Clinical trial NCT00221845: Effect of Strict Blood Pressure Control and ACE-Inhibition on Progression of Chronic Renal Failure in Pediatric Patients
Official title: Molecular Mechanisms of Disease Progression and Renoprotective Pharmacotherapy in Children With Chronic Renal Failure
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Children
Chronic Renal Failure
Hypertension
Acquired Kidney Disease
Congenital Kidney Disease
Keywords: Ramipril
Hypertension
Chronic renal failure
Disease progression
Left ventricular hypertrophy
Intima media thickness
Cardiovascular disease
Biomarkers
Gene polymorphisms
Lead sponsor: Heidelberg University
Sponsor class: OTHER
Collaborators: name: European Commission
name: Boehringer Ingelheim
name: Baxter Healthcare Corporation
name: Aventis Pharmaceuticals
First posted: 2005-09-22
Enrollment: 400
Sex: ALL
Minimum age (years): 3
Maximum age (years): 18
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility criteria: Inclusion Criteria:

* 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

Exclusion Criteria:

* 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

Primary outcomes:
measure: Time interval to renal 'loss' as defined by an absolute decrease in creatinine clearance by 50 % or attainment of renal replacement therapy.
timeFrame: two-monthly
Secondary outcomes:
measure: Effect of treatment on urinary protein excretion
timeFrame: two-monthly
measure: Effect of treatment on blood pressure
timeFrame: two-monthly
measure: Safety of treatment
timeFrame: initially weekly, than two-monthly
Other outcomes:
Locations:
city: Prague
country: Czech Republic
facility: University Hospital Motol, 1st Department of Pediatrics
city: Paris
country: France
facility: Hopital Necker, Division of Pediatric Nephrology
city: Paris
country: France
facility: Inserm U574
city: Strasbourg
country: France
facility: Hopiteaux Universitaires de Strasbourg
city: Berlin
country: Germany
facility: Humboldt University Berlin, Charité Children's Hospital, Department of Pediatric Nephrology
city: Essen
country: Germany
facility: University Hospital Essen, Department of Pediatrics, Pediatric Nephrology Unit
city: Hamburg
country: Germany
facility: University Hospital Hamburg-Eppendorf, University Children's Hospital, Dept. of Pediatric Nephrology
city: Hannover
country: Germany
facility: Hannover Medical School, Children's Hospital Div. II, Pediatric Nephrology
city: Heidelberg
country: Germany
facility: Division of Pediatric Nephrology, Children's Hospital, University of Heidelberg
city: Leipzig
country: Germany
facility: Urban Hospital St. Georg, Department of Pediatrics, Pediatric Nephrology Unit
city: Mainz
country: Germany
facility: Johannes Gutenberg University Mainz, Department of Pediatrics,
city: Marburg
country: Germany
facility: Philipps University Marburg, Dept. of Pediatrics
city: Rostock
country: Germany
facility: University Children's Hospital, Dept. of Nephrology
city: Budapest
country: Hungary
facility: Semmelweis University Budapest, 1st Department of Pediatrics
city: Genoa
country: Italy
facility: G.Gaslini Institute, Nephrology Unit
city: Milano
country: Italy
facility: Azienda Ospedaliera, Istitui Clinici di Perfezionamento, Servizio die Emodialisi Pediatrica
city: Padova
country: Italy
facility: Azienda Ospedaliera die Padova. U.O. Nefrologia Dialisi e Trapianto - Dipartimento di Pediatria
city: Rome
country: Italy
facility: Ospedale Pediatrico Bambino Gesù, Division of Nephrology and Dialysis
city: Torino
country: Italy
facility: Ospedale Infantile Regina Margherita, U.O.A. Nefrologia, Dialisi, Trapianto
city: Vilnius
country: Lithuania
facility: Vilnius University Children's Hospital, Pediatric Department, Nephrology Unit
city: Cracow
country: Poland
facility: Jagellonian University Medical College, Department of Pediatric Nephrology
city: Gdansk
country: Poland
facility: Medical University of Gdansk, Pediatric Nephrology Department
city: Szczecin
country: Poland
facility: Clinic of Pediatrics, Pomeranian Academy of Medicine
city: Warsaw
country: Poland
facility: Children's Memorial Health Hospital, Nephrology and Kidney Transplantation Department
city: Porto
country: Portugal
facility: Hospital S. Joao-Faculade de Medicina do Porto, Dept. of Pediatrics
city: Belgrade
country: Serbia
facility: Faculty of Medicine Belgrade, University Children's Hospital, Nephrology Unit
city: Stockholm
country: Sweden
facility: Karolinska Institute, Huddinge University Hospital, Dept. of Pediatrics
city: Zürich
country: Switzerland
facility: University Children's Hospital, Nephrology Unit
city: Adana
country: Turkey
facility: Cukurova University School of Medicine, Dept. of Pediatric Nephrology
city: Ankara
country: Turkey
facility: Hacettepe University, Faculty of Medicine, Pediatric Nephrology and Rheumatology
city: Istanbul
country: Turkey
