The International Society of Nephrology has decided to create a collection of video recordings of a number of the leading nephrologists and workers in related fields who helped to lay the foundation of nephrology as we know it today.
Claus Brun belongs evidently to the group of founders of nephrology as a specialty. He was one of the two people who introduced the percutaneous renal biopsy in the late 40s. He laid down the basis for our understanding of renal histopathology as revealed in the biopsy and its correlation with functional and clinical data. He eagerly participated in the international exchange of ideas during these early days and was one of the first presidents of our International Society. It is therefore natural that we who are working in the field today are highly interested in learning from him about techniques and ideas prevailing in the field during the 40s, 50s and 60s.
Claus Brun was born in 1914 in Copenhagen. He performed his studies at the Medical School of the University of Copenhagen and graduated in 1940. He worked for almost his entire professional life at the old Municipal Hospital in Copenhagen. He retired in 1984 but has continued his lifelong work with kidney biopsies at the ............................... Hospital in Copenhagen, where one of his pupils, Professor Sven Larson?, had generously made a place for him in the Department of Pathology and this is where we are sitting at the moment.
(to Dr. Brun) I have known you and we have worked together with you since the late 50s. We have therefore felt it natural that I should talk with you about your early experiences. Now, Claus, when you went to the University just after your left the gymnasium? you made the choice of medicine as your study. Was this choice automatic because you had had some influences in your home from your father or was this choice from other places?
CB: I had influence from my father who was a doctor but even more important was we had a very good teacher in biology in school which created my interest in physiology and biology and on top of that I had read Michael ?Vanders from Van de Koop? and led to my starting a small bacteriological lab in my parentís flat, where there was a pantry. So it came quite naturally that I chose medicine.
SO: You grew bacteria in your kitchen? Your motherís kitchen!
When you began your study of medicine the conditions must have been very different from those of today. Can you describe what it was like to study medicine at the Copenhagen University in the 40s?
CB: It was quite different than today. It was not so much a medical school as it was the students themselves who organized most of it and one important thing was to have a bicycle because you had to move from the University to the different hospitals in Copenhagen. You spent quite a lot of time on your bicycle.
SO: Very soon after you graduated as a doctor, you went into the field of kidney diseases and you have ever since your first published paper in 1943 which dealt with the determination in blood and urine of Diodrast, until the last one which appeared a few years ago. You have worked almost exclusively in nephrology and related subjects. How did you decide to concentrate upon this field?
CB: The reason for going into renal work, originally not so much pathology as renal physiology, was that in the late 40s we had access to papers from the United States, especially Homer Smith, who by the way would have been 100 years old this month. This opened up all the possibilities to measure filtration rate, renal blood flow, tubular mass and that is where we started out - in this completely new field, where we could, under different conditions study the kidney function. And that is where we started.
SO: Can you describe the situation with nephrology, if this term existed at all, in Denmark and internationally at the time when you began your work? It was of course before anybody had as much as thought of dialysis and transplantation.
CB: Probably it was not really nephrology. It was a small part of internal medicine, where could offer patients with kidney diseases was nothing more than endless bedrest and diet and that was about all. I was interested in the low protein diet. I had a patient who had a chronic interstitial nephritis and I made a prescription book with different dishes and I went to the Institute for Technology and tried to make bread with a low protein content. It made the patients happy that somebody looked after them and talked to them and corrected their acidosis and gave them a diet book but of course it didnít really mean anything for the prognosis.
SO: I think this was very original because that has evolved to a specialty - dietary therapy today.
Can you describe the spiritual and physical environment found in the Department of Professor Carl Igorsson? at the Copenhagen Municipal Hospital? How was the daily work organized? I am thinking here about your senior colleagues. Whom of them became particularly important for your career?
