Tubular Cell Senescence in the Donated Kidney Predicts Allograft Function, but Not Donor Remnant Kidney Function, in Living Donor Kidney Transplantation

Abstract

Background: It is uncertain whether kidneys from marginal donors are suitable for live kidney transplantation. In deceased donor kidneys, tubular cell senescence affects allograft function. However, the degree of cell senescence in a living donor kidney with marginal factors has not been reported. In this study, we assessed the association of tubular cell senescence with allograft and remnant kidney function by a prospective observational clinical study. Methods: Thirty-eight living donor kidney transplantations were analyzed prospectively. Tissue sections obtained from preimplantation kidney biopsies were immunostained for p16^INK4a to indicate cell senescence. Various kidney biomarkers were analyzed in urine and blood samples. Results: Of the 38 donors, 21 had marginal factors. Severe tubular senescence was found in living donors with overlapping marginal criteria. Tubular senescence in living donor kidneys was significantly related to donor age and lower recipient kidney function at 1 year after transplantation independently of donor age (β = –0.281; p = 0.050) but did not affect remnant kidney function after donation. Pretransplantation donor pre-estimated glomerular filtration rate and hypertension did not show a significant area under the curve (AUC) for prediction of high tubular senescence. High plasma levels of soluble αKlotho were associated with a higher predictive value for low tubular cell senescence with an AUC of 0.78 (95% CI 0.62–0.93; p < 0.01). Conclusions: The nuclear p16-staining rate in donated kidney tubules is a predictor for allograft kidney function but not donor remnant kidney function. Detection of tubular cell senescence may facilitate selection of appropriate living donor candidates.

Marine n-3 Polyunsaturated Fatty Acids and Cellular Senescence Markers in Incident Kidney Transplant Recipients: The Omega-3 Fatty Acids in Renal Transplantation (ORENTRA) Randomized Clinical Trial

“…Well-known risk factors for chronic kidney disease, such as type II diabetes, hypertension, and glomerular diseases, may all cause accelerated cellular senescence [32][33][34] , which in turn will contribute to disease progression through the SASP secretome. In addition, cellular senescence is linked to interstitial fibrosis and tubular atrophy and chronic allograft nephropathy in kidney transplantation [6][7][8][9][10][11][12][13] . While elimination of senescent cells has shown promising results in animal studies 14,15 , effective senolytic agents are still in an early stage of development 16 .…”

“…In kidney transplantation, grafts with interstitial fibrosis and tubular atrophy 6 and chronic allograft rejection 7 express higher levels of p16 INK4a than what is expected for their age, consistent with accumulation of senescent cells. A high p16 INK4a expression in kidney graft biopsies at the time of engraftment is a strong predictor for adverse longterm transplant outcome [8][9][10] . Immunosuppressive drugs like calcineurin inhibitors may both induce cellular senescence and hamper clearance of senescent cells [11][12][13] , causing further assault by SASP factors on adjacent tissue.…”

“…High p16 INK4a expression in kidney graft biopsies at the time of engraftment is a strong predictor of an adverse long-term transplant outcome. 8 , 9 , 10 Immunosuppressive drugs, such as calcineurin inhibitors, may induce cellular senescence and hamper the clearance of senescent cells, 11 , 12 , 13 causing further assault by SASP factors on adjacent tissue. In murine studies, p16 INK4a deletion has been shown to prevent kidney tubulointerstitial injury, alleviate senescence, inhibit the secretion of SASP factors, and promote proliferation, 14 which may explain the reduced interstitial fibrosis and tubular atrophy as well as improved graft survival.…”

Summary of the 2018 ISN Frontiers Meeting: Kidney Disease and Cardiovascular Disease

“…The quality of donated kidneys directly affects recipient allograft functions and acute allograft rejection. Quality of donated kidneys has been evaluated based on physical or pathological assessment of donors and/or donated kidneys, 99 which may facilitate a better allograft outcome.…”

Post‐transplant immunoglobulin A deposition and nephropathy in allografts

“…Baseline (implantation) kidney biopsies include biopsies obtained before perfusion (zero‐hour biopsy), biopsies taken 1 h after perfusion (1‐h biopsy) and a combination. Even in the kidneys of living donors who do not have abnormal urine or kidney dysfunction, fibrous intimal thickening in the interlobular artery, interstitial fibrosis, glomerulosclerosis, tubular cell senescence, latent mesangial IgA deposition (IgAD), latent IgG deposition in the glomerular tuft, and in rare cases, zebra bodies, which indicate Fabry disease, can be observed in the donated kidneys. This information from baseline biopsies is necessary to determine whether the histopathological changes originate de novo or were already present in the donated kidneys, if any histopathological changes are detected in the allograft after transplantation.…”