Help guide our efforts to modernize
Send us your comments by March 14, 2020. Menu

Mineralocorticoid Receptor Antagonist and Kidney Allograft Histology

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. Identifier: NCT01510795
Recruitment Status : Unknown
Verified January 2012 by Clinical Hospital Merkur.
Recruitment status was:  Enrolling by invitation
First Posted : January 18, 2012
Last Update Posted : January 18, 2012
Information provided by (Responsible Party):
Clinical Hospital Merkur

Brief Summary:
Chronic allograft nephropathy is one of dominant causes of long term kidney transplant failure. Its main histological determinant is interstitial fibrosis and tubular atrophy. Mechanisms of these changes are multifactorial and are not completely elucidated. Epithelial mesenchymal transition (EMT) might be one of the mechanisms. On molecular level role of renin angiotensin aldosterone system (RAAS) has been recognized. Recently, mineralocorticoid hormone aldosterone has been proposed as a possible direct contributor to the progression of renal injury and fibrosis, beside his well known role as a regulator of extracellular fluid volume and sodium and potassium balance. In this study the investigators will determine the impact of mineralocorticoid receptor antagonist use on progression of chronic scores in transplanted kidney over one year. The investigators hypothesis is that spironolactone use in kidney transplant patients will slow down progression of chronic histological changes- interstitial fibrosis, tubular atrophy and arteriolar hyalinosis.

Condition or disease Intervention/treatment Phase
Kidney Failure, Chronic Drug: spironolactone Phase 4

Detailed Description:

Chronic allograft nephropathy (CAN) is the main cause of long term kidney transplant failure. Its main histological determinant is interstitial fibrosis and tubular atrophy, but mechanisms of these changes are not completely elucidated and seem to be multifactorial. It seems that these histological changes develop as a consequence of immunological and non-immunological mechanisms. Study from Nankivell and al. defined two phases of CAN, early, attributed to immunological mechanisms; acute rejection, persistent subclinical rejection and ischemic- reperfusion injury, and late injury, characterized with progressive arteriolar hyalinosis, glomerulosclerosis andInterstitial fibrosis and tubular atrophy (IF/TA), which was attributed in part to calcineurin inhibitor use and in part to ongoing immunologic injury.

In vitro studies and animal studies have shown epithelial mesenchimal transition as one of possible mechanisms and early markers of subsequent IF/TA. EMT is defined as process where completely differentiated epithelial cells undergo transition into fibroblast phenotype cells.

It is known that on molecular level RAAS has crucial role in development of progressive renal injury and fibrosis. Role of angiotensin II in progression of chronic kidney injury is established and well known. It mediates kidney injury by increasing intraglomerular capillary pressure leading to ultrafiltration of plasma proteins and by promoting cell growth and fibroproliferative effects.

It is hypothesized that aldosterone as a component of RAAS may also have direct role in proinflammatory and profibrotic mechanisms of initiation and progression of kidney injury. Aldosterone is a mineralocorticoid hormone produced in adrenal cortex zona glomerulosa and has crucial role as a regulator of extracellular fluid volume and sodium and potassium balance.

It has been shown in the rat models that aldosterone activates mTOR kinase, which promotes cell proliferation and contributes in early phases of injury healing. However, a prolonged activation of mTOR seems to promote development of interstitial fibrosis.

Although the molecular pathways of aldosterone-mediated renal injury have not yet been fully elucidated, aldosterone may directly contribute to the final common pathway of renal fibrosis. In vitro studies have shown that aldosterone significantly increases TGF beta and fibronectin production by mesangial cells in culture and that this event is abolished by the aldosterone antagonist spironolactone. Randomized studies have shown beneficial role of blockade of mineralocorticoid receptors in heart failure. Also studies have shown beneficial role of mineralocorticoid receptor blockade with nonselective antagonist spironolactone in reducing albuminuria in both diabetic and non diabetic chronic kidney disease (CKD) and antiproteinuric effect of a selective aldosterone inhibitor, eplerenone in type 2 diabetic patients with microalbuminuria. Role of mineralocorticoid receptor blockade in kidney transplant recipients has not been extensively evaluated so far.

In this study we hypothesized that use of a mineralocorticoid receptor antagonist, spironolactone, may contribute to slower progression of chronic histological changes in renal allografts.

Layout table for study information
Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 40 participants
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Impact of a Mineralocorticoid Receptor Antagonist on Chronic Histological Changes in Renal Allograft
Study Start Date : January 2012
Estimated Primary Completion Date : June 2013
Estimated Study Completion Date : January 2014

Resource links provided by the National Library of Medicine

Arm Intervention/treatment
No Intervention: retrospective control
Active Comparator: spironolactone Drug: spironolactone
Spironolactone initiated at 3 months posttransplant at 25 mg qd and up-titrated to 50 mg qd after 14 days. Spironolactone therapy will be maintained for 9 months.
Other Name: Aldactone

Primary Outcome Measures :
  1. Difference in 6-month changes in chronic Banff scores between spironolactone and retrospective control group [ Time Frame: 6 months ]

Secondary Outcome Measures :
  1. Difference in chronic Banff scores between spironolactone and retrospective control group at 12 months, eGFR at 6 and 12 months, urinary protein/creatinine ratio and urinary albumin/creatinine ratio at 6 and 12 months [ Time Frame: 6-12 months ]

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.

Layout table for eligibility information
Ages Eligible for Study:   18 Years to 75 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  • kidney and kidney-pancreas recipients, including patients with delayed graft function ( DGF). DGF will be defined as the dialysis need in first 7 days after transplantation

Exclusion Criteria:

  1. Baseline plasma potassium level above 5.1 µmol/L
  2. Patients on ACE inhibitor or ARB-s therapy
  3. Patients with eGFR < 30 ml/min (estimated by MDRD formula)
  4. Patents younger than 18 yr
  5. Patients with hypersensitivity to spironolacton

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 identifier (NCT number): NCT01510795

Sponsors and Collaborators
Clinical Hospital Merkur
Layout table for investigator information
Principal Investigator: Bojana Maksimović, MD Clinical Hospital Merkur
Study Director: Mladen Knotek, MD, PhD Clinical Hospital Merkur

Layout table for additonal information
Responsible Party: Clinical Hospital Merkur Identifier: NCT01510795    
Other Study ID Numbers: CHMN1012
First Posted: January 18, 2012    Key Record Dates
Last Update Posted: January 18, 2012
Last Verified: January 2012
Keywords provided by Clinical Hospital Merkur:
Kidney transplantation
Mineralocorticoid receptors
Additional relevant MeSH terms:
Layout table for MeSH terms
Renal Insufficiency
Kidney Failure, Chronic
Kidney Diseases
Urologic Diseases
Renal Insufficiency, Chronic
Mineralocorticoid Receptor Antagonists
Hormone Antagonists
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Diuretics, Potassium Sparing
Natriuretic Agents