CB: I found a group of young doctors, all the same age or a little older, who were Bjorn Borg?, Tony Hilton?, Fleming? Roscoe? Christian Kromer?, Sven Larsen?, who were equally interested in renal physiology as myself and the daily work was organized so that in the morning from 8 till 1 oíclock did routine work. At that time we had no central clinical lab so the young doctors took all blood samples, blood pressures etc., and when we were finished there, in the afternoon we could start doing experiments and thatís where we used the new methods for measuring kidney function. Afternoons were spent with the patient or experimental person doing special work interested in kidney function. Then we had no or very little help from technicians. We did analysis in the evening which turned out to be quite cumbersome and of course there was no calculating means apart from the slide rule so it took a long time. I remember that we made a study of kidney function in the .upright position, we placed the patient on a tilting table so he was standing but not resting on his legs and that led to at least some of the patients after some time had collapse because all the blood went down to the legs. We did a rough experiment in that we had two patients - one on the tilting table and one in bed, equally hydrated and when the tilting table patient collapsed we took half a litre of blood from him and infused it into the hydrated horizontal lying person and it turned out that his urine flow stopped also. Then we took half a litre of blood from the normal person and reintroduced it into the collapsed patient. We called it post syncope oliguria.
SO: This was a very interesting experiment but I guess that you would have to get permission to do that today!
CB: Iím fully aware of that. I think there were several things we did that would not be accepted today. It is very difficult today to do something that has not been done before.
SO: Well Claus, a little later in this conversation we should talk in detail about the original accomplishment which most nephrologists connect with your name - the percutaneous renal biopsy. Before and after the time when you and Iversen introduced this method, you and your colleagues were strongly occupied with the development of dialysis. I know that you worked with intestinal dialysis just before 1949. as far as I remember. Could you describe the technique and results of this early beginning of treatment with dialysis?
CB: The technique I can describe, the result is a little bit more difficult. I introduced a tube, a nasal tube, down into the duodenum and put a rectal tube in the other end and then I flushed the complete interstinum with different solutions and of course I found out that you had to use special osmotic active substances to prevent
SO: Was that a method you originally introduced or did you get inspiration from other authors?
CB: It was mentioned to Iversen by Professor Barbor? who had heard about it and he asked me if I could try to do it and it turned out, if you mention results, that if you had a lactose solution flushing the interstinum, you could remove urea, sodium, potassium and glucose but you could not remove uric acid, creatinine and phosphate. So it was more or less a cosmetic treatment. But I made the patients look better after I had given them transfusion and removed their acidosis but it was not a really effective treatment of uremia so I gave it up.
SO: You used that for acute uremia and not for chronic patients?
CB: No, that was for chronic patients. We had not run into many acute renal failures until years later.
SO: There must have been many difficulties to overcome in your initial attempts to develop efficient and safe artificial kidneys. I know that you tried several technical possibilities. Can you describe the first machines?
CB: There were machines working in Lund in Sweden. Nils Alwal had a machine which was working and Kolff in Holland had a similar one. In those two machines there was a great drawback in that you were not quite sure where the patientís blood was. Sometimes it was all in the machine and sometimes in the body. So when I was in the United States and saw the plate dialyzer developed by Skeggs and Leonard I found out that here you had a constant or easily controllable volume and I thought that this must be the ideal. On top of that with Kolff dialyzers you had to rely on sausage skin for membrane used as a rather thick cellophane. With the Skeggs and Leonard kidney you could easily choose the membrane yourself and I found some very thin cellophane which was only a few microns thick.
SO: Was that the machine with the really big drum?
CB: The big drum was Kolffís machine. Alwalís was also a big drum. I sort of missed out in this development because I got an invitation when van Slyke came through our lab and he advised me to come to the United States where I could work with Homer Smith in his Department of Physiology in New York. So I was out of the picture for more than a year but when I came home, I found Alwalís dialyzer standing on top of a cupboard with a lot of dust on it and nobody had used it.
SO: When you returned you decided to develop your own machine.
CB: Based on Skeggs and Leonardís.
SO: So that was a modification. You got some help from the veterinary high school?
