Renal transplant loss due to chronic allograft nephropathy, recently designated as interstitial fibrosis/tubular atrophy not otherwise specified (IF/TA NOS), is widely acknowledged as a major problem that has increased in relative importance as the incidence of early graft loss from acute rejection declined. Histological IF/TA, regardless of the cause, is almost universally present in the allograft within a few months of transplantation. Currently, there are no therapeutic options once the clinical manifestations of IF/TA have developed. Measures not focused on altering immunosuppressants to prevent IF/TA NOS have not been tested. This application requests continued support for an ongoing renal biopsy based randomized controlled trial that has successfully completed recruitment. This study, initiated with NIH support and recipient of continued DSMB approval will complete the exit phase during the 5 years of this proposal. This trial, Angiotensin II Blockade for Chronic Allograft Nephropathy (ABCAN), will determine whether angiotensin II receptor blockade can, in the first 5 post-kidney transplant years, prevent cortical interstitial volume expansion (an accurate predictor of long term graft function) and graft loss from biopsy proven IF/TA particularly its major cause;IF/TA NOS. The ongoing studies will characterize the interstitial ultrastructural compositional changes that occur in renal allografts with IF/TA, the effects of treatment on these changes and will also provide descriptors of the incidence and predictors of the development of IF/TA. We will also determine the impact of angiotensin II receptor blockade on the rate of GFR decline, the incidence and progression of post transplant proteinuria and the nature of the permselectivity defects responsible for the proteinuria. The ancillary studies will also describe the natural history of IF/TA and elucidate early markers and predictors of this important disorder. Lastly, we will have acquired a rich repository of urine, serum, DNA and renal tissue that can be shared with other investigators in the scientific community.

Public Health Relevance

Chronic allograft nephropathy continues to be a major cause of kidney transplant loss and return to dialysis. Treatment options are limited and the course of the disease tends to be progressive. This trial is designed to prevent a major mediator of this process, namely the expansion of the cortical interstitial compartment of the kidney where most of the scarring occurs. The drug being studied, Losartan, has proven efficacious in a number of kidney diseases.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project--Cooperative Agreements (U01)
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Special Emphasis Panel (ZRG1-RUS-F (51))
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Flessner, Michael Francis
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University of Minnesota Twin Cities
Internal Medicine/Medicine
Schools of Medicine
United States
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Weber, M; Berglund, D; Reule, S et al. (2015) Daily fluid intake and outcomes in kidney recipients: post hoc analysis from the randomized ABCAN trial. Clin Transplant 29:261-7
Kukla, Aleksandra; Issa, Naim; Jackson, Scott et al. (2014) Cystatin C enhances glomerular filtration rate estimating equations in kidney transplant recipients. Am J Nephrol 39:59-65
Issa, Naim; Ortiz, Fernando; Reule, Scott A et al. (2014) The renin-aldosterone axis in kidney transplant recipients and its association with allograft function and structure. Kidney Int 85:404-15
Hart, Allyson; Jackson, Scott; Kasiske, Bertram L et al. (2014) Uric acid and allograft loss from interstitial fibrosis/tubular atrophy: post hoc analysis from the angiotensin II blockade in chronic allograft nephropathy trial. Transplantation 97:1066-71
Ibrahim, Hassan N; Jackson, Scott; Connaire, Jeffery et al. (2013) Angiotensin II blockade in kidney transplant recipients. J Am Soc Nephrol 24:320-7
Kukla, Aleksandra; El-Shahawi, Yasser; Leister, Erin et al. (2010) GFR-estimating models in kidney transplant recipients on a steroid-free regimen. Nephrol Dial Transplant 25:1653-61