Angiotensin II Blockade for Chronic Allograft Nephropathy

NCT ID: NCT00067990

Last Updated: 2017-09-18

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE4
• Total Enrollment: 153 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2002-12-31
• Study Completion Date: 2011-06-30

Brief Summary

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.

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.

Conditions

Kidney Disease; Proteinuria

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: PREVENTION
• Blinding Strategy: TRIPLE

Study Groups

Losartan 100mg

Losartan 100 mg per day to be started within three months of transplantation and continuing treatment for five years.

Group Type: EXPERIMENTAL

Losartan 100mg

Intervention Type: DRUG

To be started within three months of transplant and continued for five years.

Placebo

No intervention with continuing follow-up for five years.

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

No treatment with continued follow-up for five years.

Interventions

Losartan 100mg

To be started within three months of transplant and continued for five years.

Intervention Type: DRUG

Placebo

No treatment with continued follow-up for five years.

Intervention Type: DRUG

Other Intervention Names

Losartan

Eligibility 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).

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

NIH

Sponsor Role: collaborator

Merck Sharp & Dohme LLC

INDUSTRY

Sponsor Role: collaborator

University of Minnesota

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Hassan N. Ibrahim, M.D., M.S.

Role: PRINCIPAL_INVESTIGATOR

University of Minnesota

Bertram Kasiske, M.D.

Role: PRINCIPAL_INVESTIGATOR

Hennepin County Medical Center, Minneapolis

Locations

Hennepin County Medical Center

Minneapolis, Minnesota, United States

University of Minnesota

Minneapolis, Minnesota, United States

Countries

United States

References

Ibrahim HN, Jackson S, Connaire J, Matas A, Ney A, Najafian B, West A, Lentsch N, Ericksen J, Bodner J, Kasiske B, Mauer M. Angiotensin II blockade in kidney transplant recipients. J Am Soc Nephrol. 2013 Feb;24(2):320-7. doi: 10.1681/ASN.2012080777. Epub 2013 Jan 10.

Reference Type: BACKGROUND

PMID: 23308016 (View on PubMed)

Natale P, Mooi PK, Palmer SC, Cross NB, Cooper TE, Webster AC, Masson P, Craig JC, Strippoli GF. Antihypertensive treatment for kidney transplant recipients. Cochrane Database Syst Rev. 2024 Jul 31;7(7):CD003598. doi: 10.1002/14651858.CD003598.pub3.

Reference Type: DERIVED

PMID: 39082471 (View on PubMed)

Kukla A, Issa N, Jackson S, Spong R, Foster MC, Matas AJ, Mauer MS, Eckfeldt JH, Ibrahim HN. Cystatin C enhances glomerular filtration rate estimating equations in kidney transplant recipients. Am J Nephrol. 2014;39(1):59-65. doi: 10.1159/000357594. Epub 2014 Jan 18.

Reference Type: DERIVED

PMID: 24457184 (View on PubMed)

Issa N, Ortiz F, Reule SA, Kukla A, Kasiske BL, Mauer M, Jackson S, Matas AJ, Ibrahim HN, Najafian B. The renin-aldosterone axis in kidney transplant recipients and its association with allograft function and structure. Kidney Int. 2014 Feb;85(2):404-15. doi: 10.1038/ki.2013.278. Epub 2013 Aug 21.

Reference Type: DERIVED

PMID: 23965522 (View on PubMed)

Other Identifiers

R01DK060706

Identifier Type: NIH

Identifier Source: secondary_id

View Link

ANGIOB

Identifier Type: -

Identifier Source: org_study_id

NCT01467895

Identifier Type: -

Identifier Source: nct_alias