Transplantation Center , Department of Medicine , Lausanne University Hospital and University of Lausanne , Lausanne , Switzerland.
Service of Nephrology and Hypertension, Department of Medicine , Lausanne University Hospital and University of Lausanne , Lausanne , Switzerland.
J Am Soc Nephrol. 2023 Nov 1;34(11):1776-1792. doi: 10.1681/ASN.0000000000000192. Epub 2023 Jul 13.
The complement system is paramount in the clearance of pathogens and cell debris, yet is increasingly recognized as a key component in several pathways leading to allograft injury. There is thus a growing interest in new biomarkers to assess complement activation and guide tailored therapies after kidney transplantation (KTx). C5 blockade has revolutionized post-transplant management of atypical hemolytic uremic syndrome, a paradigm of complement-driven disease. Similarly, new drugs targeting the complement amplification loop hold much promise in the treatment and prevention of recurrence of C3 glomerulopathy. Although unduly activation of the complement pathway has been described after brain death and ischemia reperfusion, any clinical attempts to mitigate the ensuing renal insults have so far provided mixed results. However, the intervention timing, strategy, and type of complement blocker need to be optimized in these settings. Furthermore, the fast-moving field of ex vivo organ perfusion technology opens new avenues to deliver complement-targeted drugs to kidney allografts with limited iatrogenic risks. Complement plays also a key role in the pathogenesis of donor-specific ABO- and HLA-targeted alloantibodies. However, C5 blockade failed overall to improve outcomes in highly sensitized patients and prevent the progression to chronic antibody-mediated rejection (ABMR). Similarly, well-conducted studies with C1 inhibitors in sensitized recipients yielded disappointing results so far, in part, because of subtherapeutic dosage used in clinical studies. The emergence of new complement blockers raises hope to significantly reduce the negative effect of ischemia reperfusion, ABMR, and nephropathy recurrence on outcomes after KTx.
补体系统在清除病原体和细胞碎片方面至关重要，但越来越多的研究表明，它也是导致同种异体移植物损伤的几个途径的关键组成部分。因此，人们越来越关注新的生物标志物来评估补体激活，并在肾移植（KTx）后指导个体化治疗。C5 阻断剂已经彻底改变了移植后非典型溶血性尿毒症综合征的治疗管理，这是非典型补体驱动疾病的一个范例。同样，针对补体扩增环的新药在治疗和预防 C3 肾小球病的复发方面也有很大的应用前景。尽管在脑死亡和缺血再灌注后描述了补体途径的过度激活，但迄今为止，任何减轻由此产生的肾损伤的临床尝试都提供了混合的结果。然而，在这些情况下，干预时机、策略和补体阻滞剂的类型需要进行优化。此外，离体器官灌注技术的快速发展为将靶向补体的药物递送至肾移植提供了新的途径，风险有限。补体在供体特异性 ABO 和 HLA 靶向同种抗体的发病机制中也起着关键作用。然而，C5 阻断剂总体上未能改善高致敏患者的结局，也未能预防进展为慢性抗体介导的排斥反应（ABMR）。同样，在致敏受者中进行的 C1 抑制剂的良好研究迄今为止也没有令人满意的结果，部分原因是临床研究中使用的治疗剂量不足。新的补体阻滞剂的出现有望显著降低缺血再灌注、ABMR 和肾病复发对 KTx 后结局的负面影响。
