Donor‐derived cell‐free DNA as a biomarker for rejection after kidney transplantation: a systematic review and meta‐analysis

Abstract

Summary A systematic review and meta‐analysis were performed to investigate the value of donor‐derived cell‐free DNA (dd‐cfDNA) as a noninvasive biomarker in diagnosing kidney allograft rejection. We searched PubMed, Web of Science and the Cochrane Library for original research papers published between January 1994 and May 2020 on dd‐cfDNA fractions in blood of kidney allograft recipients. A single‐group meta‐analysis was performed by computing pooled estimates for dd‐cfDNA fractions using the weighted median of medians or quantile estimation (QE) approach. Weighted median differences in medians (WMDMs) and median differences based on the QE method were used for pairwise comparisons. Despite heterogeneity among the selected studies, the meta‐analysis revealed significantly higher median dd‐cfDNA fractions in patients with antibody‐mediated rejection (ABMR) than patients without rejection or patients with stable graft function. When comparing patients with T cell‐mediated rejection (TCMR) and patients with ABMR, our two statistical approaches revealed conflicting results. Patients with TCMR did not have different median dd‐cfDNA fractions than patients without rejection or patients with stable graft function. dd‐cfDNA may be a useful marker for ABMR, but probably not for TCMR.

Diagnostic value of donor‐derived cell‐free DNA to predict antibody‐mediated rejection in donor‐specific antibody‐positive renal allograft recipients

“…[ 14 ], among 79 patients with lower grade TCMR/borderline lesion, only 42 patients had elevated dd‐cfDNA (>0.5%), and these patients showed adverse graft function, more frequent de novo DSA formation and future/persistent rejection. In contrast, in a recent meta‐analysis of four studies evaluating dd‐cfDNA in relation to TCMR (35 samples), dd‐cfDNA levels were not elevated [ 17 ]. The elevated fraction of dd‐cfDNA in the single patient with BKVAN may be in line with an earlier report of 10 patients with BK viremia, where dd‐cfDNA levels correlated tightly with viral load and biopsy‐diagnosed BKVAN [ 29 ].…”

Donor-Derived Cell-Free DNA in Kidney Transplantation: Origins, Present and a Look to the Future

“…With respect to ACR, dd-cfDNA levels were lower in T cell-mediated rejection (TCMR) Banff 1A with median values of 0.2% in the DART study, with similar values demonstrated in another study [ 8 , 10 ]. This finding has been further validated in two meta-analyses showing that dd-cfDNA could not distinguish milder forms of TCMR from no rejection [ 11 , 12 ]. Although utilizing alternate assays of dd-cfDNA may enhance detection of TCMR [ 13 ], it may still lack optimal sensitivity in detecting all cases of TCMR.…”

Donor‐derived cell‐free DNA and renal allograft rejection in surveillance biopsies and indication biopsies

“…However, like in any assay, lowering the cutoff would not only increase sensitivity, but also would lead to an increase in false positive results which may prompt unnecessary anti‐rejection treatment. Similarly, a higher cutoff for the diagnosis of rejection, as suggested by some studies that showed higher median value (2.50%) of dd‐cfDNA fraction in patients with ABMR, would lead to an increase in false negative results 9 . More recently, the combination of the quantity of dd‐cfDNA threshold and the dd‐cfDNA fraction threshold has been suggested to improve sensitivity in the detection of active rejection in renal allograft patients 10 .…”

“…Similarly, a higher cutoff for the diagnosis of rejection, as suggested by some studies that showed higher median value (2.50%) of dd-cfDNA fraction in patients with ABMR, would lead to an increase in false negative results. 9 More recently, the combination of the quantity of dd-cfDNA threshold and the dd-cfDNA fraction threshold has been suggested to improve sensitivity in the detection of active rejection in renal allograft patients. 10 Our analysis is limited by the overall small number of surveillance biopsies performed and the significant number of unacceptable dd-cfDNA samples excluded from the analysis.…”