The ESCAPE Trial was a landmark RCT initiated and executed by our Consortium. We investigated whether intensified blood-pressure control aimed at achieving 24-hour blood-pressure levels in the low range of normal would slow the progression of renal disease in children with CKD. Between April 1999 and December 2001, 465 children aged 3-17 years with eGFR of 15 to 18 ml/min/1.73 m2 were screened and 385 included in the trial at 33 European pediatric nephrology units.
Patients were randomly assigned to intensified blood-pressure control (with a target 24-hour mean arterial pressure below the 50th percentile) or conventional blood-pressure control (mean arterial pressure in the 50th to 95th percentile). To that end, all patients received the ACE inhibitor ramipril at a fixed dose (6 mg/m2/day). The patients randomized for intensified blood pressure control, if required, were prescribed additional antihypertensive drugs not targeting the renain angiotensin system. Study visits were performed every two months, and ambulatory 24-hour blood pressure monitoring was performed every 6 months over a 5-year period.
The primary end point was the time to a decline of 50% in GFR or progression to end-stage renal disease. A total of 29.9% of the patients in the group that received intensified blood-pressure control reached the primary end point, as compared with 41.7% in the group that received conventional blood-pressure control (hazard ratio, 0.65; confidence interval, 0.44 to 0.94; P = 0.02). Proteinuria gradually rebounded during ongoing ACE inhibition after an initial 50% decrease, despite persistently good blood-pressure control. Achievement of blood-pressure targets and a decrease in proteinuria were significant independent predictors of delayed progression of renal disease.
The results of the trial lead to a redefinition of blood pressure targets in children with CKD. The 2016 revision of the European Society of Hypertension guideline for blood pressure management in children recommends a target blood pressure below the 75th percentile in hypertensive children without proteinuria, and below the 50th percentile in those with proteinuria. The 2017 American Academy of Pediatrics guideline even defines the 50th percentile as the recommended blood pressure target for all children with CKD. Hence, the ESCAPE Trial can be considered a true example of a practice-changing clinical trial.
These were the trial investigators: Elke Wühl, Heidelberg, Antonella Trivelli, Genova, Stefano Picca, Rome, Mieczyslaw Litwin, Warsaw, Amira Peco-Antic, Belgrade, Aleksandra Zurowska, Gdansk, Sara Testa, Milano, Augustina Jankauskiene, Vilnius, Sevinc Emre, Istanbul, Alberto Caldas-Afonso, Porto, Ali Anarat, Adana, Patrick Niaudet, Paris, Sevgi Mir, Izmir, Aysin Bakkaloglu, Ankara, Barbara Enke, Hannover, Giovanni Montini, Padova, Ann-Margret Wingen, Essen, Peter Sallay, Budapest, Nikola Jeck, Marburg, Ulla Berg, Stockholm, Salim Caliskan, Istanbul, Simone Wygoda, Leipzig, Katharina Hohbach-Hohenfellner, Mainz, Jiri Dusek, Prague, Tomasz Urasinski, Szeczin, Klaus Arbeiter, Vienna, Thomas Neuhaus, Zurich, Jutta Gellermann, Berlin, Dorota Drozdz, Krakov, Michel Fischbach, Strasbourg, Kristina Müller, Hamburg, Marianne Wigger, Rostock, Licia Peruzzi, Torino, Otto Mehls, Heidelberg, and Franz Schaefer, Heidelberg.
The ESCAPE cohort has been a rich source of information and biospecimens which fueled numerous post-hoc analyses, biomarker and genetic research. The following publications used data and materials from the ESCAPE cohort:
- Atkinson MA, Xiao R, Köttgen A, Wühl E, Wong CS, Wuttke M, Bayazit AK, Çalişkan S, Warady BA, Schaefer F, Furth SL.
Genetic associations of hemoglobin in children with chronic kidney disease in the PediGFR Consortium.
Pediatr Res. 2018 Aug 15.
- van den Belt SM, Heerspink HJL, Gracchi V, de Zeeuw D, Wühl E, Schaefer F; ESCAPE Trial Group.
Early Proteinuria Lowering by Angiotensin-Converting Enzyme Inhibition Predicts Renal Survival in Children with CKD.
J Am Soc Nephrol. 2018;29:2225-2233.
