Nobakht Ehsan, Jagadeesan Muralidharan, Paul Rohan, Bromberg Jonathan, Dadgar Sherry
Division of Renal Diseases and Hypertension, Department of Medicine, George Washington University School of Medicine, Washington, DC.
Department of Surgery, University of Maryland School of Medicine, Baltimore, MD.
Transplant Direct. 2021 Jan 7;7(2):e650. doi: 10.1097/TXD.0000000000001102. eCollection 2021 Feb.
Desirable outcomes including rejection- and infection-free kidney transplantation are not guaranteed despite current strategies for immunosuppression and using prophylactic antimicrobial medications. Graft survival depends on factors beyond human leukocyte antigen matching such as the level of immunosuppression, infections, and management of other comorbidities. Risk stratification of transplant patients based on predisposing genetic modifiers and applying precision pharmacotherapy may help improving the transplant outcomes. Unlike certain fields such as oncology in which consistent attempts are being carried out to move away from the "error and trial approach," transplant medicine is lagging behind in implementing personalized immunosuppressive therapy. The need for maintaining a precarious balance between underimmunosuppression and overimmunosuppression coupled with adverse effects of medications calls for a gene-based guidance for precision pharmacotherapy in transplantation. Technologic advances in molecular genetics have led to increased accessibility of genetic tests at a reduced cost and have set the stage for widespread use of gene-based therapies in clinical care. Evidence-based guidelines available for precision pharmacotherapy have been proposed, including guidelines from Clinical Pharmacogenetics Implementation Consortium, the Pharmacogenomics Knowledge Base National Institute of General Medical Sciences of the National Institutes of Health, and the US Food and Drug Administration. In this review, we discuss the implications of pharmacogenetics and potential role for genetic variants-based risk stratification in kidney transplantation. A single score that provides overall genetic risk, a polygenic risk score, can be achieved by combining of allograft rejection/loss-associated variants carried by an individual and integrated into practice after clinical validation.
尽管目前采用了免疫抑制策略并使用预防性抗菌药物，但包括无排斥反应和无感染的肾脏移植在内的理想结果仍无法得到保证。移植物存活取决于人类白细胞抗原匹配之外的因素，如免疫抑制水平、感染以及其他合并症的管理。基于易感基因修饰因子对移植患者进行风险分层并应用精准药物治疗可能有助于改善移植结果。与肿瘤学等某些领域不断尝试摆脱“试错法”不同，移植医学在实施个性化免疫抑制治疗方面滞后。在免疫抑制不足和过度免疫抑制之间维持不稳定平衡的必要性，再加上药物的不良反应，要求在移植中基于基因进行精准药物治疗指导。分子遗传学的技术进步使得基因检测的可及性提高且成本降低，并为基因疗法在临床护理中的广泛应用奠定了基础。已经提出了基于证据的精准药物治疗指南，包括临床药物基因组学实施联盟、美国国立卫生研究院国家综合医学科学研究所的药物基因组学知识库以及美国食品药品监督管理局的指南。在本综述中，我们讨论了药物遗传学的意义以及基于基因变异的风险分层在肾脏移植中的潜在作用。通过将个体携带的同种异体移植排斥/丢失相关变异进行组合，并在临床验证后整合到实践中，可以得到一个提供总体遗传风险的单一评分，即多基因风险评分。
