OBJECTIVE To develop and validate an integrative system to predict long term kidney allograft failure. DESIGN International cohort study. SETTING Three cohorts including kidney transplant recipients from 10 academic medical centres from Europe and the United States. PARTICIPANTS Derivation cohort: 4000 consecutive kidney recipients prospectively recruited in four French centres between 2005 and 2014. Validation cohorts: 2129 kidney recipients from three centres in Europe and 1428 from three centres in North America, recruited between 2002 and 2014. Additional validation in three randomised controlled trials (NCT01079143, EudraCT 2007-003213-13, and NCT01873157). MAIN OUTCOME MEASURE Allograft failure (return to dialysis or pre-emptive retransplantation). 32 candidate prognostic factors for kidney allograft survival were assessed. RESULTS Among the 7557 kidney transplant recipients included, 1067 (14.1%) allografts failed after a median post-transplant follow-up time of 7.12 (interquartile range 3.51-8.77) years. In the derivation cohort, eight functional, histological, and immunological prognostic factors were independently associated with allograft failure and were then combined into a risk prediction score (iBox). This score showed accurate calibration and discrimination (C index 0.81, 95% confidence interval 0.79 to 0.83). The performance of the iBox was also confirmed in the validation cohorts from Europe (C index 0.81, 0.78 to 0.84) and the US (0.80, 0.76 to 0.84). The iBox system showed accuracy when assessed at different times of evaluation post-transplant, was validated in different clinical scenarios including type of immunosuppressive regimen used and response to rejection therapy, and outperformed previous risk prediction scores as well as a risk score based solely on functional parameters including estimated glomerular filtration rate and proteinuria. Finally, the accuracy of the iBox risk score in predicting long term allograft loss was confirmed in the three randomised controlled trials. CONCLUSION An integrative, accurate, and readily implementable risk prediction score for kidney allograft failure has been developed, which shows generalisability across centres worldwide and common clinical scenarios. The iBox risk prediction score may help to guide monitoring of patients and further improve the design and development of a valid and early surrogate endpoint for clinical trials. TRIAL REGISTRATION Clinicaltrials.gov NCT03474003.

中文翻译：

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接受肾移植患者同种异体移植物丢失风险的预测系统：国际推导和验证研究。


目的 开发并验证预测长期同种异体肾移植衰竭的综合系统。设计国际队列研究。设置 三个队列，包括来自欧洲和美国 10 个学术医疗中心的肾移植受者。参与者 派生队列：2005 年至 2014 年间在四个法国中心前瞻性招募的 4000 名连续肾接受者。验证队列：2002 年至 2014 年间招募的来自欧洲三个中心的 2129 名肾接受者和来自北美三个中心的 1428 名肾接受者。在三个随机中进行的额外验证对照试验（NCT01079143、EudraCT 2007-003213-13 和 NCT01873157）。主要观察指标 同种异体移植失败（返回透析或先发性再移植）。评估了同种异体肾移植存活的 32 个候选预后因素。结果 在 7557 名肾移植受者中，有 1067 名（14.1%）同种异体移植在中位移植后随访时间为 7.12 年（四分位数间距 3.51-8.77）后失败。在衍生队列中，八个功能、组织学和免疫学预后因素与同种异体移植失败独立相关，然后合并为风险预测评分 (iBox)。该分数显示了准确的校准和区分（C 指数 0.81，95% 置信区间 0.79 至 0.83）。 iBox 的性能也在欧洲（C 指数 0.81、0.78 至 0.84）和美国（0.80、0.76 至 0.84）的验证队列中得到证实。 iBox 系统在移植后评估的不同时间进行评估时显示出准确性，并在不同的临床场景中进行了验证，包括使用的免疫抑制方案类型和对排斥治疗的反应，并且优于之前的风险预测评分以及仅基于功能的风险评分参数包括估计的肾小球滤过率和蛋白尿。最后，三项随机对照试验证实了 iBox 风险评分在预测长期同种异体移植丢失方面的准确性。结论 已经开发出一种综合、准确且易于实施的同种异体肾移植失败风险预测评分，该评分显示了全球各中心和常见临床情况的通用性。 iBox 风险预测评分可能有助于指导患者监测，并进一步改进临床试验有效的早期替代终点的设计和开发。试验注册 ClinicalTrials.gov NCT03474003。