Abstract
BackgroundDespite significant improvements in life expectancy of kidney transplant patients due to advances in surgery and immunosuppression, Chronic Allograft Nephropathy (CAN) remains a daunting problem. A complex network of cellular mechanisms in both graft and peripheral immune compartments complicates the non-invasive diagnosis of CAN, which still requires biopsy histology. This is compounded by non-immunological factors contributing to graft injury. There is a pressing need to identify and validate minimally invasive biomarkers for CAN to serve as early predictors of graft loss and as metrics for managing long-term immunosuppression.MethodsWe used DNA microarrays, tandem mass spectroscopy proteomics and bioinformatics to identify genomic and proteomic markers of mild and moderate/severe CAN in peripheral blood of two distinct cohorts (n = 77 total) of kidney transplant patients with biopsy-documented histology.FindingsGene expression profiles reveal over 2400 genes for mild CAN, and over 700 for moderate/severe CAN. A consensus analysis reveals 393 (mild) and 63 (moderate/severe) final candidates as CAN markers with predictive accuracy of 80% (mild) and 92% (moderate/severe). Proteomic profiles show over 500 candidates each, for both stages of CAN including 302 proteins unique to mild and 509 unique to moderate/severe CAN.ConclusionsThis study identifies several unique signatures of transcript and protein biomarkers with high predictive accuracies for mild and moderate/severe CAN, the most common cause of late allograft failure. These biomarkers are the necessary first step to a proteogenomic classification of CAN based on peripheral blood profiling and will be the targets of a prospective clinical validation study.
Highlights
Kidney transplantation offers a significant improvement in life expectancy and quality of life for patients with end stage renal disease[1]
These biomarkers are the necessary first step to a proteogenomic classification of Chronic Allograft Nephropathy (CAN) based on peripheral blood profiling and will be the targets of a prospective clinical validation study
There has been some evolution of terminology to better describe the histological basis of this chronic, progressive nephropathy, commonly referred to as chronic allograft nephropathy (CAN) and more recently as interstitial fibrosis and tubular atrophy (IF/TA)[4,5,6]
Summary
Kidney transplantation offers a significant improvement in life expectancy and quality of life for patients with end stage renal disease[1]. A chronic, progressive allograft dysfunction of uncertain etiology continues to be a primary cause of graft loss[2,3]. There has been some evolution of terminology to better describe the histological basis of this chronic, progressive nephropathy, commonly referred to as chronic allograft nephropathy (CAN) and more recently as interstitial fibrosis and tubular atrophy (IF/TA)[4,5,6]. Despite significant improvements in life expectancy of kidney transplant patients due to advances in surgery and immunosuppression, Chronic Allograft Nephropathy (CAN) remains a daunting problem. A complex network of cellular mechanisms in both graft and peripheral immune compartments complicates the non-invasive diagnosis of CAN, which still requires biopsy histology. This is compounded by non-immunological factors contributing to graft injury. There is a pressing need to identify and validate minimally invasive biomarkers for CAN to serve as early predictors of graft loss and as metrics for managing long-term immunosuppression
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