CB: #9; He had got a scholarship with which he actually bought a Skeggs and Leonard so it was available in Denmark. Then we started out on some poor dogs and a few pigs to do the initial "mistakes" on animals. After a while we carried out a human dialysis.
SO: Iíd hoped that we could talk a little about your work in Homer Smithís Department. Would that be appropriate now or would you say more about Homer Smith later on?
CB: It was a very great experience to me and medical life in the United States at that time was quite different from what Iíd experienced in the University of Copenhagen and the Municipal Hospital.
SO: That was in New York?
CB: Yes. With one exception - when it got too hot and humid in New York, the whole lab moved to Maine, to a desert island, which had a wonderful climate and natural beauty and the object of our studies was to try to find out what happened to kidney function in seals who were diving, which was quite difficult. The diving experiment was created by putting a funnel on their snouts. When they dive the seals had the same reflexes and the pulse rate went down to 30 or 40 per minute. We had the seals on a dock with a sort of fence around it. We took them up to the lab, put a catheter in the bladder and needles in the flipper veins and gave them inulin and paraminohippuric acid and then tried to see what happened. It was very difficult.
One of the difficulties was that there was no plastic tubing at that time so we used needles.
SO: What kind of studies did you do?
CB: I did some clearance studies, osmotic clearances which was purely kidney physiology and nothing to do with the patients but I would like to add that while on the desert island the reason it was such a wonderful experience was that there was a group of kidney physiologists who worked with different animals. We worked with the seals, some worked with sharks, some with chickens, some with lobsters and once a week there was a lecture given by the different people, who demonstrated their work. It was very inspiring. I enjoyed it tremendously.
Back in New York we continued doing clearance studies and taking part of a lot of conferences. I remember especially one ordinary weekly Wednesday meeting when Homer Smith came home from Switzerland, where he had met Virs Harbetout? and seen the peculiar idea that the nephron was not a straight line but it was bent and the osmotic pressure in the papilla of the kidney was much higher than in the cortex. Homer Smith said that he did not understand it but it was like that.
SO: We will now turn the introduction of the percutaneous biopsy. Had there been possibilities before that to study renal histomorphology in the living patient? I am of course excluding surgical material.
CB: There was a paper studying kidney histology on hypertension patients but it was a terrible technique.
SO: That was a very special situation. That was Castlemanís work.
CB: But needle biopsies had been performed before, especially Perez in Cuba had published work on kidney puncture, as he called it, on kidneys of normal size. He published it in 1950 so it was actually published a year before our first paper. We did our first biopsy in May 1949 and we didnít know of Perezí work because it was in Spanish and in a cancer paper published in Havana.
Alwal performed a kidney biopsy in 1944 in Sweden and he didnít publish until 1952 because the patient had died and originally he thought that the patient had died from the biopsy but later he changed his opinion and found that heíd probably died of the x-ray procedure involving a contrast medium.
Otherwise we believed that we were the first.
SO: Iversen and Rohan? performed the first liver biopsy some years before. It would be natural to assume that the group at the Copenhagen Municipal Hospital got the idea to repeat this "hat trick" as we would call it. Was this the inspiration or did you feel a strong demand to reinforce your diagnostic possibilities within the field of kidney disease?
CB: Of the liver biopsy that Iversen and Rohan published in 1939, just before the War was our main inspiration but at that time Iversen had asked me to look after uremic patients, give them a small home where I could have the patients and study the physiology. At that time we occasionally got anuric patients from the psychiatric department in another hospital where they treated acute poisoning cases, barbiturate poisoning mainly. The first patient who was biopsied in our hands was such a patient, where there was no other renal disease and anuria probably caused by prolonged shock and he also had carbon monoxide poisoning. With such a patient, you donít know what is happening with his kidneys. It was natural to adapt the kidney biopsy technique.
SO: So that the first biopsy was done on that particular patient.
CB: Yes, and it was performed with the patient in a sitting position and we got out a very tiny piece of tissue, including three glomeruli which looked normal.
SO: Show us the needle and demonstrate.
