Early History of the European / ESCAPE Study Group

A personal perspective

The young Alexander conquered India.
Was he alone?
Caesar beat the Gauls.
Did he not have even a cook with him?

Bert Brecht

Questions of a Reading Worker

I have often been asked for details about how and why the European/ESCAPE Study Group was founded. I would like to give a brief personal account, which I feel is important for understanding successful multicenter study activities.

In the 1970’s and 1980’s, the German Working Group of Pediatric Nephrology (APN) under the leadership of the distinguished Johannes Brodehl, performed several important controlled German multicenter treatment studies into patients with frequently relapsing or steroid-resistant NS. However, due to competition for leadership and a relatively low number of relevant patients, aspiring scientists found it difficult to initiate additional German multicenter studies covering different topics and questions. The situation was quite similar in other European countries and fueled wide-spread frustration and counterproductive rivalry.

In 1986, I decided to invite not the established leaders, but younger colleagues and friends from diverse Pediatric Nephrology centers all over Europe including the East for a meeting in Heidelberg. We discussed a possible cooperation in prospective randomized trials. At that time, one of the intriguing scientific and clinical questions was whether or not dietary intervention is able to modify the decline of renal function in patients with CKD. A randomized controlled European multicenter study with adequately sized cohorts of pediatric patients seemed to be a good approach to find some answers, and also promised to have a good chance of receiving external funding.

The group chose its name ‘European Study Group of Nutritional Treatment of Chronic Renal Failure in Childhood’. It was agreed to postpone the usual questions about who would lead and coordinate the project and who was going to publish until after the main work was done. Instead, friendship, synergy, enjoyment of the job at hand, and learning from and teaching each other would be at the core of this collaboration. Teaching and detailed discussion have remained very important components of our twice-yearly study meetings up until today.

Together we developed a study protocol and applied for a grant at the German BMFT (Federal Ministry of Education and Research) to study the effects of a low protein diet on the progression of CKD in children. Luckily, we gained financial support of DM 1.2M (€600.000) in 1987 (BMFT 07047420). Around the same time, the MDRD study (Modification of Diet in Renal Disorders) in adults was supported with $52M by the NIH. What an amazing difference between children and adults! The results of both studies were presented for the first time at the Annual ASN meeting in Baltimore in November 1994. No beneficial effects of low protein diet on CKD progression rate were noted from both studies(1,2). The results were spectacular as the opposite had been a nearly undisputed doctrine for more than two decades.

In 1997, the Journal rules for publication were rather inadequate. The Lancet did not allow more than four authors for a big multicenter study like ours. Even a footnote on the first page listing the names of all participants was sadly refused, and the list of contributors was moved to the very end of the article. Acknowledging the collaborators as “investigators” instead of just listing them under ‘acknowledgements’ was the only concession The Lancet was prepared to offer.

Scientific Contributors must always be listed adequately. Without their work, the ongoing success of the European Study / ESCAPE study group would never have been possible. Therefore, the names of all early founders and contributors are presented here again: S.Ploos van Amstel (Amsterdam), I. Rätsch, C. Catassi, (Ancona); K. van Acker (Antwerp); K. Michelis, T.Kapogiannis (Athens); F. Jung, T. Lennert, S. Gellert (Berlin); T.Tulassay, P.Sallay (Budapest); T. von Lilien, U.Querfeld (Cologne); K.-E.Bonzel (Essen); M-A.von Wendt-Göknur (Erlangen); R.Gusmano, E. Verrina (Genova); W.Reitsma-Bierens (Groningen); G. Offner (Hannover); C. Fabian-Bach, O. Mehls, F. Schaefer, A,-M- Wingen (Heidelberg); A. Appiani, B. Bettinelli (Milan); M.deJong (Nijmwegen); J. Feber, J. Jander (Prague); S. Picca, G.Rizzoni (Rome); H.J.Stolpe, M. Wigger (Rostock); J. Kist -van Holthe, J. Hop, J. Nauta, E. Wolff (Rotterdam); U. Berg (Stockholm), M. Fischbach (Strasbourg); E. Dobos, S. Turi (Szeged); E. Balzer (Vienna); T. Neuhaus (Zürich)

In 1997 we had a winning team, and there were now new challenges ahead. After completing the dietary intervention study, the European Study group were keen to carry out further multicenter studies, and to ensure further success, we needed to attract further funding.
Based on the results of the diet modification-Study we applied for grants at the Boehringer Ingelheim Foundation and at the European Commission, which would allow us to perform a clinical trial (later called ‘ESCAPE trial’) to analyze the effects of intensified blood pressure control on the progression rate of CKD in children.

