We propose to investigate the pharmacogenomics ofthe calcineurin inhibitors (CNI) and mycophenolate in kidney transplantation. Despite the tremendous therapeutic advances that these drugs have provided, their use is still limited by toxicities and therapy failures. Unfortunately, we are unable to discern which patients will develop toxicity or fail therapy. For these patients the consequences can be severe including return to dialysis, retransplantation and death. Monitoring of blood levels has improved our ability to improve and tailor therapy once immune suppression is initiated;however, initial doses are largely empiric and use the crude "one size fits all" approach. This results in subtherapeutic and supratherapeutic levels in a substantial number of patients. There are also a substantial number oif patients who despite achieving therapeutic levels will fail therapy and develop toxicity. We will address major therapy limitations - toxicity and failure - through this application. Genetic variation may be an important factor in predicting who will develop toxicity or fail therapy. We will conduct a genome wide association study in 3000 kidney transplant recipients to define single nucleotide polymorphisms (SNPs) associated with tacrolimus blood levels, and calcineurin inhibitor (CNI) related nephrotoxicity, immune suppressant related new onset diabetes after transplant (NODAT), and mycophenolate related leukopenia and anemia. The findings will then be validated in 3000 additional kidney transplant recipients. We will also study, in a subset of 600 recipients, the relationships between SNPs of the pharmacologic targets, CN and inosine monophosphatase dehydrogenase (IMPDH), mRNA expression of these targets, their protein activity in PBMCs and rejection and toxicities. Our goal is to develop clinical dosing models for the CNIs using clinical factors and SNPs such that we can individualize dosing and to identify genetic factors associated with CNI or mycophenolate toxicities such that regimens may be individually tailored to avoid or minimize the risk agent(s). The long term goal is to provide every patient the dose appropriate for them and the immunosuppressive regimen with the lowest toxicity risk and highest success. SNPs identified in this project will then be combined with important SNPs identified as important towards acute rejection, chronic graft dysfunction and graft failure in project 1.

Public Health Relevance

Immunosuppressive drugs are associated with substantial toxicities and some patients fail therapy. Genetic factors may be associated with these events. Pretransplant testing for these factors will allow for the tailoring of regimens to the individual with the greatest chance of success.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Program--Cooperative Agreements (U19)
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Special Emphasis Panel (ZAI1-MFH-I)
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University of Minnesota Twin Cities
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Oetting, William S; Guan, Weihua; Schladt, David P et al. (2014) Telomere length of recipients and living kidney donors and chronic graft dysfunction in kidney transplants. Transplantation 97:325-9
Claes, Kathleen J; Heye, Sam; Bammens, Bert et al. (2013) Aortic calcifications and arterial stiffness as predictors of cardiovascular events in incident renal transplant recipients. Transpl Int 26:973-81
Israni, Ajay K; Leduc, Robert; Jacobson, Pamala A et al. (2013) Inflammation in the setting of chronic allograft dysfunction post-kidney transplant: phenotype and genotype. Clin Transplant 27:348-58
Israni, Ajay K; Riad, Samy M; Leduc, Robert et al. (2013) Tacrolimus trough levels after month 3 as a predictor of acute rejection following kidney transplantation: a lesson learned from DeKAF Genomics. Transpl Int 26:982-9
Jacobson, Pamala A; Schladt, David; Israni, Ajay et al. (2012) Genetic and clinical determinants of early, acute calcineurin inhibitor-related nephrotoxicity: results from a kidney transplant consortium. Transplantation 93:624-31
Jacobson, Pamala A; Schladt, David; Oetting, William S et al. (2011) Genetic determinants of mycophenolate-related anemia and leukopenia after transplantation. Transplantation 91:309-16
Jacobson, Pamala A; Oetting, William S; Brearley, Ann M et al. (2011) Novel polymorphisms associated with tacrolimus trough concentrations: results from a multicenter kidney transplant consortium. Transplantation 91:300-8
Oetting, William S; Schladt, David P; Leduc, Robert E et al. (2011) Validation of single nucleotide polymorphisms associated with acute rejection in kidney transplant recipients using a large multi-center cohort. Transpl Int 24:1231-8
Passey, Chaitali; Birnbaum, Angela K; Brundage, Richard C et al. (2011) Dosing equation for tacrolimus using genetic variants and clinical factors. Br J Clin Pharmacol 72:948-57
Mannon, Roslyn B (2010) Immune monitoring and biomarkers to predict chronic allograft dysfunction. Kidney Int Suppl :S59-65

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