YP: In October 1998, Dr. Van Ypersele retired from his position as Head of the Renal Unit he had founded 35 years earlier. He still maintains productive clinical and scientific activity. As his successor, I readily accepted the invitation to interview him for the ISN Video Legacy Project. This exceptional career provides us actually with a unique opportunity to remind us of the early beginning of our specialty and also to learn some lessons for its future. Welcome Professor Van Ypersele. Could you tell us how you were attracted by medicine?
CY: Well that's a difficult question - certainly not by tradition. I've never had a physician in the family. When I think back I remember the pleasure I've always had looking at nature This pleasure was rekindled recently when I found in our attic my favorite book when I was 12 years old, "Nature's Calendar", with a monthly outline of the weather, plants and flowers, the insects and larger animals who became active during each period. A few years later a small microscope helped me discover a new fascinating world, including the unforgettable observation of red cells running within the blood vessels of a frog. From that time onwards it became evident for me that I would become a doctor. It was only much later that I experienced the urge to be useful for our fellow men.
YP: How did you come to nephrology?
CY: I guess that a short answer could be « through circumstances ». At the end of my medical studies in 1957, I became aware that I had none of the skills required to become a surgeon, my first choice a few years earlier. The most attractive alternative in 1956 was internal medicine. I was thus accepted as an intern in this specialty and met my first true mentor, Professor Arcq. He was then the Associate Chief of Professor J.P. Hoets' Department of Medicine. My first rotation was with him. It was to last for two more years. Professor Arcq was a very demanding man and a superb clinician with a unique talent to take a comprehensive medical history with a thorough physical examination and to discuss precisely his findings. I cannot refrain from comparing the astuteness of his diagnosis, almost always correct, based on the single clinical findings with the cumbersome discussions of the present day physicians, drowned in sophisticated biological and imaging data. Professor Arcq’s empathy with the patient was also a model for our generation. Still today, 45 years later, when I write my notes in the out-patient clinic, I keep going into the details « just in case Professor Arcq looks over my shoulder ! » I was lucky to establish with him, almost from the start a warm, confident relationship on which I could draw when times were uncertain. So my first orientation was general internal medicine.
Then came the first clue of my future in renal medicine. In 1957, a 60-year-old miner arrived on the ward with severe renal failure. A very high blood urea level in those days was a virtual death sentence. I had heard that the Flemish Department of Medicine a few hundred yards away had received an artificial kidney. Nobody in our Department thought much of it but still nobody opposed my naive request to dialyze the patient. I still remember the adventure with a dozen people around the machine, a constant flow of samples towards the laboratory, constant anxiety when blood pressure fell or when nausea and vomiting intervened. The patient survived. I discovered that the patient presentation was reminiscent of a case of salt losing nephritis described in the New England Journal of Medicine. Then, with the help of sympathetic nurses, I started a balance study to demonstrate that a low salt diet raised the patient's blood urea level, lowered his body weight and that a high salt and high bicarbonate intake reversed the situation. How naive ! With a friend I entered the confusing world of water and electrolytes with Gamble's book, "Extracellular Fluid" as the bible. We spoke a new language of anions and cations, acidosis and alkalosis. In the desert of the Department of Medicine we became rapidly the so-called prophets.
A few months later a consultant in Cardiology, Lucien Brasseur, asked me to perform a study on the effects of a carbonic anhydrous inhibitor on the ventilation of patients with chronic obstructive lung disease. I guess that I had been selected for my ability to obtain accurate urine collections and also because as a bachelor, living at the hospital, I was available day and night.
Still, this challenge introduced me to the world of acid base balance and also to the names of two American investigators whose work published in the Journal of Clinical Investigation I tried to understand - William B. Schwartz and A.S. Relman. With renal failure, water and electrolytes, my appetite for renal medicine was whetted.
When I asked Professor Arcq whether there was any future in this direction he discouraged me. « The aspects of renal disease, he told me, that are not included in urology would necessarily remain part of general internal medicine. » The prevalence of the disease in his practice was too low to imagine that a specialist could thrive. Still I had taken so much pleasure during the last year that I wanted to go further. Professor Lambin, the highly respected Chief of the Department of Medicine was a hematologist. My question surprised him. "What should be the specific tools of a renal specialist", he asked, and he saw none. Nevertheless, he told me that if I wanted to pursue it, I should learn cystoscopy. In his mind the clinical identity of the pneumologist depended on bronchoscopy, so why not cystoscopy if I was interested in the kidney. Undeterred, I decided to spend a year with Europe's leading expert in renal diseases, Professor Hamburger. I had earned a travel fellowship as a reward for research work done on rat placenta in Professor Hoet's laboratory. I thus arrived at the Hopital Necker in Paris in September 1959. For the subsequent years I had applied for a fellowship in William B. Schwartz's laboratory in Boston.
Looking back to this period I realize how naive I was ! This has taught me that an enthusiastic drive, even rooted on fragile foundations, may be more important than a careful decision analysis. Who could have suspected in 1959 the development of nephrology during the subsequent decade ? There I was en route for nephrology.
YP: What were your early experiences?
