Longitudinal variance of Donor‐Derived Cell‐Free DNA (dd‐cfDNA) in Stable Kidney Transplant (KTx) patients are influenced by donor/recipient variables

Abstract

Background:The longitudinal time-course of dd-cfDNA after kidney transplant (KTx) is not well-described. The cut off values of dd-cfDNA in KTx derive from biopsycoupled single measurements. Meaningful interpretation necessitates understanding of: (1) time variance of dd-cfDNA levels post-KTx, (2) factors determining biologic variability, and (3) relationship to donor and recipient characteristics. We hypothesized that an understanding of the aforementioned factors would better inform clinical decision-making using dd-cfDNA.Methods: One hundred and twenty five KTx patients with dd-cfDNA obtained longitudinally were included. Univariate analyses were directed at inter-patient variability and intra-patient inter-occasion variability of dd-cfDNA. Multivariate linear regression was used in analyses accounting for repeat measures.Results: At 1-month post KTx median dd-cfDNA: (1) were higher in repeat KTx (.57%, P < .001), and dual KTx (1.10%, P = ns) versus a first KTx (.31%); (2) showed a significant difference in donor after cardiac death (DCD [.45%]) versus living related (LRD [.27%]) donors (P = .036). Longitudinal (1-3 months) dd-cfDNA measurements showed a significant downtrend for all donor types. Panel-reactive antibodies (PRA) were positively correlated with dd-cfDNA.Conclusions: Repeat Tx, dual Tx, DCD, and PRA are associated with a higher dd-cfDNA.Incorporation of donor/recipient variables and time down post transplant is material for rational interpretation of dd-cfDNA.

Understanding Donor-derived Cell-free DNA in Kidney Transplantation: An Overview and Case-based Guide for Clinicians

“…Relevant clinical factors should be considered when adopting this approach, such as type of donor, degree of recipient sensitization, and duration since transplant, because these may impact ddcfDNA levels independently of allograft pathology. 61…”

“…Given biological and technical variations in assays, validation studies have identified that, for a result to represent a clinically significant change in serial sampling, the change must exceed 61% to 66%. 61,83 Whether serial measurements of ddcfDNA could adequately account for the influence of biological variation can only be assessed in further controlled studies.…”

“…28,30,46,47,51,52,60 Additionally, only a minority of studies examined the value of serial testing. 28,31,46,47,61 Most participants were tested within the first year following transplantation, whereas long-term KTRs were less frequently included. 37,46,50,52,53 Study reference populations were reported to have median baseline ddcfDNA levels ranging from 0.21% to 0.46%.…”

“…Relevant clinical factors should be considered when adopting this approach, such as type of donor, degree of recipient sensitization, and duration since transplant, because these may impact ddcfDNA levels independently of allograft pathology. 61 Published diagnostic performance metrics for assays examining plasma ddcfDNA as a diagnostic biomarker of rejection in KTRs with clinical allograft dysfunction are presented in Figures 1-3. Most studies report parameters in the top quantile of diagnostic performance, but assays were generally more sensitive than specific and had better negative predictive value (NPV) than positive predictive value (PPV).…”

The Current State of Donor-Derived Cell-Free DNA Use in Allograft Monitoring in Kidney Transplantation

“…Additionally, as initial validation studies were performed on single timepoints wherein rejection was suspected and a biopsy was performed, appropriate ddcfDNA levels for given periods of time post-transplant are not well understood. Indeed, many recipient factors (e.g., panel reactive antibody [PRA], repeat transplant status) interact with donor factors (e.g., donation after circulatory death [DCD]) over time to influence ddcfDNA levels in the absence of suspicion of rejection [ 29 ]. Sureshkumar et al in 2020 conducted a retrospective study that evaluated the influence of obesity on ddcfDNA levels.…”