ISN VIDEO LEGACY PROJECT

DR. HUGH de WARDENER

 

 


Beginnings

HD: I’ve got a very complicated background, terribly complicated. The name is French, but in the French Revolution, my family went off to Austria to avoid their heads being cut off. And then my grandfather, on my father’s side, was at the battle of Solferino, which was a terrible disgrace because the Italians beat the Austrians, and he was in the Austrian army. So he immigrated to America, and there he had three children, one of who was my father, who then came to France, with his mother, and he was sent to school in England. So there was my father in France/England, and my mother came from Albuquerque, New Mexico, and came to learn a bit of singing in Paris, and they met there. So these two Americans had this child, me, 1915. So first I was half-American and half-French, and then I became English, when I realized I had to do military service in France, and I didn’t want to. I hardly knew anybody in France, or America; all my friends were in England, so I became naturalized English, while I was a medical student.

HD: I was originally being trained to be an engineer at school. Then I realized I couldn’t do mathematics. I just didn’t really like them, and at that time, we were very poor. I always wanted to be a doctor, but I did not think we could afford it, and I wrote one despairing letter to my mother, and I said, “Is it possible?” She said, “Yes! Yes.” So I switched into medicine, which I had always wanted.

Interviewer: Then you were a student at St. Thomas’?

HD: St. Thomas’, yes.

Interviewer: You qualified as a student at St. Thomas’, and what happened to you then?

HD:  I couldn’t wait to get a job at Thomas’. I applied for one job and I didn’t get it, and I was left with five pounds. So I just took the next job I was offered, which was in Scunthorpe, which was a wonderful practice, I must admit. There was a house physician, a house surgeon, and a resident surgeon. And that was all, for about 150, 200 beds. And I was the eye houseman, the ENT houseman, I did casualty every other night, and about a week after I arrived at Scunthorpe, the consultant physician, my boss, wrapped himself around a tree, and I never saw him again. And there was no registrar. So here I was, newly qualified, in charge of all the medical beds, and children. It was very wearing, I mean. But it was extremely good for me. I don’t know how good it was for the patient. I learned a lot.

Military Experience

HD: I wanted to join the RAF, but there was a lot of competition for that, and I had to fill out a form, and I said I spoke French, obviously. Born there. In fact I spoke French before… I didn’t speak English till I was eight. So I was sent to Singapore, soon as I joined the army.

Interviewer: Because you spoke French?

HD: I don’t know really. I should have said I spoke Malay, might have got to France.

Interviewer: So you went in the Royal Medical Corps, presumably, wasn’t it? Sent to Singapore… Can you tell use what happened there?

HD: As you know, it was a disaster. The guns all pointed the wrong way. Singapore was a fortress against a sea attack. Nobody had envisaged that an army would come down the mainland, the peninsula. So the Nips did what they liked, and they just walked down, and we arrived a month before the final armistice, so to speak. And I went upcountry for about a week, and then, came quickly back again, retreating fast. And on the 15th of February, 6 p.m., 1942, the war finished out there, and it was a wonderful relief. We were defeated, but the noise had been so awful, terrible, and there we were, prisoners of war.

HD: We moved up. The trip up to Siam was quite a horrific one. We were in rubber trucks, rather packed in, and the nice Malays, the good ones, were throwing pineapples at us. Well that’s all right, but when you’re traveling forty miles an hour, and a pineapple comes into the compartment, it produces an effect. And it took about two and a half, three days to get up there from Singapore. It was pretty hot. And we were sent to build a railway. And we were lucky, because we were some of the first to arrive. So we built the beginning of the railway, nearest what civilization there was. Whereas the last lot, the people who tried to stay behind, did stay behind until the very end, they went right through us, and they went right up to the top of the mountain, and they were decimated by disease; I think it was 60% mortality, something like that. But we built a bit, and then we moved on, built another bit, and so on.

Interviewer: So presumably you were again working as a medical officer, treating the people. Diptheria, cholera.

HD: That’s right. Well the excitement… the first thing I was put in charge of was the diptheria ward, where the only thing you could do was keep them still, make certain they didn’t sit up. And considering the places where they slept was covered with lice, it was not really easy to stay still.

