Biomarkers for early and late stage chronic allograft nephropathy by proteogenomic profiling of peripheral blood.
BACKGROUND
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.


METHODS
We 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.


RESULTS
Gene 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.


CONCLUSIONS
This 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.
Kurian
Sunil M
SM
Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA, USA.
Heilman
Raymond
R
Mondala
Tony S
TS
Nakorchevsky
Aleksey
A
Hewel
Johannes A
JA
Campbell
Daniel
D
Robison
Elizabeth H
EH
Wang
Lin
L
Lin
Wen
W
Gaber
Lillian
L
Solez
Kim
K
Shidban
Hamid
H
Mendez
Robert
R
Schaffer
Randolph L
RL
Fisher
Jonathan S
JS
Flechner
Stuart M
SM
Head
Steve R
SR
Horvath
Steve
S
Yates
John R
JR
Marsh
Christopher L
CL
Salomon
Daniel R
DR
D015415:Biomarkers / Q000097:blood*; D002853:Chromatography, Liquid; D020869:Gene Expression Profiling; D023281:Genomics; D006801:Humans; D007674:Kidney Diseases / Q000097:blood*; D016030:Kidney Transplantation; D020411:Oligonucleotide Array Sequence Analysis; D040901:Proteomics; D053719:Tandem Mass Spectrometry; D014184:Transplantation, Homologous
D015415:Biomarkers