Urine mRNA Profiling for Renal Allograft Surveillance

Weill Medical Coll Of Cornell Univ, New York NY

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Abstract

The overall objective of this project is to develop a noninvasive diagnostic test that is predictive, diagnostic and prognostic of human renal allograft rejection. In an exploratory study, we found that the levels of expression of mRNA encoding cytotoxic proteins perforin and granzyme B in urinary cells of renal allograft recipients are diagnostic of acute rejection of human renal allografts. We now propose to further develop and refine the noninvasive diagnosis of acute rejection. The specific aims of this investigation are: Specific aim 1. To test the hypothesis that mRNA profiling of urinary cells is diagnostic of subclinical rejection. We will measure mRNA for perforin, granzyme B, fas ligand, CD3 epsilon chain (CD3), interferon gamma (IFN-gamma), and interleukin-15 (IL-15) in urine specimens obtained at the time of protocol biopsies and determine the sensitivity and specificity of mRNA levels in diagnosing subclinical rejection. Specific aim 2. To test the hypotheses that: a) alterations in mRNA levels in sequential urine specimens predict the development of acute rejection, and b) mRNA profiles predict renal allograft function. We will determine whether acute rejection episodes can be predicted by alterations in mRNA levels measured in sequential urine specimens. In addition to mRNAs listed under Specific Aim 1, we will measure level of expression of mRNA for Bcl-2, A20, hemeoxygenase-1 (HO1), Bax, and transforming growth factor-beta1 (TGF-beta1) in urinary cells and test the hypothesis that the mRNA levels predict renal allograft function. Specific aim 3. To investigate whether mRNA profiles of urinary cells are diagnostic of clinical acute rejection and to determine whether mRNA profiles are prognostic with respect to responsiveness to antirejection therapy with corticosteroids, and in identifying allografts at risk for progressive decline in renal function. We will determine whether the level of expression of mRNA for granzyme B, perforin, and CD3, IFN-gamma and IL-15 are diagnostic of clinical acute rejection and are higher in those with corticosteroid resistant acute rejections compared to corticosteroid sensitive acute rejections. We will also determine whether hyperexpression of mRNA for cytotoxic proteins and for Bax and TGF-beta1 is associated with graft functional decline whereas lack of hyperexpression of mRNA for cytotoxic proteins, Bax and TGF-beta1 and hyperexpression of mRNA for Bcl-2, A20 and HO1 is associated with stable renal function.