Molecular Patterns of Subclinical and Clinical Rejection of Kidney Allograft: Quantity Matters

Abstract

Background/Aims: Subclinical rejection diagnosed from protocol biopsies is thought to be a risk factor of long- term allograft dysfunction. The reason why in some patients subclinical rejection does not represent risk for progression is not fully understood. Methods: The intragraft expression of 376 target genes involved in chemokine defense, apoptosis, inflammation, tolerance and TGF-β signalling pathways was measured using quantitative real-time RT-PCR (2^-∆∆^Ct) method in subclinical inflammation (SCI, n=10), clinical inflammation in acute T-cell mediated rejection (CI, n=10) and no rejection samples (n=9). Results: Clinical inflammation group showed a increased expression of genes for chemotaxis mediating cytokines (CCL1, CCL17, CCL24, CCL25, CCL26), cytokine receptors (CCR1, CCRL2, IL1RAPL2, CXCR5), proinflammatory cytokines (IL12A, LTA), inflammatory mediator (PTAFR), complement protein C3, executioner protein of apoptosis (CASP7), growth factor (TGFA), colony stimulating factor (CSF-2), proteins involved in dendritic cells differentiation and interaction (CD209, LAMP3), regulation of immune response (LILRB2, LILBRB4). The quantitative difference in transcripts signature between SCI and CI is consistent with stronger proinflammatory setting of CI. Prostaglandin E2 receptor gene expression was independently associated with lower risk of further graft function deterioration (OR 0.11, CI 0.01-0.78, p<0.0001). Conclusion: Subclinical acute kidney inflammation has transcriptional profile of immune injury of lower extend compared to clinical acute inflammation.

Early Predictors of Acute Kidney Injury: A Narrative Review

“…In the study of AKI following cardiac surgery, IL-6 was increased in AKI group within 6 h postoperatively, with the sensitivity in diagnosing AKI reaching 88% [95]. For kidney allograft, compared to clinical acute inflammation, subclinical acute kidney inflammation has lower extend of transcriptional profile of immune injury and inflammatory mediator such as cytokine receptors (CCRL2, CCR1, CXCR5, IL1RAPL2), proinflammatory cytokines (LTA, IL12A), complement protein C3 and inflammatory mediator (PTAFR) [96].…”

Key driver genes as potential therapeutic targets in renal allograft rejection

“…Second, our meta-analysis incorporated both clinical cases of AR (identified on indication biopsies) and subclinical cases (AR identified on protocol biopsies), and the significance of subclinical rejection with subsequent graft loss has been the subject of some debate. However, our group has shown in a multicenter prospective GoCAR cohort that allografts with subclinical rejection at 3 months posttransplant have reduced allograft survival (26), and studies that evaluated the gene expression profile of biopsies with clinical AR and subclinical AR suggest the 2 entities represent a continuum of alloimmune activation and are not distinct (79,80). Our findings here support these observations, with significant correlation of KDG expression with subsequent graft loss in both our GoCAR data set comprising protocol biopsies samples and the external validation data set comprising indication biopsies.…”

Lymphotoxin expression in human and murine renal allografts

“…Other groups have shown expression of LTα in acutely rejecting kidney grafts [ 26 , 47 ]. Using cDNA from the ERCB-KFB, we confirmed these findings and also detected robust upregulation of LTβ, and LIGHT in borderline rejection and AR when compared to controls from kidney biopsies of living donors before implantation ( Fig 3 ).…”