Cellular senescence in pretransplant renal biopsies predicts postoperative organ function

Abstract

SummaryOlder 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.

Pathfinder Cells Provide A Novel Therapeutic Intervention For Acute Kidney Injury

“…Higher levels of p16 ink4a expression are associated with poorer function as measured by serum creatinine and urine proteinto-creatinine ratio (UPCR) levels at 6 months and 1 year posttransplant. 29,30 This correlates with the findings from this study that control mice that presented with higher serum creatinine levels also exhibited higher expression levels of p16 ink4a . Within the time course of this experiment, we would have expected to see an initial rise in p21, peaking by day 7, then reducing to control levels by day 14, with a correlated increase in p16 ink4a expression from day 7, peaking at day 14.…”

“…We and others have previously demonstrated that p16 ink4a is a superior marker for the assessment of renal function. 4,5 p16 ink4a expression was significantly lower in the kidneys of PC-treated mice than those mice treated with saline ( p = 0.009; Fig. 2A, 2B).…”

“…In each instance, the organ shows accelerated bioaging, with an accumulation of senescent cells, correlated with increased CDKN2A (p16 ink4a ) expression. [4][5][6] One hypothesis suggests that replacement of such cells is required to enhance function and regenerate the organ. Precedence for this hypothesis exists in a recent report that indicates that the removal of p16 ink4a -expressing cells from tissues delays the onset of agerelated pathologies.…”

A molecular signature for delayed graft function

“…Notably, deaths due to chronic kidney disease have increased globally, despite significant decline in other aetiologies (Christopher & Murray, 2015). This is pertinent to researchers investigating ageing, as accelerated cellular and physiological ageing are underlying components of renal dysfunction (Kooman, Kotanko, Schols, Shiels, & Stenvinkel, 2014; McGlynn et al, 2009; Schmitt, Susnik, & Melk, 2015), where systemic differences are layered on top of the dysregulated ageing process and patients show a higher incidence of mortality in comparison to healthy chronologically age‐matched individuals. As the prevalence of CKD parallels an increased prevalence in type 2 diabetes, obesity and a sedentary lifestyle (Stengel, Tarver‐Carr, Powe, Eberhardt, & Brancati, 2003), an allostatic outcome reflecting the “burden of life style” may be present next to the renal dysfunction.…”

Pre-transplant biomarkers and prediction of post-transplant outcomes in kidney transplantation

“…Essentially, these expression dissimilarities were recognized by the time of procurement (before cold ischemia) in brain-death donor kidneys, and after first warm ischemia in deceased donor kidneys (21). In addition, in targeted studies (22)(23)(24), mRNA levels of cyclin-dependent kinase inhibitor 2A (CDKN2A) in pretransplant kidney biopsies, one of the markers of cellular senescence, was documented as the most solid posttransplant predictor of serum creatinine at 6 months and one year in confront with clinical factors as age of donor and cold ischemic time. In addition, CDKN2A was also a solid predictor of DGF (24).…”