title: Cellular senescence in pretransplant renal biopsies predicts postoperative organ function.
abstract: Older and marginal donors have been used to meet the shortfall in available organs for renal transplantation. Post-transplant renal function and outcome from these donors are often poorer than chronologically younger donors. Some organs, however, function adequately for many years. We have hypothesized that such organs are biologically younger than poorer performing counterparts. We have tested this hypothesis in a cohort of preimplantation human renal allograft biopsies ( n = 75) that have been assayed by real-time polymerase chain reaction for the expression of known markers of cellular damage and biological aging, including CDKN2A, CDKN1A, SIRT2 and POT1. These have been investigated for any associations with traditional factors affecting transplant outcome (donor age, cold ischaemic time) and organ function posttransplant (serum creatinine levels). Linear regression analyses indicated a strong association for serum creatinine with pre-transplant CDKN2A levels ( p = 0.001) and donor age ( p = 0.004) at 6 months post-transplant. Both these markers correlated significantly with urinary protein to creatinine ratios ( p = 0.002 and p = 0.005 respectively), an informative marker for subsequent graft dysfunction. POT1 expression also showed a significant association with this parameter ( p = 0.05). Multiple linear regression analyses for CDKN2A and donor age accounted for 24.6% ( p = 0.001) of observed variability in serum creatinine levels at 6 months and 23.7% ( p = 0.001) at 1 year posttransplant. Thus, these data indicate that allograft biological age is an important novel prognostic determinant for renal transplant outcome.
authors.affiliation: Department of Surgery, University of Glasgow, UK.
authors.forename: Liane M
authors.initials: LM
authors.lastname: McGlynn
authors.forename: Karen
authors.initials: K
authors.lastname: Stevenson
authors.forename: Kelly
authors.initials: K
authors.lastname: Lamb
authors.forename: Samer
authors.initials: S
authors.lastname: Zino
authors.forename: Michaela
authors.initials: M
authors.lastname: Brown
authors.forename: Alberto
authors.initials: A
authors.lastname: Prina
authors.forename: David
authors.initials: D
authors.lastname: Kingsmore
authors.forename: Paul G
authors.initials: PG
authors.lastname: Shiels
mesh_terms: D000293:Adolescent; D000328:Adult; D000367:Age Factors; D000368:Aged; D001706:Biopsy; D002453:Cell Cycle / Q000502:physiology; D016922:Cellular Senescence / Q000502:physiology; D002648:Child; D050377:Cold Ischemia; D003404:Creatinine / Q000097:blood; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000096:biosynthesis; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000096:biosynthesis; D006801:Humans; D007668:Kidney / Q000166:cytology / Q000502:physiology*; D016030:Kidney Transplantation; D008875:Middle Aged; D000089804:Shelterin Complex; D056565:Sirtuin 2; D037761:Sirtuins / Q000096:biosynthesis; D034501:Telomere-Binding Proteins / Q000096:biosynthesis; D014019:Tissue Donors; D055815:Young Adult
chemical_list: C493956:CDKN1A protein, human; D019941:Cyclin-Dependent Kinase Inhibitor p16; D050759:Cyclin-Dependent Kinase Inhibitor p21; C440849:POT1 protein, human; D000089804:Shelterin Complex; D034501:Telomere-Binding Proteins; D003404:Creatinine; C474199:SIRT2 protein, human; D056565:Sirtuin 2; D037761:Sirtuins