Effect of Strict Blood Pressure Control and ACE-Inhibition on Progression of Chronic Renal Failure in Pediatric Patients (ESCAPE)
Molecular Mechanisms of Disease Progression and Renoprotective Pharmacotherapy in Children With Chronic Renal Failure
연구 개요
상태
상세 설명
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.
연구 유형
등록 (실제)
단계
- 3단계
연락처 및 위치
연구 장소
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Berlin, 독일, 13353
- Humboldt University Berlin, Charité Children's Hospital, Department of Pediatric Nephrology
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Essen, 독일, 45122
- University Hospital Essen, Department of Pediatrics, Pediatric Nephrology Unit
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Hamburg, 독일, 20246
- University Hospital Hamburg-Eppendorf, University Children's Hospital, Dept. of Pediatric Nephrology
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Hannover, 독일, 30623
- Hannover Medical School, Children's Hospital Div. II, Pediatric Nephrology
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Heidelberg, 독일, 69120
- Division of Pediatric Nephrology, Children's Hospital, University of Heidelberg
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Leipzig, 독일, 04129
- Urban Hospital St. Georg, Department of Pediatrics, Pediatric Nephrology Unit
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Mainz, 독일, 55131
- Johannes Gutenberg University Mainz, Department of Pediatrics,
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Marburg, 독일, 35037
- Philipps University Marburg, Dept. of Pediatrics
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Rostock, 독일, 18050
- University Children's Hospital, Dept. of Nephrology
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Vilnius, 리투아니아, 2600
- Vilnius University Children's Hospital, Pediatric Department, Nephrology Unit
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Belgrade, 세르비아, 11000
- Faculty of Medicine Belgrade, University Children's Hospital, Nephrology Unit
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Stockholm, 스웨덴, 14186
- Karolinska Institute, Huddinge University Hospital, Dept. of Pediatrics
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Zürich, 스위스, 8032
- University Children's Hospital, Nephrology Unit
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Genoa, 이탈리아, 16148
- G.Gaslini Institute, Nephrology Unit
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Milano, 이탈리아, 20122
- Azienda Ospedaliera, Istitui Clinici di Perfezionamento, Servizio die Emodialisi Pediatrica
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Padova, 이탈리아, 35128
- Azienda Ospedaliera die Padova. U.O. Nefrologia Dialisi e Trapianto - Dipartimento di Pediatria
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Rome, 이탈리아, 00165
- Ospedale Pediatrico Bambino Gesù, Division of Nephrology and Dialysis
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Torino, 이탈리아, 10126
- Ospedale Infantile Regina Margherita, U.O.A. Nefrologia, Dialisi, Trapianto
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Prague, 체코 공화국, 150 18
- University Hospital Motol, 1st Department of Pediatrics
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Adana, 칠면조, 01330
- Cukurova University School of Medicine, Dept. of Pediatric Nephrology
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Ankara, 칠면조, 06100
- Hacettepe University, Faculty of Medicine, Pediatric Nephrology and Rheumatology
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Istanbul, 칠면조, 34303
- Istanbul University, Cerrahpasa Medical Faculty, Dept, of Pediatrics
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Istanbul, 칠면조, 34390
- University of Istanbul, Istanbul Medical Faculty, Dept. of Pediatrics
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Izmir, 칠면조, 35100
- Ege University Medical Faculty, Dept. of Pediatric Nephrology
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Porto, 포르투갈, 4202 - 451
- Hospital S. Joao-Faculade de Medicina do Porto, Dept. of Pediatrics
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Cracow, 폴란드, 30-663
- Jagellonian University Medical College, Department of Pediatric Nephrology
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Gdansk, 폴란드, 80-211
- Medical University of Gdansk, Pediatric Nephrology Department
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Szczecin, 폴란드, 71-344
- Clinic of Pediatrics, Pomeranian Academy of Medicine
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Warsaw, 폴란드, 04-736
- Children's Memorial Health Hospital, Nephrology and Kidney Transplantation Department
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Paris, 프랑스, 75015
- Hopital Necker, Division of Pediatric Nephrology
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Paris, 프랑스, 75015
- Inserm U574
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Strasbourg, 프랑스, 67098
- Hopiteaux Universitaires de Strasbourg
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Budapest, 헝가리, 1083
- Semmelweis University Budapest, 1st Department of Pediatrics
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참여기준
자격 기준
공부할 수 있는 나이
건강한 자원 봉사자를 받아들입니다
연구 대상 성별
설명
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
공부 계획
연구는 어떻게 설계됩니까?
디자인 세부사항
- 주 목적: 치료
- 할당: 무작위
- 중재 모델: 병렬 할당
- 마스킹: 없음(오픈 라벨)
무기와 개입
참가자 그룹 / 팔 |
개입 / 치료 |
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활성 비교기: Conventional BP Control
Targeted 24-hour mean arterial pressure will be the 50th-95th percentile for age.
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ACE inhibitor ramipril (6 mg/m²/day) will be given to all subjects.
다른 이름들:
Any antihypertensive drugs except ACE inhibitors and angiotensin receptor blockers will be allowed.
In patients who show persistent or breakthrough proteinuria at the end of the initial study period, telmisartan (50 mg/m²/day) will be added to the existing medication.
다른 이름들:
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실험적: Intensified BP Control
Targeted 24-hour mean arterial pressure will be the 5th to 50th percentile for age.
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ACE inhibitor ramipril (6 mg/m²/day) will be given to all subjects.
다른 이름들:
Any antihypertensive drugs except ACE inhibitors and angiotensin receptor blockers will be allowed.
In patients who show persistent or breakthrough proteinuria at the end of the initial study period, telmisartan (50 mg/m²/day) will be added to the existing medication.
다른 이름들:
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연구는 무엇을 측정합니까?
주요 결과 측정
결과 측정 |
기간 |
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Time interval to renal 'loss' as defined by an absolute decrease in creatinine clearance by 50 % or attainment of renal replacement therapy.
기간: two-monthly
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two-monthly
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2차 결과 측정
결과 측정 |
기간 |
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Effect of treatment on urinary protein excretion
기간: two-monthly
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two-monthly
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Effect of treatment on blood pressure
기간: two-monthly
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two-monthly
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Safety of treatment
기간: initially weekly, than two-monthly
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initially weekly, than two-monthly
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공동 작업자 및 조사자
수사관
- 수석 연구원: Franz Schaefer, MD, University of Heidelberg, Children's Hospital
- 수석 연구원: Otto Mehls, MD, University of Heidelberg, Children's Hospital
간행물 및 유용한 링크
일반 간행물
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
연구 기록 날짜
연구 주요 날짜
연구 시작
기본 완료 (실제)
연구 완료 (실제)
연구 등록 날짜
최초 제출
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처음 게시됨 (추정)
연구 기록 업데이트
마지막 업데이트 게시됨 (추정)
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추가 정보
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