Interview with Prof P. Ronco

Prof P. Ronco INSERM Unit 489 and Department of Nephrology, Tenon Hospital, Paris, France

Prof Massy: Why did you go into medicine?

Prof Ronco: As a child and a teenager, I liked biological sciences very much. I wanted to know more about the function of human cells and organs. As an undergraduate, I started an intensive mathematics/physics cursus because my teachers wanted me to apply for the major French “Grandes Ecoles” (prestigious university-level colleges which prepare students for senior posts in public administration, engineering and business), but I soon tired of equations and decided to move to the medical faculty.

Prof Massy: How did you become interested in renal diseases? How important were your mentors in your choices?

Prof Ronco: As a Master student after the third year of my internship, for the first time I entered the INSERM research Unit, joined with the Nephrology Department at the Tenon Hospital, both of which had been founded by Professor Gabriel Richet after leaving Necker. I had the opportunity to work with Pierre Verroust and the former Liliane Morel-Maroger (before she became Mrs Striker). From the very first moment that I started a Master thesis on glomerulonephritis induced by lymphocytic choriomeningitis virus in neonate mice as a model of immune complex-mediated glomerulonephritis, I knew that I had found my way in biology and medicine. Soon after, as a Resident in Gabriel Richet's department, I was impressed by intellectual precision of Professor Richet, and the incredible talent that he had in bringing together collaborators with such strong and diverse characters. The secret probably lies in the fact that all of the collaborators were independent investigators involved to varying extents in bench-to-bedside research but at the same time, each needed the others in order to be able to push their work to the highest level. Meetings with clinicians, renal pathologists, immunologists and physiologists were pure delight for the young man that I was.

Prof Massy: What lessons can we learn from your fascinating new experience regarding the relationship between neutral endopeptidase (NEP) as the podocyte target antigen and the membranous nephropathy?

Prof Ronco: In the early 1980s, after defending my Ph.D. thesis, I embarked with Pierre Verroust on a research programme focused on the molecular pathomechanisms of Heymann's nephritis, a faithful model of membranous nephropathy (MN) in the rat. We contributed to the characterization of the target antigen expressed on podocytes, now called megalin. However, we rapidly realized that megalin could not be taken as being responsible for human MN because it is not expressed on human podocyte nor it is found in immune deposits in patients with MN. Concomitantly, we had produced monoclonal antibodies against other glomerular antigens, including neutral endopeptidase (NEP), that were expressed in human podocytes, and we had obtained experimental evidence that anti-NEP could induce glomerular deposits in the rabbit. We therefore speculated that NEP might be also involved in human MN.

Twenty years later, we had the opportunity to investigate with Albert Bensman's group (Armand-Trousseau Hospital, Paris) a neonate that was born with renal failure, nephrotic syndrome and histologically-proven MN. By performing a very simple experiment, that is incubation of the mother's serum with normal human, rabbit and rat kidney sections, we found that the serum contained high titers of an antibody that reacted with glomeruli and the brush-border of the proximal tubule, but with a species-dependent pattern that was reminiscent of what we had observed more than 20 years previously with anti-NEP antibodies. From this very first experiment, we knew that the mother had produced anti-NEP antibodies that had found their way to the fetus' glomeruli (see our couple of articles in NEJM 2002, 346:2053 and Lancet 2004, 364:1252).

What we had not expected was the mother's NEP deficiency, which we showed to be caused by truncating mutations in the MME gene coding for NEP. The pathophysiologic scenario then became crystal clear. The mother had became immunized against the NEP antigen expressed on the placenta, and the antibodies had been transferred transplacentally to the fetus, reaching their antigenic targets in glomeruli. The mother had not developed the renal disease simply because her podocytes did not express the NEP antigen. This unexpected finding provided the first example of feto-maternal allo-immunization affecting an organ distinct from the blood system.

