BACKGROUND: Antibody-mediated rejection (AMR) remains associated with reduced kidney graft survival and no clear prognostic marker is available. METHODS: We investigated whether donor-specific antibodies (DSA) ability to bind C1q in comparison with AMR C4d status, both indirect signs of complement activation, improve risk stratification at time of AMR. Hence, among 467 patients in whom 1 or more graft biopsies were performed between 2008 and 2015, we included 56 with AMR according to Banff '15 criteria. Using concurrent sera, we prospectively identified DSA by single-antigen beads (IgG and C1q) assays. RESULTS: Antibody-mediated rejection C4d (+) (n = 28) was associated with preformed DSA (P = 0.007), whereas DSA C1q (+) (n = 25) cases had stronger IgG-DSA (P < 0.001). At AMR, graft function was similar between DSA C1q groups, but in the first year after, it improved in DSA C1q (-), whereas a steady decline was observed in DSA C1q (+) cases, remaining significantly lower from 1 year until 4 years after AMR. DSA C1q (+) was significantly associated with reduced graft survival (P = 0.021), whereas AMR C4d (+) was not (P = 0.550). Importantly, a similar negative impact of DSA C1q (+) on graft survival was observed within AMR C4d (+) (P = 0.040) and (-) (P = 0.036), cases. In multivariable analysis, DSA C1q (+) (hazard ratio, 3.939, P = 0.005) and de novo DSA (hazard ratio, 4.409, P = 0.033) were independent predictors of graft failure, but stronger IgG-DSA was not. Similar results were obtained considering C1q-DSA and IgG-DSA strength as continuous variables. CONCLUSIONS: C1q-DSA assessment at AMR can be a valuable tool in detecting patients with higher risk of graft failure.
BACKGROUND: Antibody-mediated rejection (AMR) remains associated with reduced kidney graft survival and no clear prognostic marker is available. METHODS: We investigated whether donor-specific antibodies (DSA) ability to bind C1q in comparison with AMR C4d status, both indirect signs of complement activation, improve risk stratification at time of AMR. Hence, among 467 patients in whom 1 or more graft biopsies were performed between 2008 and 2015, we included 56 with AMR according to Banff '15 criteria. Using concurrent sera, we prospectively identified DSA by single-antigen beads (IgG and C1q) assays. RESULTS: Antibody-mediated rejection C4d (+) (n = 28) was associated with preformed DSA (P = 0.007), whereas DSAC1q (+) (n = 25) cases had stronger IgG-DSA (P < 0.001). At AMR, graft function was similar between DSAC1q groups, but in the first year after, it improved in DSAC1q (-), whereas a steady decline was observed in DSAC1q (+) cases, remaining significantly lower from 1 year until 4 years after AMR. DSAC1q (+) was significantly associated with reduced graft survival (P = 0.021), whereas AMR C4d (+) was not (P = 0.550). Importantly, a similar negative impact of DSAC1q (+) on graft survival was observed within AMR C4d (+) (P = 0.040) and (-) (P = 0.036), cases. In multivariable analysis, DSAC1q (+) (hazard ratio, 3.939, P = 0.005) and de novo DSA (hazard ratio, 4.409, P = 0.033) were independent predictors of graft failure, but stronger IgG-DSA was not. Similar results were obtained considering C1q-DSA and IgG-DSA strength as continuous variables. CONCLUSIONS:C1q-DSA assessment at AMR can be a valuable tool in detecting patients with higher risk of graft failure.
Authors: Seline A Zwarthoff; Kevin Widmer; Annemarie Kuipers; Jürgen Strasser; Maartje Ruyken; Piet C Aerts; Carla J C de Haas; Deniz Ugurlar; Maurits A den Boer; Gestur Vidarsson; Jos A G van Strijp; Piet Gros; Paul W H I Parren; Kok P M van Kessel; Johannes Preiner; Frank J Beurskens; Janine Schuurman; Daniel Ricklin; Suzan H M Rooijakkers Journal: Proc Natl Acad Sci U S A Date: 2021-06-29 Impact factor: 11.205