From Stable Values to Diagnostic Thresholds: Interpreting Donor‐Derived Cell‐Free DNA in Pediatric Kidney Transplantation

Dear Editor,

I read with great interest the multicenter study by Steinke et al. examining donor‐derived cell‐free DNA (dd‐cfDNA) in clinically stable pediatric kidney transplant recipients and the influence of donor–recipient size mismatch [1]. The study addresses an important pediatric question, as thresholds derived from adult populations may not translate directly to children. However, the conclusion that dd‐cfDNA values well below 1% “reinforce the generalizability” of the adult‐derived 1% cutoff deserves a more cautious interpretation.

The cohort was deliberately restricted to clinically stable recipients without de novo donor‐specific antibodies, biopsy‐proven rejection, or BK viremia/nephropathy [1]. This design is well suited to describing the distribution of dd‐cfDNA in stable children, but it does not, by itself, validate a diagnostic threshold for rejection. Validation of a threshold requires assessment of patients both with and without the target condition against an appropriate reference standard. Demonstrating that most stable recipients have values below 1% does not establish that children with rejection will reliably exceed that threshold.

This distinction matters clinically. In a biopsy‐linked pediatric cohort, Dandamudi et al. reported that a 1% cutoff had 96.5% specificity but only 33.3% sensitivity for biopsy‐proven acute rejection [2]. More recently, Kilduff et al. found a sensitivity of 52% across all biopsies and only 13% in surveillance biopsies, with a negative predictive value of 59% in the surveillance setting [3]. Other pediatric data have shown more favorable performance [4]. Taken together, these findings suggest that the operating characteristics of a fixed threshold vary substantially according to rejection phenotype and biopsy context [2, 3, 4].

Importantly, Steinke et al. also showed that dd‐cfDNA was influenced by donor–recipient size relationships: a body surface area mismatch > 1.5 and small recipients of kidneys from obese donors were associated with higher dd‐cfDNA levels [1]. This observation strengthens, rather than resolves, the concern surrounding a single fixed percentage threshold. In children, recipient size, graft‐to‐recipient size mismatch, time after transplantation, and longitudinal changes may all be relevant when interpreting an individual value.

The principal clinical concern is not simply that a stable child may occasionally have a value above 1%, but that a value below 1% could be interpreted as sufficiently reassuring to defer further evaluation. Adult data likewise show that the 1% threshold is not an infallible rule‐out test for all forms of active rejection [5]. This is particularly relevant to subclinical or T cell‐mediated rejection, in which false reassurance from a biomarker could delay an otherwise indicated biopsy.

The study therefore makes an important contribution by characterizing dd‐cfDNA behavior in stable pediatric recipients and highlighting the influence of size mismatch. Its findings are strongest when interpreted as defining a stable pediatric distribution rather than validating the 1% diagnostic cutoff. The logical next step is prospective, biopsy‐anchored evaluation across rejection phenotypes, ideally incorporating serial dd‐cfDNA trajectories and donor–recipient size relationships.

Funding

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Ethics Statement

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Conflicts of Interest

The author declares no conflicts of interest.

Linked Articles

This article is linked to Steinke et al. papers. To view this article, visit https://doi.org/10.1111/petr.70416.

Data Availability Statement

The manuscript does not include any original data.