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

Abstract

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.