CY: Well, Professor Hamburger was my first experience at the Necker hospital. He was already then the Nestor of European renal medicine. The elegance of his presentations, the refinement of his thought, his unfailing courtesy, were all impressive. Taken together with a first rate scientific mind they would lead him to the most exclusive circles in France : the Academie des Sciences and, eventually, the Academie Française. In the late 50's Hamburger was one of the rare « patrons » in Paris who realized that the future of science was carried by English. At the age of 50, he decided to learn the language. I was to witness his first steps in Boston two years later : they were amazing. He was already in command of the subtleties of English, both in speech and in writing. Necker in the late 50s was buzzing with activities. Every week we had a « colloque » anatomo clinique based on biopsy findings. Renal biopsy was still performed by the surgeon in the operating room. The pathologists, Hyacinte de Montera and Renée Habib, were arguing heatedly with Hamburger and the other clinicians. This was the time of the identification of the various forms of glomerulonephritis. Without realizing it, I was witnessing the birth of a new science, although I often had the impression to go back to my first love, botany.
Patients came in from all over France and its colonial empire for the treatment of acute renal failure. To be involved for a foreign fellow required an excellent connection with the head nurse, a dominating figure in French public hospitals. Belgium chocolates brought to her at regular intervals helped me quite a lot! As soon as a new patient was admitted she called me. The terrifying experience of acute hemodialysis in Louvain became a more sober but still demanding routine.
Clinical training was provided during the Professors' ward rounds. Three times a week, with an impressive following of visiting physicians, colleagues, interns, externs, surrounded by the nursing staff, Professor Hamburger or one of his collaborators would listen to the case presentation, examine the patient, discuss the diagnosis and decide the therapeutic course. I remember once being squeezed in a small room in which the famous painter Jacques Duchamp dit Villon, a companion of Picasso at the Bateau Lavoir had been admitted the night before. His condition was mild. Majestically, Hamberger bowed in front of the aged frail man. "Dear Master," he said, "I will give you the best advice of medicine. You are to leave without delay before catching a hospital bug."
Attending the boss's outpatient clinic was also an interesting experience. A dozen visitors were seated along the walls. The professor was behind the desk listening to an intern who read the case history and the results of the biological examinations performed a week earlier. The patient was then examined, a few additional questions were asked by Hamburger, who went on commenting on the case and its treatment, eventually dictating a letter to the general practitioner. I was not aware at that moment that I was gaining there the clinical experience I was to lean on a few years later, upon my return to Louvain. There were no textbooks, only personal transmission of experience.
The time spent with the patient was mainly in the morning. The afternoon was dedicated to some clinical research. I had access to the well-furnished library of the Department. But the most stimulating input came from another former coworker of Hamburger, Gabriel Richet. At that time Richet had left Hamburger's unit and was in charge of an outpatient clinic at Necker.
He had a very acute sense of responsibility towards his juniors and especially foreign fellows. Very quickly he gave me his time generously. My research topic was the milk alkali syndrome, two cases of which had been admitted recently and with Richet's guidance, I read the recent papers on calcium metabolism published in the American Journal of Physiology or in the Journal of Clinical Investigation. We discussed them at his home, rue du Lille. Despite the fact that he was not a prospective co-author, he reviewed my manuscript, asking questions, arguing heatedly. These were unforgettable times. He thus soon became my second mentor. A long lasting friendship would ensue up to this day. Richet helped me enter Bill Schwartz's laboratory at Tufts New England Medical Center in Boston. Indeed my initial request to work there had been turned down : my referees were unknown. Richet took it upon himself and in January 1960 Bill Schwartz notified me of my acceptance.
In June 1960 I thus left Paris for Boston. Now I knew what nephrology was all about even though I realized that I still had a long way to go before reaching a decent level of competence. I was not aware then that this mythic level would always remain elusive for me. More importantly, I had established several lasting friendships that would prove as important, from a personal point of view, as the clinical experience gained in Paris.
My first meeting with Bill Schwartz, WBS remains vivid in my memory. Upon my arrival in his office in early July 1960 I told the attending secretary with my broken English that I was the new fellow and that I wanted to meet Professor Schwartz. I waited on a small chair. Nobody came. Oh yes, a young fellow in sporty attire, addressed me for an unknown reason. I kept repeating that I was waiting there for Professor Schwartz. It took me several minutes before I realized that the young unacademic fellow was nobody else than WBS himself. My paradigm of academic medicine had suddenly and drastically changed. These Boston years, from 1960 to 1962, have shaped my future. I had applied for a fellowship with a renowned investigator on the basis of his interest and achievements in the field of acid base physiology. I got much more : behind the scientist I found a mentor, a master, who shared generously his talents, his demands, his insecurity, his constant drive towards excellence. Looking back on these years four decades later, I realize that the most important asset of training abroad is exposure to a strong charismatic personality, willing to share time, qualities as well as anxieties with his fellows. That is still true today, despite the present urge to send young people to acquire new techniques. The truth of the matter is an older colleagues used to repeat "You don't teach what you know, you teach who you are."
