Sodium Bicarbonate and Non-HLA Autoantibody or HLA Antibody Trajectories in Long-term Kidney Transplant Recipients With Metabolic Acidosis: A Post Hoc Analysis of the Preserve-Transplant Randomized Controlled Trial

Background. Long-term kidney allograft loss remains a major challenge, driven in part by chronic allograft injury, microvascular inflammation, and antibody-mediated rejection. Beyond HLA donor-specific antibodies, non-HLA autoantibodies such as angiotensin II type 1 receptor (AT1R) and endothelin receptor type A (ETAR) antibodies may contribute. Metabolic acidosis, common after transplantation, has been linked to inflammatory activation, endothelial dysfunction, and upregulation of angiotensin II, aldosterone, and endothelin-1 pathways. Together, these findings raise the hypothesis that metabolic acidosis may contribute to chronic alloimmune and profibrotic injury by amplifying vasculopathy, antibody-mediated microvascular inflammation, and consequently long-term graft dysfunction. Methods. This post hoc analysis used prospectively collected data and biobank samples from a randomized, placebo-controlled trial of oral sodium bicarbonate in stable long-term kidney transplant recipients with metabolic acidosis (Preserve-Transplant Study). Non-HLA autoantibodies (AT1R-, ETAR-Abs) and HLA antibodies were measured at baseline and 24 mo, alongside allograft function, acid–base parameters, and immunosuppression. Results. AT1R and ETAR antibodies were highly prevalent in the study population. We found no evidence of differences in autoantibody levels between the sodium bicarbonate and control groups over 24 mo. Similarly, donor-specific antibodies and cumulative mean fluorescence intensity (MFI) of overall HLA antibodies did not differ between treatment groups. Furthermore, baseline non-HLA autoantibody levels or positivity for both AT1R- and ETAR-Abs were not associated with estimated glomerular filtration rate (eGFR) slope, whereas cumulative MFI of overall HLA antibodies and donor-specific antibodies were associated with eGFR slope. Conclusions. In this post hoc analysis of a randomized controlled trial with stable long-term kidney transplant recipients, we found no evidence to suggest differences in antibody levels of non-HLA autoantibodies (AT1R- and ETAR-Abs) or cumulative MFI of HLA antibodies, including formation of donor-specific antibodies, between the sodium bicarbonate and control groups over 24 mo. Baseline non-HLA autoantibodies were not associated with eGFR slope. These exploratory findings require confirmation in larger prospective studies.