Complement-Binding Donor-Specific Anti-HLA Antibodies: Biomarker for Immunologic Risk Stratification in Pediatric Kidney Transplantation Recipients

Abstract

Antibody-mediated rejection is a common cause of early kidney allograft loss but the specifics of antibody measurement, therapies and endpoints have not been universally defined. In this retrospective study, we assessed the performance of risk stratification using systematic donor-specific antibody (DSA) monitoring. Included in the study were children who underwent kidney transplantation between January 1, 2010 and March 1, 2018 at Stanford, with at least 12-months follow-up. A total of 233 patients were included with a mean follow-up time of 45 (range, 9–108) months. Median age at transplant was 12.3 years, 46.8% were female, and 76% had a deceased donor transplant. Fifty-two (22%) formed C1q-binding de novo donor-specific antibodies (C1q-dnDSA). After a standardized augmented immunosuppressive protocol was implemented, C1q-dnDSA disappeared in 31 (58.5%). Graft failure occurred in 16 patients at a median of 54 (range, 5–83) months, of whom 14 formed dnDSA. The 14 patients who lost their graft due to rejection, all had persistent C1q-dnDSA. C1q-binding status improved the individual risk assessment, with persistent; C1q binding yielding the strongest independent association of graft failure (hazard ratio, 45.5; 95% confidence interval, 11.7–177.4). C1q-dnDSA is more useful than standard dnDSA as a noninvasive biomarker for identifying patients at the highest risk of graft failure.

Association of HLA B‐ and T‐cell molecular mismatches with HLA antibodies, rejection, and graft survival in pediatric kidney transplantation

“…Nevertheless, four out of five dnDSAs appeared within 5 years posttransplant (Figure 1), consistent with other studies reporting a median time to detection of dnDSA of about 2-4 years. 36,37,45,52,53 We also speculated whether the low incidence of dnDSA could be due to a low number of HLA antigens or molecular incompatibilities. However, the observed median HLA antigen mismatch of five is comparable to other studies.…”

Association of Circulating Anti-HLA Donor-Specific Antibodies and Their Characteristics, including C1q-Binding Capacity, in Kidney Transplant Recipients with Long-Term Renal Graft Outcomes

“…It has been shown that circulating C1q-binding anti-HLA DSAs after therapeutic intervention for ABMR may reflect the effect of treatment and predict long-term allograft survival [ 51 ]. In a recent study, it was demonstrated that timely treatment with an augmented immunosuppressive protocol of C1q-binding anti-HLA DSA-associated ABMR, with early detection and elimination of C1q-binding anti-HLAs, may be associated with better outcomes [ 52 ]. A large multicenter randomized clinical trial is needed to assess the role of the C1q-binding capacity of anti-HLA DSAs in kidney transplant recipients.…”

Immune monitoring in pediatric kidney transplant

“…In a larger cohort of 233 pediatric kidney recipients, 52 (22%) of whom developed C1q + DSA were treated with intensified immunosuppression, intravenous immunoglobulin, and rituximab which lead to resolution of C1q + DSA in 58.5% of treated patients. In these two pediatric studies, all patients with graft loss due to rejection had persistent C1q + DSA 34 . A 2022 meta‐analysis of 26 studies estimated that patients with C1q + DSA had a 2.4 times increased risk of graft failure (95% CI 1.66–3.47, p < .00001) and a 3.13 times increased risk of death (95% CI 1.06–9.23, p = .04) compared to those with C1q‐DSA 35 .…”

“…In these two pediatric studies, all patients with graft loss due to rejection had persistent C1q + DSA. 34 A 2022 meta-analysis of 26 studies estimated that patients with C1q + DSA had a 2.4 times increased risk of graft failure (95% CI 1.66-3.47, p < .00001) and a 3.13 times increased risk of death (95% CI 1.06-9.23, p = .04) compared to those with C1q-DSA. 35 While C1q testing is available for clinical practice, its overall utility remains controversial due to the strong association between C1q binding activity and MFI 36 or antibody titer, 37 and studies suggesting that C1q binding activity measurements can be affected by diluting or concentrating the serum samples.…”