CB: It is the same needle that we used for liver biopsies, at the approximate place where we expected the kidney to be. The needle had a stylet inside, so you could introduce the needle through connective tissue onto the kidney and then you removed the stylet and placed the syringe on the needle, and then you pushed the needle forward into the kidney tissue and cut a cylinder of kidney tissue and so as not to lose it during the procedure, you created a vacuum in the syringe and took out the syringe and needle together and the kidney tissue would end up under the piston afterwards.
After the technique had been used by Kark and his colleagues in Chicago and he came to Copenhagen, it turned out that he placed the patient on a pillow on the stomach to press the kidney up and of course this made it much easier to find the kidney and as a means of location, first we tried to do it by taking photographs of the kidney with a piece of lead on the skin but it is not very much helped because the kidney is quite movable. It was very useful to have a thin needle as a pilot needle and it turned out that when the tip of the thin needle reached the kidney, it started to move with the respiration.
SO: Was this an idea of Karkís or did you do that in Copenhagen?
CB: Karkís, yes.
Then you measured the distance from the surface to the kidney and then you used the biopsy needle and put a mark on it. It improved our results considerably. In the first biopsies, we only got about one-third of positive kidney tissue but with Karkís technique we improved it to at least 60%. Later on we of course used an image amplifier technique. So nowadays, you know precisely where you are in the kidney.
It had one advantage which we donít have today. You got wonderfully long biopsies, sometimes up to 4 or 5 cms! Now with the modern techniques with the pistol mount automatic technique it is apt to give you too much medulla and too little cortex. The old techniques was most difficult to perform but you got more cortex.
SO: Did any complications occur in the first series of biopsies? Did you meet with opposition from colleagues or from patients?
CB: The only opposition we met had something to do with our very first biopsy. We were very proud of this tiny piece of tissue and Iversen and I went down to our pathologists because he had been in more or less the same situation as liver biopsies, and told them, "Here you have something you have never seen before. Kidney tissue from a patient with an unknown renal disease." To our great surprise it didnít ring a bell with anybody in the Pathology Department.
SO: Dear Mr. Chanc.........? He was a very fine pathologist but he was old fashioned and a classical pathologist and he did not like this "keyhole" pathology very much.
CB: Yes, he called it "keyhole" and Iím sure it is "keyhole" pathology. Iím still surprised that it works as well as it does. I have the impression that the reason we can use it at all is that it is a long piece of kidney tissue and not from only one tiny spot. It wouldnít work nearly as well if you didnít have a couple of cms of kidney tissue.
Then we went and sought help from Professor ................ in the Forensic Medicine Department at the University and he taught me kidney histology because at that time I was working on my thesis on acute renal failure and I had to give a description of the kidney tissue and he was quite helpful, Hal Gamson?
SO: And afterwards you yourself became a very skilled pathologist.
CB: Actually from the very beginning I had looked at all the kidney biopsies. I learned that from Iversen who also looked at his liver biopsies. I am very grateful to some pathologists, especially to you and you let me in.
SO: I was so young that at that time I could see the chance to get to the disease.
CB: I never had a hard word from the pathologists in Copenhagen.
SO: No thatís true. All the other pathologists recognized you. Well, could you describe what you found in the very first biopsy? That was a case of acute anuria as you told us but what did you find in the specimen?
CB: I saw exactly the same things that are seen today in what you call acute tubular necrosis and my contribution to the diagnosis I think could be that I got the pathologist to put the diagnosis in quotation marks because the strange thing was there was not much necrosis to be seen, not in the first one nor in the later one.
SO: Why do you think they called it and still call it "acute tubular necrosis" since there is no necrosis?
CB: Well we were thinking of acute renal failure due to poisoning with mercury, and artery thrombosis and renal artery thrombosis.
SO: Of course another reason would be that they were accustomed to looking at autopsy specimens.
CB: I think it was about the same time but it was before I went into the biopsy. I tried to study kidney tissue in pathology by working for half a year in the Pathology Institute looking at rotten kidney and I didnít get any wiser!