Interviewer: Sorry, why did they have to stay still? I’m…

HD: Well, diptheria, sever diptheria, one of the things that kills you, is something to do with your heart. I’m not quite certain why it kills you suddenly. You can of course die slowly, which is terrible. We had one or two of those. The liver gets very large very rapidly. I imaging it’s a mixture of toxin and high venous pressure, but anyhow, very painful, and most distressing. But the other form of death is the person sits up, or does something sudden physically, boom, out. And I knew that much about diptheria, and the person I had taken over from had rather a few deaths, rather a lot of deaths from this, so I thought, “That’s one thing I can avoid.” And so we did that. And then when we moved, I was put in charge of the cholera. Cholera developed, and not so many recovered from cholera as recovered from diptheria. It was a horrific time, during the monsoon, of course, the river, corpses coming down, and we were put in an area on the other side of a ravine, some sort of isolation, and the slipperiness of it all was intense. People carrying these feces in this mud, trying to get to the pit, in the middle of the night.

Interviewer: Yes, horrendous. You were telling me something about how they were extracting plasma from people who had recovered from diptheria.

HD: Oh diptheria, yes. Well, I had practical experience with that myself, because I got a diptheric ulcer, which was extremely painful. And what we did, we bled people who recovered from diptheria, stirred their blood a bit to make it clot, so as to remove the red cells, and then gave about 50 mL of the plasma with all its antibodies. I must say it worked. I mean, on me, which was a very minor attack, within about an hour or two, the pain stopped, the redness around diminished, and it began to suppurate. So it was on its way. But for the severe cases, I don’t think it did much good.

Interviewer: You continued your studies on Wernicke’s, and…

HD: Well we got four more cases amongst the people upriver.

Interviewer: What happened then, in terms of the Japanese…

HD: Oh, well eventually the railway was built, and we all came down it. We hadn’t imagined that we were going to actually ride this thing, and many people remembered some of the things they’d done to sabotage the embankments. And then we had to ride this thing down. But we arrived safely at the other end.

HD: The army was extremely good to people who came back from POWs. They said, “Oh go away for a year, and you’d better just recover, convalescent.” So I went to Thomas’ and got a job in a course, sort of a registrar, and a course, and a membership. And I got my membership at the end of a year, then was found to have TB. So I spent another year in the army, and they said, “Where would you like to go?” and I said, “Thomas’.” They said, “All right. Off you go to Thomas’.” So I really had two years of convalescence, one without TB, and one with TB. Then I eventually went back to Thomas’ after having finished with my tuberculosis.

Interviewer: So when that had got better you then started working as a registrar, and on the medical unit there.

HD: As a registrar, yes. Well first I went to St. Heliers, and I set up the diabetic clinic there, seemed to me it was pretty… a bit disorganized, and I think it’s still going. And I was there about a year, and then I went to St. Thomas’ and joined the medical unit, which was at the Department of Medicine.

Work on Wernicke's Encephalopathy

HD: Until the end of that year, 1942, we were in Singapore, and I was working in a huge building called the Robert’s Building, which had 800 dysentery cases, and I looked after a ward of 80. I mean it was divided into 10 wards of 80 each, and eventually, I got dysentery myself, and we had a very good colonel, a field ambulance. When I recovered, he said, “What would you like to do?” So I said, “I would really like to find out why these people are dying, because they’re not dying of dysentery.” So he says, “All right. Off you go.”

The problem was they were going into coma, and there were three things. Retrospectively, it’s easy. There was encephalitis lethargica, one or two cases. There was a syndrome, which is now known due to riboflavin deficiency, with optic atrophy, and spastic legs, and a very raw tongue. And then there was Wernicke’s encephalopathy, which, I must say, it wasn’t I who recognized it, it was a pathologist who recognized it at post mortem. It’s very, very classical punctate hemorrhages in mammillary bodies and parts adjacent. And we were very lucky; we had a quarterly journal of medicine, which had an account… I can’t remember if it was Wernicke’s encephalopathy or it was B1 deficiency, but anyhow, Wernicke’s encephalopathy came into it, and so it was clearly a B1 deficiency, and there were B1 deficiencies occurring in the dysentery ward in these patients, beriberi of various kinds. So we had a box of one hundred ampules of B1, 5 mg, I think, or it might have been 1 mg, anyhow, very powerful stuff in those days, and that was what we had to treat this incidence of Wernicke’s. And I spent my time going around asking all the people in charge of these wards, if there were any such cases they were worried about. And I was therefore able to follow the onset of Wernicke’s, and then stop it with treatment.

