This recent study using QUOD kidney samples by Roy Zhang and colleagues, led by Prof Menna Clatworthy at the University of Cambridge, reported a novel method for assessing the biological age of kidneys prior to transplantation.
The demand for kidneys for transplantation far outweighs the supply, leaving many patients, such as those with end-stage kidney failure, waiting for many years, during which their health may further deteriorate. To meet the shortfall, kidneys may be accepted from donation after circulatory death (DCD) donors or older donors, increasing the risk of delayed graft function (DGF) and poorer post-transplant outcomes.
At present, there is no reliable method for stratifying marginal donor organs. Zhang’s study addressed this by examining biopsies from DCD kidneys taken at the time of organ retrieval that went on to be transplanted. They aimed to characterise these organs to determine their “biological age” by identifying and comparing the molecular processes that occurred in kidneys with good and poor one-year graft function. They also investigated how donor age affects post-transplantation outcome.
Zhang identified distinct gene expression patterns in kidneys that developed DGF and poor graft function compared with those with good graft function, highlighting specific pathways as well as the presence of cell types that were associated with different graft outcomes. Gene set enrichment analysis showed that while immune pathways were enriched in kidneys with both high and low 12-month graft function, the nature of these pathways was very different. In particular, kidneys that showed good function at 12 months post transplantation, with a high estimated glomerular filtration rate (eGFR), were enriched for genes within the innate immune system, which is the part of the immune system that allows immediate response. On the contrary, kidneys with a low eGFR were enriched in genes involved in the adaptive immune system, which allows specific memory responses to be generated. More detailed investigation into the key genes driving this enrichment in kidneys with a poor 12-month graft function revealed upregulation of genes associated with T and B cells, as well as genes expressed in myofibroblasts and fibroblasts, which are cells known to be involved in forming scar tissue.
Histological analysis revealed increased fibrosis and interstitial lymphocytic infiltrate in kidneys with poor 12-month graft function, whereas samples with good 12-month graft function showed an increase in glomerular and tubulointerstitial neutrophils.
Specific genetic signatures associated with increased donor age and DGF and poorer long-term graft function (one-year eGFR) were also found. Weighted gene coexpression network analysis identified a gene module enriched for “allograft rejection”, which included many adaptive immune genes, and also various adaptive immune cell types, that was positively correlated with donor age and negatively correlated with 12-month graft function.
In brief, the study found that kidneys with good graft function showed acute inflammation and neutrophil/tubular signatures, whereas adaptive immune and fibrosis signatures were associated with poor long-term graft function. These findings have huge implications for kidney transplantation as identification of a transcriptional signature of organ “molecular age” in retrieval biopsies may assist decision-making around organ utilisation.
This study was published in Kidney International.
