Molecular diagnostics identifies risks for graft dysfunction despite borderline histologic changes

Abstract

The significance of borderline changes in kidney allograft biopsies is widely debated. To help resolve this, we studied differences in intrarenal gene expression patterns between early clinical and 3-month protocol biopsies, all of which had borderline histologic changes. The gene expression profiles in training set of patients by microarray analysis and data were validated in a larger cohort using RT-qPCR. There was greater expression of immunity- and inflammation-related genes in the early clinical biopsies compared to the 3-month protocol biopsies with borderline changes. In early clinically manifested borderline changes, graft deterioration within 24 months due to chronic rejection was associated with increased activation of immune, defense, and inflammatory processes. Regression modeling identified higher donor age and expression of macrophage receptor CLEC5A as risk factors for progression. In the 3-month protocol biopsies with borderline changes, graft dysfunction was associated with increased expression of fibrinogen complex transcripts. The discrimination power of fibrinogen was confirmed by cross-validation on two independent cohorts. Thus, our study highlights variations in gene expression between clinical and subclinical borderline changes despite similar histological findings. The data also support a recommendation for frequent patient monitoring, especially in those with borderline changes who received grafts from older donors.

Review: The transcripts associated with organ allograft rejection

“…Other published studies of rejection-associated transcripts [40][41][42][43][44][45][46] differ in platforms, histologic classifications, case mix, and organs studied, which complicates direct comparisons. We have related our rejection transcripts to lists of transcripts associated with "acute rejection": Table 2).…”

“…Other published studies of rejection-associated transcripts [40][41][42][43][44][45][46] differ in platforms, histologic classifications, case mix, and organs studied, which complicates direct comparisons. We have related our rejection transcripts to lists of transcripts associated with "acute rejection": IFNG-inducible chemokines CXCL10, CXCL11 CXCL9, CXCL10, CXCL11, -IFNG-inducible enzymes, small molecules PLA1A APOL3, BTN3A3, FAM26F,GBP1, GBP2, GBP4, GBP5, IDO1, IRF1, PLA1A, WARS ANKRD22, APOL2, GBP5 43 ; Acute Rejection Transcripts in kidney (ARTs) 48 ; and clinical Acute Rejection (cAR) in kidney.…”

Transcriptome Analysis in Renal Transplant Biopsies Not Fulfilling Rejection Criteria

“…This study showed that the borderline category is usually no rejection, and it can be associated with acute kidney injury and inflammatory primary renal diseases, suggesting that the treatment in these cases should not be focused on renal allograft rejection [43]. In contrast, Hrubá et al observed an increase in immunity and inflammation genes in biopsies for clinical indication with borderline changes performed early in comparison with borderline 3-month protocol biopsies [44]. This increase observed within two weeks of transplantation may be influenced by the initial alloimmune response and by the ischemic injury as well.…”

IL-6 production by monocytes is associated with graft function decline in patients with borderline changes suspicious for acute T-cell-mediated rejection: a pilot study

“…Our findings are also consistent with recent gene expression profile microarray data from renal biopsies of patients with BL. Hruba et al [23] observed and validated that donor age and expression of the macrophage receptor C-type lectin domain family 5 member A (CLEC5A) were independent factors of progression in patients with BL. CLEC5A expression is prominent on recruited blood monocytes that enter the tissue upon inflammation and differentiate into proinflammatory cells [24].…”

“…After 72 h, flow cytometry evaluation revealed decreased proliferation of CFSElabeled CD8 + and CD4 + T cells cocultured with kidney DCs compared with splenic DCs (*P = 0.02, n = 3 in each group) (e) A 10-fold lower IL-2 levels were observed when CD8 + T cells were cocultured with kidney DCs compared with splenic DCs (n = 2 in each group). examining gene expression profile in patients with BL [23]. Furthermore, the magnitude of the association observed between DeGFR and IL-6 levels is clinically relevant.…”