Donor‐derived cell‐free DNA (dd‐cfDNA) for detection of allograft rejection in pediatric kidney transplants

Abstract

In pediatric transplantation, acute rejection is a major contributor of graft failure. Current approaches include kidney biopsy in response to graft dysfunction and/or the emergence of donor‐specific HLA antibodies (DSA). However, biopsy is associated with potential complications. Thus, there is a need for non‐invasive diagnostics. Detection of donor‐derived cell‐free DNA (dd‐cfDNA, AlloSure) > 1% is associated with rejection in adult kidney transplants. Here, we evaluate the utility of dd‐cfDNA for identifying allograft rejection in pediatric patients. Between 10/2017 and 10/2019, 67 patients, who underwent initial testing with dd‐cfDNA as part of routine monitoring or in response to clinical suspicion for rejection, were included. Biopsies were performed when dd‐cfDNA > 1.0% or where clinical suspicion was high. Demographics, dd‐cfDNA, antibody status, and biopsies were collected prospectively. Data were analyzed to determine predictive value of dd‐cfDNA for identifying grafts at risk for rejection. 19 of 67 patients had dd‐cfDNA testing as part of routine monitoring with a median dd‐cfDNA score of 0.37 (IQR: 0.19‐1.10). 48 of 67 patients who had clinical suspicion of rejection had median dd‐cfDNA score of 0.47 (0.24‐2.15). DSA‐positive recipients had higher dd‐cfDNA scores than those who were negative or had AT1R positivity alone (P = .003). There was no association between dd‐cfDNA score and strength of DSA positivity. 7 of 48 recipients had a biopsy with a dd‐cfDNA score <1%; two showed evidence of rejection. Neither DSA nor AT1R positivity was statistically associated with biopsy‐proven rejection. However, dd‐cfDNA >1% was diagnostic of rejection with sensitivity of 86% and specificity of 100% (AUC: 0.996, 0.98‐1.00; P = .002). dd‐cfDNA represents a non‐invasive method for early detection of rejection in pediatric renal transplants. Our study shows dd‐cfDNA to be highly predictive of histological rejection and superior to other indicators such as graft dysfunction or antibody positivity alone. Further studies are necessary to refine these initial observations.

Utility of Donor-Derived Cell-Free DNA in Detecting ABMR in Patients With AT1R Antibodies

“…6 These findings are in line with a recent study in pediatric kidney transplants, wherein, dd-cfDNA being superior to AT1R antibodies in predicting presence of ABMR. 7 Dd-cfDNA, therefore, has a utility in discriminating harmful from non-harmful presence of AT1R antibodies. In addition, in light of the aforementioned findings, dd-cfDNA may have utility in discerning pathogenicity of other non-HLA antibodies given increasing recognition of their contribution in mediating allograft injury.…”

Dynamics of Donor-Derived Cell-Free DNA at the Early Phase After Pediatric Kidney Transplantation: A Prospective Cohort Study

“…Flare-up was defined when ddcfDNA elevated by over 30% from stable level as well as the peak level was over 1% during elevation. One percent was used as the threshold of flare-up because it was often used for the diagnosis of rejection and impaired renal allograft function in prior studies (14).…”

“…The median donor-recipient height ratio was 0.83 (0.62-0.88). The median weight and height of donors were 15 (13)(14)(15)(16)(17)(18)(19)(20)(21) kg and 102 (90-120) cm, respectively, while the median weight and height of recipients were 31 (18.5-38.5) kg and 137 (115-150) cm. All kidneys were from deceased donors and eight (35.1%) of them were from donation after circulatory death (DCD).…”

“…Contrary to the accumulating data of ddcfDNA in adult KTx, only one study exploring ddcfDNA in pediatric KTx has been reported. Puliyanda et al provided the evidence that ddcfDNA could be a useful indicator for identifying acute rejection in pediatric kidney transplantation (14). The dynamics of ddcfDNA in pediatric KTx, which may be different from that in adult KTx, has not been well-investigated.…”

Donor-Derived Cell-Free DNA (ddcf-DNA) and Acute Antibody-Mediated Rejection in Kidney Transplantation

“…Unfortunately, data for this patient population are also extremely limited. Puliyanda et al examined 67 pediatric kidney transplant recipients who underwent transplantation at two centers between October 2017 and October 2019 [ 24 ]. During that time, the patients underwent an assessment of ddcf-DNA using the AlloSure assay, either as part of routine monitoring (19 patients) or in response to a clinical suspicion of rejection (48 patients).…”