facility: Istanbul University, Cerrahpasa Medical Faculty, Dept, of Pediatrics
city: Istanbul
country: Turkey
facility: University of Istanbul, Istanbul Medical Faculty, Dept. of Pediatrics
city: Izmir
country: Turkey
facility: Ege University Medical Faculty, Dept. of Pediatric Nephrology
Study officials:
affiliation: University of Heidelberg, Children's Hospital
name: Franz Schaefer, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Heidelberg, Children's Hospital
name: Otto Mehls, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: ESCAPE Trial Group; Wuhl E, Trivelli A, Picca S, Litwin M, Peco-Antic A, Zurowska A, Testa S, Jankauskiene A, Emre S, Caldas-Afonso A, Anarat A, Niaudet P, Mir S, Bakkaloglu A, Enke B, Montini G, Wingen AM, Sallay P, Jeck N, Berg U, Caliskan S, Wygoda S, Hohbach-Hohenfellner K, Dusek J, Urasinski T, Arbeiter K, Neuhaus T, Gellermann J, Drozdz D, Fischbach M, Moller K, Wigger M, Peruzzi L, Mehls O, Schaefer F. Strict blood-pressure control and progression of renal failure in children. N Engl J Med. 2009 Oct 22;361(17):1639-50. doi: 10.1056/NEJMoa0902066.
citation: Tabatabaeifar M, Schlingmann KP, Litwin M, Emre S, Bakkaloglu A, Mehls O, Antignac C, Schaefer F, Weber S; ESCAPE Trial Group. Functional analysis of BMP4 mutations identified in pediatric CAKUT patients. Pediatr Nephrol. 2009 Dec;24(12):2361-8. doi: 10.1007/s00467-009-1287-6. Epub 2009 Aug 14.
citation: Gimpel C, Wuhl E, Arbeiter K, Drozdz D, Trivelli A, Charbit M, Gellermann J, Dusek J, Jankauskiene A, Emre S, Schaefer F; ESCAPE Trial Group. Superior consistency of ambulatory blood pressure monitoring in children: implications for clinical trials. J Hypertens. 2009 Aug;27(8):1568-74. doi: 10.1097/HJH.0b013e32832cb2a8.
citation: Grenda R, Wuhl E, Litwin M, Janas R, Sladowska J, Arbeiter K, Berg U, Caldas-Afonso A, Fischbach M, Mehls O, Sallay P, Schaefer F; ESCAPE Trial group. Urinary excretion of endothelin-1 (ET-1), transforming growth factor- beta1 (TGF- beta1) and vascular endothelial growth factor (VEGF165) in paediatric chronic kidney diseases: results of the ESCAPE trial. Nephrol Dial Transplant. 2007 Dec;22(12):3487-94. doi: 10.1093/ndt/gfm300. Epub 2007 Sep 26.
citation: Chinali M, de Simone G, Matteucci MC, Picca S, Mastrostefano A, Anarat A, Caliskan S, Jeck N, Neuhaus TJ, Peco-Antic A, Peruzzi L, Testa S, Mehls O, Wuhl E, Schaefer F; ESCAPE Trial Group. Reduced systolic myocardial function in children with chronic renal insufficiency. J Am Soc Nephrol. 2007 Feb;18(2):593-8. doi: 10.1681/ASN.2006070691. Epub 2007 Jan 10.
citation: Schonfelder EM, Knuppel T, Tasic V, Miljkovic P, Konrad M, Wuhl E, Antignac C, Bakkaloglu A, Schaefer F, Weber S; ESCAPE Trial Group. Mutations in Uroplakin IIIA are a rare cause of renal hypodysplasia in humans. Am J Kidney Dis. 2006 Jun;47(6):1004-12. doi: 10.1053/j.ajkd.2006.02.177.
citation: Matteucci MC, Wuhl E, Picca S, Mastrostefano A, Rinelli G, Romano C, Rizzoni G, Mehls O, de Simone G, Schaefer F; ESCAPE Trial Group. Left ventricular geometry in children with mild to moderate chronic renal insufficiency. J Am Soc Nephrol. 2006 Jan;17(1):218-26. doi: 10.1681/ASN.2005030276. Epub 2005 Nov 9.
citation: Wuhl E, Mehls O, Schaefer F; ESCAPE Trial Group. Antihypertensive and antiproteinuric efficacy of ramipril in children with chronic renal failure. Kidney Int. 2004 Aug;66(2):768-76. doi: 10.1111/j.1523-1755.2004.00802.x.
citation: Jourdan C, Wuhl E, Litwin M, Fahr K, Trelewicz J, Jobs K, Schenk JP, Grenda R, Mehls O, Troger J, Schaefer F. Normative values for intima-media thickness and distensibility of large arteries in healthy adolescents. J Hypertens. 2005 Sep;23(9):1707-15. doi: 10.1097/01.hjh.0000178834.26353.d5.
citation: Litwin M, Wuhl E, Jourdan C, Trelewicz J, Niemirska A, Fahr K, Jobs K, Grenda R, Wawer ZT, Rajszys P, Troger J, Mehls O, Schaefer F. Altered morphologic properties of large arteries in children with chronic renal failure and after renal transplantation. J Am Soc Nephrol. 2005 May;16(5):1494-500. doi: 10.1681/ASN.2004110932. Epub 2005 Mar 16.
citation: Wuhl E, Hadtstein C, Mehls O, Schaefer F; ESCAPE Trial Group. Ultradian but not circadian blood pressure rhythms correlate with renal dysfunction in children with chronic renal failure. J Am Soc Nephrol. 2005 Mar;16(3):746-54. doi: 10.1681/ASN.2004070537. Epub 2005 Jan 12.
citation: Hadtstein C, Wuhl E, Soergel M, Witte K, Schaefer F; German Study Group for Pediatric Hypertension. Normative values for circadian and ultradian cardiovascular rhythms in childhood. Hypertension. 2004 Mar;43(3):547-54. doi: 10.1161/01.HYP.0000116754.15808.d8. Epub 2004 Jan 26.
citation: Wuhl E, Hadtstein C, Mehls O, Schaefer F; Escape Trial Group. Home, clinic, and ambulatory blood pressure monitoring in children with chronic renal failure. Pediatr Res. 2004 Mar;55(3):492-7. doi: 10.1203/01.PDR.0000106863.90996.76. Epub 2003 Nov 19.