I was also fortunate to be associated during these two years with another fellow, Paul F. Gulyassy who subsequently taught nephrology on the west coast. Paul was not only enthusiastic and dedicated to our common work but also an expert wine taster, interested in music and literature. We had to form a very strong team because our research project was demanding ; metabolic studies, lasting several weeks, transformed successive weekends into working days. We learned perseverance, accuracy, double checking of results, but also the pleasure of the discovery of emerging new patterns - the intensity of discussions on various interpretations and then also the long lasting ascetic process of writing. Very often Bill pushed us through a dozen versions of the manuscript, each of which required a complete retyping in those days. But what a transformation. Bill believed in his fellows who were really part of his family. Unforgettable years that evolved into a long lasting profound friendship. A lot of fellows went through the same grinding mill. They are here on this picture. The bonds forged in these and subsequent years were for life – Jerry Kassirer, the future Editor-in-Chief of the New England Journal of Medicine, Paul Gulyassy, Jordie Cohen, Nick Madias, John Harrington in the States. Joe Rosenfeld in Israel, Adolph Polak in the United Kingdom and so many others. We did not know at that time that our lives would remain indelibly marked by our common heritage. The Boston years were also an opportunity to put a face on famous names. In Atlantic City as well as in Boston I met the founding fathers of nephrology, John Merrill, Bud Relman, Bob Berliner, Don Seldin and many others.
Eventually I had to return home to serve in the army but with the intention of coming back to the States as often as possible. My last visit, a few months ago, was to celebrate the fiftieth anniversary of the foundation of the renal unit at Tufts by Bill. Over a hundred fellows and former fellows came from all over the world to express their gratitude during an unforgettable reunion around a very unique personality.
YP: Now what about your return to Belgium?
CY: Well I first had to go through the 15 months of military duty. That gave me time to reflect on of what I was to do. Professor Hoet in whose laboratory I had worked as a student tried to get me a position as an established investigator of the Belgian National Fund for cientific Research and he eventually succeeded. No clinical positions were then available in the department of Medicine. Even the professors earned their livings as private physicians. The salary of the University and of the City Hospital was symbolic. A surprising discovery that would lead me subsequently to a fight to create mandates for the young permanent clinician who wanted to join the staff after training abroad.
In 1963 a young surgeon who had trained with Professor Morelle, our Professor of Surgery in Louvain was back from the United States after a stay at the Peter Bent Brigham Hospital in Boston where he had worked in the laboratory of Joe Murray. His dream was to transplant kidneys. In Belgium renal transplantation had been abandoned since the mid 50s after a few trials that came out of the transplantation of Marius Renard attempted in 1953 by Hamburger. In those days there was no immunosuppressive therapy so that the kidneys were quickly rejected. In 1959, however, Hamburger, following Murray and Merrill, had started a new program of ransplantation between twins after whole body irradiation.
The young surgeon, Guy Alexandre, was audacious enough to perform the first cadaver renal transplantation without further delay in June 1963. A few months later he performed the first bilateral nephrectomy in Belgium in a young woman suffering from malignant hypertension.
Can you imagine a bilateral nephrectomy. Nobody had heard of such an operation. This was most unusual, innovative and ….. shocking. The patient was kept alive by peritoneal dialysis and it was at this moment that I started a long lasting, sometimes stormy cooperation with Guy Alexandre. I was still at the military hospital serving in the army but I was allowed to spend my afternoons at the University of Louvain. This provided me with my first opportunity to apply what I had learned in my balance studies. The young emaciated woman was gaining weight. For me it was obvious that she was drinking. Alexandre was most skeptical when he heard my views which he qualified as being the erratic reasoning typical of internists. He knew that she was not drinking. Indeed she had denied it in front of him and he could not even imagine that a patient could lie to her surgeon and especially himself. Twenty years later the patient confessed that in those days indeed she was drinking from her hot water bottle!
Around that time Professor Hoet called me to warn me that I didn't have the choice. I had to start a hemodialysis program to support transplantation. In the United States as well as in Hamburger's Department dialysis was not considered a very scientific endeavor and this was still the case two years later when Hugh de Wardener visited Bill Schwartz while I was in Boston. He came to convince some leading nephrologists like Bill that it was their responsibility to develop chronic dialysis and I must say that he had very little success with the Salt and Water Club pundits of Boston who looked upon transplantation and subsequently dialysis as accessories that might threaten the development of « real research ».
On January 29th, 1965 I thus performed the first hemodialysis in our Hospital with a Sweden Freezer machine acquired with a grant from the Belgian Fund for Medical Research. Everything went well despite my anxieties. Indeed several previous trials with dogs had ended in the death of the animal. It was only several months later that I learned that the dog was especially liable to hemodynamic disturbances after hemodialysis. In February we had already done 15 hemodialyses each of which was a stress. At this stage the hospital decided to make a dialysis room in the hastily adapted toilets of the ground floor. At that time I was fortunate to hire our first technician with whom I was going to have a life long successful working relationship, Andre Stragier.
At this early stage the fundamental collaborations were already set: Guy Alexandre for transplantation, Andre Stragier for dialysis. Dialysis was performed only overnight, twice, 12 hours per week. During the day indeed I had to carry on experimental work for my PhD thesis. L. Brasseur, my cardiology colleague working under the aegis of Professor F. Lavenne, the Professor of Cardiology, had provided me with a small lab space. My first experience in the wards of internal medicine benefited from the end of my stay in the army. I now had time to see hospitalized patients, mainly to discuss electrolyte abnormalities, a topic still very mysterious for all the other clinicians, fortunately. I had to fight to record serum creatinine rather than blood urea to assess renal function. Shortly thereafter I was called for the first time to the clinic to see an outpatient who requested a « kidney specialist » and there I came most happy and proud. Upon questioning it appeared that the kidneys were very painful indeed : every time the patient bent to collect something on the floor, he suffered from an excruciating pain ! The limits between nephrology and rheumatology were not yet very clear.
