Longitudinal Evaluation of Donor-Derived Cellfree DNA in Pediatric Kidney Transplantation

Abstract

Background and objectivesDonor-derived cellfree DNA (cfDNA) is a less-invasive marker of allograft injury compared with kidney biopsy. However, donor-derived cfDNA has not yet been extensively tested in children, where the test may have different characteristics.Design, setting, participants, & measurementsWe assayed donor-derived cfDNA (AlloSure; CareDx) from 290 stored plasma samples from a prospective biobank at our center, collected from 57 children monthly in the first year postkidney transplant between January 2013 and December 2019. We assessed the kinetic changes in donor-derived cfDNA levels within the first year post-transplant. We analyzed donor-derived cfDNA levels for associations with biopsy-proven acute rejection using area under the receiver operating characteristic curve to longitudinal plasma and urine BK viral loads using linear mixed models. We analyzed the prognostic effect of an elevated donor-derived cfDNA level on the eGFR 30 days after the assayviaKolmogorov–Smirnov two-sample tests or on measured GFR or interstitial fibrosis at 12 months post-transplant.ResultsThe donor-derived cfDNA levels in children remained persistently elevated for at least 4 months post-transplant, more so if there is greater disparity in size between the donor and the recipient, before reaching a steady low level. A donor-derived cfDNA level of >1% discriminated between biopsy-proven acute rejection with a receiver operating characteristic area under the curve of 0.82 (95% confidence interval, 0.71 to 0.93). During BK viruria or viremia, patients had a significantly higher median donor-derived cfDNA than before or after and a significant rise within the same patient. A donor-derived cfDNA of >0.5% predicted a wider spread in the eGFR over the next 30 days but not the 12-month outcomes.ConclusionsIn children, donor-derived cfDNA is a valuable, less invasive biomarker for assessment of allograft rejection and injury.PodcastThis article contains a podcast athttps://www.asn-online.org/media/podcast/CJASN/2022_10_27_CJN03840322.mp3

Utilization of donor‐derived Cell‐Free DNA in pediatric kidney transplant recipients: A single center study

“…In our cohort of pediatric kidney transplant recipients, a dd‐cfDNA level of >1% was associated with BPAR, consistent with the published literature examining dd‐cfDNA in kidney transplantation, despite no change in CrCl 6,14 . We also found that dd‐cfDNA levels were higher in patients with AMR compared to those with TCMR, consistent with other studies 15 .…”

“…However, the low sensitivity for diagnosing rejection may preclude dd-cfDNA from being used as the sole screening tool, as suggested by Chang et al 16 Different dd-cfDNA cutoffs have been examined with varying results. Dandamudi et al 14 found that at a dd-cfDNA cutoff of >0.5% to diagnose rejection, the sensitivity improved to 78% but specificity decreased to 79%, similar to our cohort. In the ADMIRAL study, investigators evaluated the use of dd-cfDNA monitoring in 1092 adult kidney transplant recipients.…”

“…A dd-cfDNA cutoff of >1% was diagnostic of rejection with a sensitivity of 86% and specificity of 100%. Dandamudi et al 14 0.82. They also found that a dd-cfDNA cutoff >1% was diagnostic of rejection, with a sensitivity of 33% and specificity of 96%.…”

“…A dd‐cfDNA cutoff of >1% was diagnostic of rejection with a sensitivity of 86% and specificity of 100%. Dandamudi et al 14 studied dd‐cfDNA in stored plasma samples from 57 pediatric kidney transplant recipients during the first‐year post‐transplant. They demonstrated a strong association between dd‐cfDNA and biopsy‐proven rejection with an AUC 0.82.…”

“…rejection, the median time to attain dd-cfDNA <1% post-rejection treatment was 8.5 days(3.0-19.5). In episodes of TCMR (n = 18), 8/18 (44.4%) had dd-cfDNA >1%, and after treatment 7 decreased to <1% at a median of 9 days (range[8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24]. In episodes of AMR (n = 10), 9/10 had dd-cfDNA >1%, and after treatment only 1 decreased to <1% at 102 days.…”