Elevated intragraft expression of innate immunity and cell death-re­la­ted markers characterizes deceased donor conditions and is a risk factor for adverse graft outcome

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J. Yang, G. Haasnoot, C. van Kooten, M.J.K. Mallat, H.J.W. de Fijter, I. Bajema, F.H.J. Claas, M. Eikmans

Chair(s): dr. Dennis A. Hesselink, internist-nefroloog, Erasmus MC & dr. Marieke Roemeling, internist i.o., UMC Groningen

Wednesday 9 march 2016

16:20 - 16:30h at Zaal 1 & 2

Categories: Parallelsessie (klinisch)

Parallel session: Parallelsessie V - Klinisch

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Background:
The innate immune response, including the Toll-like receptors (TLRs) and the complement system, is increasingly being recognized in allograft injury after kidney transplantation. We aimed to establish the relationship between innate immune gene expression at the moment of implantation or acute rejection and graft outcome.

Method:
A total of 19 genes, including TLRs, complement components and regulators, and apoptosis-related genes, were analyzed at the mRNA level by qPCR in 123 biopsies with acute rejection (AR) and paired pre-implantation biopsies (n=75), within the first 6 months post-transplant. Expression levels before transplantation were tested in relation to the type of donor (deceased or living; making up 78% and 22%, respectively, of the group) and occurrence of delayed graft function (DGF). The expression levels during AR were investigated for association with steroid-responsiveness and graft loss.

Results:
Before transplantation, expression of C2, C3, and the Bax/Bcl2 ratio were significantly higher (P<0.01) in tissue samples from deceased donors as compared to living donors. Within the deceased donor group there were no associations between gene expression and DGF. During AR, all TLRs and C2 and C3 showed increased expression compared with pre-implantation conditions whereas three complement regulators and C4 and Bcl2 showed decreased expression. During AR, expression of none of the genes was associated with steroid response. However, relatively high TLR4 expression and Bax/Bcl2 ratio at time of AR were related to adverse graft outcome. Fifteen patients with a high Bax/Bcl2 ratio in their deceased donor graft (higher than that in the living donor group) had significantly (P<0.05) worse death-censored graft survival (61.3%) at 6-year post-transplant compared to those with a low ratio (89.4%) and those with a living donor graft (95.8%). In Cox regression analysis, TLR4 and Bax/Bcl2 ratio in the deceased donor group predicted outcome independently of previously identified clinical risk factors of graft loss.

Conclusion:
The elevated expression of C2, C3, and Bax/Bcl2 ratio in deceased donor transplants supports the notion that complement and apoptosis pathway activity is already enhanced before kidney transplantation. The relationship of high Bax/Bcl2 ratio during AR with graft loss may point to an adverse effect of intragraft cell death, and thereby possibly enhanced immunogenic danger signals, on graft outcome.