*Purpose: Percutaneous renal allograft biopsy is the current gold standard for detecting acute rejection after kidney transplantation (KT). Noninvasive tests such as plasma-based donor-derived cell-free DNA (dd-cfDNA) assays have been proposed as an alternative to biopsy. We sought to examine the value of dd-cfDNA testing at one month following KT in different donor and recipient categories.

*Methods: We performed a single center retrospective review of all adult KT and simultaneous pancreas-KT (SPKT) patients (pts) who underwent dd-cfDNA testing between January 2018 and September 2020. The diagnosis of acute rejection was based on histopathology obtained from percutaneous, ultrasound-guided, needle biopsies. Our center’s standard practice included dd-cfDNA testing and performing surveillance kidney biopsies at 1 month following KT. The dd-cfDNA test was considered elevated if >1.0%.

*Results: During the study period, 2193 dd-cfDNA tests were performed in 665 de novo pts; only 2% of samples were unacceptable. Higher mean 1-month dd-cfDNA levels were noted in the following categories: Retransplants (n=30, 1.8 ± 2.1); highly sensitized pts (PRA 98-100%, n=27, 1.6 ± 2.0; for highly sensitized retransplants, n=18, 2.0 ± 2.3; for highly sensitized primary KTs, n=9, 0.7 ± 0.5); SPKTs (n=27, 0.9 ± 1.1); and pts who underwent early reoperations (n=16, 0.85 ± 0.9). In all other KT categories, mean 1-month dd-cfDNA levels were lower and similar: DCD donor KTs (n=53, 0.56 ± 0.4), living donor KTs (n=51, 0.47 ± 0.4); acute kidney injury (AKI) donor KTs (n=23, 0.47 ± 0.6); standard criteria donor (SCD) KTs (n=91, 0.47 ± 0.4); expanded criteria donor (ECD) KTs (n=44, 0.46 ± 0.5); dual KTs (n=16, 0.45 ± 0.4); and pts with delayed graft function (DGF, n=50, 0.46 ± 0.4). In 58 primary KT pts with negative 1-month surveillance biopsies, corresponding mean 1-month dd-cfDNA levels were 0.49 ± 0.4. In 10 pts with positive 1-month surveillance biopsies, corresponding mean 1-month dd-cfDNA levels were 1.5 ± 1.8. In 26 pts with a 1-month dd-cfDNA level >1.0, the subsequent incidence of acute rejection was 27%; in 22 pts with a 1-month dd-cfDNA level ≥2.0, the subsequent incidence of acute rejection was 50% (mean follow-up 14 months).

*Conclusions: We noted a bimodal distribution of 1-month dd-cfDNA levels. Higher mean 1-month dd-cfDNA levels (range 0.85-2.0) were associated with retransplants, high PRA pts, SPKTs, and pts with early reoperations; 22-44% of pts in these categories had 1-month dd-cfDNA levels >1.0. Conversely, primary KT alone pts (DCD, living donor, AKI donor, SCD, ECD, dual KT, those with DGF) had lower 1-month dd-cfDNA levels (range 0.45-0.56) and only 7-14% had 1-month dd-cfDNA levels >1.0. One-month surveillance biopsy results correlated with corresponding dd-cfDNA levels. Elevated 1-month dd-cfDNA levels occur in pts at a higher risk for acute rejection, suggesting that these pts need to be monitored more closely.

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