Interviewer: Of course at that time, presumably, the diet was appalling, so that is why you got the vitamin deficiencies, and then you got the dysentery on top, which precipitated the crisis. And you recorded all this.

HD: Yes, I made a lot of notes, a great package, which I then took on with me when we went to Siam later.

Interviewer: But what sort of training in medical research had you had up till then. I mean why do you think you were sort of doing this. I mean there can’t be very many others.

HD: I’ve always… I mean right from the beginning, before I was qualified, I always thought of being in medicine as being in research. It was a sort of intuitive feeling, that that’s what you did, if you were lucky enough, when you could, and I’ve always wanted to know ‘why’, ‘how’, and here was a very good example.

HD: Over a period of time, the war, by now, was improving, and the Nips realized that they were losing, and they began to try to prevent any form of evidence of how they treated their prisoners. And the best way to do that was to search them when they were moved, because back then, you had nowhere to hide. And I wanted to hang on to all these case notes about Wernicke’s, because I realized they were precious, and nobody had every studied Wernicke’s before. Nobody had ever established that Wernicke’s encephalopathy was actually due to B1 deficiency till that time, because Wernicke’s up till then was alcohol, not diet ridden. So I got together with a few friends, and we put our notes in a four gallon tin, which was soldered, and then wrapped a cape. And then dug a hole, about two or three feet deep in a grave, where somebody had been buried eight feet deep, and we put our notes there. And we took bearings of various trees, because we didn’t know when we’d get back, and we didn’t know who’d be there when the war was over. As a matter of fact, it was only three months later, and one of the three was in the camp, and he rescued it. It was just about time. The cape had gone, and there were holes appearing in the solder, in the tin, but anyhow they were safe and I brought it back.

Interviewer: Subsequently you published some…

HD: I published a paper on that, yes, “Fifty-two cases of Wernicke’s encephalopathy.”

Beginnings of Interest in the Kidney

HD: I was really forced into the kidney. I mean I joined departments because I wanted to do research, I did some research with Maureen Young, who is in Department of Physiology, and did research on polycythemia vera. And we had a lovely hypothesis because we’d discovered that the blood of polycythemics used oxygen at a very fast rate. In fact we left some blood on the bench. We went for lunch; when we came back it was dark blue, and we didn’t think that was normal blood. Normal blood didn’t go dark blue. So from then on we studied it.

The one thing that came out of it: we established that people with polycythemia vera had a low oxygen tension in their arterial blood, and that has been shown since and is solid. But before we got that far, we had a lovely hypothesis that it was the white cells of polycythemic people, who consumed a very high rate of oxygen, high amount of oxygen, and therefore in the bone marrow, they would lower the oxygen tension, and that was why there were a lot of red cells. Well it turned out there were just too many white cells, which was the leukocytosis of polycythemia.

Then one day, I was walking to outpatients, I was a bit late in the morning, and Sharpey Schafer, came alongside of me, who was my professor, and he said, “I wonder if you could go and help George Prunty.” George Prunty was professor of chemical pathology, and had just worked out the technique for doing pH and inulin. He says he’s done this, but he doesn’t know what to do with it. So I said, “I don’t want to go into the kidney, no, it’s much too mathematical.” I had this thing; I don’t like mathematics. He said, “Well just go and talk to him. Just have a chat.” So much against my will, I went upstairs to see Prunty, and in fact the person who had done it in his department was Dick Sweeney, who was an extremely nice bloke, who’d been a POW, also the Japanese, but I didn’t know him then. He was in Japan, saw the atom bomb, in fact, go off. Charming bloke. And he taught me how to do pH, and how to do inulin. I thought, “All right, well, here I am, we might as well do pH and inulin clearance in patients with polycythemica, which I had. I had a whole group of them. And we went on from there.”