I was fortunate enough to complete this work in about 2 years with Hanna Debiec - a basic scientist working in my lab as a Research Director. This was made possible by the training that we received in Richet's lab. Some took the bench-to-bedside route, starting out with a PhD in basic research like Hanna. Most of us went from bedside to bench. The training takes longer, but those willing to invest extra time in getting to grips with both basic and clinical research can reap the benefits, not least in job satisfaction (Nature 2003, 424:1090).

Prof Massy: Who are the colleagues that you admire you most for their intellectual acumen and for their scientific and ethical rigor?

Prof Ronco: I admire those colleagues who have dedicated years to demonstrating very carefully elegant concepts with major clinical implications. I personally believe that continuity in science is the key for long-lasting success. Along these lines, Barry Brenner and his group have brought about a major leap in the field of renoprotection by showing unambiguously that nephron loss and ensuing activation of the renin-angiotensin system are key factors in renal disease progression. My admiration also goes to the late Giuseppe Andres who contributed to pushing renal immunopathology to maturity with unrivalled intellectual elegance and humanity.

Prof Massy: Reasoning on a global and/or European scale, what is the main challenge facing Nephrology today?

Prof Ronco: The main challenge of Nephrologists is to screen subjects at risk for ESRD and cardiovascular disease because we now have effective treatment in hand to prevent the progression of renal diseases and their cardiovascular complications. Because of the decreasing number of Nephrologists in Western Countries, this challenge will require the development of networks between general practitioners, diabetologists, cardiologists, and nephrologists, also including dieteticians and specialized renal nurses.

On the other hand, the main challenge of Nephrology is to survive as a medical speciality at a time when fewer medical students are choosing Nephrology because of the large burden of clinical work that the day-to-day clinical tasks require. Collaborative basic and clinical research programmes should be implemented. Strengthening links between Nephrology Centres in Europe is urgently needed to increase the visibility of Nephrology at the EC level and to boost these collaborative research projects. I believe that ERA-EDTA could greatly contribute to the implementation of this ambitious but mandatory programme.

Prof Massy: How can we best promote "Academic Medicine"?

Prof Ronco: We should favour the development of Nephrology Centres of Excellence all over Europe to promote bench-to-bedside and bedside-to-bench training. We need to train more students and to be more attractive. There are a number of good students, but they go to more basic disciplines such as immunology or genetics because of the heavy burden of clinical work in Nephrology. We need to create more tenure positions to alleviate this workload, and to make the career more flexible. Risk-taking and career flexibility should be more strongly encouraged from the very first years of the medical cursus. A nice example which should be expanded is the school of INSERM, founded by Christian Brechot (Director General of INSERM, the French Institute for Medical Research), which trains the most brilliant Medical Students in science from the second year of their medical cursus. These students can defend their Ph.D. thesis before their internship.

Prof Massy: How do you foresee French nephrology in 2015? What kind of organizational, technical and scientific evolution do you envisage in 10 years' time?

Prof Ronco: Because of population ageing and of the rapid expansion of patients at risk for diabetes, with diabetic nephropathy and vascular disease, one can predict an epidemic of end-stage renal failure and one should fear a controlled access to dialysis. We need to find appropriate organizational structures to implement programmes directed at identifying patients at high-risk of chronic kidney disease and enrolling them into a preventive programme. The health network type of organization certainly is a path that should be explored and developed.

For the development of “Academic Nephrology”, it is mandatory to develop the Centres of Excellence that I mentioned previously. They will be the places where new therapeutic approaches based on basic and clinical research will, hopefully, blossom.

Prof Massy: How do you manage to combine your research, editorial and managerial duties with that of Director of a busy Nephrology Unit?

Prof Ronco: Each day is a big challenge, and I must confess it is an challenging task to combine all the above duties, but it is worth trying. I am fortunate to have excellent collaborators and friends both in the INSERM Unit and the Clinical Department that I have the privilege to head. A key issue is to favour the promotion of each of them. Their needs are different but it seems that all enjoy working in a friendly atmosphere with a strong scientific discipline. However, the growing burden of administrative work has become unbearable. More flexibility and fewer regulations would certainly alleviate the programme directors' workload and thus create time for more efficient scientific direction and networking.

Prof Massy: How do you relax in your time away from your work?