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

Huanxi Zhang,Qun Su,Longshan Liu,Huiting Huang,Liuhong Zeng,Zu Liu,Xirui Li,Chunting Zheng,Jiali Wang,Mingzhi Ye,Jun Li,Bowen Xu,Changxi Wang,Qian Fu

doi:10.3389/fimmu.2020.00342

Abstract

ObjectiveTo evaluate the diagnostic performance of donor-derived plasma cell-free DNA (cfDNA) in discriminating antibody-mediated rejection (ABMR) or de novo donor-specific antibodies (DSA) without histological lesions in kidney allograft recipients.MethodsIn 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.ResultsTotally 37 consecutive patients received kidney allografts, including 18 recipients in the ABMR group and 19 recipients in the stable allograft group (7 DSA-positive 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 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%.ConclusionDonor-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.

Highlights

Antibody-mediated rejection (ABMR) is an important determinant of long-term outcome of kidney allografts [1]
When a cell-free DNA (cfDNA) threshold of 1% was chosen, it had a sensitivity of 88.9% and a specificity of 73.7%
Our receiver operating characteristic (ROC) analysis further showed an AUC of 0.90, suggesting that donor-derived plasma cfDNA fraction is of good diagnostic performance

Summary

Introduction

Antibody-mediated rejection (ABMR) is an important determinant of long-term outcome of kidney allografts [1]. Kidney needle biopsy, though invasive and cost ineffective, remains the gold standard for diagnosis of ABMR. Serum creatinine often leads to delayed or missed diagnosis of ABMR due to its suboptimal sensitivity and specificity. Subclinical ABMR cannot be detected by monitoring serum creatinine. Circulating donor specific antibodies (DSAs) against human leukocyte antigens (HLA) promote ABMR development [2]. Only 30–40% DSA positive kidney allograft recipients develop ABMR [3].

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Conclusion