2010 - Transplantomics and Biomarkers in Transplantation

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Presenter: Maarten, Naesens, Stanford, USA
Authors: Maarten Naesens

Maarten Naesens, Department of Nephrology and Renal Transplantation, University Hospitals Leuven, Leuven, Belgium; Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, USA
Learning Objectives:
1. Progression of histological injury of a kidney allograft is associated with important gene expression alterations over time, and future histological phenotypic changes are preceded by changes on the molecular level. 
2. The variability of the clinical background and the complexity of the histological picture need to be taken into account when patient samples are used for transcriptomic analysis. 
3. Even in the absence of acute rejection, it becomes clear that the innate and adaptive immune systems play an important role in the evolution of histological injury over time after renal transplantation.
In renal transplantation, slowly progressive chronic tubulo-interstitial damage jeopardizes long-term renal allograft survival. Both immune and non-immune mechanisms contribute to this progressive renal allograft scarring, as is demonstrated in protocol biopsy studies. Until now the specific tools to prevent this progression of chronic histological damage have not yet been identified. Micro-array technology can be applied on biopsy samples in order to get a better insight in these molecular changes and pathways, and could yield promising targets for timely intervention. 
In this presentation, protocol biopsy results are used to demonstrate the pathways involved in the evolution of histological injury over time. Previous and recent micro-array data are reviewed that shed light on the risk factors and mechanisms of chronic histological damage. As is demonstrated in these studies, it has to be emphasized that great care should be given to careful patient selection, unbiased and detailed histological scoring and strict sample classification. The complexity of the histological picture and the important clinical variability has to be taken into account when transcriptomic data are analyzed in clinical samples. The complexity of the clinical parameters, the complex physiology and immunology, the complex histological outcome, the multitude of data per sample and the complex data analysis can only lead to biologically and clinically meaningful results with a multidisciplinary, holistic approach. 
Finally, it is becoming clear that immune and non-immune factors are impossible to separate from each other after transplantation, and many non-immune phenomena also lead to immune activation. Immune activation is already evident in biopsies of deceased donor kidneys prior to implantation compared to living donor kidneys. When rejection-free renal allograft biopsies obtained post-transplantation are compared to pre-implantation samples, there is also a major shift in global gene

expression, with highly significant overrepresentation of immune genes involved in mostly adaptive immune responses. In post-transplantation samples of patients who did not experience delayed graft function, clinical or subclinical rejection episodes, there is a highly significant association of established, ongoing and most importantly, future chronic histological damage with regulation of adaptive immunity but also innate immune response genes. 
These findings underscore the complexity of the immunological processes in human kidney transplantation, and corroborate the idea that inflammation that is quantitatively below the diagnostic threshold of acute T-cell mediated rejection is involved in early subclinical stages of progressive renal allograft damage. Timely intervention aimed at influencing these early immune responses could well be the clue to slow or abort the progression of chronic renal graft scarring and improve long-term graft survival.

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