Interest in Sodium

HD: The sodium came about because we got interested in emotional diuresis. In fact I called it “compulsive”… What did we call it? We had a name for it, published the name. Well I forget what we called the paper, but anyhow, there was one particular patient, who had hypertension, and we put a catheter into her bladder, and she poured salt and water out. Well everybody said she’d had a drink. So we kept her in, we dehydrated her, she lost weight, plasma osmolarity rose. Put a catheter in; poured out salt and water. And the GFR as measured by creatinine excretion didn’t change. So this was fascinating; this was an unknown phenomenon. How was she doing this? And really that is what led to the experiments in dogs. Showing that there were other influences on sodium excretion, other than GFR, or aldosterone.

Interviewer: Do you want to say a little bit about those experiments, and how…

HD: Yes, we… It started over coffee, with Ivor Mills. Ivor Mills had come back from the NIH, where he had been playing with aldosterone. In fact he came back with some aldosterone, very precious at that time. We were having coffee, and I don’t know how the conversation led to it, but I remember saying to him, “I’m sure we can make a person have a sodium diuresis right through your aldosterone. I don’t think it’s very important.” He was shocked. I said, “All right, we’ll set up an experiment.” And I wanted to do this, really. I wanted to show, because of this emotional diuresis, I wanted to show that you could lower the GFR, and still get a rise in sodium excretion. And it was even better with Ivor Mills’ aldosterone, because we gave aldosterone, in large doses before we started. So we did. We got a dog, and put a balloon in the upper aorta, and blew the balloon up. GFR dropped. We then started saline. Saline went up. We went in, and the sodium excretion went up, the GFR went down. And then of course there was all the problems that it might be dilution of the blood by the saline that was causing the diuresis, and not something else, so we did other experiments cross-circulation experiments, that showed that was not so. So we put up the hypothesis that there was a natiuretic substance in the blood, causing the sodium diuresis. And we got a lot of stick over the years about that.

Interviewer: Why do you think that was?

HD: Oh for one thing, nobody would repeat the experiment for at least two years.

Interviewer: It was a pretty clear-cut experiment, wasn’t it?

HD: Of course, but clear-cut results, complex in setting it up, so on. And it wasn’t so much that they disagreed with the results, they disagreed with the idea that there might be a circulating substance, and then, because of that, got rid of the results too. And for years we were ribbed all the time, I mean, “Where’s the white powder, Hugh?” at various meetings. And that search went on for a long time, and we looked for it. And over the years, it became a search for a sodium-potassium ATPase inhibitor, and it was obvious that you could get extracts, the concentration of which went up and down with volume expansion, which did inhibit sodium-potassium ATPase. And suddenly, de Bold came out with a natriuretic hormone, which was not a sodium-potassium ATPase inhibitor. So we were right, there was a natriuretic substance with volume expansion, but the stuff we were looking for, sodium-potassium ATPase inhibitor, was not it. Atrial natriuretic peptide was not the substance we were looking for. So we continued to search for a sodium-postassium ATPase inhibitor, and, again, we didn’t get that. As you know, Hamlyn found that eventually.

Work on Renal Biopsy

HD: I was the first to do renal biopsies in England. I read this paper in Kidney International, by Brun and Iverson, who were the first to do it in the world, to do biopsies, and we started. And there was a very nice pathologist, who’s name I can’t… I can never remember names anymore, but anyhow, I asked him if he would look at these biopsies. And he says, “Yes, if you’ll look at them with me, because it’s going to be very strange. It’s going to be quite new.” So right from the beginning, I looked at the biopsies with him, and I learned a lot of histology, and this led…. Well, we did biopsies in various conditions, and that was quite interesting, but I think the most interesting thing, the most original paper we published was a paper showing that the histological lesion, the severity of the histological lesions in glomerulonephritis, were not related to the GFR. They were much more related to the interstitial and tubular changes. Well of course, as a physician, looking after the patients, knowing their GFR, it was very obvious. If you were a pathologist, you didn’t know what the GFR was. If you were a clinician, you didn’t really look at the biopsy very carefully, so that’s what came from that. And that has stuck, of course. I mean now that’s developed as quite a thing, and all that has been confirmed several times. And people are now working, as you know, on why that is.

