Liver transplant (LT) recipients have amongst the highest rates of chronic kidney disease (CKD) of all non- renal solid organ transplant recipients. The impact of CKD in this population is substantial, leading to early and late morbidity and mortality and kidney organ resource utilization. The strategy that LT providers currently employ, which is to wait until renal dysfunction is clinically apparent to institute a treatment strategy, s often too late and ineffective - a major reason why CKD develops and progresses in these patients. These approaches might be imminently improved if mechanisms of renal injury were better clarified and if more successful, proactive strategies to detect renal injury before it is clinically established were available. This proposal aims to determine whether this can be done with the aid of predictive biomarkers detecting subclinical renal injury so as to design novel biomarker-guided interventional studies to minimize CKD in this population. Our long-term goal is thus to utilize predictive proteomic biomarkers that will identify LT recipients at risk for CKD and suitable candidates for interventions aimed at reducing this risk. As a step in that direction, the objective of this R21 application is to determine if early proteomic signatures are present in LT recipients with preserved renal function who eventually develop CKD within 1-5 years of LT. We hypothesize that such an array of serum proteins can predict the future development of CKD and identify patients in need of early interventional strategies (e.g. the next proposal). The study is planned with the following two specific aims:
Aim 1. To determine if a proteomic signature of subclinical renal injury is present early after LT that predicts the development of chronic kidney disease.
Aim 2. To analyze the significance of serial changes in proteomic signatures during the course of chronic kidney disease progression in liver transplant recipients. We are uniquely positioned to conduct this research because: 1) biosamples [Baylor; NIAID CTOT14 trial (U01 AI084146)] collected from LT recipients with early preserved renal function who subsequently did or did not develop CKD will be readily available to analyze for predictive signatures; 2) an established collaboration exists between the Northwestern, Baylor, Scripps and a proteomics company Rules Based Medicine (RBM) who have the licensed multi-analyte proteomic panels - all with distinct roles to accomplish our goals. The approach will be to initialy test and validate early post-LT proteomic discovery panels as predictive of impending CKD in independent cohorts (Baylor & CTOT14 biorepositories). We will then test serial CTOT14 samples to evaluate the evolution of protein signatures with GFR measures, providing insights into renal injury and refining prediction.This R21 will specifically provide funding for the CKD LT proteomics research in CTOT14 that is no longer available, as RBM lost the SBIR that was the original funding mechanism. Upon completion, we will have validated predictive signatures that could transform the field by promoting proactive, biomarker-driven investigations of approaches to preserve renal function in this population. 1
Acute and chronic kidney disease occurs frequently after liver transplantation and is associated with significant complications. The objective of this R21 is to determine if we can identify blood proteins in liver transplant recipients that precede the development of advanced kidney disease. This project would set the stage for future important studies using these protein markers to determine which recipients are at risk for kidney disease and in need of treatments to prevent this major complication.
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| Levitsky, J; O'Leary, J G; Asrani, S et al. (2016) Protecting the Kidney in Liver Transplant Recipients: Practice-Based Recommendations From the American Society of Transplantation Liver and Intestine Community of Practice. Am J Transplant 16:2532-44 |
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