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Volume: 20 Issue: 4 April 2022


Plasma Cell-Free DNA as a Novel Method for Early Detection of Acute Rejection in Uterine Transplant

Dear Editor:

Uterine transplant (UTx) has been proven as an innovative procedure to address absolute uterine infertility.1 Because UTx is transitioning from an “experimental procedure” to a clinical option, we can look back and see the many advancements that have driven the ethical, technical, and conceptual maturation of the field. This process has followed an evolution similar to that of solid-organ transplants (SOT): initial innovation, technical/pharmacologic development, establishment and broadening of donor and recipient pools, and finally standardization of practices aimed to transform the survival and quality of life of patients. However, there still exists many necessary further pursuits of growth, one of which being the monitoring and treatment of rejection.

Because the field of vascularized composite allograft has largely been informed by SOT past experiences, we again look to the innovation of this field for solutions. The early detection and treatment of rejection in any SOT/vascularized composite allograft is challenging. Histologic analysis of allograft biopsies is the standard and most accurate method; however, in some allografts, chemical biomarkers (ie, creatinine, liver enzymes, glucose, C-peptide) have been found to be useful in guiding when allograft biopsies should be performed. For UTx, there are currently no such chemical biomarkers, making cervical biopsies the only tools available in detection of rejections.2 Standard protocols include very frequent cervical biopsies at every 1 to 2 weeks after transplant and during pregnancy.1 The established recommendation has been to wait at least 1 year after transplant before attempting pregnancy; therefore, patient follow-up time, in which numerous cervical biopsies must be performed, is long.1

Apart from the invasive nature of cervical biopsies, technical difficulties, especially in cases with vaginal stricture or neovagina, can increase the risk of infection in an immunocompromised individual, as well as can result in bleeding and cervical scarring/insufficiency. In pregnant patients, cervical biopsies may lead to fetal infection or even loss in extreme instances.

In recent years, clinical grade sequencing tools have been developed for quantifying donor driven cell-free-DNA (DDCF-DNA) assays to detect early and subclinical acute rejection episodes in kidney, heart, lung, and liver transplants.3-5 These tests measure single-nucleotide polymorphisms as a surrogate of DDCF-DNA in recipients, without separate donor/recipient genotyping. A rise in blood cell-free DNA in the recipient is used for transplant surveillance, early rejection detection, and differen-tiation from other malfunction etiologies (ie, acute tubular necrosis and infections).3-5 The DDCF-DNA assay involves a rapid blood test and may also be used to personalize titration of immunosuppression and monitor responses to rejection managements.

A noninvasive way to reliably predict rejection episodes in UTx is of utmost importance, with DDCF-DNA assays potentially offering a substitute or could be used in conjunction with the currently available rejection detection methods (ie, cervical biopsies). Although DDCF-DNA may have its own limitations, including inaccurate results following allograft biopsies (1 day), blood transfusion (30 days), and its use with multiorgan transplants and immediately after pregnancy,3,4 its use in other SOTs has shown a promising future and its potential application in UTx. This would require validation in future clinical studies.


  1. Testa G, McKenna GJ, Gunby RT Jr, et al. First live birth after uterus transplantation in the United States. Am J Transplant. 2018;18(5):1270-1274. doi:10.1111/ajt.14737
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  2. Agarwal A, Johannesson L, Findeis SK, et al. Clinicopathologic analysis of uterine allografts including proposed scoring of ischemia-reperfusion injury and T cell-mediated rejection-Dallas UtErus Transplant Study: a pilot study. Transplantation. 2022;106(1):167-177. doi:10.1097/TP.00000000000036332021
    CrossRef - PubMed
  3. Paul RS, Almokayad I, Collins A, Raj D, Jagadeesan M. Donor-derived cell-free DNA: advancing a novel assay to new heights in renal transplantation. Transplant Direct. 2021;7(3):e664. doi:10.1097/TXD.0000000000001098
    CrossRef - PubMed
  4. Knüttgen F, Beck J, Dittrich M, et al. Graft-derived cell-free DNA as a noninvasive biomarker of cardiac allograft rejection: a cohort study on clinical validity and confounding factors (published online ahead of print, February 25, 2021. Transplantation. 2021. Doi:10.1097/TP.0000000000003725.
    CrossRef - PubMed
  5. Zhao D, Zhou T, Luo Y, et al. Preliminary clinical experience applying donor-derived cell-free DNA to discern rejection in pediatric liver transplant recipients. Sci Rep. 2021;11(1):1138. doi:10.1038/s41598-020-80845-6
    CrossRef - PubMed

Volume : 20
Issue : 4
Pages : 440 - 441
DOI : 10.6002/ect.2021.0237


From the 1Plastic and Reconstructive Surgery Department, Temple University Hospitals, Philadelphia, Pennsylvania; the 2Plastic and Reconstructive Surgery Department, Rush University Medical Center, Chicago, Illinois; the 3Annette C. and Harold C. Simmons Transplant Institute, Baylor University Medical Center, Dallas, Texas; and the 4Department of Obstetrics and Gynecology, Baylor University Medical Center, Dallas, Texas, USA
Acknowledgements: The authors have not received any funding or grants in support of the presented research or for the preparation of this work and have no declarations of potential conflicts of interest.
Corresponding author: Alireza Hamidian Jahromi, Department of Plastic and Reconstructive Surgery, 3401 N Broad Street, Philadelphia, PA 19103, USA
Phone: +1-318-518-4600