Division of Transplantation, Department of Surgery and
Division of Transplantation, Department of Surgery and.
J Am Soc Nephrol. 2020 Jan;31(1):12-21. doi: 10.1681/ASN.2019070651. Epub 2019 Dec 2.
Patients with ESKD who would benefit from a kidney transplant face a critical and continuing shortage of kidneys from deceased human donors. As a result, such patients wait a median of 3.9 years to receive a donor kidney, by which time approximately 35% of transplant candidates have died while waiting or have been removed from the waiting list. Those of blood group B or O may experience a significantly longer waiting period. This problem could be resolved if kidneys from genetically engineered pigs offered an alternative with an acceptable clinical outcome. Attempts to accomplish this have followed two major paths: deletion of pig xenoantigens, as well as insertion of "protective" human transgenes to counter the human immune response. Pigs with up to nine genetic manipulations are now available. In nonhuman primates, administering novel agents that block the CD40/CD154 costimulation pathway, such as an anti-CD40 mAb, suppresses the adaptive immune response, leading to pig kidney graft survival of many months without features of rejection (experiments were terminated for infectious complications). In the absence of innate and adaptive immune responses, the transplanted pig kidneys have generally displayed excellent function. A clinical trial is anticipated within 2 years. We suggest that it would be ethical to offer a pig kidney transplant to selected patients who have a life expectancy shorter than the time it would take for them to obtain a kidney from a deceased human donor. In the future, the pigs will also be genetically engineered to control the adaptive immune response, thus enabling exogenous immunosuppressive therapy to be significantly reduced or eliminated.
终末期肾病患者如果适合进行肾移植，他们将面临来自已故人类供体的肾脏严重且持续短缺的问题。因此，这些患者需要等待中位数为 3.9 年才能获得供体肾脏，而在此期间，大约 35%的移植候选者已经死亡或已从等待名单中移除。血型为 B 或 O 的患者可能会经历更长的等待时间。如果来自基因工程猪的肾脏提供了一种可接受的临床结果的替代方案，这个问题可能会得到解决。为了实现这一目标，人们已经尝试了两条主要途径：删除猪异种抗原，以及插入“保护性”人类转基因，以对抗人体免疫反应。现在已经有了多达九种基因改造的猪。在非人类灵长类动物中，给予新型药物来阻断 CD40/CD154 共刺激途径，如抗 CD40 mAb，可以抑制适应性免疫反应，导致猪肾移植物在没有排斥特征的情况下存活数月（由于感染并发症，实验已终止）。在没有先天和适应性免疫反应的情况下，移植的猪肾脏通常表现出优异的功能。预计在 2 年内将进行临床试验。我们建议，对于那些预期寿命短于从已故人类供体获得肾脏所需时间的选定患者，提供猪肾移植是合乎伦理的。在未来，这些猪还将进行基因工程改造，以控制适应性免疫反应，从而使外源性免疫抑制治疗显著减少或消除。
