Allograft Function and Baseline Donor-Derived Cell-Free DNA in Kidney Transplant Recipients: One Size Doesn’t Fit All

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Donor-derived cell-free DNA (dd-cfDNA) predicts acute rejection in kidney allografts.^1-3 Cellular senescence and injury constantly release cfDNA fragments into circulation. DNA fragments are cleared from the blood by the kidneys and liver with a half-life of ∼30 minutes.⁴ It is unclear whether reduced estimated glomerular filtration rate (eGFR) in kidney transplant recipients (KTRs) would result in higher baseline dd-cfDNA values. Variations in baseline dd-cfDNA at different eGFRs in stable KTRs were explored in the current study.

We identified KTRs between September 2017 and June 2020 who had dd-cfDNA levels (AlloSure, CareDx, Brisbane, CA) at or around 8 weeks post-transplantation. A dd-cfDNA value ≥ 1% prompted allograft biopsy. KTRs with biopsy evidence for rejection or other injuries were excluded. Patients were divided based on MDRD equation-based eGFR using 8-week serum creatinine (<30, 30-59, and ≥60 mL/min/1.73m²). Baseline 8-week dd-cfDNA levels were compared between different eGFR groups using t-test.

Among 156 patients, 36 with biopsy-proven rejection were excluded from the analysis. The remaining 120 (40 living and 80 deceased donor KTRs) were stratified based on eGFR as follows: <30 mL/min/1.73m² (n=18), 30-59 mL/min/1.73m² (n=72), ≥60 mL/min/1.73m² (n=30). Baseline 8-week dd-cfDNA values were significantly higher in groups with eGFR <30 vs. ≥60 mL/min/1.73m² (0.74±0.65 vs. 0.25±0.12, p=0.005); <30 vs. 30-59 mL/min/1.73m² (0.74±0.65 vs. 0.38±0.34, p=0.03) and 30-59 vs. ≥60 mL/min/1.73m² (0.38±0.34 vs. 0.25±0.12, p=0.004). There was a significant linear correlation between dd-cfDNA levels and eGFR, as shown in Figure 1.

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Figure 1:

Relationship between baseline dd-cfDNA and estimated glomerular filtration rate (eGFR). Blue squares represent individual dd-cfDNA values. Black line represents correlation between dd-cfDNA values and GFR. dd-cfDNA: Donor derived cell free DNA.

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We found a significant correlation between baseline dd-cfDNA levels and eGFR. Decreasing renal clearance of DNA fragments and possibly higher levels of intra-graft inflammation with declining GFR are plausible explanations.⁵ These observations point towards the possible need for stratifying baseline dd-cfDNA based on the level of allograft function.