Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Randomized Controlled Trial
. 2025 Jun 30;40(7):1384-1395.
doi: 10.1093/ndt/gfae282.

Donor-derived cell-free DNA monitoring for early diagnosis of antibody-mediated rejection after kidney transplantation: a randomized trial

Aylin Akifova  1 , Klemens Budde  1 , Kerstin Amann  2 , Maike Buettner-Herold  2 , Mira Choi  1 , Michael Oellerich  3 , Julia Beck  4 , Kirsten Bornemann-Kolatzki  4 , Ekkehard Schütz  4 , Friederike Bachmann  1 , Fabian Halleck  1 , Ellen von Hoerschelmann  1 , Nadine Koch  1 , Eva Schrezenmeier  1 , Evelyn Seelow  1 , Johannes Waiser  1 , Bianca Zukunft  1 , Kai-Uwe Eckardt  1 , Jan Halbritter  1 , Ralph Kettritz  1 , Covadonga López Del Moral  1   5 , Nils Lachmann  6 , Diana Stauch  6 , Matthias Niemann  7 , Danilo Schmidt  8 , Philip F Halloran  9 , Bilgin Osmanodja  1
Affiliations
Randomized Controlled Trial

Donor-derived cell-free DNA monitoring for early diagnosis of antibody-mediated rejection after kidney transplantation: a randomized trial

Aylin Akifova et al. Nephrol Dial Transplant. .

Abstract

Background: 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 with clinical indication biopsy.

Methods: 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/1.73 m2, but without previous biopsy-proven AMR, to either dd-cfDNA-guided biopsy (intervention group) or clinician-guided biopsy (control group) over a 12-month period. In both groups, dd-cfDNA was assessed at inclusion and 1, 3, 6, 9 and 12 months. In the intervention group, dd-cfDNA >50 copies/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.

Results: Thirty-nine of 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, interquartile range (IQR) 1.7-5.3 vs median 14.5 months, IQR 13.3-16.7, P = .003]. Longitudinal dd-cfDNA monitoring had 77% positive predictive value and 85% negative predictive value for AMR.

Conclusions: Dd-cfDNA-guided biopsy in KTR with prevalent dnDSA can reduce the time to AMR diagnosis and hereby expedite therapy initiation.

Trial registration: ClinicalTrials.gov, NCT04897438.

Keywords: biomarkers; cell-free nucleic acids; graft rejection; kidney transplantation; randomized controlled trial.

PubMed Disclaimer

Conflict of interest statement

The authors of this manuscript have conflicts of interest to disclose. A.A. received travel support from Chiesi. K.B. received grants from Alexion, Astellas, AstraZeneca, Chiesi, CSL Behring, MSD, Otsuka, Stada, and Takeda, consulting fees from Aicuris, Alexion, Astellas, AstraZeneca, Bayer, Bristol-Myers Squibb, Carealytics, CareDx, Chiesi, CSL Behring, Fresenius, Hansa, HiBio, MSD, Natera, Neovii, Paladin, Pfizer, Pirche, Sanofi, Stada, Takeda, Veloxis, Vifor and Xenothera, honoria from Astellas, AstraZeneca, Chiesi, Fresenius, MSD, Paladin, Sanofi and Takeda, travel support from AstraZeneca, Chisi, HiBio, MSD, Neovii, Paladin, Stada, Takeda and Veloxis, participated in the advisory boards of Aicuris, Alexion, Astellas, AstraZeneca, Bristol Myers-Squibb, Carealytics, CareDx, Chiesi, CSL Behring, HiBio, MSD, Natera, Neovii, Paladin, Pfizer, Stada, Takeda, Veloxis and Vifor, and has fiduciary roles at Deutsche Transplantationsgesellschaft and Eurotransplant. K.A. received honoria from Novartis, Otsuka, Vifor, GSK, Stadapharma, AstraZeneca and Alexion, payment for expert testimony and participation in an advisory board for Novartis, and hold stocks from Novartis, Pfizer and Merck. M.B-H. received grants from Deutsche Forschungsgemeinschaft (TRR 374C2, TRR221Z01) and honoraria for lectures or articles from Pfizer, Sanofi, Springer, Thieme and Novartis. M.O. acts as a consultant to Oncocyte. J.B., K.B.-K. and E.Schütz are employees of Chronix Biomedical GmbH, a subsidiary of Chronix Biomedical Inc. (an Oncocyte company), which holds intellectual property rights (EP 3004388B1, EP3201361B1 and US10570443B2). E.Schütz, J.B. and K.B.-K. hold stocks from Oncocyte. F.H. received grants from MSD, Hansa Pharma and Chiesi, consulting fees from Orifarm, honoria from Hansa Pharma and Sanofi, travel support by Hansa Pharma, and participates an advisory board for TolerogenixX GmbH. E.Schrezenmeier received grants from the Else-Kröner-Fresenius-Stiftung and Deutsche Forschungsgemeinschaft, consulting fees from Novartis, Honoria from AstraZeneca and GSK, travel support from Chiesi, and is part of the DGfN program committee. K.-U.E. received grants from Amgen, AstraZeneca, Bayer, Evotec and Vifor, consulting fees from Akebia, AstraZeneca, Bayer, Otsuka and Retrophin, and is member of an advisory board for AstraZeneca. J.H. received grants from Deutsche Forschungsgemeinschaft (HA 6908/4–1x). R.K. received grants from Deutsche Forschungsgemeinschaft (KE576/10–1, SFB1365), honoria from med update and Vifor Pharma, and participates in advisory boards for Insmed Incorporated, and Boehringer Ingelheim. C.L.D.M. received a research grant from IDIVAL-Valdecilla (Santander, Cantabria, Spain). M.N. works for PIRCHE AG, which develops and operates the PIRCHE web service. P.F.H. received grants and consultation fees from Natera and funding from Thermo Fisher Scientific, has a licensing agreement with Thermo Fisher Scientific, and received consulting fees from Natera and Argenx BV. B.O. received travel reimbursement from Oncocyte. The remaining authors have nothing to disclose.

