We plan a multi-center study to accurately describe the natural history of late kidney transplant failure, and to dissect out individual entities leading to late deterioration of function and to graft loss. Previous studies, and the current literature, attribute most chronic graft dysfunction (CGD) to a process called chronic rejection (CR) or chronic allograft nephropathy (CAN). Most recipients with this diagnosis have undergone biopsy late in their clinical course (if ever) at which time the histologic findings are non-specific. Our focus is to test the hypothesis that CGD is usually attributable to definable factors and not to a mysterious indefinable force known, as CR. Defining individual factors will permit future development of intervention trials. Our hypotheses are: 1) there are multiple, definable entities leading to CGD (and graft loss); 2) these entities can be differentiated by clinical, radiological, serologic, and pathologic studies. 3) progression of CGD is due to an identifiable, currently operating injurious process and not the consequence of a past injury.
Specific Aims of this grant are to: 1) determine, in a previously tx cross-sectional cohort, whether clinical, laboratory, and pathologic studies (conventional histology, immunohistology, special stains) at the time of initial graft dysfunction will allow definition of different clinico-pathologic entities (possibly with differing clinical courses); 2) determine, in a prospective cohort, whether clinical, laboratory, and pathologic studies (conventional histology, immunohistology, special stains) at the time of initial graft dysfunction will confirm the definition of different entities (possibly with differing clinical courses); 3) determine whether markers of fibrogenic activity and/or inflammation, the presence of anti-human leukocyte antibody (HLA) antibodies, or other clinical correlates can define specific pathophysiologic features that correlate with progression and with the rate of progression of CGD. Defining clinico-pathologic entities (and their individual clinical courses) will provide a knowledge base for future studies of CGD. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01AI058013-03
Application #
7210729
Study Section
Special Emphasis Panel (ZRG1-HOP-N (90))
Program Officer
Odim, Jonah
Project Start
2005-02-15
Project End
2010-01-31
Budget Start
2007-02-01
Budget End
2008-01-31
Support Year
3
Fiscal Year
2007
Total Cost
$1,767,902
Indirect Cost
Name
University of Minnesota Twin Cities
Department
Surgery
Type
Schools of Medicine
DUNS #
555917996
City
Minneapolis
State
MN
Country
United States
Zip Code
55455
Seibert, Stephan R; Schladt, David P; Wu, Baolin et al. (2018) Tacrolimus trough and dose intra-patient variability and CYP3A5 genotype: Effects on acute rejection and graft failure in European American and African American kidney transplant recipients. Clin Transplant 32:e13424
Snoek, Rozemarijn; van Setten, Jessica; Keating, Brendan J et al. (2018) NPHP1 (Nephrocystin-1) Gene Deletions Cause Adult-Onset ESRD. J Am Soc Nephrol 29:1772-1779
Okour, Malek; Jacobson, Pamala A; Ahmed, Mariam A et al. (2018) Mycophenolic Acid and Its Metabolites in Kidney Transplant Recipients: A Semimechanistic Enterohepatic Circulation Model to Improve Estimating Exposure. J Clin Pharmacol 58:628-639
Dorr, Casey R; Wu, Baolin; Remmel, Rory P et al. (2018) Identification of genetic variants associated with tacrolimus metabolism in kidney transplant recipients by extreme phenotype sampling and next generation sequencing. Pharmacogenomics J :
Sanghavi, K; Brundage, R C; Miller, M B et al. (2017) Genotype-guided tacrolimus dosing in African-American kidney transplant recipients. Pharmacogenomics J 17:61-68
Oetting, William S; Dorr, Casey; Remmel, Rory P et al. (2017) Concepts of Genomics in Kidney Transplantation. Curr Transplant Rep 4:116-123
Oetting, W S; Schladt, D P; Guan, W et al. (2016) Genomewide Association Study of Tacrolimus Concentrations in African American Kidney Transplant Recipients Identifies Multiple CYP3A5 Alleles. Am J Transplant 16:574-82
Pulk, Rebecca A; Schladt, David S; Oetting, William S et al. (2015) Multigene predictors of tacrolimus exposure in kidney transplant recipients. Pharmacogenomics 16:841-54
International Genetics & Translational Research in Transplantation Network (iGeneTRAiN) (2015) Design and Implementation of the International Genetics and Translational Research in Transplantation Network. Transplantation 99:2401-12
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

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