Early clinical experience using donor-derived cell-free DNA to detect rejection in kidney transplant recipients

Huang, Edmund; Sethi, Supreet; Peng, Alice; Najjar, Reiad; Mirocha, James; Haas, Mark; Vo, Ashley; Jordan, Stanley C.

doi:10.1111/ajt.15289

Cited by 145 publications

(169 citation statements)

References 15 publications

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“…First, the sample size in this single-center study was not large enough. Nevertheless, the number of patients in the experimental groups (e.g., ABMR group, DSA + subgroup of the stable graft function group) was comparable with that of the previously published studies (25,28). Second, to further define the discriminative power of cfDNA fraction for complications of kidney transplants, investigators should include more samples with the other pathological lesions in future studies.…”

Section: Discussionsupporting

confidence: 59%

“…Bloom et al (22) found that cfDNA fraction was higher in ABMR group compared with TCMR group and cfDNA fraction tended to be higher in TCMR types ≥ IB than type IA, suggesting the association of cfDNA fraction with the severity of TCMR. Huang et al (25) supported this conclusion and demonstrated that cfDNA fraction was higher in ABMR compared with TCMR while cfDNA fraction was not able to discriminate TCMR from no rejection. However, Oellerich et al (23) and Sigdel et al (24) showed that cfDNA fraction increased in either ABMR or TCMR and it was unable to discriminate them.…”

Section: Discussionmentioning

confidence: 97%

“…In DSA positive patients, cfDNA fraction above the threshold could be used for diagnosing ABMR, which had better performance compared with in all the kidney allograft recipients with indicational biopsy (PPV 44%) (22). In 2019, Huang et al (25) also conducted a study with similar purpose, in which there were 7 patients with histologic findings suspicious for ABMR on biopsy who did not meet Banff 2013 criteria for ABMR given the absence of DSA. Only 2 of these 7 patients had a cfDNA <1.0%; the remaining 5 had high levels of cfDNA that ranged from 1.3 to 7.7%.…”

Section: Discussionmentioning

confidence: 99%

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Diagnostic Performance of Donor-Derived Plasma Cell-Free DNA Fraction for Antibody-Mediated Rejection in Post Renal Transplant Recipients: A Prospective Observational Study

Zhang

Zheng

et al. 2020

Front. Immunol.

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Objective: To evaluate the diagnostic performance of donor-derived plasma cell-free DNA (cfDNA) in discriminating antibody-mediated rejection (ABMR) or de novo donorspecific antibodies (DSA) without histological lesions in kidney allograft recipients. Methods:In this prospective single center observational study, we enrolled kidney allograft recipients between November, 2016 and September, 2017 at the First Affiliated Hospital of Sun Yat-sen University. Kidney allograft recipients with ABMR, de novo DSA but no histological lesions or negative DSA, and stable renal function were included. The plasma cfDNA fraction was measured using a targeted, single nucleotide polymorphism (SNP)-based assay. Pathological diagnosis was made according to the 2015 Banff Kidney Rejection Classification. The area under the ROC curve (AUC-ROC) was determined using the bootstrapping method to estimate median and 95% confidence interval (95% CI). The sensitivity, specificity and Youden index, positive predictive value (PPV), and negative predictive value (NPV) were calculated for specific cfDNA fractions.Results: Totally 37 consecutive patients received kidney allografts, including 18 recipients in the ABMR group and 19 recipients in the stable allograft group (7 DSApositive and 12 DSA-negative). All patients in the ABMR group were DSA positive and 7 patients in the stable group were DSA positive but had no pathologically proven ABMR. The median donor-derived plasma cfDNA fraction was 2.4% (Q1 1.52% -Q3 3.70%) in the ABMR group, and was significantly higher than that of the stable group (0.65%, Q1 Frontiers in Immunology | www.frontiersin.org February 2020 | Volume 11 | Article 342 Zhang et al.Donor-Derived cfDNA in Kidney ABMR 0.57% -Q3 0.97%; P < 0.001), but comparable with that of the DSA-positive patients in the stable allograft group (P = 0.074). The AUC-ROC of cfDNA was 0.90 (95% CI, 0.79-0.98). When a cfDNA threshold of 1% was chosen, it had a sensitivity of 88.9% and a specificity of 73.7%. The PPV was 76.2% and the NPV was 87.5%.Conclusion: Donor-derived plasma cfDNA fraction increased in kidney allograft recipients with ABMR. Detection of donor-derived plasma cfDNA fraction may contribute to the discrimination between ABMR and stable renal allograft function and may aid early recognition of earlier stage antibody-mediated injury.

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Section: Discussionsupporting

confidence: 59%

Section: Discussionmentioning

confidence: 97%

Section: Discussionmentioning

confidence: 99%

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Diagnostic Performance of Donor-Derived Plasma Cell-Free DNA Fraction for Antibody-Mediated Rejection in Post Renal Transplant Recipients: A Prospective Observational Study

Zhang

Zheng

et al. 2020

Front. Immunol.

