Meier Raphael P H, Pierson Richard N, Fishman Jay A, Buhler Leo H, Bottino Rita, Ladowski Joseph M, Ekser Burcin, Wolf Eckhard, Brenner Paolo, Ierino Francesco, Mohiuddin Muhammad, Cooper David K C, Hawthorne Wayne J
Department of Surgery, University of Maryland School of, Medicine, Baltimore, Maryland, USA.
Division of Cardiac Surgery and Center for Transplantation Sciences, Department of Surgery, Massachusetts General Hospital, Boston, Massachusetts, USA.
Xenotransplantation. 2025 Mar-Apr;32(2):e70003. doi: 10.1111/xen.70003.
Porcine kidney xenotransplantation for end-stage renal disease (ESRD) has reached the stage of clinical testing following major advances in donor pig genetic modifications and effective immunosuppressive strategies through decades of rigorous translational research. Reports of pig kidney xenograft survival beyond 1 year posttranplant in nonhuman primate (NHP) models justify optimism for its potential as an alternative to allotransplantation. In the United States, experimental transplantations of genetically engineered (GE) porcine kidneys into brain-dead subjects and a small number of ESRD patients have shown no evidence of hyperacute rejection and adequate pig kidney function for up to several months. Here we discuss pre-clinical/clinical results, infectious disease, ethical, and regulatory considerations, and propose evidence-based recommendations. For initial clinical trials in kidney xenotransplantation, we make the following recommendations: (i) transplantation with organs from a triple knockout (TKO) donor pig, preferably with added human transgenes, (ii) an immunosuppressive regimen with induction therapy to deplete T (and possibly B) cells, and maintenance therapy based on a cluster of differentiation (CD)40/CD154 co-stimulation pathway blockade, (iii) the patient should be fully acceptable as a candidate for allotransplantation but should be unlikely ever to receive an allograft. Patients aged 60-69 years (extendable to 40-75 years, if one of the criteria mentioned below is present), of blood group B or O, and with diabetes are most at risk in this regard. Other patients who could be considered are (i) those who have lost two or more previous kidney allografts from recurrent disease in the graft, (ii) those with broad human leukocyte antigen (HLA)-reactivity but no evidence of anti-pig antibodies, including swine leukocyte antigen (SLA), and (iii) those with failing vascular access. Clinical pilot studies in carefully and highly selected patients with no alternative therapy will provide the foundation upon which to base subsequent formal expanded clinical trials.
经过数十年严格的转化研究，在供体猪基因改造和有效的免疫抑制策略方面取得重大进展后，用于终末期肾病（ESRD）的猪肾异种移植已进入临床试验阶段。在非人灵长类动物（NHP）模型中，猪肾异种移植术后存活超过1年的报告为其作为同种异体移植替代方案的潜力带来了乐观前景。在美国，将基因工程（GE）猪肾移植到脑死亡受试者和少数ESRD患者体内的实验表明，长达数月均未出现超急性排斥反应，且猪肾功能良好。在此，我们讨论临床前/临床结果、传染病、伦理和监管方面的考虑因素，并提出基于证据的建议。对于肾异种移植的初始临床试验，我们提出以下建议：（i）使用来自三基因敲除（TKO）供体猪的器官进行移植，最好添加人类转基因；（ii）采用诱导疗法耗尽T（可能还有B）细胞的免疫抑制方案，并基于分化簇（CD）40/CD154共刺激途径阻断进行维持治疗；（iii）患者应完全符合同种异体移植候选标准，但不太可能接受同种异体移植。60 - 69岁（如果存在以下提及的标准之一，可扩展至40 - 75岁）、血型为B或O且患有糖尿病的患者在这方面风险最高。其他可考虑的患者包括：（i）因移植肾复发疾病而失去两个或更多先前同种异体肾移植的患者；（ii）具有广泛人类白细胞抗原（HLA）反应性但无抗猪抗体（包括猪白细胞抗原（SLA））证据的患者；（iii）血管通路功能衰竭的患者。在没有替代疗法的经过仔细和严格挑选的患者中进行临床试点研究，将为后续正式的扩大临床试验奠定基础。
