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Team IDs Gene Expression Patterns Associated With Kidney Transplant Rejection

NEW YORK (GenomeWeb) – By profiling gene expression patterns in biopsy samples taken a year after kidney transplant, a Scripps Research Institute-led team has identified molecular features that appear to mark the risk of both acute rejection and a related condition that appears to coincide with more long-term declines in graft survival.

As they reported online today in the American Journal of Transplantation, the researchers did array-based gene expression testing on graft biopsy samples from 234 individuals who'd undergone kidney transplantation a year earlier. In the subset of individuals with interstitial fibrosis and tubular atrophy (IFTA) — a condition that often accompanies inflammation in individuals with decreased risk of graft survival — they found substantial overlap with gene expression patterns detected in acute transplant rejection.

Those share expression profiles persisted regardless of inflammation status associated with the IFTA, prompting the team to speculate that chronic transplant rejection may stem from similar, but more drawn out, activation of immune pathways contributing to acute rejection.

"Immune-mediated rejection is a single entity at the molecular level," senior author Daniel Salomon, a molecular and experimental medicine researcher at Scripps, said in a statement. "The new view that emerges from this research is that almost all transplant organ failure is due to inadequate immunosuppression, and with that understanding comes a potential for a major change in the practice of post-transplant drug therapy."

In particular, Salomon and his colleagues urged ongoing molecular surveillance of biopsy samples from transplant recipients in the months and years after transplantation to pick up gene expression warnings of rejection or graft damage.

Past studies suggest that around one-quarter of individuals who receive a kidney transplant will show histological signs of IFTA in biopsy samples taken a year or more after transplantation, a condition characterized by scarring in the kidney's cortical structures. Because the presence of IFTA in combination with inflammation has been linked to decreased graft survival, the team set out to tease apart molecular features of IFTA and its potential ties to acute transplant rejection.

As part of a retrospective study of kidney transplant outcomes, the researchers used microarrays to profile gene expression in samples from 234 individuals about one year after transplant. The group, which was followed for an average of more than four years, included 99 individuals with normally functioning kidney transplants, 54 acute rejection cases, and 81 cases of IFTA with or without acute rejection or inflammation. Using light histology, the team further classified the IFTA biopsy samples into groups with inflammation, without inflammation, or with accompanying acute rejection.

Despite these histological sub-classifications, however, the researchers saw gene expression patterns that resembled one another across the IFTA samples, including those with less obvious histology-based graft risk features.

In general, the IFTA samples showed gene expression profiles pointing to inflammatory immune activity and metabolic pathway activation patterns similar to those identified in the acute rejection samples. Indeed, the IFTA samples showed between 72 percent and 81 percent overlap with the differentially expressed genes the team described in grafts associated with acute rejection.

Using the long-term patient outcome data, the investigators went on to demonstrate that the presence of this rejection-related gene expression pattern was a better indicator of graft loss over time than histology or inflammation in the IFTA samples.

The researchers are exploring the possibility of using blood tests to track transplant-related gene expression patterns rather than using more invasive biopsy samples. They also plan to investigate expression patterns outside of the transplant realm, including studies of autoimmune conditions such as ulcerative colitis.