The specific goal is to test the hypotheses that messenger RNA expression profiles (mRNA profiles) and microRNA expression profiles (miRNA profiles) of urinary cells/peripheral blood cells/ renal allograft biopsies are predictive and diagnostic of acute rejection, subclinical acute rejection, and chronic allograft nephropathy (CAN) in renal allograft recipients randomized to either a low dose or a standard dose tacrolimus regimen.
Specific Aim 1 : To evaluate the prognostic utility of urinary cell/peripheral blood cell/allograft biopsy mRNA/miRNA profiles, measured at the time of randomization, for predicting the subsequent development of (i) clinical acute rejection;(ii) subclinical acute rejection and (iii) CAN.
Specific Aim 2 : To determine whether renal allograft recipients randomized to a low tacrolimus regimen exhibit a different longitudinal pattern of mRNA/miRNA profiles in urinary cells/peripheral blood cells compared to recipients randomized to a standard tacrolimus regimen.
Specific Aim 3 : To evaluate the diagnostic utility of urinary cell/peripheral blood cell/ allograft biopsy mRNA/miRNA profiles for the diagnosis of subclinical acute rejection or CAN. The study cohort for the proposed study will be 160 renal allograft recipients enrolled in our single center randomized controlled trial (RCT) comparing a low tacrolimus regimen (target trough level: 3.0 to 5.0ng/ml) with a standard tacrolimus regimen (6.0-8.0ng/ml). Randomization will occur at 3 months post-transplantation and the subjects will undergo protocol renal allograft biopsy at the time of randomization and at 12 and 33 months post-randomization. The RCT is supported by the combination of a NIH- Clinical and translational award to Weill Cornell, industry, and institutional funds and no funds are requested for the performance of RCT in this application. This mRNA/miRNA profiling study leverages the RCT and the proposed research may lead to the development of noninvasive and mechanistically informative molecular biomarkers for the safe minimization of immunosuppressive therapy in organ graft recipients.

Public Health Relevance

The use of immunosuppressive drugs is associated with an excess of infections, malignancy and cardiovascular and metabolic aberrations in organ graft recipients. Thus, immunosuppression minimization is a major goal in organ transplantation. We propose to develop gene-based diagnostic tests for guiding the minimization of immunosuppressive therapy in organ graft recipients.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Method to Extend Research in Time (MERIT) Award (R37)
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Transplantation, Tolerance, and Tumor Immunology (TTT)
Program Officer
Hayes, Deborah
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Weill Medical College of Cornell University
Internal Medicine/Medicine
Schools of Medicine
New York
United States
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Lee, John Richard; Magruder, Matthew; Zhang, Lisa et al. (2018) Gut microbiota dysbiosis and diarrhea in kidney transplant recipients. Am J Transplant :
Burnham, Philip; Dadhania, Darshana; Heyang, Michael et al. (2018) Urinary cell-free DNA is a versatile analyte for monitoring infections of the urinary tract. Nat Commun 9:2412
Thareja, Gaurav; Yang, Hua; Hayat, Shahina et al. (2018) Single nucleotide variant counts computed from RNA sequencing and cellular traffic into human kidney allografts. Am J Transplant 18:2429-2442
August, Phyllis; Suthanthiran, Manikkam (2017) Sex and Kidney Transplantation: Why Can't a Woman Be More Like a Man? J Am Soc Nephrol 28:2829-2831
Suhre, Karsten; Schwartz, Joseph E; Sharma, Vijay K et al. (2016) Urine Metabolite Profiles Predictive of Human Kidney Allograft Status. J Am Soc Nephrol 27:626-36
Lee, John R; Muthukumar, Thangamani; Dadhania, Darshana et al. (2015) Gut microbiota and tacrolimus dosing in kidney transplantation. PLoS One 10:e0122399
Kannabhiran, Dinesh; Lee, John; Schwartz, Joseph E et al. (2015) Characteristics of Circulating Donor Human Leukocyte Antigen-specific Immunoglobulin G Antibodies Predictive of Acute Antibody-mediated Rejection and Kidney Allograft Failure. Transplantation 99:1156-64
Matignon, Marie; Ding, Ruchuang; Dadhania, Darshana M et al. (2014) Urinary cell mRNA profiles and differential diagnosis of acute kidney graft dysfunction. J Am Soc Nephrol 25:1586-97
Lee, John R; Muthukumar, Thangamani; Dadhania, Darshana et al. (2014) Urinary cell mRNA profiles predictive of human kidney allograft status. Immunol Rev 258:218-40
Lee, John R; Dadhania, Darshana; August, Phyllis et al. (2014) Circulating levels of 25-hydroxyvitamin D and acute cellular rejection in kidney allograft recipients. Transplantation 98:292-9

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