Akifova Aylin, Budde Klemens, Amann Kerstin, Buettner-Herold Maike, Choi Mira, Oellerich Michael, Beck Julia, Bornemann-Kolatzki Kirsten, Schütz Ekkehard, Bachmann Friederike, Halleck Fabian, von Hoerschelmann Ellen, Koch Nadine, Schrezenmeier Eva, Seelow Evelyn, Waiser Johannes, Zukunft Bianca, Eckardt Kai-Uwe, Halbritter Jan, Kettritz Ralph, Del Moral Covadonga López, Lachmann Nils, Stauch Diana, Niemann Matthias, Schmidt Danilo, Halloran Philip F, Osmanodja Bilgin
Department of Nephrology and Intensive Care, Charité - Universitätsmedizin Berlin, Berlin, Germany.
Department of Nephropathology, Institute of Pathology, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany.
Nephrol Dial Transplant. 2024 Nov 29. doi: 10.1093/ndt/gfae282.
Donor-derived cell-free DNA (dd-cfDNA) shows good diagnostic performance for the detection of antibody-mediated rejection (AMR) in kidney transplant recipients (KTR). However, the clinical benefits of dd-cfDNA monitoring need to be established. Early diagnosis of AMR at potentially reversible stages may be increasingly important due to emerging treatment options for AMR.We hypothesized that monitoring dd-cfDNA in KTR with de novo donor-specific anti-HLA antibodies (dnDSA) and performing kidney biopsy in case of increased dd-cfDNA may reduce time to AMR diagnosis in comparison to clinical indication biopsy.
In this diagnostic, single-center, open-label, randomized clinical trial, we assigned 40 KTR with prevalent dnDSA and estimated glomerular filtration rate ≥20 mL/min/1.73m2, but without previous biopsy-proven AMR, to either dd-cfDNA-guided biopsy (intervention group) or clinician-guided biopsy (control group) over a 12-months period. In both groups, dd-cfDNA was assessed at inclusion and 1, 3, 6, 9, and 12 months. In the intervention group, dd-cfDNA > 50cp/mL indicated a biopsy. Biopsies for clinical indication could be performed at any point during the study period in both groups. A protocol biopsy was scheduled after 12 months for patients without dd-cfDNA-guided biopsy or clinical indication biopsy until study completion. The primary endpoint was time from study inclusion to diagnosis of active or chronic active AMR.
39/40 patients had functioning grafts at study completion. From these, 26 patients underwent biopsy, 13 in each group. AMR was diagnosed earlier in the intervention group than in the control group (median 2.8 months, IQR 1.7-5.3 vs. median 14.5 months, IQR 13.3-16.7, p = 0.003). Longitudinal dd-cfDNA monitoring had 77% positive predictive value and 85% negative predictive value for AMR.
Dd-cfDNA-guided biopsy in KTR with prevalent dnDSA can reduce the time to AMR diagnosis and hereby expedite therapy initiation. (NCT04897438).
供体来源的游离DNA（dd-cfDNA）在检测肾移植受者（KTR）的抗体介导排斥反应（AMR）方面具有良好的诊断性能。然而，dd-cfDNA监测的临床益处尚待确定。由于AMR出现了新的治疗选择，在潜在可逆阶段对AMR进行早期诊断可能变得越来越重要。我们假设，与临床指征活检相比，监测新发供体特异性抗HLA抗体（dnDSA）的KTR中的dd-cfDNA，并在dd-cfDNA升高时进行肾活检，可能会缩短AMR诊断时间。
在这项诊断性、单中心、开放标签、随机临床试验中，我们将40例患有普遍dnDSA且估计肾小球滤过率≥20 mL/min/1.73m2但既往无活检证实的AMR的KTR患者，在12个月内随机分为dd-cfDNA引导活检组（干预组）或临床医生引导活检组（对照组）。两组在纳入时以及第1、3、6、9和12个月时评估dd-cfDNA。在干预组中，dd-cfDNA>50cp/mL表明需要进行活检。两组在研究期间的任何时间都可进行临床指征活检。对于未进行dd-cfDNA引导活检或临床指征活检的患者，计划在12个月后进行方案活检，直至研究结束。主要终点是从研究纳入到诊断为活动性或慢性活动性AMR的时间。
40例患者中有39例在研究结束时移植肾功能良好。其中，26例患者接受了活检，每组13例。干预组比对照组更早诊断出AMR（中位数2.8个月，IQR 1.7 - 5.3 vs.中位数14.5个月，IQR 13.3 - 16.7，p = 0.003）。dd-cfDNA的纵向监测对AMR的阳性预测值为77%，阴性预测值为85%。
对患有普遍dnDSA的KTR进行dd-cfDNA引导活检可缩短AMR诊断时间，从而加快治疗启动。（NCT04897438）
