Supplementary Material for: The Role of Angiopoietins in Cardiovascular Outcomes of Kidney Transplant Recipients- An Ancillary Study From the FAVORIT

Introduction: Kidney transplant recipients (KTRs) have increased risk of cardiovascular disease (CVD) mortality. We investigated vascular biomarkers, angiopoietin-1 and angiopoietin-2 (angpt-1, -2), in CVD development in KTRs. Methods: This ancillary study from the FAVORIT, evaluates the associations of baseline plasma angpt-1,-2 levels in CVD development (primary outcome) and graft failure (GF) and death (secondary outcomes) in 2000 deceased donor KTRs. We used Cox regression to analyze the association of biomarker quartiles with outcomes. We adjusted for demographic, CVD and transplant-related variables; medications; urine albumin-to-creatinine ratio and randomization status. We calculated areas under the curves (AUC) to predict CVD or death, and GF or death by incorporating biomarkers alongside clinical variables. Results: Participants’ median age was 52 IQR [45, 59] years: with 37% women and 73% identifying as white. Median time from transplantation was 3.99 IQR [1.58, 7.93] years and to CVD development was 2.54 IQR [1.11-3.80] years. Quartiles of angpt-1 were not associated with outcomes. Whereas higher levels of angpt-2 (quartile 4) were associated with about 2 times the risk of CVD, GF and death [aHR 1.85 (1.25 - 2.73), P<.01; 2.24 (1.36 - 3.70), P<.01; 2.30 (1.48 - 3.58), P<.01, respectively] as compared to quartile 1. Adding angiopoietins to pre-existing clinical variables improved prediction of CVD or death (AUC improved from 0.70 to 0.72, P=0.005) and GF or death (AUC improved from 0.68 to 0.70, P =0.005). Angpt-2 may partially explain the increased risk of future CVD in KTRs. Further research is needed to assess the utility of using angiopoietins in the clinical care of KTRs. Conclusion: Angpt-2 may be a useful prognostic tool for future CVD in KTRs. Combining angiopoietins with clinical markers may tailor follow-up to mitigate CVD risk.

研究背景：肾移植受者（kidney transplant recipients, KTRs）发生心血管疾病（cardiovascular disease, CVD）相关死亡的风险显著升高。本研究针对肾移植受者中心血管疾病的发生发展，探讨了血管生物标志物血管生成素-1与血管生成素-2（angiopoietin-1 and angiopoietin-2, angpt-1、angpt-2）的相关作用。
研究方法：本研究为FAVORIT研究的附属分析，纳入2000例尸体供肾肾移植受者，评估基线血浆angpt-1、angpt-2水平与心血管疾病发生（主要终点）、移植肾功能失功（graft failure, GF）及死亡（次要终点）的关联。本研究采用Cox回归分析生物标志物四分位水平与各研究终点的关联，并校正了人口学特征、心血管疾病及移植相关变量、用药情况、尿白蛋白/肌酐比值与随机分组状态等混杂因素。此外，本研究通过将生物标志物与临床变量相结合，计算曲线下面积（areas under the curves, AUC）以预测心血管疾病或死亡、移植肾功能失功或死亡的发生风险。
研究结果：研究对象的中位年龄为52岁，四分位间距（interquartile range, IQR）为45~59岁；其中女性占比37%，白人占比73%。从肾移植至研究随访的中位时间为3.99年，四分位间距为1.58~7.93年；从肾移植至心血管疾病发生的中位时间为2.54年，四分位间距为1.11~3.80年。angpt-1的四分位水平与各研究终点均无显著关联。与之相反，与第1四分位组相比，angpt-2高水平组（第4四分位组）的心血管疾病、移植肾功能失功及死亡风险均升高约2倍[校正后风险比（adjusted hazard ratio, aHR）分别为1.85（95%置信区间：1.25~2.73），P<0.01；2.24（95%置信区间：1.36~3.70），P<0.01；2.30（95%置信区间：1.48~3.58），P<0.01]。在已有的临床变量基础上加入血管生成素类标志物，可提升心血管疾病或死亡、移植肾功能失功或死亡的预测效能：前者的曲线下面积从0.70提升至0.72（P=0.005），后者从0.68提升至0.70（P=0.005）。angpt-2或可部分解释肾移植受者未来发生心血管疾病的风险升高机制，未来仍需开展进一步研究以评估血管生成素类标志物在肾移植受者临床诊疗中的应用价值。
研究结论：angpt-2或可作为预测肾移植受者未来发生心血管疾病的有效预后工具。将血管生成素类标志物与临床指标相结合，可制定个体化随访方案以降低肾移植受者的心血管疾病风险。