YP: After this start, how has transplantation progressed?
CY: Guy Alexandre was a very dynamic, demanding and successful surgeon. Early in 1966, he had already performed 35 transplantations, mainly from cadaver graft, occasionally from living donors. He led the way in Belgium undoubtedly. Among all things, he was among the first in the world to successfully apply the criteria of cerebral death. Bilateral nephrectomy as a treatment for malignant hypertension resistant to volume depletion was still alien to the practice of our Department of Medicine. In 1965 I remember my mentor, Professor Arcq, who told me about his dismay. "This cannot be done" he said, "this is experimental adventureness and therefore unacceptable." Nothing was yet published in the world literature. As the number of patients increased we started an outpatient clinic for their follow-up. The surgeon was in charge of the acute phase of transplantation, kidney harvesting and immunosuppressive therapy, whereas I was responsible for the medical problems of the early follow-up as well as for the outpatient detection of rejection episodes. Such an arrangement was rather unusual in Europe, where nephrologists usually dominated the surgeons, whereas the reverse was most frequent in the United States.
Thanks to the meticulous charts of the patients, an heritage of my training in internal medicine, we quickly gathered enough material to initiate a number of clinical studies. We just had to bend to collect the gold nuggets.
In 1972, with the help of the Department of Orthopedics, we reported the first large studies on femoral head necrosis, underlining the role of steroids and defining therapeutic strategies to repair the damaged hip. More than 20 years later, our team was still involved in this topic when E. Goffin described a new syndrome of microfractures developing within a few weeks after transplantation. Throughout we benefited from the highly sophisticated help of the radiologists who mastered the ever-improving imaging techniques. Also, from 1974 onwards, we became interested in hypertension in transplanted patients and described its prevalence as well as its etiological factors. Yves Pirson, then one of my associates and my interviewer today and successor, published in 1977 in the New England Journal of Medicine the frightening consequences for the transplanted patient of a hepatitis B infection acquired during the hemodialysis period.
Later, during a visit from John Harrington, a friend of the Boston years, I discovered that he too had a few cases of « de novo » membranous glomerulonephritis in renal grafts. With the help of our pathologist, Jean Pierre Cosyns, and together with the Boston team we reported in 1982 the first series of this then unusual complication. It's worth pointing out that clinical research in transplantation was among the first to rely on multicentre studies, a concept that was virtually non-existent in the 60s. This collaborative research remains very active today. A few months ago we performed the 3000th renal transplant. Everything that we achieved in the domain of transplantation was the fruit of an intense collaboration with other specialists: surgeons, pathologists, and radiologists. I guess that nephrology was one of the first subspecialties to transcend the barriers between disciplines, thriving on a great variety of expertises.
YP: Didn't you develop dialysis at the same time?
CY: Indeed. As I told you it was not evident for somebody trained mainly in water and electrolytes physiology to initiate dialysis, especially as this technique was not taken very seriously by the leaders in nephrology except a few precursors like Hugh de Wardener. At that time the literature referred to the « artificial kidney » between quotation marks. However, as I already mentioned, I had no choice. I had to provide replacement therapy for patients awaiting transplantation. From the first moment, together with Guy Alexandre, we realized that dialysis and transplantation were complementary. It is evident today but in those days the debate was fierce. In the 60s Hugh de Wardener opposed the excellent comfortable survival on dialysis with the first results of transplantation and advocated the only dialysis approach. In 1963 I relied on peritoneal dialysis and started hemodialysis in January 1965. The extension was very rapid. In those days we had to rely on ingenuity. There were no standards, no KT over V to quantitate the dialysis doses, no quality control of dialysate. To overcome the lack of space the same dialysate irrigated three successive dialyzers. The assembly of the Kiil dialyzer was a demanding cumbersome process. It started, as depicted here, with the deposition of twice two wet membranes on the Kiil board. Blood ports were included in each layer to allow blood access. The last board we then put on top and the whole dialyzer was fastened by a series of muscle requiring bolts. Then came the anxiety generating test for air tightness. Failure meant to start from scratch. Later when the patients arrived, they were met by the nurses and the doctors, including here one of my first collaborators, Dr. Edgar Coche and myself. Andre Stragier proved amazingly creative to develop gadgets simplifying our task or to improve dialysis technique. He published several such contributions in the Proceedings of the European Dialysis and Transplant Association which had just been founded in 1964. His enthusiasm was such that I invited him to join me at the 1966 annual meeting of the EDTA in Lyon and I was amazed at his ability to contact prominent people whom I eventually knew less well than him. I remember joining one of them who would then turn to Andre Stragier and asked him "Does this fellow work in your unit?" Andre has remained a creative and regular contributor to several journals up to his retirement this year. Pretty soon he became one of the pillars of the European Dialysis and Transplant Nurses Association which I had initiated together with Stanley Shaldon in 1972.
