Effect of Strict Blood Pressure Control and ACE-Inhibition on Progression of Chronic Renal Failure in Pediatric Patients
- Conditions
- ChildrenChronic Renal FailureHypertensionAcquired Kidney DiseaseCongenital Kidney Disease
- Interventions
- Drug: ACE InhibitionDrug: Intensified Blood Pressure Control
- Registration Number
- NCT00221845
- Lead Sponsor
- Heidelberg University
- 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 hypo/dysplastic 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 and/or 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 and/or 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.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 400
- Age 3-18 years
- Moderate state of renal failure (creatinine clearance 15 - 75 ml / min / 1.73 m²)
- Mean arterial blood pressure (ABPM) > 50.percentile and/or antihypertensive treatment
- Written informed consent
- Age <3 years or >18 years at start of study
- Unstable clinical condition (vomiting, anorexia, etc) or superimposed important disease
- Unilateral or bilateral renal artery stenosis
- Urological surgery possibly affecting renal function expected during study period
- Insufficient compliance with prescribed antihypertensive medication during the run-in period
- Secondary renal diseases such as lupus, amyloidosis and primary hyperoxaluria, and patients treated with immunosuppressive agents (including corticosteroids)
- Severe primary cardiac disease, hepatic insufficiency and malabsorption syndrome
- Erythropoietin or growth hormone therapy with a duration of less than 3 months prior to run-in period
- Pregnancy
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Conventional BP Control ACE Inhibition Targeted 24-hour mean arterial pressure will be the 50th-95th percentile for age. Conventional BP Control Intensified Blood Pressure Control Targeted 24-hour mean arterial pressure will be the 50th-95th percentile for age. Conventional BP Control Add-on Angiotensin Receptor Blockade Targeted 24-hour mean arterial pressure will be the 50th-95th percentile for age. Intensified BP Control ACE Inhibition Targeted 24-hour mean arterial pressure will be the 5th to 50th percentile for age. Intensified BP Control Intensified Blood Pressure Control Targeted 24-hour mean arterial pressure will be the 5th to 50th percentile for age. Intensified BP Control Add-on Angiotensin Receptor Blockade Targeted 24-hour mean arterial pressure will be the 5th to 50th percentile for age.
- Primary Outcome Measures
Name Time Method Time interval to renal 'loss' as defined by an absolute decrease in creatinine clearance by 50 % or attainment of renal replacement therapy. two-monthly
- Secondary Outcome Measures
Name Time Method Effect of treatment on urinary protein excretion two-monthly Effect of treatment on blood pressure two-monthly Safety of treatment initially weekly, than two-monthly
Trial Locations
- Locations (33)
University Hospital Motol, 1st Department of Pediatrics
🇨🇿Prague, Czech Republic
University Hospital Essen, Department of Pediatrics, Pediatric Nephrology Unit
🇩🇪Essen, Germany
Hopital Necker, Division of Pediatric Nephrology
🇫🇷Paris, France
Humboldt University Berlin, Charité Children's Hospital, Department of Pediatric Nephrology
🇩🇪Berlin, Germany
Hopiteaux Universitaires de Strasbourg
🇫🇷Strasbourg, France
Inserm U574
🇫🇷Paris, France
Hannover Medical School, Children's Hospital Div. II, Pediatric Nephrology
🇩🇪Hannover, Germany
Division of Pediatric Nephrology, Children's Hospital, University of Heidelberg
🇩🇪Heidelberg, Germany
Urban Hospital St. Georg, Department of Pediatrics, Pediatric Nephrology Unit
🇩🇪Leipzig, Germany
University Hospital Hamburg-Eppendorf, University Children's Hospital, Dept. of Pediatric Nephrology
🇩🇪Hamburg, Germany
Philipps University Marburg, Dept. of Pediatrics
🇩🇪Marburg, Germany
Johannes Gutenberg University Mainz, Department of Pediatrics,
🇩🇪Mainz, Germany
University Children's Hospital, Dept. of Nephrology
🇩🇪Rostock, Germany
Semmelweis University Budapest, 1st Department of Pediatrics
🇭🇺Budapest, Hungary
G.Gaslini Institute, Nephrology Unit
🇮🇹Genoa, Italy
Azienda Ospedaliera, Istitui Clinici di Perfezionamento, Servizio die Emodialisi Pediatrica
🇮🇹Milano, Italy
Ospedale Pediatrico Bambino Gesù, Division of Nephrology and Dialysis
🇮🇹Rome, Italy
Azienda Ospedaliera die Padova. U.O. Nefrologia Dialisi e Trapianto - Dipartimento di Pediatria
🇮🇹Padova, Italy
Ospedale Infantile Regina Margherita, U.O.A. Nefrologia, Dialisi, Trapianto
🇮🇹Torino, Italy
Vilnius University Children's Hospital, Pediatric Department, Nephrology Unit
🇱🇹Vilnius, Lithuania
Medical University of Gdansk, Pediatric Nephrology Department
🇵🇱Gdansk, Poland
Children's Memorial Health Hospital, Nephrology and Kidney Transplantation Department
🇵🇱Warsaw, Poland
Hospital S. Joao-Faculade de Medicina do Porto, Dept. of Pediatrics
🇵🇹Porto, Portugal
Karolinska Institute, Huddinge University Hospital, Dept. of Pediatrics
🇸🇪Stockholm, Sweden
Cukurova University School of Medicine, Dept. of Pediatric Nephrology
🇹🇷Adana, Turkey
Istanbul University, Cerrahpasa Medical Faculty, Dept, of Pediatrics
🇹🇷Istanbul, Turkey
Clinic of Pediatrics, Pomeranian Academy of Medicine
🇵🇱Szczecin, Poland
Faculty of Medicine Belgrade, University Children's Hospital, Nephrology Unit
🇷🇸Belgrade, Serbia
University Children's Hospital, Nephrology Unit
🇨🇭Zürich, Switzerland
Hacettepe University, Faculty of Medicine, Pediatric Nephrology and Rheumatology
🇹🇷Ankara, Turkey
Ege University Medical Faculty, Dept. of Pediatric Nephrology
🇹🇷Izmir, Turkey
University of Istanbul, Istanbul Medical Faculty, Dept. of Pediatrics
🇹🇷Istanbul, Turkey
Jagellonian University Medical College, Department of Pediatric Nephrology
🇵🇱Cracow, Poland