Novel Candidate Markers Characterizing Cellular Senescence in Aged Zero Hour Kidney Biopsies Predict Post Transplant Outcome.

Abstract

Advanced donor age adversely affects allograft outcome following renal transplantation.Candidate genes involved in cellcycle regulation and telomere shortening have been already described as markers for cellular senescence.There is still a lack of biomarkers for defining older and marginal organs in order to adopt immunosuppression for improved long-term outcome.To characterize senescence in the donor organ, we first studied gene expression for selected candidate markers(CM) in a small sample cohort of 57 zero hour kidney biopsies derived from deceased donors.Among them 26 biopsies were derived from donors>55 yrs(mean66.5±7.4) and 31 specimens were derived from donors<55 yrs(mean 41.35±8.4).Compared with younger donors,elderly donors revealed a significant de novo mRNA expression of CM including immunoproteasome subunits PSMB8,9,10;(p<0.001 respectively), MHC classII transcripts including HLA-DRB(p<0.01)or transcripts of the receptor NKG2D(p=0.0036).Next, we confirmed gene expression of CM in an independent patient cohort consisting of 139 biopsy samples.Based on sample size,3 groups were defined according to donor age:0-30yrs(group I,21±4.9yrs,n=30),31-54yrs(group II, 46.5±6.6yrs,n=50)and>55 yrs(group III,64.07±7yrs,n=59).Whereas no differences were observed between group I and group II, aged kidneys(group III) revealed a significant gene expression of PSMB9(p=0.0405) and PSMB10(p=0.0223) compared with middle aged kidneys(group II).In addition,HLA-DRB(p=0.0215) and PSMB9(p=0.0129) were significantly induced in group III in comparison with group I.Strikingly,transcripts of the activating NK cell receptor NKG2D revealed the highest gene induction in group III versus group II and group I(p<0.001,respectively) indicating enhanced infiltration of NKG2D+ CD8+ T cells or NK cells in elderly kidneys. Linear restriction analysis revealed a strong correlation especially for pre-transplant NKG2D mRNA expression with serum creatinine levels at hospital discharge(p=0.0003), at 3months(p=0.004) and at 6months post transplantation(p=0.0031).Our results reveal novel candidate markers in aged renal allografts providing help in the assessment of organ quality and implicating the potential of pretreatment strategies.