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

肾移植是治疗肾功能衰竭患者的黄金标准。然而，器官的供应在数量和质量上都是有限的。这就需要在捐赠者死亡后捐献的肾脏或来自风险增加的非最佳捐赠者的肾脏进行移植。这些肾脏与长时间缺乏足够的氧气供应和细胞损伤增加有关，从而导致移植后立即增加器官损伤。这可能会缩短肾脏的长期存活时间，导致患者需要再次移植，加剧器官短缺的危机。我们开发了一种新的抗补体疗法，该疗法基于一种名为因子H的血液防御蛋白及其相关蛋白之一。我们的药物被称为HDM-FH(同源二聚体最小因子H)。HDM-FH在实验性肾脏疾病啮齿动物模型中被发现是非常有效的。HDM-FH在移植中应该有明确的用途。补体系统通常可以抵御入侵的病原体，并有助于清除体内的细胞废物。然而，补体可能会变得过于活跃，从而引发炎症。在移植中，移植的器官可被检测为异体(如病原体)，而补体的激活可导致器官排斥。这种排斥反应可能是即时的，也可能需要数年时间，因为补体激活会触发复杂的过程。因此，在移植的最初几分钟内预防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者的健康。在纽卡斯尔，我们正在研究通过一种名为体外常温机器灌流(简称EVNP)的技术来改善肾脏功能的方法，即在实验室中，将用于移植的器官用含氧血液加热，并允许在器官移植前在医院之间运输(在没有氧气的冷液中)时的休克恢复。EVNP在重新调整原本可能被认为不适合移植的器官方面显示出了希望。我们的计划是试图通过使用这个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者体内，从而进一步改善EVNP后器官移植的结果。在移植后，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(废弃的人肾-被移植外科医生认为不适合移植)和猪肾(大小等与人类相似，可从农场生产中获得)对药物的暴露，并评估在EVNP期间它与器官的结合情况。然后，我们将在实验室通过使用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一点。在成功完成这些实验后，我们将使用猪肾脏的EVNP并将其移植到少量猪(最多12头)中，以尽可能强大的方式测试我们的药物。这些猪移植实验(结合现有的猪肾脏EVNP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任何与其使用相关的意外事件。这些研究将指导我们在人体移植研究中测试这些药物。此外，这些药物在保护肾脏免受补体影响方面的成功，可能会导致这些药物在其他需要控制补体的情况下使用，比如罕见的肾脏疾病C3G。总体而言，这项研究旨在带来更好的器官移植成功，即使是来自被认为濒临移植的器官。这最终将使成千上万等待肾移植的人受益匪浅。

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.