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“…Early dd‐cfDNA studies identified that not all TCMR diagnoses were associated with an elevation of dd‐cfDNA and were criticized for missing some cases of TCMR 1A . However, could dd‐cfDNA be differentiating which TCMR 1As are true active rejection episodes with injury and which may be benign infiltrate without injury?…”

Section: Introductionmentioning

confidence: 99%

High levels of dd-cfDNA identify patients with TCMR 1A and borderline allograft rejection at elevated risk of graft injury

Stites

Kumar

Olaitan

et al. 2020

American Journal of Transplantation

112

111

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The clinical importance of subclinical, early T cell–mediated rejection (Banff TCMR 1A and borderline lesions) remains unclear, due, in part to the fact that histologic lesions used to characterize early TCMR can be nonspecific. Donor‐derived cell‐free DNA (dd‐cfDNA) is an important molecular marker of active graft injury. Over a study period from June 2017 to May 2019, we assessed clinical outcomes in 79 patients diagnosed with TCMR 1A/borderline rejection across 11 US centers with a simultaneous measurement of dd‐cfDNA. Forty‐two patients had elevated dd‐cfDNA (≥0.5%) and 37 patients had low levels (<0.5%). Elevated levels of dd‐cfDNA predicted adverse clinical outcomes: among patients with elevated cfDNA, estimated glomerular filtration rate declined by 8.5% (interquartile rate [IQR] −16.22% to −1.39%) (−3.50 mL/min/1.73 m2 IQR −8.00 to −1.00) vs 0% (−4.92%, 4.76%) in low dd‐cfDNA patients (P = .004), de novo donor‐specific antibody formation was seen in 40% (17/42) vs 2.7% (P < .0001), and future or persistent rejection occurred in 9 of 42 patients (21.4%) vs 0% (P = .003). The use of dd‐cfDNA may complement the Banff classification and to risk stratify patients with borderline/TCMR 1A identified on biopsy.

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“…For the diagnosis of ABMR, the AUC using ddcfDNA reached 0.91 (95% CI 0.82–0.98). Similarly, Huang and colleagues just recently evaluated ddcfDNA levels in 63 patients with suspicion of rejection and reported higher levels in patients with ABMR compared to those with no rejection ( P < 0.001) or cell‐mediated rejection ( P = 0.01) with an AUC for ABMR of 0.82 (95% CI: 0.71–0.93) . In contrast to the abovementioned studies, we focused on the early post‐transplant phase with a median time to sample collection of 8 days after transplantation.…”

Section: Discussionmentioning

confidence: 99%

Quantitative PCR of INDEL s to measure donor‐derived cell‐free DNA —a potential method to detect acute rejection in kidney transplantation: a pilot study

et al. 2019

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Summary The quantification of donor‐derived cell‐free DNA (ddcfDNA) in recipient's plasma is a novel, but technically challenging noninvasive method to assist the diagnosis of acute rejection (AR). A quantitative real‐time PCR (qPCR) approach targeting insertion/deletion polymorphisms (INDEL) was adapted to measure ddcfNA in plasma samples from 29 kidney transplant recipients obtained at time of clinically indicated biopsies (eight patients with a histologically verified AR, nine with borderline rejection and 12 without evidence of rejection). Measured ddcfDNA levels of smaller INDEL amplicon targets differed significantly (P = 0.016, Kruskal–Wallis H test) between recipients with biopsy‐proven AR (median 5.24%; range 1.00–9.03), patients without (1.50%; 0.41–6.50) and patients with borderline AR (1.91%; 0.58–5.38). Similarly, pairwise testing by Mann–Whitney U‐tests revealed significant differences between recipients with AR and without AR (P = 0.012) as well as patients with AR and borderline histology (P = 0.015). Receiver operating characteristic (ROC) analysis revealed an area under the ROC curve for discriminating AR and non‐AR biopsies of 0.84 (95% CI: 0.66–1.00). The determined cutoff value of 2.7% ddcfDNA showed a sensitivity of 0.88 (95% CI: 0.63–1.00) and specificity of 0.81 (95% CI: 0.64–0.98). INDEL qPCR represents a novel method to quantify ddcfDNA on standard qPCR instruments within 6–8 h with high sensitivity and specificity to detect AR.

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Early clinical experience using donor-derived cell-free DNA to detect rejection in kidney transplant recipients

Cited by 145 publications

References 15 publications

Diagnostic Performance of Donor-Derived Plasma Cell-Free DNA Fraction for Antibody-Mediated Rejection in Post Renal Transplant Recipients: A Prospective Observational Study

Diagnostic Performance of Donor-Derived Plasma Cell-Free DNA Fraction for Antibody-Mediated Rejection in Post Renal Transplant Recipients: A Prospective Observational Study

High levels of dd-cfDNA identify patients with TCMR 1A and borderline allograft rejection at elevated risk of graft injury

Quantitative PCR of INDEL s to measure donor‐derived cell‐free DNA —a potential method to detect acute rejection in kidney transplantation: a pilot study

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