Overview:
Detecting Graft Damage
Philip J. O’Connell MB,BS, PhD.
Centre for Transplant and Renal Research, Westmead Millennium Institute, University of Sydney, Westmead Hospital,
Australia

Renal allograft tubulointerstitial damage is characterised by interstitial fibrosis, tubular atrophy, vascular changes and glomerulosclerosis. Multiple immune and non-immune mechanisms have been implicated in its pathogenesis. However, the molecular pathways and signaling networks involved are poorly defined. Whilst there are many potential causes of injury, there are limited biological pathways that result in fibrosis. At present the pathogenesis of renal allograft fibrosis is controversial. In all likelihood the key initiating events change over time and differ between different patient cohorts. Fibrosis is the result of ongoing activation of myofibroblasts, which can be derived from multiple sources. Some studies have identified EMT as an important source. Others have identified myofibroblasts to be of recipient origin. In the context of renal transplantation, early inflammatory events are important in the recruitment of myofibroblasts. Acute cellular rejection and subclinical rejection have been identified as important causes of IF/TA in the first two years of transplantation. In mechanistic studies of fibrosis chemokines such as CCL2 and CCL3 are important for the recruitment of myofibroblasts and Th2 T cell responses induce dysregulated alternatively activated (M2) macrophages that secrete TGFb. This link between inflammation and fibrosis may be an important initiator of fibrosis after transplantation. Gene array studies have been undertaken in several renal transplant cohort studies and show a consistent pattern of gene expression pathways linking immune and fibrotic gene expression profiles. In longitudinal studies gene expression profiles predictive of fibrosis can predate histological evidence and has the potential to be predictive of future damage. Data linking macrophage infiltration and T-cell mediated immune activation with the development of fibrosis will be presented, whilst evidence of EMT in longitudinal cohort studies was largely lacking. Gene expression profiles that are predictive of future fibrosis can be developed as a biomarker assay that is a better predictor than histology or clinical data and has the potential to better define the pathogenesis of the condition.