2010 - Transplantomics and Biomarkers in Transplantation

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Presenter: Manikkam, Suthanthiran, New York, USA
Authors: Manikkam Suthanthiran

Manikkam Suthanthiran, Stanton Griffis Distinguished Professor of Medicine; Chief, Nephrology and Transplantation Medicine; New York Presbyterian Hospital-Cornell, New York, NY, USA
Development of predictive, diagnostic and prognostic biomarkers of allograft status and outcome is important and challenging, and may be rewarded with individualized therapy of the organ graft recipient.  

Learning Objectives:
1. To improve understanding of allograft rejection.
2. To improve understanding of molecular markers of allograft rejection.
3. To improve understanding of biomarkers of allograft status.
In order to noninvasively characterize renal allograft status and outcome we performed urinary cell mRNA profiling studies and report that: (a) Urinary cell levels of mRNA for perforin and granzyme B are significantly higher in renal allograft recipients with a biopsy confirmed episode of acute rejection than in the patients without an episode of acute rejection (Li et al. NEJM 2001); (b) CD103 mRNA levels are higher in urinary cells from renal allograft recipients with a biopsy confirmed episode of acute rejection than in the patients without acute rejection (Ding et al. Transplantation 2003); (c) Both IP-10 and CXCR3 mRNA levels are highly associated with acute rejection (Tatapudi et al. Kidney International 2004); (d) Whereas mRNA for FOXP3, CD25, CD3ε-chain and perforin are all higher during an episode of acute rejection than in the group with CAN or normal biopsy group, levels of mRNA for FOXP3 alone: (1) inversely correlate with serum creatinine levels measured at the time of biopsy in the acute rejection group; (2) predict the reversal of acute rejection, and (3) identify subjects at risk for graft failure within six months after the incident episode of acute rejection (Muthukumar et al. NEJM 2005).
We subscribe to the definition proposed by the NIH Biomarker Definition Working Group: “A characteristic that is objectively measured and evaluated as an indicator of normal biological processes, pathogenic responses, or pharmacological responses to a therapeutic intervention”. In this light, mRNA profiles, measured at the time of allograft biopsy and predicting acute rejection with a high specificity and sensitivity serve as a diagnostic biomarker; mRNA levels, measured during an episode of acute rejection and predicting responsiveness to anti-rejection therapy serve as a prognostic biomarker. The ongoing NIH sponsored Cooperative Clinical Trials in Transplantation should validate or refute the hypothesis that urinary cell mRNA profiles function as predictive biomarkers (mRNA levels in sequential samples will predict the subsequent development of acute rejection or maintenance of  stable graft function) and noninvasive diagnostic biomarkers (mRNA levels measured at the time of diagnostic allograft biopsies will predict allograft histopathology) of acute rejection of renal allografts. These trials are also designed to test the hypothesis that sequential urinary cell mRNA profiles predict renal allograft status (stable graft function vs. acute rejection) and function. Should future studies demonstrate that the measured biomarker is causatively involved in the biologic process studied (e.g., acute rejection), the biomarker can be designated as a mechanistic biomarker, and help accomplish the objective of developing mechanism based therapy.

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