Bloom Roy D, Bromberg Jonathan S, Poggio Emilio D, Bunnapradist Suphamai, Langone Anthony J, Sood Puneet, Matas Arthur J, Mehta Shikha, Mannon Roslyn B, Sharfuddin Asif, Fischbach Bernard, Narayanan Mohanram, Jordan Stanley C, Cohen David, Weir Matthew R, Hiller David, Prasad Preethi, Woodward Robert N, Grskovic Marica, Sninsky John J, Yee James P, Brennan Daniel C
Department of Medicine, University of Pennsylvania, Perelman School of Medicine and Penn Kidney Pancreas Transplant Program, Philadelphia, Pennsylvania.
Department of Surgery and Department of Microbiology and Immunology and.
J Am Soc Nephrol. 2017 Jul;28(7):2221-2232. doi: 10.1681/ASN.2016091034. Epub 2017 Mar 9.
Histologic analysis of the allograft biopsy specimen is the standard method used to differentiate rejection from other injury in kidney transplants. Donor-derived cell-free DNA (dd-cfDNA) is a noninvasive test of allograft injury that may enable more frequent, quantitative, and safer assessment of allograft rejection and injury status. To investigate this possibility, we prospectively collected blood specimens at scheduled intervals and at the time of clinically indicated biopsies. In 102 kidney recipients, we measured plasma levels of dd-cfDNA and correlated the levels with allograft rejection status ascertained by histology in 107 biopsy specimens. The dd-cfDNA level discriminated between biopsy specimens showing any rejection (T cell-mediated rejection or antibody-mediated rejection [ABMR]) and controls (no rejection histologically), <0.001 (receiver operating characteristic area under the curve [AUC], 0.74; 95% confidence interval [95% CI], 0.61 to 0.86). Positive and negative predictive values for active rejection at a cutoff of 1.0% dd-cfDNA were 61% and 84%, respectively. The AUC for discriminating ABMR from samples without ABMR was 0.87 (95% CI, 0.75 to 0.97). Positive and negative predictive values for ABMR at a cutoff of 1.0% dd-cfDNA were 44% and 96%, respectively. Median dd-cfDNA was 2.9% (ABMR), 1.2% (T cell-mediated types ≥IB), 0.2% (T cell-mediated type IA), and 0.3% in controls (=0.05 for T cell-mediated rejection types ≥IB versus controls). Thus, dd-cfDNA may be used to assess allograft rejection and injury; dd-cfDNA levels <1% reflect the absence of active rejection (T cell-mediated type ≥IB or ABMR) and levels >1% indicate a probability of active rejection.
同种异体移植活检标本的组织学分析是用于区分肾移植排斥反应与其他损伤的标准方法。供体来源的游离DNA（dd-cfDNA）是一种对同种异体移植损伤的非侵入性检测方法，它可能使对同种异体移植排斥反应和损伤状态的评估更加频繁、定量且安全。为了探究这种可能性，我们前瞻性地在预定时间间隔以及临床指示进行活检时采集血样。在102名肾移植受者中，我们测量了血浆中dd-cfDNA的水平，并将这些水平与107份活检标本中通过组织学确定的同种异体移植排斥反应状态相关联。dd-cfDNA水平在显示任何排斥反应（T细胞介导的排斥反应或抗体介导的排斥反应[ABMR]）的活检标本与对照组（组织学上无排斥反应）之间具有显著差异，P<0.001（曲线下面积[AUC]为0.74；95%置信区间[95%CI]为0.61至0.86）。dd-cfDNA水平为1.0%时，主动排斥反应的阳性预测值和阴性预测值分别为61%和84%。区分ABMR与无ABMR样本的AUC为0.87（95%CI为0.75至0.97）。dd-cfDNA水平为1.0%时，ABMR的阳性预测值和阴性预测值分别为44%和96%。dd-cfDNA的中位数在ABMR组为2.9%，T细胞介导的≥IB型为1.2%。T细胞介导的IA型为0.2%，对照组为0.3%（T细胞介导的≥IB型排斥反应与对照组相比，P=0.05）。因此，dd-cfDNA可用于评估同种异体移植排斥反应和损伤；dd-cfDNA水平<1%反映无主动排斥反应（T细胞介导的≥IB型或ABMR），而水平>1%表明存在主动排斥反应的可能性。