In the late 1960s I had visited Stanley Shaldon at his National Kidney Centre to discover home hemodialysis. We started such a program in Belgium in 1970. Again it was an adventure. It took us four years of constant struggle to convince the health care insurance to recognize and fund this therapeutic modality. The medical authorities opposed this breach of the medical monopoly - perform an extracorporeal blood circulation without physician and nurse - can you imagine! In the 1980s we initiated self dialysis in a limited care facility in Belgium. Peritoneal dialysis used in 1963 had been abandoned when hemodialysis became operational. However, in 1978, one of my first coworkers, Jean Marie Vandenbroucke developed a new program of peritoneal dialysis which is still very successful today, under the guidance of E. Goffin. The promotion of extra-hospital dialysis proved very difficult in Belgium. As a result of the unusual density of hospital dialysis centres, we succeeded mainly thanks to the dedication of the nursing staff whose chief, Tony Govaerts, spared no effort to provide a maximum of autonomy to the patients entrusted to him. The nursing staff has developed audiovisual techniques to educate the patients on home dialysis and several of their original videotapes have been recognized by various awards. Thanks to these efforts we offer today all the modalities of renal replacement therapy and it is my firm belief that each patient should eventually choose the renal replacement method that best suits him. This concept has been largely propagated by our nurses within the EDTA, the American Nephrology Nurses Association (ANNA) and the World Federation for Renal Care (WFRC) of which they are active participants. Nephrology has thus provided one of the first examples of a very close collaboration between physicians and nursing staff. A very common concept nowadays but it was prophetic in the 1960s and 70s. Finally, the increase in the number of patients led not only to the expansion within our group, but convinced us also that we had to promote hospital dialysis throughout the French speaking part of the country. People who had trained with us initiated several centres and thus laid the foundation of a very active network with warm friendly relations, nurturing continuous medical education, as well as joint research projects.
YP: And how about the research in this area?
CY: The various modalities of renal replacement therapy provided curious minds with a number of research topics. The dissemination of hepatitis had become a catastrophe for the dialysis unit. In the United Kingdom cosmonaut garbs were even proposed to nurses caring for contaminated patients ! We were certainly less apprehensive. I keep remembering the anxiety of one of our British colleagues who during a visit was invited to share our sandwiches in a room next to the dialysis room.
In 1972 we assessed the situation in our unit. We isolated the infected patients and thus controlled the spread of the disease. Still we had to wait for an efficient vaccine to settle the issue. Hepatitis has remained a topic of interest. After the discovery of the hepatitis virus C, another of my associates, Michel Jadoul described in 1993 the prevalence and the incidence of HCV infection in dialyzed patients. He was among the first to demonstrate that contamination was mediated mainly by nurses. Michel advocated the strict enforcement of a certain number of hygienic practices. He was against the isolation of HCV contaminated patients implemented at that time by several foreign units. He pursued his multicentric study and demonstrated that indeed the mere application of strict rules by the nursing staff led to a zero incidence of HCV hepatitis.
Another topic was initiated in 1985 when our rheumatology colleagues, the late Jean Pierre Huaux and Charles Nagant discovered amyloid deposits within the femoral heads of patients on long term dialysis referred to them by Flemish colleagues. Our radiologist, B. Maldague and subsequently Jacques Malghem had developed a great experience of the diagnosis of bone cysts associated with light chain amyloidosis. We relied on their skills to evaluate our dialyzed patients and discovered that the prevalence of bone amyloidosis was markedly higher in patients given dialysis with a poorly bio compatible membrane such as cuprophane than in those dialyzed with the synthetic membrane AN69. However, the difference was not significant. We thus initiated a Franco-Belgian multicentre study. Together with the radiologists we refined the diagnostic criteria of dialysis amyloidosis whose constituent protein beta-2-microglobulin had been discovered by Gejyo.
In 1991, we eventually demonstrated that indeed AN69 had a protective effect against dialysis amyloidosis, a-beta-2m. Almost simultaneously, Michel Jadoul reported the first case of a-beta-2m in a patient given only peritoneal dialysis. He further demonstrated that up to 10 years after a successful transplantation, a-beta-2m did not regress.
More recently, with the help of a young pathologist, Christian Garbar, he defined the prevalence of histologic 2-beta-2m deposits in patients treated by hemo- or by peritoneal dialysis and delineated the various steps of their morphogenesis. Together with the Japanese group of Toshio Miyata, we demonstrated that advanced glycation and lipoxidation of beta-2-microglobulin was not critical for the genesis of a-beta-2m deposits. Here again we caught an opportunity and advanced with the help of various specialists in rheumatology, radiology, pathology, our network of various dialysis centres and foreign laboratories. It is the same multidisciplinary approach that was used by Goffin to ascertain risks inherent in peritoneal dialysis : patients with AIDS, alterations of the peritoneal membrane, and especially those linked with advanced glycation or carbonyl compounds, benefits of new glucose free dialysates. Together with our Japanese colleagues and Olivier Devuyst who had taken over the responsibility of our research lab, molecular biology techniques were developed to understand the various phases of peritoneal membrane failure. This recent experience rekindled the amusement and the excitement I had enjoyed almost 40 years ago during the exploration of unknown territories. We were lucky to be on the forefront in these areas.
YP: Have you been equally lucky in clinical nephrology?
