Angiotensin II Blockade for Chronic Allograft Nephropathy

• ClinicalTrials.gov Identifier: NCT00067990
• Recruitment Status: Completed
• First Posted: September 5, 2003
• Results First Posted: September 18, 2017
• Last Update Posted: September 18, 2017
• Sponsor: University of Minnesota
• Collaborators: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK); Merck Sharp & Dohme Corp.
• Information provided by (Responsible Party): University of Minnesota

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Kidney Disease; Proteinuria	Drug: Losartan 100mg; Drug: Placebo	Phase 4

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 Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 153 participants
• 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
• Study Start Date: December 2002
• Actual Primary Completion Date: June 2011
• Actual Study Completion Date: June 2011

Arms and Interventions

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 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.

Outcome Measures

Primary Outcome Measures :

1. 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 :

1. 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)

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• 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

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

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
• Principal Investigator: Bertram Kasiske, M.D.; Hennepin County Medical Center, Minneapolis

More Information

Publications:

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.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

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. Erratum in: Kidney Int. 2015 Jan;87(1):243. Najafian, Behzad [Added].

• Responsible Party: University of Minnesota
• ClinicalTrials.gov Identifier: NCT00067990
• Obsolete Identifiers: NCT01467895
• Other Study ID Numbers: ANGIOB; R01DK060706 ( U.S. NIH Grant/Contract )
• First Posted: September 5, 2003
• 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:

chronic allograft nephropathy; post transplant proteinuria

Additional relevant MeSH terms:

Kidney Diseases; Proteinuria; Urologic Diseases; Urination Disorders; Urological Manifestations; Losartan; Anti-Arrhythmia Agents; Antihypertensive Agents; Angiotensin II Type 1 Receptor Blockers; Angiotensin Receptor Antagonists; Molecular Mechanisms of Pharmacological Action