The unifying principle of this proposal is that post-transplant renal injury is a complex process that leads to progressive, chronic renal insufficiency and constitutes a major clinical barrier to the success of organ transplants. We believe there is now opportunity in transplant proteogenomics to investigate what is common and unique in the biomarker signatures and mechanisms of immunity, drug toxicity and the concomitant medical risk factors that drive renal injury in kidney, liver and heart transplant patients. Additionally, in heart and liver patients it is now clear that progressive kidney dysfunction is common and devastating. There is a pressing medical need for a minimally invasive, objective metric of optimal immunosuppression to monitor therapy and insure long-term success. However, another pressing need is also evident: a sensitive metric of early, non-immune renal injury that pre-dates creatinine elevations and allows individualized therapeutic interventions before irreversible renal damage is present.
Specific Aim 1 is to validate proteogenomic-based, peripheral blood biomarker panels in a serial and prospective monitoring strategy in kidney transplant recipients including protocol kidney biopsies. We are testing the hypotheses that they will diagnose as well as predict acute rejection and the progressive sub-clinical renal injury that ultimately results in chronic allograft nephropathy with interstitial fibrosis and tubular atrophy.
Specific Aim 2 is a prospective blood and biopsy monitoring study in liver and heart transplant recipients using the biomarker panels for acute rejection and chronic renal injury that were discovered and validated in kidney transplants. We are testing the hypothesis that the chronic kidney injury in renal allografts and the chronic native kidney disease of liver and heart transplant recipients involve a set of shared mechanisms. We also propose that there are shared mechanisms for acute rejection and tissue injury in all organ transplants that will be reflected in peripheral blood proteogenomic assays. The development and validation of minimally-invasive biomarkers to diagnose, let alone predict, acute rejection and chronic kidney tissue injury, would be a major advance in the clinical management of kidney, liver and heart transplant recipients and a big step toward the ability to individualize post-transplant therapy for optimal efficacy and safety.

Public Health Relevance

Immunosuppression prevents organ rejection;however, it increases other medical risks including renal injury in liver, kidney, and heart transplant patients. There is presently no adequate, minimally invasive measure to inform the optimal balance of immunosuppression efficacy and risk on an individual patient basis. This study will develop blood biomarker-based metrics as a benchmark for adequate, long-term immunosuppression and detect non-immune renal injury before creatinine elevations are present.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01AI084146-05
Application #
8527681
Study Section
Special Emphasis Panel (ZAI1-SV-I (M1))
Program Officer
Hayes, Deborah
Project Start
2009-09-21
Project End
2014-08-31
Budget Start
2013-09-01
Budget End
2014-08-31
Support Year
5
Fiscal Year
2013
Total Cost
$1,990,908
Indirect Cost
$209,542
Name
Northwestern University at Chicago
Department
Surgery
Type
Schools of Medicine
DUNS #
005436803
City
Chicago
State
IL
Country
United States
Zip Code
60611
Head, Steven R; Komori, H Kiyomi; LaMere, Sarah A et al. (2014) Library construction for next-generation sequencing: overviews and challenges. Biotechniques 56:61-4, 66, 68, passim
Kurian, S M; Williams, A N; Gelbart, T et al. (2014) Molecular classifiers for acute kidney transplant rejection in peripheral blood by whole genome gene expression profiling. Am J Transplant 14:1164-72
Levitsky, Josh; Mathew, James M; Abecassis, Michael et al. (2013) Systemic immunoregulatory and proteogenomic effects of tacrolimus to sirolimus conversion in liver transplant recipients. Hepatology 57:239-48
Podshivalova, Katie; Salomon, Daniel R (2013) MicroRNA regulation of T-lymphocyte immunity: modulation of molecular networks responsible for T-cell activation, differentiation, and development. Crit Rev Immunol 33:435-76
Leventhal, Joseph R; Mathew, James M; Salomon, Daniel R et al. (2013) Genomic biomarkers correlate with HLA-identical renal transplant tolerance. J Am Soc Nephrol 24:1376-85
Grover, Rajesh K; Cheng, Julong; Peng, Yingjie et al. (2012) The costimulatory immunogen LPS induces the B-Cell clones that infiltrate transplanted human kidneys. Proc Natl Acad Sci U S A 109:6036-41
Levitsky, J; Salomon, D R; Abecassis, M et al. (2011) Clinical and plasma proteomic markers correlating with chronic kidney disease after liver transplantation. Am J Transplant 11:1972-8