Ignite Creation Date:
2024-05-05 @ 12:03 PM
Last Modification Date:
2024-10-26 @ 9:19 AM
Study NCT ID:
NCT00221845
Status:
COMPLETED
Last Update Posted:
2010-01-12
First Post:
2005-09-15
Brief Title:
Effect of Strict Blood Pressure Control and ACE-Inhibition on Progression of Chronic Renal Failure in Pediatric Patients
Sponsor:
Heidelberg University
Organization:
Heidelberg University
Study Overview
Official Title:
Molecular Mechanisms of Disease Progression and Renoprotective Pharmacotherapy in Children With Chronic Renal Failure
Status:
COMPLETED
Status Verified Date:
2010-01
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
ESCAPE
Brief Summary:
In children with chronic kidney disease progression to end-stage renal failure is associated with high patient morbidity and poor quality of life In adults inhibition of the renin angiotensin system RAS slows down the rate of renal failure progression This concept is as yet unproven in children in whom chronic renal failure CRF is more commonly due to hypodysplastic malformations than to acquired glomerulopathies as typical for adult chronic kidney disease The current project aims at assessing the genetic and molecular mechanisms and cardiovascular consequences of progressive CRF and to develop a strategy of pharmacological renoprotection in children
Detailed Description:
Chronic kidney diseases affecting the nephron mass are characterized by a progressive decline of glomerular filtration rate GFR occurring irrespectively of the cause of the renal damage once a critical number of nephrons has been lost Current clinical research efforts focus on preventive strategies to slow down or arrest disease progression Systemic hypertension and glomerular hyperfiltration with resulting proteinuria and activation of vasoactive profibrotic and proinflammatory systems have been identified as major causes of further nephron damage Angiotensin converting enzyme ACE inhibitors are not only potent antihypertensive agents but also reduce proteinuria glomerulosclerosis and tubulointerstitial fibrosis via reduction of the local angiotensin tone in the kidney and have been demonstrated to slow down renal failure progression in adult patients Childhood-onset ESRD is a rare but particularly devastating disease with poor life expectancy and quality of life Chronic renal failure in children is caused by a different spectrum of nephropathies than in adults with a preponderance of congenital or inherited abnormalities Since hypertension proteinuria and tubulointerstitial fibrosis are also common in pediatric chronic renal failure there is a rationale for pharmacological renoprotection by ACE inhibition in children The prospective randomized European clinical trial launched by our consortium will provide the critical mass to assess several aspects of renoprotective therapy in children Specifically the trial is designed to address the following scientific objectives
Objective 1 is to evaluate whether ACE inhibition is equally effective in slowing down the progression rate of chronic renal failure in children with different congenital and acquired renal disorders 400 pediatric patients will be stratified according to their underlying diseases and the rate of loss in glomerular filtration rate will be assessed from 6 months before to 5 years after start of treatment with the ACE inhibitor ramipril
Objective 2 of the trial is to evaluate whether renal failure progression in patients treated with a fixed dose of ramipril can be further slowed down by additional antihypertensive treatment achieving a blood pressure below the 50th percentile To this end patients will be randomized upon initiation of ramipril to either intensified aiming below 50th percentile of 24-hour mean arterial pressure or conventional antihypertensive treatment
Several gene polymorphisms have been described that may affect the rate of renal failure progression andor the individual susceptibility to ACE inhibition These polymorphisms include genes encoding for key proteins of the renin-angiotensin system and extracellular matrix turnover In addition we will screen for novel polymorphisms in genes determining structural proteins of the glomerular filter and search for gene mutations causing renal hypo-dysplasia Objective 3 is to evaluate whether any of these mutations predict spontaneous disease progression and the therapeutic response to ACE inhibition and intensified blood pressure control
Glomerular endothelin ET1 synthesis is upregulated in chronic renal failure and urinary ET1 excretion is correlated with disease progression ET1 antagonists partially preserve renal function and decrease proteinuria independent of the angiotensin tone Objective 4 of the trial is to assess ET1 turnover before and after start of ACE inhibition and to evaluate a possible predictive role of ET1 andor ET1 degrading peptidase excretion for the persistence of proteinuria and disease progression during ACE inhibition and intensified antihypertensive therapy
Long-term survival of children with chronic renal failure is compromised by precocious atherosclerosis and excessive cardiovascular morbidity Objective 5 is to assess and correlate prospectively the metabolic causes and morphological consequences of uremic cardiovascular disease in children and to define their relationship with disease progression during ACE inhibition and intensified blood pressure control Homocysteine metabolism apolipoprotein variability gene polymorphisms putatively involved in atherosclerosis inflammation states myocardial function and carotid intima-media thickness will be assessed and compared to a reference group of age-matched healthy children
Objective 1 is to evaluate whether ACE inhibition is equally effective in slowing down the progression rate of chronic renal failure in children with different congenital and acquired renal disorders 400 pediatric patients will be stratified according to their underlying diseases and the rate of loss in glomerular filtration rate will be assessed from 6 months before to 5 years after start of treatment with the ACE inhibitor ramipril
Objective 2 of the trial is to evaluate whether renal failure progression in patients treated with a fixed dose of ramipril can be further slowed down by additional antihypertensive treatment achieving a blood pressure below the 50th percentile To this end patients will be randomized upon initiation of ramipril to either intensified aiming below 50th percentile of 24-hour mean arterial pressure or conventional antihypertensive treatment
Several gene polymorphisms have been described that may affect the rate of renal failure progression andor the individual susceptibility to ACE inhibition These polymorphisms include genes encoding for key proteins of the renin-angiotensin system and extracellular matrix turnover In addition we will screen for novel polymorphisms in genes determining structural proteins of the glomerular filter and search for gene mutations causing renal hypo-dysplasia Objective 3 is to evaluate whether any of these mutations predict spontaneous disease progression and the therapeutic response to ACE inhibition and intensified blood pressure control
Glomerular endothelin ET1 synthesis is upregulated in chronic renal failure and urinary ET1 excretion is correlated with disease progression ET1 antagonists partially preserve renal function and decrease proteinuria independent of the angiotensin tone Objective 4 of the trial is to assess ET1 turnover before and after start of ACE inhibition and to evaluate a possible predictive role of ET1 andor ET1 degrading peptidase excretion for the persistence of proteinuria and disease progression during ACE inhibition and intensified antihypertensive therapy
Long-term survival of children with chronic renal failure is compromised by precocious atherosclerosis and excessive cardiovascular morbidity Objective 5 is to assess and correlate prospectively the metabolic causes and morphological consequences of uremic cardiovascular disease in children and to define their relationship with disease progression during ACE inhibition and intensified blood pressure control Homocysteine metabolism apolipoprotein variability gene polymorphisms putatively involved in atherosclerosis inflammation states myocardial function and carotid intima-media thickness will be assessed and compared to a reference group of age-matched healthy children
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None