Mineralocorticoid Receptor Antagonist and Kidney Allograft Histology
Information source: Clinical Hospital Merkur
ClinicalTrials.gov processed this data on August 23, 2015 Link to the current ClinicalTrials.gov record.
Condition(s) targeted: Kidney Failure, Chronic
Intervention: spironolactone (Drug)
Phase: Phase 4
Status: Enrolling by invitation
Sponsored by: Clinical Hospital Merkur Official(s) and/or principal investigator(s): Bojana Maksimović, MD, Principal Investigator, Affiliation: Clinical Hospital Merkur Mladen Knotek, MD, PhD, Study Director, Affiliation: Clinical Hospital Merkur
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.
Clinical Details
Official title: Impact of a Mineralocorticoid Receptor Antagonist on Chronic Histological Changes in Renal Allograft
Study design: Allocation: Non-Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Primary outcome: Difference in 6-month changes in chronic Banff scores between spironolactone and retrospective control group
Secondary outcome: 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
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.
Eligibility
Minimum age: 18 Years.
Maximum age: 75 Years.
Gender(s): Both.
Criteria:
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
Locations and Contacts
Additional Information
Starting date: January 2012
Last updated: January 17, 2012
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