Antibodies against ARHGDIB are associated with long-term kidney graft loss

Abstract

The clinical significance of non-HLA antibodies on renal allograft survival is a matter of debate, due to differences in reported results and lack of large-scale studies incorporating analysis of multiple non-HLA antibodies simultaneously. We developed a multiplex non-HLA antibody assay against 14 proteins highly expressed in the kidney. In this study, the presence of pretransplant non-HLA antibodies was correlated to renal allograft survival in a nationwide cohort of 4770 recipients transplanted between 1995 and 2006. Autoantibodies against Rho GDP-dissociation inhibitor 2 (ARHGDIB) were significantly associated with graft loss in recipients transplanted with a deceased-donor kidney (N = 3276) but not in recipients of a living-donor kidney (N = 1496). At 10 years after deceased-donor transplantation, recipients with anti-ARHGDIB antibodies (94/3276 = 2.9%) had a 13% lower death-censored covariate-adjusted graft survival compared to the anti-ARHGDIB-negative (3182/3276 = 97.1%) population (hazard ratio 1.82; 95% confidence interval, 1.32-2.53; P = .0003). These antibodies occur independently from donor-specific anti-HLA antibodies (DSA) or other non-HLA antibodies investigated. No significant relations with graft loss were found for the other 13 non-HLA antibodies. We suggest that pretransplant risk assessment can be improved by measuring anti-ARHGDIB antibodies in all patients awaiting deceased-donor transplantation.

Keywords: ARHGDIB; kidney transplantation; non-HLA antibodies.

Figure 1

Impact of cut‐off for the presence of non‐HLA antibodies against ARHGDIB on graft survival. A, In this figure the hypothesis is displayed that the presence of a non‐HLA antibody is associated with graft failure. B, Using acquired data from non‐HLA measurements, we determined the difference in graft survival between the non‐HLA antibody negative and positive group for various cut‐off values at 1, 5, and 10 years after transplantation in a univariate Kaplan‐Meier analysis. Here, the results for directly coupled ARHGDIB are used as an example. The highest difference in graft survival between the ARHGDIB‐positive and ‐negative group was achieved with a cut‐off for signal‐to‐background ratio of 10 in combination with a cut‐off for absolute MFI of 500. The graft survival difference for this cut‐off between the ARHGDIB‐positive and ‐negative group was 5.9%, 10.9%, and 13.1% at 1, 5, and 10 years after transplantation, respectively. C, Shown are the percentages of ARHGDIB‐positive patients for each cut‐off. For the selected cut‐off there are 2.8% (134 of 4770) positive patients [Color figure can be viewed at http://www.wileyonlinelibrary.com]

Figure 2

Graft survival according to the presence of pretransplant non‐HLA antibodies in deceased donor and living‐donor kidney transplantation. Inverse probability weighting (IPW) adjusted Kaplan‐Meier estimate (AKME) for death‐censored graft survival according to the presence of ARHGDIB in 3276 deceased (A) and 1494 living‐donor (B) transplantations. AKME was adjusted for the following covariates: recipient age (quadratic) and donor age (quadratic), cold ischemia time (for donation after brain death and donation after cardiac death), time on dialysis in years (quadratic), induction therapy with IL‐2 receptor blocker, and the presence of pretransplant donor‐specific anti‐HLA antibodies (DSA) [Color figure can be viewed at http://www.wileyonlinelibrary.com]

Figure 3

ARHGDIB expression in the kidney. A, In a transplanted kidney without histological abnormalities, weak ARHGDIB expression is seen in endothelial cells of interlobular arteries (large arrows), endothelial cells of peritubular capillaries (small arrows), and endothelial cells of glomerular capillaries (arrow heads). B, In a transplanted kidney with acute tubular necrosis, strong ARHGDIB expression is seen in endothelial cells of interlobular arteries (large arrows), endothelial cells of peritubular capillaries (small arrows), and endothelial cells of glomerular capillaries (solid arrow heads). In addition, positive staining for ARHGDIB is also seen in some podocytes (open arrow heads) and lymphocytes (asterisks) [Color figure can be viewed at http://www.wileyonlinelibrary.com]