SO: What you found in the acute anuria was dilatation of the tubules.
CB: Dilatation of the proximal and distal tubules, some peculiar looking casts but may be the most important thing was the glomeruli looked normal.
SO: But what did you find when you looked through the microscope at this very first biopsy?
CB: Well, one of the problems was that we didnít really know how fresh kidney tissue looked. We could at least see that the glomeruli looked perfectly normal and that the tubules were dilated, and especially in the distal tubules there were some peculiar looking casts with a brownish reddish pigment in them. Furthermore, there was some cellular interstitial infiltration and some edema.
SO: But no necrosis. You did not find any tubular necrosis?
CB: No. And the vessel in the kidney looked normal to us but it was difficult to interpret fresh renal tissue because we had never seen it before.
SO: Even today we talk about "acute tubular necrosis", sometimes as a clinical diagnosis. Why has it not been possible to eradicate this erroneous term?
CB: I donít understand it because my accomplishment in physiology might be that I got the pathologist to put the quotation marks around this diagnosis and the nomenclature of acute renal failure has been displayed by everybody wanting to give it a new name. There are longer names which make study difficult and I think it would be far less complicated if you gave it a number!
SO: Did any complications occur in the first series of biopsies?
CB: No, we were probably very lucky. We of course had some hematuria and occasional blood clots but no complications in the first series. Later on we lost one kidney because a patient had to be dialyzed shortly after the renal biopsy and then he started to bleed and the bleeding was uncontrollable and the kidney was removed.
SO: But that is the only serious complication during this time.
CB: Yes, and the patient survived.
SO: What was the position of your colleagues and what was the feelings of the patients. Were they afraid of the procedure?
CB: No. The procedure was not very painful. It was taken from the back of the patient since the kidneys are not so big and we gave a good solid local anesthesia and it was only a short moment when you cut the actual kidney tissue there was some pain. But even when I had to repeat biopsies on some patients, there were no protests.
I never met any opposition from colleagues and after Karkís publication on renal biopsies, it spread rapidly in the United States and at the meeting in London.
SO: Yes I would like to hear something about the Ciba meeting in London. That was in the mid 60s?
CB: 1961. A person could calculate about more than 5000 biopsies had been performed in about ten years.
SO: I can recall that one of the participants was very critical and denied that a biopsy could provide data which was not available from clinical investigation.
CB: Yes, Wilson said that "acute renal failure was absolutely no indication............................."
But it spread nevertheless.
It led to the discussion which weíve had over and over again: "Is it permissible to do a test on a patient which might not be of interest to the particular patient but it might be of value to another patient with the same disease, for example diabetic kidneys and I donít think there is any clear cut answer to that but if you have to improve...
SO: Did you investigate the histopathology of other clinical syndromes? We have heard much about the acute anuria and the diseases which they cause.
CB: Yes, we were especially interested in the nephrotic syndrome and glomerulonephritis.
SO: What about the position of Hamburger in France. I would like to hear something about that?
CB: He invited me down to do a biopsy on a nephrotic patient there and the biopsy was quite successful.
SO: So this was the first biopsy in France.
CB: Yes. And I came out with a nice piece of kidney tissue and nothing happened to the patient but I think I shocked the French doctors because after that they started using open biopsies, cutting down on the kidney, and with great difficulty extracting kidney tissue. It is not so easy as it sounds to take renal tissue in an open biopsy.
SO: You were never really fond of this procedure. You called it "by fork and knife"!
CB: Of course it facilitated the location of the kidney but the technique of locating the kidney has been improved considerably during the years. Our first attempts were completely blind and then we put a piece of lead on the skin of the patient and used it as a marker for where the kidney was but it didnít help very much because the kidneys are quite movable. Then we used urography and pyelography so you had a set up of the kidney and with an amplifier technique you could actually place your biopsy needle on the lower pole of the kidney, away from the big vessels. That was a very useful technique which I used for many years. Later on we used ultrasound which gave a good picture of the kidney and facilitated the "hit" rate.
