Angiotensin II Blockade for Chronic Allograft Nephropathy

September 13, 2017 updated by: University of Minnesota

Angiotensin II Blockade for the Prevention of Cortical Interstitial Expansion and Graft Loss in Kidney Transplant Recipients

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.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

Renal transplant loss due to chronic allograft nephropathy (CAN) is widely acknowledged as a major problem that has increased in relative importance as the incidence of early graft loss from acute rejection has declined. Studies from various centers, including the University of Minnesota, suggest that, after excluding patients dying with a functioning graft, as many as 80% of patients who will return to dialysis do so because of CAN. At the present time there are no therapeutic options once the clinical manifestations of CAN have developed. Testing measures to prevent CAN have not been addressed.

The overall purpose of this project is to investigate the role of the renin-angiotensin-aldosterone system (RAAS) in the development of CAN. This system plays an important role in the progression of many experimental and clinical renal diseases. Furthermore, blockade of this system with angiotensin converting enzyme inhibitors and angiotensin II receptor blockers has yielded beneficial results in retarding injury and progression in numerous intrinsic renal diseases. This study specifically investigates the long term benefit of the angiotensin II receptor blocker, losartan, in the prevention of cortical interstitial volume expansion (an accurate predictor of long term graft function) and graft loss from biopsy proven CAN in a 5 year, randomized, double masked, placebo controlled study of kidney transplant recipients. This clinical trial will directly test the hypothesis that blockade of the renin angiotensin aldosterone system will provide a substantial benefit through blood pressure lowering independent mechanisms, namely, interruption of fibrogenic pathways, anti-proteinuric actions, amelioration of hyperfiltration and possibly some immunomodulatory effects.

The proposed studies will also characterize the interstitial ultrastructural compositional changes that occur in the renal allografts with CAN, the effects of treatment on these changes and provide a complete description of the incidence and predictors for the development of transplant glomerulopathy. These studies will also determine the impact of angiotensin II receptor blockade on the rate of decline of glomerular filtration rate, as well as the impact of glomerular size on the rate of graft loss from CAN, the incidence and the progression of post transplant proteinuria, the nature of the permselectivity defects responsible for the proteinuria and will also explore the association of proteinuria with graft loss from CAN. This trial will also help construct a profile for the RAAS in the transplant recipients and explore the relationship between two genes polymorphisms, ACE and TGF-Beta, and CAN.

These studies should help to describe the natural history, nature and pathogenesis of CAN, elucidate early markers and predictors of this important disorder and, perhaps, define a safe and useful preventative strategy.

Study Type

Interventional

Enrollment (Actual)

153

Phase

  • Phase 4

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • Minnesota
      • Minneapolis, Minnesota, United States, 55415
        • Hennepin County Medical Center
      • Minneapolis, Minnesota, United States, 55455
        • University of Minnesota

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  • Age > 18 years.
  • Recipients of a first or a second renal transplant alone or in combination with a pancreas transplantation.
  • Informed consent
  • Adequate baseline biopsy; at least 10 cortical projection fields.

Exclusion Criteria:

  • Age < 18 years.
  • Serum creatinine 2.5mg/dL.
  • Persistent hyperkalemia; potassium > 5.4 mEq/L.
  • Known hypersensitivity to losartan or iodine allergy.
  • Documented renal artery stenosis by duplex ultrasonography.
  • Recipients of grafts from an HLA-identical sibling.
  • Recipients whose primary renal disease is primary hyperoxaluria,dense-deposit disease, focal segmental glomerulosclerosis or hemolytic uremic syndrome.
  • Women of childbearing age who wish to become pregnant and/or are unwilling to use contraceptive measures or who are pregnant.
  • Recipients requiring ACE inhibitors or AII blockers for a cardiovascular indication (e.g. systolic dysfunction).
  • Recipients who are > 55 years old and had a history of cardiovascular disease (coronary artery disease, stroke or peripheral vascular disease).

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Prevention
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Triple

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Losartan 100mg
Losartan 100 mg per day to be started within three months of transplantation and continuing treatment for five years.
Drug: Losartan 100mg
To be started within three months of transplant and continued for five years.
Other Names:
  • Losartan
Placebo Comparator: Placebo
No intervention with continuing follow-up for five years.
Drug: Placebo
No treatment with continued follow-up for five years.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Doubling of Interstitium or Any ESRD
Time Frame: Baseline to 5 years
Doubling of the interstitial or any defined ESRD (including IF/TA)
Baseline to 5 years

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Number of Participants With Cortical Interstitial Volume Expansion or Any ESRD
Time Frame: Baseline and 5 Years Post Transplant
Number of subjects who had doubling of the interstitial or any end stage renal disease (ESRD) not attributed to interstitial fibrosis and tubular atrophy (IF/TA)
Baseline and 5 Years Post Transplant

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

University of Minnesota

Collaborators

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Merck Sharp & Dohme LLC

Investigators

  • Principal Investigator: Hassan N. Ibrahim, M.D., M.S., University of Minnesota
  • Principal Investigator: Bertram Kasiske, M.D., Hennepin County Medical Center, Minneapolis

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

December 1, 2002

Primary Completion (Actual)

June 1, 2011

Study Completion (Actual)

June 1, 2011

Study Registration Dates

First Submitted

September 3, 2003

First Submitted That Met QC Criteria

September 4, 2003

First Posted (Estimate)

September 5, 2003

Study Record Updates

Last Update Posted (Actual)

September 18, 2017

Last Update Submitted That Met QC Criteria

September 13, 2017

Last Verified

September 1, 2017

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • ANGIOB
  • R01DK060706 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

IPD Plan Description

There are no plans to share individual participant data.

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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