B3GALT5 regulates renal A/B antigen levels: a determinant of prognosis and rejection in ABO-incompatible kidney transplantation

Background: ABO-incompatible (ABOi) kidney transplantation alleviates the shortage of donor kidneys. However, interventions targeting blood group antibodies alone cannot fully prevent antibody-mediated rejection. We investigated how blood group antigens affect prognosis and rejection in ABOi kidney transplantation and explored their regulatory mechanisms. Methods: We prospectively enrolled 28 consecutive ABOi kidney transplant recipient-donor pairs. We performed immunohistochemical staining for A/B antigens on intraoperative donor kidney biopsies. Graft A/B antigen expression levels were assessed in relation to post-transplant anti-A/B antibody titres, graft function, and rejection. We used transcriptome sequencing, immunohistochemistry, immunofluorescence, Western blotting, and polymerase chain reaction to preliminarily explore the regulatory mechanisms of blood group antigens. Results: We identified three expression levels of antigen A (strong, medium, and weak) and two of antigen B (strong and weak) in the grafts. Recipients of grafts with strong antigen expression showed a numerically higher proportion of immunoglobulin M (IgM) elevation. Three recipients developed blood group antibody-mediated rejection, and their graft blood group antigen levels were higher than those in other individuals (difference = 10,301.8; 95% confidence interval (CI) = 4,389.5, 14,413.2, uncorrected P = 0.0088). Recipients of grafts with weak antigen expression exhibited an improvement in estimated glomerular filtration rate within one month post-transplant (regression coefficient = 15.13; 95% CI = 0.172, 30.077, uncorrected P = 0.047). Additionally, B3GALT5, B3GNT3, and FUT9 were significantly correlated with renal blood group antigen levels, and B3GALT5 overexpression reduced blood group A antigen levels in human kidney-2 and human umbilical vein endothelial cells. Conclusions: Graft A/B antigen expression levels may be associated with anti-A/B IgM/immunoglobulin G titres, renal function, and rejection, but these findings are exploratory and require validation in larger cohorts. Furthermore, B3GALT5 shows a significant correlation with renal blood group antigen levels, and modulation of B3GALT5 can alter blood group antigen expression.