CY: The term "nephrology" proposed in 1960 by Jean Hamburger during the first International Congress of Nephrology was slowly progressing together with clinical nephrology. During the 60s the anatomo clinic method had peaked in French nephrology and was spreading in the Anglo Saxon world. Percutaneous renal biopsy became an unavoidable diagnostic tool. Despite my fear of possible complications, I had to undertake in 1965 my first biopsy in the comforting presence of a gastroenterologist trained to perform liver biopsies under laparoscopy control. It wasn't really the same thing ! From this period I have kept a critical approach of the indications of renal biopsy : what is the advantage for the patient? For his treatment? I remember heated exchanges with my friend and mentor, Gabriel Richet, in whose Department in the Hopital Tenon in Paris biopsy had become a routine. Critical assessment of these biopsies required a very well trained pathologist. Gabriel Richet and his pathologist, at Tenon, Liliane Morel-Maroger, trained our young colleague, Jean Pierre Cosyns so that in the late 1970s our team benefited from his experience. Clinical nephrology rests still today on a careful history and a thorough clinical examination inherited from Professor Arcq together with a few laboratory tests evaluated with the logic learned in Boston. Clinical nephrology remains today very close to general internal medicine when it deals with the multiple problems complicating chronic renal insufficiency, transplantation and dialysis. Somehow Professor Arcq was right in 1958 when he predicted that nephrology required a good general internist. As a result of his conviction I contributed later to the definition of training of nephrologists in Europe.
More clinical research developed again as a result of the hazards of interesting observations.
Andre Stragier was the first to point out in our unit that bilateral nephrectomy worsened the anemia of dialyzed patients. A critical analysis of several cases led us to conclude in 1969 that indeed the atrophic kidneys of the dialyzed uremic patient still had a non-excretory function. We later confirmed the significant role of the remnant kidney as determinants of serum levels of beta-2-microglobulin or of pentosidine, an advanced glycation end product.
A few years later we were struck by a series of three patients with acute renal failure that evolved spontaneously towards healing. Interestingly, the three patients worked in the same research laboratory close to our hospital and were in contact with a strain of rats with hereditary myeloma, the lou strain famous throughout the world as a research tool. I discussed these cases of acute interstitial nephritis in a Nephrology Forum held in St. Luc in 1979 and concluded that they were probably caused by an unknown virus. It took us a few more years to discover that the virus was a Hantavirus, the cause of nephropatia epidemica, an anatomical entity, then restricted to Scandinavia and western Russia. In a multicentric study carried out with French centres we demonstrated that this virus is also endemic in western Europe. As a byproduct of this research we also discovered that our three patients had been contaminated by the myeloma rats which harbored the virus.
It is also by chance that several years later, as a matter of fact rather recently, we met two young women with terminal renal failure due to an acellular intensely sclerosing interstitial nephritis. Our colleagues of the Free University of Brussels told us that they also had met two such patients and had further discovered that they had been treated in the same slimming clinic. Our two patients confessed that indeed they had also attended this clinic. Further inquiry disclosed that the physicians of this clinic had included recently in their pills two Chinese herbs. Many more patients were subsequently identified. With Jean Pierre Cosyns we were able to describe the pathology of these kidneys and reported in 50% of them, unfortunately, the presence of pre-malignant urothelial lesions that evolved into a carcinoma in a few patients. Our Brussels colleagues had suggested that an error in the type of Chinese herbs had led to contamination with aristolochic acid. Together with a German team we confirmed this hypothesis by demonstrating the presence of aristolochic acid adducts on the DNA of the renal tissue of our patients. Subsequently we identified a tubular proteinuria in these patients and described the natural history of the disease. Jean Pierre Cosyns very recently demonstrated the development of typical lesions of Chinese herbs nephropathy in rabbits given pure aristolochic acid. These observations have had an extensive media coverage, not only in Belgium but throughout the western world. It indeed questioned the safety of unchecked phyto therapy provided in many places. It identified also ethical issues of medical responsibilities and led to the ban of these products in western Europe.
Chance again in 1994 when I met a young promising Japanese investigator, Toshio Miyata during a French-Japanese symposium. With his help we delineated the role of advanced glycation in the onset of dialysis amyloidosis. This has led to a series of studies on advanced glycation and lipid oxidation end products, their clearance by dialysis, the discovery that they resulted from the accumulation of precursor carbonyl compounds. Interestingly, this research crossed the path of Oliver Devuyst who, in our nephrology laboratory, carried on parallel studies on the production of nitric oxide by the peritoneal membrane. More fascinating research would ensue.
YP: During your stay in the States you worked mainly on acid base balance. Did you pursue this field upon your return to Belgium?
CY: Oh for sure. Thanks to the help of Professors L. Brasseur and F. Lavenne, I continued experimental balance studies in Louvain. My only limit was then the time left for this endeavor after my clinical commitments.
We were thus the first to demonstrate that the acid base equilibrium reached in chronic hypercapnia was the same in man as in dogs. On the basis of this paper published in 1966 in the New England Journal of Medicine I proposed a normogram to unravel the acid base disorders superimposed on chronic respiratory acidosis. With the further help of a pneumologist, Albert Frans, we quantified the normal ventilatory response to chronic metabolic alkalosis and acidosis and were able to expand the diagnostic normogram to all metabolic and respiratory acid base disorders. A few months ago, while lecturing in Cambridge, I had the delightful surprise to discover that this normogram was still used in the United Kingdom.