Interviewer: That’s an interesting, another interesting observation. Why did you look at the biopsy when everyone was concentrating on the glomerulus? Why did you look at the tubules and interstitial…

HD: I mean I think one of the obvious examples of this is amyloid. You had these great chunks in the glomeruli that looked like bits of pink, not much there, and yet the GFR in some cases, wasn’t all that bad. I think that was what first put me on to it, and then I began to look at others. And there was a discrepancy.

Work on Compulsive Water Drinking

HD: We tried our best to make a diagnosis. It’s very difficult to make a diagnosis, and this led to other experiments. We established, because of the compulsory water drinkers, we established the fact that drinking a lot of water diminished your ability to concentrate the urine. And that was confirmed later by great friends of mine in America, and this obviously makes it very difficult to use a dehydration test to distinguish between diabetes insipidus and compulsory water drinking, whatever you like to call it, because the urine osmolality is not going to rise very high. And Erasmus Barlow and I, who was a psychiatrist, a great friend, and published a paper in a quarterly journal on compulsory water drinking, and they were fascinating cases, I must admit, the things they got up to. They drink up to ten, fifteen litres a day, for no reason, no reason at all. We tried to treat them. We put them to sleep, for several days, let the sleep lighten occasionally, clean their teeth, and give them a scrub, then put them back to bed and sleep. The only thing about that, it cured them all right, but they developed some other, abnormal function. I mean their arm, paralysis of an arm, or something. It’s a self-curing disease, I think, really. You don’t hear of elderly people with compulsive water drinking, so you just sort of hang on, hang in there, and eventually it goes.

Work on Urinary Infections

HD: Now I got involved in urinary infections. Particularly, mainly through biopsies. We biopsied acute pyelonephriits. Horrific sight, bits of necrosis all over the place. I’d never, I don’t think you ever see that in a person. People who died, in the old days of pyelonephritis – the kidney was destroyed. But an attack of pyelonephritis, which is controlled by antibiotics, you don’t think of as multiple areas of necrosis in the kidney. So that, that really woke me to the dangers of ascending infection, which I then pursued when I got into Charing Cross.

Interviewer: And what do you feel about that now? I mean what has happened?

HD: People know about giving prophylactic antibiotics now, and they treat it quickly. The real problem is urine cultures, and I don’t know how well general practitioners do urine cultures no, but I imagine, eventually, propaganda from everybody, that you ought to culture the urine in urine infections. That doesn’t stop you from treating right away, but you ought to know what you’re treating.

Work on Fainting

HD: We also did a lot of blood flows, and glomerular filtration rates, in fainting subjects, and one day, I was the subject, and it consisted of being on a tilting table, and being bled, and of course, you’d bleed into your legs, because you were standing up. You’re not standing, you’re supported by a seat, and I remember, as I started to faint, I said something about, “I feel sick.” And then I vomited, and there was a sister, holding the catheter in my bladder, just under me, and she stuck to her post! She held the catheter! And I remember the last thing was that one could hear. I could still hear. I’d lost sight, but I could still hear. This all happened over a few seconds, but I could still hear, and then I woke up, having recovered.

Writing the First Book on the Kidney

HD: That was sort of Schafer-stimulated, though he didn’t know it. We were having coffee, he was a great one for coffee at ten o’clock, and I suddenly discovered – I was senior lecturer by that time – he told me that the position didn’t have tenure. Well I said, “Everybody else does.” He said, “But no, not at Thomas’.” There I’d been sitting relatively comfortably, thinking the future was not too bad, and now, there was an end to senior lectureship. I might be kicked out any moment. So I thought, “Well, I’d better do something to get the name better known, and I’ll write a book about the kidney, because there was no book about the kidney, at all.” There was Homer Smith’s book, and that was about physiology of the kidney and mainly about PAH and inulin clearance, and there was another book about hypertension, very, very heavy going, and a bit about the kidney in there, but not very interesting. And there was nothing about glomerulonephritis, pyelonephritis, nephrotic syndrome, renal failure, and all this, and renal function, biopsies. So not knowing very much about the kidney, I must admit, I wrote a book about it. Which is quite good, because it earned me quite a bit of money, certainly made the name better known, and I learned about the kidney.

