Abstract
Chronic antibody-mediated rejection (AMR) is a key limiting factor for the clinical outcome of a kidney transplantation (Ktx), where early diagnosis and therapeutic intervention is needed. This study describes the identification of the biomarker CXC-motif chemokine ligand (CXCL) 9 as an indicator for AMR and presents a new aptamer-antibody-hybrid lateral flow assay (hybrid-LFA) for detection in urine. Biomarker evaluation included two independent cohorts of kidney transplant recipients (KTRs) from a protocol biopsy program and used subgroup comparisons according to BANFF-classifications. Plasma, urine and biopsy lysate samples were analyzed with a Luminex-based multiplex assay. The CXCL9-specific hybrid-LFA was developed based upon a specific rat antibody immobilized on a nitrocellulose-membrane and the coupling of a CXCL9-binding aptamer to gold nanoparticles. LFA performance was assessed according to receiver operating characteristic (ROC) analysis. Among 15 high-scored biomarkers according to a neural network analysis, significantly higher levels of CXCL9 were found in plasma and urine and biopsy lysates of KTRs with biopsy-proven AMR. The newly developed hybrid-LFA reached a sensitivity and specificity of 71% and an AUC of 0.79 for CXCL9. This point-of-care-test (POCT) improves early diagnosis-making in AMR after Ktx, especially in KTRs with undetermined status of donor-specific HLA-antibodies.
Highlights
Kidney transplantation (Ktx) is the most frequent transplantation worldwide, but transplant survival is limited by a high incidence of late antibody-mediated rejection (AMR) [1,2]
Since AMR is a major risk for late transplant function loss [48,49], reliable and timely diagnosis making of AMR after Ktx is of major clinical importance
Some but not all papatients with AMR exhibited increased serum creatinine, which is supported by a recent tients with AMR exhibited increased serum creatinine, which is supported by a recent molecular in-depth analysis of indication biopsies [50] that frequently turns out to be acute molecular in-depth analysis of indication biopsies [50] that frequently turns out to be acute kidney injury and/or chronic kidney disease rather than transplant rejection in patients kidney injury and/or chronic kidney disease rather than transplant rejection in patients with low eGFR
Summary
Kidney transplantation (Ktx) is the most frequent transplantation worldwide, but transplant survival is limited by a high incidence of late antibody-mediated rejection (AMR) [1,2]. It has been shown that circulating DSAs in KTRs with an inconspicuous clinical course do not necessarily indicate ongoing rejection of the graft, and in some cases with a histological finding suspicious for AMR, single antigen HLA-DSA cannot be identified by solid phase assays (SPA) and new methods for HLA antibody screening were built up [7,8]. This has been demonstrated in a recent cross-sectional analysis of stable recipients with DSA-positivity 6 months post
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