More work has followed on the role of chloride in urinary concentration, of cations such as sodium or potassium in the genesis of diuretic induced metabolic alkalosis, on the regulation of endogenous acid production by the digestive tract. When Oliver Devuyst came back from Baltimore in 1996 the research activities of the laboratory were transformed. My old metabolic cages were abandoned and modern molecular biology techniques were introduced. Dogs were replaced by mice or even by tissue cultures. From this transition I learned how much the pursuit of stimulating research requires a constant renewal of men and tools.
YP: Professor Ypersele, how do you see the future?
CY: I'm convinced that the future arises in the secret of winter. I do believe that it is already present today but somehow hidden. The young shoots are there but remain to be recognized. Very often we carry the future in our minds without knowing it.
When Y. Pirson described in 1987 a family with the hemolytic uremic syndrome, we did not know that he had initiated clinical genetics in our Department. With the help of an international consortium he later localized the genetic abnormality. Once primed his interest for familial disease opened new fields of discovery. Very often in cooperation with foreign groups and together with other members of the unit, he described various types of Alport syndrome, a new eye abnormality associated with this disease, hereditary hepatic diseases, familial renal disease with either hyperuricemia or with amyloidosis and many others. On the other hand molecular biology has opened also new paths. Oliver Devuyst recently demonstrated that the mice knock out model for chloride channel CCL5 developed at Johns Hopkins is similar to Dent’s disease. He also unraveled the cellular mechanisms of aristolochic acid toxicity, the molecular abnormalities of various channels impairing peritoneal membrane permeability. So you see the future is already well underway in our unit.
YP: You mentioned that Gamble’s book on Extracellular Fluid was in 1958 your sole basis for understanding water and electrolyte disorders. How has propagation of knowledge developed over the subsequent 40 years?
CY: The 1960s fostered the first textbooks of renal medicine. Sir Douglas Black's "Renal Disease" in 1962, Strauss and Welts' "Diseases of Kidney" in 1963 and Hamburger's team’s "Nephrology" in 1966. In the 1970s the explosion of knowledge was such that only multiauthored textbooks were possible, most contributors being close friends of the editors. As Hamburger wrote in the introduction of his multiauthored, "Nephrologie" in 1979, « the unusual friendship among nephrologists made the miracle possible. None of the contributors refused our invitation ». Our group was included in this friendship and we have contributed since to several textbooks including the most recent "Oxford Textbook of Clinical Nephrology" which provides today the eager clinician an answer, not only to most of the questions raised 40 years ago, but also to an endless number of additional ones. In contrast with the desert of the 1960s, there is now a jungle of continuously updated textbooks.
Journals have followed a parallel path. When I was on the United States we aimed only at the general journals, including the New England Journal of Medicine or the Lancet for clinical papers, the Journal of Clinical Investigation, the American Journal of Physiology and Clinical Science for experimental data. French language journals such as La Presse Medicale, or the Revue d’études cliniques et biologiques were on the wane. In 1963 the International Society of Nephrology initiated the first nephrology journal, Nephron, to be replaced subsequently by Kidney International in 1972. Clinical Nephrology started in 1974, the American Journal of Kidney Disease in 1983. In 1984, I met in London Stewart Cameron, then President of the EDTA, Sandy Davisson, Editor of its Proceedings, and Vincenzo Cambi, the Associations Secretary to decide whether there was still room for an additional, mainly European, Journal of Nephrology. We hesitantly concluded YES and launched Nephrology, Dialysis and transplantation in 1986. A number of other successful nephrology journal launched since demonstrates how myopic our hesitations were. The number of papers submitted for publication has risen in parallel but the procedures, obstacles, reviews required for acceptance have increased simultaneously. I remember that in 1969 it took a week to the Editor of the Lancet to say YES or NO, today's delays are cumbersome. The best journals give you answer within 5-6 weeks. Many others delay by several months. In 1975 Franz Ingelfinger then Editor of the New England Journal of Medicine answered us that the reviewers were against our submitted paper but that he liked it and would publish it if we provided information on one item. Today many, sometimes odd requests from the reviewers have occasionally to be complied with before acceptance. Yes, today we are better informed, sometimes over-informed than 40 years ago, but we pay a price, life is more difficult.
YP: Has your teaching adapted to this flood of new information?
CY: I should answer this question at two levels : graduate and postgraduate. Teaching at the graduate level has not changed so much. What does a general practitioner need to know to be helpful to his patients ? The only thing that changes is how to make him aware when he should refer the patient to a specialist who in some circumstances may improve the prognosis by early appropriate diagnostic maneuvers and therapy. A good example is that of the early symptoms of subacute glomerulonephritis. Graduate Teaching in nephrology has also benefited from the first steps of our understanding of water and electrolytes disorders. This domain lends itself to a quantitative and logical approach. The young anephric lady on peritoneal dialysis I have alluded to earlier could not gain weight unless she drank, an inescapable logical conclusion. I guess that it is for this reason that the nephrologists were the first to introduce decision analysis in the diagnosis and treatment of diseases. I learned quite a lot from Bill Schwartz who was a pioneer in this domain and from Jerry Kassirer who popularized this approach in many areas of internal medicine in the now famous « clinical problem solving series » eventually published from 1992 onwards in the New England Journal of Medicine. Teaching logic behind the clinical approach has proven very popular with first and second year medical students. Postgraduate education is another matter. In many countries the specific training in nephrology is now recognized as a subspecialty of internal medicine and this is the case in Belgium. In several others however it has become independent of internal medicine. Both in Belgium and at the European community level I have fought to support the former view. All the nephrologists I have trained are first general internists. How else could they cope with the multitude of complications of patients with chronic uremia given dialysis and/or transplantation. ?