Work as a Professor at Charing Cross

HD: The research that we did, was, we set up, as I said, an MRC-funded unit for renal infections. We started a tiny little metabolic unit. This is Fulham hospital, which is probably one of the oldest London LCC hospitals, but we had a little two-bedroom wards, and we turned it into a metabolic ward, which was very useful, and we studied sodium and calcium. What else did we do? And continued the biopsies, and then of course we continued the work on Sodium on dogs, and there was no animal house, this is Fulham hospital, the old Fulham hospital. So I went to the welcome and asked them for an animal house, and they gave me one in six weeks. Never forgotten it. Absolutely marvelous, they didn’t quibble, or anything. So we set up a very rudimentary animal house, but still, it worked, and we continued to do experiments. And I think we were the first to show that the plasma from volume expanded animals – blood volume expanded animals – inhibited sodium transport in fragmented tubular cells, and it also interfered with potassium transport, so that the concentration of sodium went up, and the concentration of potassium went down.

Interviewer: And you went on pursuing, trying to isolate this substance which…

HD: And we went on. Yes, I’ve always been trying to isolate something, but never getting there.

Development of the ISN and Dialysis

HD: That’s the same year. The year that I moved to Charing Cross, 1960, was the first meeting in Switzerland… no France, Evian. In Evian. And there I met people I would be seeing for a long time, subsequently: Hamburger, whom I didn’t know. In fact, I think that’s why I became president of the Society later. Hamburger was a rather powerful man in the society, and he rather liked me, because I spoke French. I think he pushed. And that’s another episode later on.

HD: At that first meeting in 1960, I met Scribner. And he was a little man who sat cross-legged in this armchair, and told us about the first three cases that he had started on what I call maintenance hemodialysis. And I must admit, I thought it was rather like watching a dog walk about on its hind legs. It didn’t seem to have any future, and I didn’t think any more about it. And the next meeting was in Prague, and I couldn’t go because of illness in the family, but the registrar went, Pete Little, and he came back and he said, “Now there are six cases, and the first three are still going.” Something like that. So I thought, “Right. It works.” So I decided we have to have it too. So I managed to get some money, and sent a nurse, a surgeon, and a physician off to Seattle to learn what to do, because I’ve always believed, “Try and be first in everything, and if you can’t be first, be second. Don’t try and be first. Don’t try and start as if nobody had done it before, because you’ll just make the same mistakes.” And we set it up. I think we heard about this in September, August-September, of1963, and we had our first patient on in I think April ’64.

Interviewer: And subsequently became one of the biggest dialysis units in the UK, didn’t it, at least for hemodialysis?

HD: Yes, well we were the first to have a maintenance hemodialysis unit in this country.  Shaldon, of course, was in there, and was dialysing patients, I guess, on that sort of basis, before us, but it was done sort of subrosa. Sheila Sherlock, who was his professor, he got into serious trouble with, because he was spending too much money, and, in fact, we had to inherit one or two of his patients. So it was the first sort of, properly set up…

Interviewer: And then I think you were involved in developing dialysis in the UK with the Ministry…

HD: Yes, I was asked to go to the Ministry of Health, to discuss this. And we had a long talk, and as a result, I was made chairman of a committee, that set up certain principles, rules, ideas; for instance, that a unit of dialysis patients should be ten, and for that you needed so many nurses, or so many doctors, technicians and so on, and if you had twenty then you sort of doubled up, not quite, and what was needed. And in fact I think, I can’t remember now, but I think we set up the first sixteen, twenty dialyses. I mean they came through us, through our auspices. And then one day, when we set up the numbers that we had been asked to set up, I said, “Well now.” We got the committee together, and we’ve got to think about the future. We were immediately dismissed. The committee was told it was no longer needed, and, as I could see, it was an attempt to stop what was obviously going to be a great drain on finances.