经开发了一种新的抗补体疗法，基于一种叫做因子H的血液防御蛋白及其相关蛋白之一。我们的药物叫做HDM-FH（同型二聚体最小因子H）。HDM-FH已被发现在实验性啮齿动物肾脏疾病模型中非常有效。HDM-FH在移植中应该有明确的用途。正常情况下，补体系统可以抵御入侵的病原体，并帮助清除体内的细胞废物。然而，补体会变得过于活跃，从而引发炎症。在移植中，移植器官可以被检测为非自体（如病原体），补体的激活可导致器官排斥。由于补体激活触发了复杂的过程，这种排斥反应可以立即发生，也可以持续数年。因此，在移植的最初几分钟内防止补体激活和相关的细胞/器官损伤将显著延长移植器官的存活时间和移植受体的健康。在纽卡斯尔，我们正在研究通过一种称为体外恒温机器灌注（简称EVNP）的技术来改善肾脏功能的方法，即，在器官移植之前，将用于移植的器官在实验室中用含氧血流预热，并允许其从医院之间运输的休克中恢复过来（在没有氧气的冷液体中）。EVNP在修复那些可能被认为不适合移植的器官方面显示出了希望。我们的计划是通过使用该系统将我们的抗补体药物引入肾脏，在那里它可以结合并等待器官移植到受体体内，从而进一步改善EVNP后移植器官的预后。移植后，HDM-FH将作为器官防御受者的免疫系统。在这项研究中，我们将模拟人类（被丢弃的人类肾脏——被移植外科医生认为不适合移植）和猪肾脏（大小与人类相似，很容易从农场生产中获得）对药物的暴露，并评估在EVNP过程中它与器官的结合程度。然后，我们将在实验室中使用EVNP系统中的全血来模拟，我们是否可以在器官上显示补体激活以及我们的药物是否可以逆转这种激活。在这些实验成功完成后，我们将使用猪肾的EVNP并将其移植到少量猪（最多12头）中，以尽可能稳健的方式测试我们的药物。这些猪移植实验（结合猪肾脏EVNP的现有数据）将为我们的抗补体药物在整个动物系统中保护肾脏的能力提供重要证据。我们将能够评估药物的安全性和使用过程中发生的任何意外事件。这些研究将指导我们在人体移植研究中测试这些药物的步骤。此外，这些药物在保护肾脏免受补体影响方面的成功可能会导致在其他需要控制补体的情况下使用这些药物，例如罕见的肾脏疾病C3G。总的来说，这项研究旨在提高器官移植的成功率，即使是那些被认为不适合移植的器官。它最终将为成千上万等待肾脏移植的人带来巨大的好处。

Kidney transplant is the gold-standard treatment for patients with renal failure. However, the supply of organs is limited in number and quality. This has necessitated the transplantation of kidneys from donation after the donors death or from non-optimal donors that are associated with increased risks. These kidneys are associated with prolonged times without adequate oxygen supply and increased cellular damage resulting in increased organ injury immediately after transplant. This can shorten the long-term survival of the kidney and result in patients requiring another transplant, compounding the organ shortage crisis.We have developed a novel anti-complement therapy based on a blood defence protein called factor H and one of its related proteins. Our drug is called HDM-FH (homodimeric minimal factor H). HDM-FH has been found to be highly effective in experimental rodent models of kidney disease. HDM-FH should have a clear use in transplantation. The complement system normally protects against invading pathogens and helps to clear cellular waste in our bodies. However, complement can become over active and it drives inflammation. In transplantation, the transplanted organ can be detected as non-self (like a pathogen) and activation of complement can lead to organ rejection. This rejection can be immediate or can take years due to complex processes that are triggered by the complement activation. Thus, preventing complement activation and associated cellular/organ injury during the first minutes of transplantation will significantly prolong the survival of transplanted organ and the well being of the transplant recipient. In Newcastle, we are working on methods to improve the function of kidney through a technique call ex vivo normothermic machine perfusion (EVNP for short), i.e. organs destined for transplant are warmed up with oxygenated blood flow in the lab and allowed to recover from the shock of being transported between hospitals (in cold liquids with no oxygen) prior to organ transplant. EVNP has shown promise in the re-conditioning of organs that might otherwise have been deemed unfit for transplant. Our plan is to try to further improve the outcome of transplanted organs after EVNP by using this system to introduce our anti-complement drug to the kidney, where it can bind and wait until the organ is transplanted into the recipient. Upon transplant, HDM-FH will then act as an organ defence against the recipients immune system. In this study, we will model exposure of human (discarded human kidneys - deemed unfit for transplant by transplant surgeons) and pig kidney (similar size etc to human, readily available from farm production) to the drug and assess how well it remains bound to the organ during EVNP. We will then model, by using whole blood in the EVNP system in the lab, whether we can show complement activation on the organ and that our drug can reverse that. After the successful completion of these experiments, we would use EVNP of pig kidney and transplantation into a small number of pigs (up to 12) to test our drugs in as robust a fashion as possible. These pig transplant experiments (in conjunction with existing data on pig kidney EVNP) would provide important evidence of the ability of our anti-complement drug to protect kidney in a whole animal system. We will be able to assess safety of the drug and any unexpected events with its use. These studies would guide us in the steps to testing these drugs in human transplant studies. Additionally, the success of these drugs in protecting kidneys from complement could lead to the use of the drugs in other situations where complement needs to be controlled, such as the rare kidney disease, C3G.Overall, this research is designed to lead to better organ transplant success, even from organs which are considered borderline for transplant. It will eventually be of significant benefit to the many thousands of people waiting on a renal transplant.