Defining Response to Standard of Care Treatment of Kidney Recipients with Antibody-Mediated Rejection: Role of C1q-binding Donor-specific Anti-HLA Antibodies

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A major hurdle to improving clinical care in kidney transplantation is the lack of biomarkers of the response to antibody-mediated rejection (ABMR) treatment. We investigated the role of C1q-binding donor-specific anti-HLA antibodies (DSAs) in defining the response to standard of care (SOC) treatment in kidney recipients with ABMR.Among 1196 kidney recipients transplanted between 2008 and 2011, we prospectively enrolled all patients with biopsy-proven active ABMR according to the most recent Banff criteria, who received SOC treatment, including plasma exchange, high-dose intravenous immunoglobulin, rituximab and steroids. Response to treatment was evaluated 3 months after ABMR diagnosis based on the kinetics of glomerular filtration rate (GFR), proteinuria, histology, DSA mean fluorescence intensity (MFI) and C1q-binding status, and correlated to allograft survival at 6 years.We included 139 pts with ABMR diagnosed at a median time of 16 months post-transplant receiving the SOC. According to C1q-binding DSA kinetics, we identified 4 groups: C1q-negative patients at diagnosis and post-treatment (C1q-/C1q-, N=43, 31%), patients with C1q-positive DSA at diagnosis and C1q-negative DSA post-treatment (C1q+/C1q-, N=58, 42%), C1q-positive patients at diagnosis and post-treatment (C1q+/C1q+, N=33, 24%), patients with C1q-negative DSA at diagnosis and C1q-positive DSA post-treatment (C1q-/C1q+, N=5, 3%). Responders to treatment included C1q-/C1q- and C1q+/C1q- patients, who showed improved GFR between ABMR diagnosis and post-treatment evaluation (39 vs 43 mL/min, p=0.04 and 29 vs 39 mL/min, p<0.001, respectively), decreased microvascular inflammation (p<0.001 for both) and tubulo-interstitial inflammation (p=0.01 and p<0.001, respectively), and reduced DSA MFI level (p<0.001 for both). Non-responders to treatment were defined by i) C1q+/C1q+ patients, showing no improvement in GFR (30 vs 31 mL/min, p=0.74) and no reduction in microcirculation inflammation (p=0.25), tubulo-interstitial inflammation (p=0.05) and in DSA MFI level (p=0.63), and ii) C1q-/C1q+ patients, who showed worsening GFR (39 vs 25 mL/min, p=0.04) and no reduction in microcirculation inflammation (p=0.48), tubulo-interstitial inflammation (p=0.78) and in DSA MFI level (p=0.08). Responders to treatment exhibited higher 6-year allograft survival compared to non-responders (83% vs 44%, p<0.001).The kinetics of C1q-binding anti-HLA DSAs identifies distinct profiles of response to SOC treatment in kidney recipients with ABMR by reflecting the functional and histological courses under treatment.

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