Background

Antibody-mediated rejection (ABMR) is characterized by a heterogeneous presentation. It occurs in clinically stable patients (sABMR) or in patients with allograft dysfunction (ABMR), but only little is known about the similitudes or discrepancies between the molecular landscape of sABMR and ABMR. We investigated whether sABMR and ABMR are associated with specific gene expression signatures in kidney allografts.

Methods

We studied 1260 consecutive kidney recipients and included patients with ABMR. We used an integrative analysis strategy comprising a systematic assessment of clinical-biological parameters, transplant characteristics, histopathology, immunohistochemistry, type of treatment and circulating anti-HLA DSA assessment at day of transplant and at the time of ABMR for all patients using Luminex SA assay.

Results

Among the 131 patients with ABMR, 99 (76%) had a clinical ABMR while 32 (24%) were sABMR. Clinical ABMR displayed a worse kidney allograft function (mean eGFR: 34.45 vs 48.24 mL/min/1.73m², p<0.001) and an increased proteinuria rate (mean proteinuria: 0.54 vs 0.31 g/g creatinine, p=0.041) compared to sABMR. Patients with clinical ABMR exhibited more C4d graft deposition (n=50 (51%) vs n=9 (29%); p=0.02), more endarteritis (mean v score: 0.38 ± 0.72; p=0.010) and more interstitial inflammation (mean i score: 0.84 ± 1.05 vs 0.375 ± 0.61; p= 0.043) compared to sABMR. Allograft gene expression showed that patients with clinical ABMR exhibited significantly more injury-repair response transcripts (p<0.001), more macrophage associated transcripts (p=0.003) and a trend towards more IFNG production and inducible transcripts (p=0.066). We compared the top 10 ABMR-related transcripts with their corresponding values (t-test) in sABMR. Among the transcripts differentially expressed between the 2 groups, five were AKI associated (LCN2, LTF, SERPINA3, SLPI and PTX3) and two were macrophages associated (CD163 and MSR1). A principal component analysis integrating the histological and molecular parameters identified a distinct histo-molecular allograft rejection phenotype in patients with clinical ABMR compared with patients with sABMR.

Conclusion

Subclinical ABMR is associated with a distinct histo-molecular phenotype of kidney allograft rejection mainly driven by AKI and macrophage burden, which could explain the difference in term of allograft survival.

CITATION INFORMATION: Aubert O, Lefaucheur C, Higgins S, Hidalgo L, Duong Van Huyen J, Viglietti D, Jouven X, Glotz D, Legendre C, Halloran P, Loupy A. Gene Expression Signature of Subclinical Allograft Kidney ABMR Compared to Clinical ABMR. Am J Transplant. 2017;17 (suppl 3).

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