While the grant decisions were pending, the European Study Group performed some voluntary Vitamin-D trials in children with CKD which were low in cost and relatively easy to perform. Several publications mirror the activity of the European Study Group now named ‘European Study group on Vitamin D in Children with Renal Failure in Childhood’ from 1996 to 1999(3). In parallel, a prospective controlled multicenter study on intensified blood pressure control in children with CKD was prepared. The activity of the group at that time was financed through ‘patchwork funding’, mainly by a generous grant of the Boehringer Ingelheim Foundation (1997), as well as grants from Baxter Mural, LaRoche, and the Kuratorium für Dialysis und Transplantation KFH, Neu-Isenburg, Germany.

Thanks to the exceptional commitment of Franz Schaefer, in 2001 the grant application at the European Commission (Fifth Framework Programme, QLRT-2001-00908) was also successful. The financial volume of this grant made much more complex investigations possible. The ESCAPE trial (patient recruitment time of 2.5 years, study period of 5 years) was performed between 1999 and 2009. Because early patient numbers were lower than expected, Turkey was included into the study in 2001, helped along by intense efforts from Aysin Bakkaloğlu in Ankara and myself. The successful inclusion of more than 100 patients from Turkey guaranteed a successful implementation and subsequent statistical evaluation of the ESCAPE trial.
After retiring from clinical work in early 2005, my leadership was succeeded by Franz Schaefer. The main clinical results from the ESCAPE trial were published in 2009(4).

Today, even the highest-ranking Journals accept a longer author list than during the last century, especially in genetic cooperative studies. Furthermore, publication search engines like PubMed list all participants of cooperative studies as coauthors. All this is good news.
It is another merit of Franz Schaefer that collaborators joining the ‘ESCAPE Network’, which was established following the ESCAPE -trial, find their names as authors and investigators on all publications. The name network indicates not only European but also worldwide cooperation with many groups and laboratories.
Several of the present studies investigate genetics and metabolomics in renal disorders. But, also the tradition of investigator initiated controlled prospective clinical studies is continued by the PREDICT-trial under the lead of Giovanni Montini. Collaborators and participants of all studies still meet two times every year for a two day-study meeting at the Wissenschaftsforum (International House of Science) of the University of Heidelberg.

Finally, I would like to express my sincere gratitude to all study members over the last three decades and specially Anne-Margret Wingen, Elke Wühl, Claus Peter Schmitt and Franz Schaefer who greatly supported our study activities during and after my active years at the Center for Pediatrics and Adolescent Medicine, University Hospitals Heidelberg. I wish the ESCAPE Network every success and many fruitful years to come.

Otto Mehls                                                                                                                            Heidelberg , November 2018


(1) Wingen AM, Fabian-Bach C, Schaefer F, Mehls O.
Randomised multicentre study of a low-protein diet on the progression of chronic renal failure in children. European Study Group of Nutritional Treatment of Chronic Renal Failure in Childhood.
Lancet 1997; 349:1117-23.

(2) Klahr S1, Levey AS, Beck GJ, Caggiula AW, Hunsicker L, Kusek JW, Striker G.
The effects of dietary protein restriction and blood-pressure control on the progression of chronic renal disease. Modification of Diet in Renal Disease Study Group.
N Engl J Med 1994; 330(:877-84.

(3) Ardissino G, Schmitt CP, Bianchi ML, Daccò V, Claris-Appiani A, Mehls O.
No difference in intestinal strontium absorption after oral or IV calcitriol in children with secondary hyperparathyroidism. The European Study Group on Vitamin D in Children with Renal Failure.
Kidney Int 2000; 58:981-8.

(4) ESCAPE Trial Group, Wühl 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, Möller 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; 361:1639-50.