Over 16,000 end-stage renal disease (ESRD) patients receive kidney transplantation (KT) yearly in the US. The advent of calcineurin inhibitor (CNI) therapy has reduced acute rejection (AR) in KT recipients. However, this decrease in AR and improvement of short term function has not translated to improved long-term allograft survival, mainly due to persistent chronic allograft dysfunction (CAD). Allograft attrition over tie remains unabated due to CAD. The lack of identifiable mechanisms of CAD has made the possibility of treatment and intervention trials a challenge. Etiology of CAD is multifactorial wit immunological and non- immunological factors. Primary immune mediators of CAD are uncontrolled T and B cell responses against the allograft while calcineurin inhibitor nephrotoxicity (CNIT) remains the main described non-immune associated factor. Although there is clear evidence that CNIs are nephrotoxic, histological changes associated with CNIT are not specific and diagnosis may be challenging. Evidence for chronic CNIT and renal dysfunction has also become a concerning issue in non-renal solid organ transplant (NRSOT) patients. Based on our preliminary data, we hypothesize that CNIT can be measured using tissue and/or urine biomarkers allowing accurate diagnosis of graft injury and evaluation of its contribution to CAD progression. We propose to address our hypothesis using the following specific aims (SAs), SA 1: To establish a molecular signature for diagnosis of CNI-kidney related injury in allograft tissue from KT recipients, by a) establishing a tissue specific CNIT signature using genome wide analysis, and b) identifying a limited panel of markers resulting from (SA1a) for diagnosis and monitoring effect of CNIT in long-term outcomes;and SA 2: To establish and evaluate the utility of urine miRNA signatures of CNIT as non-invasive biomarkers in available urine samples of KT recipients by a) establishing a miRNA signature in available paired urine samples collected at same time that those allograft tissues used in SA1a and b) evaluating the utility of the identified urine miRNA signature to assess the contribution of the long term CNI-renal toxicity in the progression to CAD. The study design includes discovery and validation patient sets and establishment of 'best set of biomarkers"""""""" for prompt shifting to clinicl setting. The proposed studies will be performed using available tissues and urine samples from a) 298 primary disease donor (DD) KT recipients (NIH # R01DK080074) and b) 100 DD KT recipients (CELL 500 study, ROCHE, PI: D Maluf) with a minimal follow-up of 3 years post-KT. The results from this proposal will provide further information about the molecular pathways that associate with CNIT and its contribution to CAD progression. Results from the proposed studies might lead to the development of novel non-invasive diagnostic biomarkers of CNIT with the overarching aim of improving long-term graft outcome. Moreover, a new accurate panel of non-invasive CNIT-biomarkers has the potential to be validated in NRSOT patients.

Public Health Relevance

Despite major progresses in short term outcomes post kidney transplantation (KT), these results do not translate to long-term outcomes mainly due progression to chronic allograft dysfunction (CAD). CAD etiology is multifactorial with immunological and non-immunological features. Calcineurin inhibitors remain the most effective and widely used immunosuppressive agents in organ transplantation. However, Calcineurin inhibitor toxicity (CNIT) has been described as one of the principal non-immunological factor associated with CAD development. Identification of genetic biomarkers associated with allograft injury associated with CNIT might have a critical impact in improving long-term outcomes post-KT and in other solid organ transplantation.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Exploratory/Developmental Grants (R21)
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Special Emphasis Panel (ZRG1-DKUS-L (11))
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Flessner, Michael Francis
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University of Virginia
Schools of Medicine
United States
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Bontha, S V; Maluf, D G; Archer, K J et al. (2017) Effects of DNA Methylation on Progression to Interstitial Fibrosis and Tubular Atrophy in Renal Allograft Biopsies: A Multi-Omics Approach. Am J Transplant 17:3060-3075
Mas, Valeria R; Le, Thu H; Maluf, Daniel G (2016) Epigenetics in Kidney Transplantation: Current Evidence, Predictions, and Future Research Directions. Transplantation 100:23-38
Gehrau, Ricardo C; Mas, Valeria R; Dumur, Catherine I et al. (2015) Donor Hepatic Steatosis Induce Exacerbated Ischemia-Reperfusion Injury Through Activation of Innate Immune Response Molecular Pathways. Transplantation 99:2523-33
Harms, Anja; Fuehner, Thomas; Warnecke, Gregor et al. (2015) Epithelial and Erythrocyte Microvesicles From Bronchoalveolar Lavage Fluid Are Elevated and Associated With Outcome in Chronic Lung Allograft Dysfunction. Transplantation 99:2394-400
Maluf, D G; Dumur, C I; Suh, J L et al. (2014) Evaluation of molecular profiles in calcineurin inhibitor toxicity post-kidney transplant: input to chronic allograft dysfunction. Am J Transplant 14:1152-1163
Maluf, Daniel G; Dumur, Catherine I; Suh, Jihee L et al. (2014) The urine microRNA profile may help monitor post-transplant renal graft function. Kidney Int 85:439-49