Figures

Graphical Abstract
Graphical Abstract
Figure 1:
Figure 1:
CONSORT diagram. We identified 260 KTR with prevalent dnDSA (MFI >1000) detected by annual screening out of which 79 fulfilled the eligibility criteria. From these, 55 were invited to participate during the recruitment period from 17 June 2021, until 4 July 2022, and 40 provided consent and were randomized. Since 1 patient died, and 13 withdrew consent for biopsy, 26 patients were included in the final analysis.
Figure 2:
Figure 2:
(A) Boxplots comparing the time from study inclusion to AMR diagnosis for patients with AMR according to treatment groups. (B) Time from study inclusion to AMR diagnosis in months for each patient with AMR diagnosis according to treatment group. Arrowheads indicate the timing of the first increase in absolute dd-cfDNA above the prespecified cutoff of 50 copies/mL for each patient, and no arrowheads indicate absolute dd-cfDNA below the prespecified cutoff over the observation period.
Figure 3:
Figure 3:
(A) Scatterplot showing the Pearson correlation coefficient between log-transformed mean dd-cfDNA in copies/mL and the molecular AMR score. (B) Scatterplot showing the Pearson correlation coefficient between log-transformed mean dd-cfDNA in copies/mL and the microvascular inflammation score (g + ptc) in conventional histopathology.
See this image and copyright information in PMC

References

    1. Sellarés J, de Freitas DG, Mengel M et al. Understanding the causes of kidney transplant failure: the dominant role of antibody-mediated rejection and nonadherence. Am J Transplant 2012;12:388–99. 10.1111/j.1600-6143.2011.03840.x - DOI - PubMed
    1. Mayrdorfer M, Liefeldt L, Wu K et al. Exploring the complexity of death-censored kidney allograft failure. J Am Soc Nephrol 2021;32:1513–26. 10.1681/ASN.2020081215 - DOI - PMC - PubMed
    1. Wiebe C, Gibson IW, Blydt-Hansen TD et al. Rates and determinants of progression to graft failure in kidney allograft recipients with de novo donor-specific antibody. Am J Transplant 2015;15:2921–30. 10.1111/ajt.13347 - DOI - PubMed
    1. Böhmig GA, Eskandary F, Doberer K et al. The therapeutic challenge of late antibody-mediated kidney allograft rejection. Transpl Int 2019;32:775–88. 10.1111/tri.13436 - DOI - PMC - PubMed
    1. Moreso F, Crespo M, Ruiz JC et al. Treatment of chronic antibody mediated rejection with intravenous immunoglobulins and rituximab: a multicenter, prospective, randomized, double-blind clinical trial. Am J Transplant 2018;18:927–35. 10.1111/ajt.14520 - DOI - PubMed

Publication types

MeSH terms

Associated data

Grants and funding