Mosaic Loss of Y Chromosome Defines a Proximal Tubular Cell State Associated with Recovery from DGF and of Allograft Quality and Functional Reserve Post DCD Kidney Transplantation

Abstract

Objective: To determine the drivers of proximal tubular cell regeneration and repair over time in the setting of recovery from delayed graft function (DGF) post donation after cardiac death (DCD) kidney transplantation.

Background: DCD Kidney allografts are at increased risk of graft loss. Despite this, due to organ shortages, DCD transplantation is increasing, which offers a novel and valuable platform for the study of adaptive/maladaptive repair mechanisms after injury.

Methods: We analyzed the dynamic transcriptional changes in serial biopsies of transplanted DCD kidneys to better understand proximal tubular cell repair and regeneration in DGF at the cellular level. We also quantified loss of Y chromosome in these kidneys to determine the impact of this phenomenon on DGF.

Results: One cell state associated with recovery from DGF had a high loss of Y chromosome fraction (29%) compared to pre-transplant healthy proximal tubules (17%) and differentially expressed APOE. A proximal tubule cell state associated with progression to DGF was defined by injury markers VCAM1 and HAVCR1 and proinflammatory and proliferative genes CCL2 and MYC and accounted for over 50% of proximal tubules in time 0 DGF kidney biopsies.

Conclusions: Taken together, our dataset of serial biopsies from DCD kidney transplants reveals insights into mechanisms driving injury and repair in the setting of DGF and offers a signature of allograft quality and functional reserve that may optimize allocation at the time of procurement.

Keywords: DCD; DGF; Signature of organ quality; Y chromosome; kidney transplantation; proximal tubular cells; single cell analysis.