Another aspect of graduate and postgraduate teaching became increasingly important for me - bedside teaching. From Professor Arcq in the late 50s I learned how much we could achieve with a sound mind and appropriate clinical skills. The increasing availability of biochemical and pathology data, of more and more sophisticated imaging techniques has eroded these skills. Only the UK has been able to nurture these unique talents. For this reason I took advantage of the personal links established within the European Society of Clinical Investigation and proposed in my Presidential address in 1977 to establish a multilateral exchange scheme for junior residents in internal medicine. The European union provided financial support. We started the experiment between the UK, Belgium, France, the Netherlands, Switzerland, Greece and Germany. Although very often difficult for administrative reasons, the scheme has prospered and is still operational today.
YP: You have mentioned a number of associations or societies. How have they developed?
CY: As you may anticipate, the development of medicine in the 60s has been matched by an intense desire to exchange personal experiences. Societies were born. Professional societies of nephrology were founded in France in 1949, in the UK in 1950, in Italy in 1957. I had the privilege to serve the Société de Nephrologie, the French society, as President between 1991 and 1993. The International Society of Nephrology was born in 1960 on the initiative of Jean Hamburger and Gabriel Richet. I served on its Council from 1990 to 1997. The EDTA was initiated in 1964 after a meeting organized in London by Stanley Shaldon on acute renal failure. We also were quickly involved. I served twice three years on its Council. The American Collegue of Physicians, the Royal Colleges of Physicians in London and Edinburgh have elected me as honorary fellow. These established friendships together with my experience with the European exchange scheme provided a basis for the creation of a European Federation of Academies of Medicine and related institutions. We took advantage of the celebration of the 150th anniversary of our Royal Academy of Medicine in 1991 to launch this initiative with the help of Gabriel Richet from the French Academie Nationale and Margaret Turner Warwick then President of the Royal College of Physicians in London.
YP : Which changes have you witnessed during these 40 years ?
CY : In the 1960s we enjoyed a wonderful freedom of initiative despite occasional reluctance from the administration or even within the medical profession : we succeeded. Today, unfortunately, freedom of action has shrunk as the financial worries of the public health service increase. My successor, Yves Pirson, is now overwhelmed by administrative requirements whose cost effectiveness I really question. Life is certainly much more difficult today.
In the 1960s together with several colleagues we developed and implemented a new statute for the increasing number of physicians fully employed by our hospital. As a result we became involved in the running of the hospital. I spent several years on the Medical Council and on the Board of Trustees of our hospital. The wind of change following 1968 transformed not only the
hospital structures but also the University's culture. Among other things, promotion became now objective and proved a major incentive to stimulate research and publications. The somehow sleepy provincial quietness of the 1960s has thus been replaced today by a "publish or perish" culture. For instance, promotions in nephrology are now determined to a large extent by scientific achievement and in such an environment the astute physician, able to weight the pros and cons to improve the patient's outcome may find some difficulties to be promoted. I believe that this is a source of significant concern for the future.
YP : How would you summarize the lessons learnt during these 4 decades ?
CY : Only a few conclusions.
First that desire and pleasure are critical driving forces in one's life. I recognize still today the delight of my early years looking at the red cells circulating in the frog spawn spread under the microscope when I was 12; following the fall in blood urea of a patient given sodium bicarbonate in my balance studies of the late 50s or watching the changes in serum bicarbonate of progressively chloride depleted dogs in Bill Schwartz's lab. The pleasure has remained the same today: Polishing a paper almost ready for submission, the desire to better understand new clinical entities whether Hantavirus disease, dialysis related amyloidosis or Chinese herbs nephropathy. I pity those colleagues who arrive daily at work without eagerness.
Second, the influence of the people you meet. I guess that without Professor Arcq, Professor Hamburger and Richet or most importantly William B. Schwartz I would be a very different man. Today looking back I feel an enormous gratitude as well as an enormous debt. Have I been able to translate to the younger generation the values fostered in my career by these men?
Third, that nephrology is a unique field. The rigorous analytic skill required to understand water and electrolyte balance taken together with the constant necessity to maintain clinical skills to cope with chronic renal failure patients has generated a demanding type of physician, especially well prepared to weigh the pros and cons in a new, money-restricted but more and more technically performing medical environment.
Fourth, that research, fundamental or clinical, requires teamwork. We relied on the help of pathologists, radiologists, biochemists, surgeons, and many others to advance our knowledge. Teamwork also with the nephrologists working outside the University Hospital, the network. Teamwork with nurses, technicians and secretaries. Teamwork vested in friendship, understanding beyond the unavoidable difficulties inherent to the human race.
My final point, is that pleasure and desire will flower as long as we remain open to the unexpected. Wasn't it Louis Pasteur who said "Le hasard ne sourit qu’à l’esprit préparé" "Chance favors only prepared minds."
Thank you Yves.