Utility and limitations of the use of donor-derived cell-free DNA in kidney transplantation

Table 9 Summary points regarding donor-derived cell-free DNA use in clinical practice

Potential benefits	Pitfalls	Unanswered questions
Noninvasive blood biomarker	Fractional quantification affected by changes in rd-cfDNA	Clinical utility and cost-effectiveness
Applicable to all solid organ transplants	Does not exclude (early) TCMR (if rd-cfDNA normal)	Ideal surveillance testing schedule
Elevations may occur up to 30 days before histological changes	Does not reliably discriminate between normal histology and interstitial fibrosis/tubular atrophy	Significance of normal level in presence of histological inflammation
Absolute quantification of dd-cfDNA not affected by changes in rd-cfDNA	Elevated in non-rejection pathologies associated with tissue injury or immunological risk (BKN, CNI toxicity)	Superiority of assay-specific optimal diagnostic threshold vs deviation from patient baseline
Avoidance of protocol biopsy if graft function stable and dd-cfDNA low	Not recommended for use in early posttransplant period	Superiority of quantitative/continuous vs qualitative/binary measurements
Avoidance of unnecessary biopsies	Not recommended for use for 24 hours post-biopsy	Superiority of fractional vs absolute quantification
Non-invasive diagnosis of acute rejection	Confounded in pregnancy	Role of urinary dd-cfDNA
Assessment of response to rejection treatment	Confounded in some repeat and multi-organ transplants	Role within a panel of biomarkers
Indicator for treatment of chronic active ABMR	-	-

rd-cfDNA: Recipient derived cell-free DNA; TCMR: T-cell mediated rejection; dd-cfDNA: Donor-derived cell-free DNA; BKN: BK nephropathy; CNI: Caòlcinerin inhibitor; ABMR: Antibody-mediated rejection.