Department of Nephrology, Fundeni Clinical Institute, Bucharest, Romania.
Division of Nephrology, University of Washington, Seattle, WA, USA.
Sci Rep. 2022 Sep 5;12(1):15061. doi: 10.1038/s41598-022-19017-7.
Donor specific anti-HLA antibodies (DSA) and donor-derived cell-free DNA (dd-cfDNA) have lead to substantial progress in the non-invasive monitoring of the renal allograft by being able to detect or rule out subclinical rejection and guide immunosuppressive changes. In this study we sought to analyze the clinical, de novo DSA (dnDSA) and histological determinants of dd-cfDNA levels. The study included a cohort of stable renal function kidney transplant (KT) recipients who underwent anti-HLA dnDSA and dd-cfDNA testing between September 2017-December 2019. Statistical models were constructed to detect association with predictors of dd-cfDNA levels and other clinical characteristics. 171 renal allograft recipients were tested for dd-cfDNA and dnDSA at a median 1.06 years posttransplant (IQR: 0.37-4.63). Median dd-cfDNA was 0.25% (IQR: 0.19-0.51), 18.7% of patients having a dd-cfDNA ≥ 1%. In a multivariate linear regression model the presence of dnDSA MFI ≥ 2500 was the best independent determinant of dd-cfDNA level (p < 0.001). Among patients tested, 54 had concurrent dd-cfDNA determination at the time of an allograft biopsy. dd-cfDNA had an AUC of 0.82 (95% CI 0.69-0.91; p < 0.001) and of 0.96 (95% CI 0.87-0.99) to discriminate any rejection and ABMR, respectively. After multivariate adjustment, the models that included ABMR (R = 0.82, R = 0.67, p < 0.001), or ptc (R = 0.79, R = 0.63, p < 0.001) showed the best correlation with dd-cfDNA level. We are confirming a strong association of dd-cfDNA with dnDSA and underlying alloimmune-mediated injury in renal allograft recipients in a cohort of patients with unsuspecting clinical characteristics for rejection and excellent allograft function. Our findings support the need for noninvasive biomarker surveillance in KT recipients and we propose that dd-cfDNA may complement dnDSA screening.
供者特异性抗 HLA 抗体（DSA）和供者游离 DNA（dd-cfDNA）的出现使得通过检测或排除亚临床排斥反应并指导免疫抑制变化，能够对肾移植受者的肾移植物进行非侵入性监测，从而取得了实质性进展。在这项研究中，我们旨在分析 dd-cfDNA 水平的临床、新出现的 DSA（dnDSA）和组织学决定因素。该研究纳入了一组稳定肾功能的肾移植（KT）受者，这些受者在 2017 年 9 月至 2019 年 12 月期间接受了抗 HLA dnDSA 和 dd-cfDNA 检测。构建统计模型以检测与 dd-cfDNA 水平和其他临床特征相关的预测因素之间的关联。在移植后中位数 1.06 年（IQR：0.37-4.63）对 171 名肾移植受者进行了 dd-cfDNA 和 dnDSA 检测。dd-cfDNA 的中位数为 0.25%（IQR：0.19-0.51），18.7%的患者 dd-cfDNA≥1%。在多元线性回归模型中，dnDSA MFI≥2500 的存在是 dd-cfDNA 水平的最佳独立决定因素（p<0.001）。在接受检测的患者中，54 名患者在移植肾活检时同时进行了 dd-cfDNA 检测。dd-cfDNA 的 AUC 为 0.82（95%CI 0.69-0.91;p<0.001），区分任何排斥反应和 ABMR 的 AUC 分别为 0.96（95%CI 0.87-0.99）。经过多变量调整后，包含 ABMR（R=0.82，R=0.67，p<0.001）或 ptc（R=0.79，R=0.63，p<0.001）的模型与 dd-cfDNA 水平的相关性最好。我们在一组临床特征无排斥反应迹象且移植物功能良好的患者中证实，dd-cfDNA 与 dnDSA 和肾移植受者潜在的同种免疫介导损伤之间存在强烈关联。我们的发现支持对 KT 受者进行非侵入性生物标志物监测的必要性，并且我们提出 dd-cfDNA 可能补充 dnDSA 筛查。