Our interests at that time included all kinds of renal diseases, especially the nephrotic syndrome, pyelonephritis which was the main subject of the renal work.
SO: It was a very common diagnosis at that time.
CB: Yes, probably widely over-diagnosed at that time. In different steps we improved on means of studying kidney tissue. First we were mostly interested in enzymes in the tubular cells which led us to fix the tissue in alcohol not to destroy the enzymes. But we suffered a little bit on the interpretation of the histology. It didnít solve any problem for us studying alkaline phosphatases.
The next step was electron microscopy. Dalgaard was taking care of that and it told us a lot about the normal tissue of the kidney; the study of the glomeruli and the membranes was very useful but again it didnít explain what was the matter with the anuric kidney.
The final step which we are still using today is of course immunological studies on the fresh kidney tissue which have told us very valuable things.
SO: I was also thinking about the technical problems you had with the cutting edge of the knife and I know that you had to look for specialists to study that problem. Is that not true?
CB: Yes. Itís true that as we saw more of the first biopsies that the techniques was not very good and most of biopsies we saw were 7 microns thick in the sections. It made a very big difference when Paul Kimmelstiel told us to cut much thinner sections so that you can look through the glomerular capillaries.
SO: But isnít it true that you went through a technical high school to ask for the right steel and the right angle of the knife?
CB: Yes. Finally, the problem was solved by some knife made in Japan which made it fairly easy to cut 2 micron thick sections.
Apart from the purely technical side it is very important to have technicians who are interested and capable of doing very fine work and I have been very lucky in having Mrs. Filat? to do the sectioning and she is trained also to study the tissue and she quite often she comes up with the diagnosis.
SO: Yes, she knows what you are looking for.
Fifty years ago there was no effective treatment of endstage renal disease and only very unsatisfactory treatment of acute renal failure. Could you give us some comments about this development and particularly about the changes in the different categories of renal diseases demanding chronic dialysis and transplantation?
CB: Itís true that the nephrology picture has changed over the years. When we started in the 40s the most common renal disease was called pyelonephritis which probably a misdiagnosis for all kinds of renal disease which showed renal atrophy and interstitial nephritis.
SO: Nonspecific changes. But I guess also that many cases of analgesic nephropathy must have been seen.
CB: We saw quite a few analgesic nephropathies but that disease seems to have been eradicated more or less.
SO: And today?
CB: Acute renal failure patients have diminished somewhat and the reason why we had so many was probably #9; lack of knowledge of treatment by salt and water. They were underhydrated or overhydrated and improvement in understanding of the specialty has stopped the great influx of acute renal failure. Of course you still see them after accidents, crush injuries and what have you but one of the most frequent objects for studying by kidney biopsy is actually the threatening rejection of renal grafts and it is very easy to perform the biopsy because the kidney is very accessible but it is more difficult to study it with tissue............ I could wish that we had more secure methods of diagnosis in early rejection.
SO: What about further progress in the field of nephrology? Where would you expect to find that?
CB: That is difficult to answer. At least I could wish that we could prevent more kidney diseases because a growing number of patients who need chronic dialysis is going to be a problem, economically and otherwise and we are not very good at preventing kidney diseases. Luckily we have had some improvement in the treatment of some patients, we can treat glomerulonephritis by plasma exchange and we can treat lupus nephritis and polyarteritis by immunosuppressant drugs but in ordinary acute post-infectious glomerulonephritis we have relatively few. We can give some antibiotics but when it starts there is not much we can do.
SO: One of the problems today of course is diabetic renal disease.
CB: Yes. And there should be possibilities of improving the patient by closer study and keeping the diabetic symptoms down but there will always be diabetic nephropathy until we have the possibility of transplanting some Langerhans cells into the patient.
SO: We should let that be the last statement in the interview and I would like to thank you very much for coming here and talking with me.
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