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Transplantation. 2019 Oct 14. doi: 10.1097/TP.0000000000003005. [Epub ahead of print]

Antibodies against ARHGDIB and ARHGDIB gene expression associate with kidney allograft outcome.

Author information

1
Histocompatibility and Immunogenetics Laboratory, Red Cross-Flanders, Mechelen, Belgium.
2
Department of Microbiology, Immunology and Transplantation, KU Leuven, University of Leuven, Belgium.
3
Laboratory of Translational Immunology, University Medical Center Utrecht, Utrecht, Netherlands.
4
Department of Imaging & Pathology, University Hospitals Leuven, Leuven, Belgium.
5
Department of Nephrology and Renal Transplantation, University Hospitals Leuven, Leuven, Belgium.

Abstract

BACKGROUND:

The impact of donor-specific anti-HLA antibodies (DSA) on antibody-mediated rejection (AMR) and kidney allograft failure is well established. However, the relevance of non-HLA antibodies remains unclear.

METHODS:

We investigated 13 pretransplant non-HLA antibodies and their association with histology of AMR (AMRh) and kidney allograft failure. We included single kidney recipients (N=203) with AMRh according to the Banff 2017 classification, and matched AMRh-free controls (N=219). Non-HLA antibodies were assessed using multiplex Luminex assay.

RESULTS:

Of the selected non-HLA antibodies (against agrin, APMAP, ARHGDIB, ARHGEF6, AT1R, ETAR, LMNB1, LPLUNC1, PECR, PLA2R, PRKCZ, TUBB4b, vimentin), only antibodies against Rho GDP-dissociation inhibitor 2 (ARHGDIB) (adjusted MFI [aMFI]≥1000), a minor histocompatibility antigen, associated with graft failure, in univariate and multivariate models (HR=2.7;95%CI,1.3-5.4;p=0.007). There was a 19.5-fold (95%CI,6.0-63.9;p<0.0001) increased risk of graft failure in patients positive for both DSA and anti-ARHGDIB antibodies (aMFI≥1000) versus patients negative for both DSA and anti-ARHGDIB antibodies, compared to a 4.4-fold (95%CI,2.4-8.2,p<0.0001) increased risk in patients with only DSA, and a 4.1-fold (95%CI,1.4-11.7;p=0.009) increased risk in patients with only anti-ARHGDIB antibodies above 2000 aMFI. AMRh associated with increased intrarenal expression of the ARHGDIB gene. In the absence of AMRh and DSA, anti-ARHGDIB antibodies were not clearly associated with graft failure.

CONCLUSIONS:

The presence of pretransplant anti-ARHGDIB antibodies has an additive effect in patients with DSA on the risk of graft failure via AMRh. Other investigated non-HLA antibodies, including antibodies against AT1R, did not contribute to risk stratification and could not explain the histology of AMR in the absence of DSA.

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