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Angiotensin II Blockade for Chronic Allograft Nephropathy

This study has been completed.
Sponsor:
ClinicalTrials.gov Identifier:
NCT00067990
First Posted: September 5, 2003
Last Update Posted: September 18, 2017
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
Collaborators:
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Merck Sharp & Dohme Corp.
Information provided by (Responsible Party):
University of Minnesota - Clinical and Translational Science Institute
  Purpose
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.

Condition Intervention Phase
Kidney Disease Proteinuria Drug: Losartan 100mg Drug: Placebo Phase 4

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary Purpose: Prevention
Official Title: Angiotensin II Blockade for the Prevention of Cortical Interstitial Expansion and Graft Loss in Kidney Transplant Recipients

Resource links provided by NLM:


Further study details as provided by University of Minnesota - Clinical and Translational Science Institute:

Primary Outcome Measures:
  • Doubling of Interstitium or Any ESRD [ Time Frame: Baseline to 5 years ]
    Doubling of the interstitial or any defined ESRD (including IF/TA)


Secondary Outcome Measures:
  • 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)


Enrollment: 153
Study Start Date: December 2002
Study Completion Date: June 2011
Primary Completion Date: June 2011 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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 Name: Losartan
Placebo Comparator: Placebo
No intervention with continuing follow-up for five years.
Drug: Placebo
No treatment with continued follow-up for five years.

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.

  Eligibility

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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).
  Contacts and Locations
Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00067990


Locations
United States, Minnesota
Hennepin County Medical Center
Minneapolis, Minnesota, United States, 55415
University of Minnesota
Minneapolis, Minnesota, United States, 55455
Sponsors and Collaborators
University of Minnesota - Clinical and Translational Science Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Merck Sharp & Dohme Corp.
Investigators
Principal Investigator: Hassan N. Ibrahim, M.D., M.S. University of Minnesota - Clinical and Translational Science Institute
Principal Investigator: Bertram Kasiske, M.D. Hennepin County Medical Center, Minneapolis
  More Information

Publications:
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: University of Minnesota - Clinical and Translational Science Institute
ClinicalTrials.gov Identifier: NCT00067990     History of Changes
Obsolete Identifiers: NCT01467895
Other Study ID Numbers: ANGIOB
R01DK060706 ( U.S. NIH Grant/Contract )
First Submitted: September 3, 2003
First Posted: September 5, 2003
Results First Submitted: March 13, 2017
Results First Posted: September 18, 2017
Last Update Posted: September 18, 2017
Last Verified: September 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Plan Description: There are no plans to share individual participant data.

Keywords provided by University of Minnesota - Clinical and Translational Science Institute:
chronic allograft nephropathy
post transplant proteinuria

Additional relevant MeSH terms:
Kidney Diseases
Proteinuria
Urologic Diseases
Urination Disorders
Urological Manifestations
Signs and Symptoms
Losartan
Angiotensin II
Angiotensinogen
Anti-Arrhythmia Agents
Antihypertensive Agents
Angiotensin II Type 1 Receptor Blockers
Angiotensin Receptor Antagonists
Molecular Mechanisms of Pharmacological Action
Vasoconstrictor Agents
Serine Proteinase Inhibitors
Protease Inhibitors
Enzyme Inhibitors