- Furth SL, Pierce C, Hui WF, White CA, Wong CS, Schaefer F, Wühl E, Abraham AG, Warady BA; Chronic Kidney Disease in Children (CKiD); Effect of Strict Blood Pressure Control and ACE Inhibition on the Progression of CRF in Pediatric Patients (ESCAPE) Study Investigators.
Estimating Time to ESRD in Children With CKD.
Am J Kidney Dis. 2018 Jun;71(6):783-792.
- Schaefer F, Trachtman H, Wühl E, Kirchner M, Hayek SS, Anarat A, Duzova A, Mir S, Paripovic D, Yilmaz A, Lugani F, Arbeiter K, Litwin M, Oh J, Matteucci MC, Gellermann J, Wygoda S, Jankauskiene A, Klaus G, Dusek J, Testa S, Zurowska A, Caldas Afonso A, Tracy M, Wei C, Sever S, Smoyer W, Reiser J; ESCAPE Trial Consortium and the 4C Study Group.
Association of Serum Soluble Urokinase Receptor Levels With Progression of Kidney Disease in Children.
JAMA Pediatr. 2017 Nov 6;171(11):e172914.
- Wuttke M, Wong CS, Wühl E, Epting D, Luo L, Hoppmann A, Doyon A, Li Y; CKDGen Consortium, Sözeri B, Thurn D, Helmstädter M, Huber TB, Blydt-Hansen TD, Kramer-Zucker A, Mehls O, Melk A, Querfeld U, Furth SL, Warady BA, Schaefer F, Köttgen A.
Genetic loci associated with renal function measures and chronic kidney disease in children: the Pediatric Investigation for Genetic Factors Linked with Renal Progression Consortium.
Nephrol Dial Transplant. 2016; 31:262-9.
- Shroff R, Aitkenhead H, Costa N, Trivelli A, Litwin M, Picca S, Anarat A, Sallay P, Ozaltin F, Zurowska A, Jankauskiene A, Montini G, Charbit M, Schaefer F, Wühl E; ESCAPE Trial Group.
Normal 25-Hydroxyvitamin D Levels Are Associated with Less Proteinuria and Attenuate Renal Failure Progression in Children with CKD.
J Am Soc Nephrol. 2016;27:314-22.
- Mehls O, Lindberg A, Haffner D, Schaefer F, Wühl E; German KIGS Board; ESCAPE Trial Group.
Long-term growth hormone treatment in short children with CKD does not accelerate decline of renal function: results from the KIGS registry and ESCAPE trial.
Pediatr Nephrol. 2015; 30(12):2145-51.
- Matteucci MC, Chinali M, Rinelli G, Wühl E, Zurowska A, Charbit M, Pongiglione G, Schaefer F; ESCAPE Trial Group.
Change in cardiac geometry and function in CKD children during strict BP control: a randomized study.
Clin J Am Soc Nephrol. 2013; 8:203-10.
- 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; 24:2361-8.
- Gimpel C, Wühl 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; 27:1568-74.
- Grenda R, Wühl 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 ET-1,TGF-beta1 and VEGF165 in paediatric chronic kidney diseases: Results of the ESCAPE trial.
Nephrol Dial Transplant. 2007; 22:3487-94.
- 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, Wühl E, Schaefer F; ESCAPE Trial Group.
Reduced systolic myocardial function in children with chronic renal insufficiency.
J Am Soc Nephrol. 2007; 18:593-8.
- Weber S, Moriniere V, Knüppel T, Charbit M, Dusek J, Ghiggeri GM, Jankauskiené A, Mir S, Montini G, Peco-Antic A, Wühl E, Zurowska AM, Mehls O, Antignac C, Schaefer F, Salomon R.
Prevalence of mutations in renal developmental genes in children with renal hypodysplasia: results of the ESCAPE study.
J Am Soc Nephrol. 2006; 17:2864-70.
- Schönfelder EM, Knüppel T, Tasic V, Miljkovic P, Konrad M, Wühl 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; 47:1004-12.
- Matteucci MC, Wühl 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 ;17:218-26.
- Wühl 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;16:746-54.
- Wühl E, Mehls O, Schaefer F; ESCAPE Trial Group.
Antihypertensive and antiproteinuric efficacy of ramipril in children with chronic renal failure.
Kidney Int 2004; 66:768-76
- Wühl 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; 55:492-7