Angiotensin II Blockade for Chronic Allograft Nephropathy

Kidney Disease Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00067990
• Other study ID #: ANGIOB
• Secondary ID: R01DK060706
• Status: Completed
• Phase: Phase 4
• First received: September 3, 2003
• Last updated: September 13, 2017
• Start date: December 2002
• Est. completion date: June 2011

Study information

• Verified date: September 2017
• Source: University of Minnesota - Clinical and Translational Science Institute
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Other known NCT identifiers

• NCT01467895

Recruitment information / eligibility

• Status: Completed
• Enrollment: 153
• Est. completion date: June 2011
• Est. primary completion date: June 2011
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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).

Related Conditions & MeSH terms

• Kidney Disease
• Kidney Diseases
• Proteinuria

Intervention

Drug:
• Losartan 100mg
To be started within three months of transplant and continued for five years.
• Placebo
No treatment with continued follow-up for five years.

Locations

Country	Name	City	State
United States	Hennepin County Medical Center	Minneapolis	Minnesota
United States	University of Minnesota	Minneapolis	Minnesota

Sponsors (3)

Lead Sponsor	Collaborator
University of Minnesota - Clinical and Translational Science Institute	Merck Sharp & Dohme Corp., National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Country where clinical trial is conducted

United States, 

References & Publications (1)

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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Doubling of Interstitium or Any ESRD	Doubling of the interstitial or any defined ESRD (including IF/TA)	Baseline to 5 years
Secondary	Number of Participants With Cortical Interstitial Volume Expansion or Any ESRD	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