Chronic Kidney Dysfunction (Videos Available)

Wednesday July 04, 2018 from 09:45 to 10:45

Room: N-102

516.2 Role of C1q-binding donor-specific anti-HLA antibodies in premature and accelerated kidney allograft interstitial fibrosis

Abstract

Role of C1q-binding donor-specific anti-HLA antibodies in Premature and Accelerated Kidney Allograft Interstitial Fibrosis

Kevin Louis1, Denis Viglietti1, Olivier Aubert1, Alexandre Loupy1, Carmen Lefaucheur1.

1Paris Translational Research Center for Organ Transplantation, Paris, France

The last Banff meeting held in 2017 has focused on the importance of a precise diagnosis of interstitial fibrosis and tubular atrophy (IF/TA) in kidney recipients by addressing specific etiological factors. Recent studies showed a significant contribution of alloimmune factors (both T cell-mediated and antibody-mediated processes) to the development of IF/TA. This study investigated the role of donor-specific anti-HLA antibodies (DSAs) and their characteristics in the progression of IF/TA.
We prospectively included 1004 kidney recipients transplanted between 2004 and 2010, with systematic assessment of injury phenotype and IF/TA Banff score on allograft biopsies performed at 1 year after transplantation. All patients were assessed for anti-HLA DSAs and their characteristics (HLA class, de novo status, mean fluorescence intensity [MFI], C1q-binding capacity) at 6 months post-transplant. Patients were followed up to 8 years and we integrated all for cause biopsies performed beyond 1 year (N=539) to assess IF/TA progression.
We identified 416 (41%) patients with IF/TA0 score, 278 (28%) patients with IF/TA1 score, 165 (16%) patients with IF/TA2 score and 145 (15%) patients with IF/TA3 score. The prevalence of anti-HLA DSAs increased with IF/TA severity: 79/416 (19%) in IF/TA0 patients, 67/278 (24%) in IF/TA1 patients, 47/165 (28%) in IF/TA2 patients and 52/145 (36%) in IF/TA3 patients. DSA MFI level was positively correlated with IF/TA severity (rho=0.21, p=0.001), with MFI of 3543±3167 in IF/TA0 patients, 4093±4779 in IF/TA1 patients, 5071±5391 in IF/TA2 patients and 7816±6222 in IF/TA3 patients. C1q-binding anti-HLA DSA prevalence also increased with IF/TA severity: 14/416 (3%) in IF/TA0 patients, 13/278 (5%) in IF/TA1 patients, 17/165 (10%) in IF/TA2 patients and 24/145 (17%) in IF/TA3 patients (p<0.001). Among all DSA characteristics, C1q binding was the most important one to predict the severity of IF/TA in random forest analysis (mean decrease in model accuracy: 22%). Patients with C1q-binding DSA had a higher IF/TA score at 1 year post-transplant compared to patients with non-C1q-binding DSA (1.8±1.2 vs. 1.1±1.1, p<0.001), increased microvascular inflammation (p<0.001) and C4d deposition in peritubular capillaries (p<0.001), and they exhibited accelerated progression of IF/TA (p=0.02) beyond 1 year post-transplant.
C1q-binding anti-HLA DSAs are associated with premature and accelerated kidney allograft fibrosis, with a biological gradient between DSA C1q-binding ability and fibrosis severity, suggesting a causal effect of anti-HLA DSAs in an alloimmune subtype of allograft fibrosis.



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