Stringer Dominic, Gardner Leanne, Shaw Olivia, Clarke Brendan, Briggs David, Worthington Judith, Buckland Matthew, Danzi Guilherme, Hilton Rachel, Picton Michael, Thuraisingham Raj, Borrows Richard, Baker Richard, McCullough Keith, Stoves John, Phanish Mysore, Shah Sapna, Shiu Kin Yee, Walsh Stephen B, Ahmed Aimun, Ayub Waqar, Hegarty Janet, Tinch-Taylor Rose, Georgiou Evangelos, Bidad Natalie, Kılıç Ayşenur, Moon Zoe, Horne Robert, McCrone Paul, Kelly Joanna, Murphy Caroline, Peacock Janet, Dorling Anthony
Biostatistics and Health Informatics, The Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK.
King's Clinical Trials Unit, King's College London, London, UK.
EClinicalMedicine. 2023 Jan 12;56:101819. doi: 10.1016/j.eclinm.2022.101819. eCollection 2023 Feb.
3% of kidney transplant recipients return to dialysis annually upon allograft failure. Development of antibodies (Ab) against human leukocyte antigens (HLA) is a validated prognostic biomarker of allograft failure. We tested whether screening for HLA Ab, combined with an intervention to improve adherence and optimization of immunosuppression could prevent allograft failure.
Prospective, open-labelled randomised biomarker-based strategy (hybrid) trial in 13 UK transplant centres [EudraCT (2012-004308-36) and ISRCTN (46157828)]. Patients were randomly allocated (1:1) to unblinded or double-blinded arms and screened every 8 months. Unblinded HLA Ab+ patients were interviewed to encourage medication adherence and had tailored optimisation of Tacrolimus, Mycophenolate mofetil and Prednisolone. The primary outcome was time to graft failure in an intention to treat analysis. The trial had 80% power to detect a hazard ratio of 0.49 in donor specific antibody (DSA)+ patients.
From 11/9/13 to 27/10/16, 5519 were screened for eligibility and 2037 randomised (1028 to unblinded care and 1009 to double blinded care). We identified 198 with DSA and 818 with non-DSA. Development of DSA, but not non-DSA was predictive of graft failure. HRs for graft failure in unblinded DSA+ and non-DSA+ groups were 1.54 (95% CI: 0.72 to 3.30) and 0.97 (0.54-1.74) respectively, providing no evidence of an intervention effect. Non-inferiority for the overall unblinded versus blinded comparison was not demonstrated as the upper confidence limit of the HR for graft failure exceeded 1.4 (1.02, 95% CI: 0.72 to 1.44). The only secondary endpoint reduced in the unblinded arm was biopsy-proven rejection.
Intervention to improve adherence and optimize immunosuppression does not delay failure of renal transplants after development of DSA. Whilst DSA predicts increased risk of allograft failure, novel interventions are needed before screening can be used to direct therapy.
The National Institute for Health Research Efficacy and Mechanism Evaluation programme grant (ref 11/100/34).
每年有3%的肾移植受者在移植肾失功后重新开始透析。抗人类白细胞抗原（HLA）抗体（Ab）的产生是已得到验证的移植肾失功的预后生物标志物。我们测试了筛查HLA抗体并联合改善依从性及优化免疫抑制的干预措施是否能预防移植肾失功。
在英国13个移植中心进行的前瞻性、开放标签、基于生物标志物的随机策略（混合）试验[欧洲临床试验注册号（EudraCT）（2012-004308-36）及国际标准随机对照试验编号（ISRCTN）（46157828）]。患者被随机分配（1:1）至非盲或双盲组，每8个月进行一次筛查。对非盲的HLA Ab+患者进行访谈以鼓励药物依从性，并对他克莫司、霉酚酸酯和泼尼松龙进行个体化优化。意向性分析的主要结局是移植肾失功时间。该试验有80%的把握度检测供者特异性抗体（DSA）+患者中风险比为0.49的情况。
从2013年9月11日至2016年10月27日，5519人接受了资格筛查，2037人被随机分组（1028人接受非盲治疗，1009人接受双盲治疗）。我们识别出198例DSA阳性患者和818例非DSA阳性患者。DSA的产生而非非DSA可预测移植肾失功。非盲DSA+组和非DSA+组移植肾失功的风险比分别为1.54（95%置信区间：0.72至3.30）和0.97（0.54 - 1.74），未提供干预效果的证据。未证明总体非盲组与双盲组比较的非劣效性，因为移植肾失功风险比的置信区间上限超过了1.4（1.02，95%置信区间：0.72至1.44）。非盲组中唯一降低的次要终点是活检证实的排斥反应。
在DSA产生后，改善依从性及优化免疫抑制的干预措施并不能延缓肾移植失败。虽然DSA可预测移植肾失功风险增加，但在筛查可用于指导治疗之前，还需要新的干预措施。
英国国家卫生研究院疗效与机制评估计划基金（编号11/100/34）
