Angiotensin II Blockade for Chronic Allograft Nephropathy

This study has been completed.
Sponsor:
Collaborators:
Merck Sharp & Dohme Corp.
Information provided by (Responsible Party):
Hassan Ibrahim, University of Minnesota - Clinical and Translational Science Institute
ClinicalTrials.gov Identifier:
NCT00067990
First received: September 3, 2003
Last updated: January 30, 2012
Last verified: January 2012
  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
Phase 4

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, 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:
  • GFR studies [ Time Frame: Yearly ] [ Designated as safety issue: Yes ]

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: Losartin Drug: Losartan
For the first 14 days after subject is randomized they will take 50mg of losartan. After the 14 days the dose will be increased to 100mg of losartan daily.

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

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
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
Please refer to this study by its ClinicalTrials.gov identifier: NCT00067990

Locations
United States, Minnesota
University of Minnesota
Minneapolis, Minnesota, United States, 55455
Hennepin County Medical Center
Minneapolis, Minnesota, United States, 55415
Sponsors and Collaborators
University of Minnesota - Clinical and Translational Science Institute
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

No publications provided

Responsible Party: Hassan Ibrahim, M.D., University of Minnesota - Clinical and Translational Science Institute
ClinicalTrials.gov Identifier: NCT00067990     History of Changes
Obsolete Identifiers: NCT01467895
Other Study ID Numbers: ANGIOB, R01DK060706, DK60706
Study First Received: September 3, 2003
Last Updated: January 30, 2012
Health Authority: United States: Federal Government

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
Angiotensin II
Losartan
Vasoconstrictor Agents
Cardiovascular Agents
Therapeutic Uses
Pharmacologic Actions
Anti-Arrhythmia Agents
Antihypertensive Agents
Angiotensin II Type 1 Receptor Blockers
Angiotensin Receptor Antagonists
Molecular Mechanisms of Pharmacological Action

ClinicalTrials.gov processed this record on April 16, 2014