ISN VIDEO LEGACY PROJECT

DR. PRISCILLA KINCAID-SMITH
INTERVIEWED BY TIM MATHEW
MELBOURNE, AUSTRALIA 1994


TM: Iíd like to welcome you to an opportunity to talk with Priscilla Kincaid-Smith. This opportunity has been created by the International Society of Nephrology who have expressed a wish to create on tape a permanent records of Priscilla and her contributions and achievements in Nephrology over the years. Priscilla, a very warm welcome

Iíd like to start by taking you back to your, what you might call formative years. You were born and educated in South Africa, went through University there, and then after graduating went to London. In South Africa, what do you recall of those years? How did they influence you in your future career.

PKS: Well Tim, I have to say initially that I had no intention, when I left school, of doing medicine. It sort of happened. My major interest in those days was in sport - in swimming and hockey and I wanted to go to University to do a physical education course. But indeed I was too young to do that. I ended up doing a medical science degree as a preparation for that and once I got in touch with medicine, I was hooked on it. So, I then continued with it.

I guess I really loved growing up in South Africa and it has always been one of my favorite countries. Iím delighted at the way things seem to be working out there for everybody. I was rather politically involved in those days against the government. I suppose that was one of the highlights of my student career apart from my real interest in medicine.

I spent two years in Johannesburg before I went to London and worked in Baragwanath Hospital which is the 2000 bed hospital across the road from Soweto and of course everybody knows about Soweto these days. I really loved that. Perhaps it developed some of my enthusiasm for treating patients and making them better. It was terribly hard work. We worked 7 days a week and 4 nights a week but we really felt we were curing people. We had wards full of treatable conditions like malaria, typhoid and amebic hepatitis. We worked very hard to diagnose and then to treat them

TM: Is this back in the 1950s?

PKS: Some of the 1950s, yes.

TM: Antibiotics just coming ?

PKS: Oh, we had a few - penicillin of course. Streptomycin only appeared just prior to my time there, when tuberculosis was a very important condition. We saw thing like plague, for example and lots of smallpox, etc. I really loved those years and I think my label as a therapeutic enthusiast in nephrology probably dates back to those times when I loved making people better.

TM: Do you remember when it was first suggested or when you first became conscious that you might go to Hammersmith?

PKS: I went to Hammersmith quite deliberately to do pathology because Iíd done the science degree majoring in histology and had an interest in pathology and had thought of a career in pathology. So I registered for the pathology course at Hammersmith, and went there to do pathology. But, in fact, after a couple years in pathology there, which I very much enjoyed, I decided that I really belonged back in the wards. So, I went back to medicine and trained, not in nephrology because there was no such thing. I trained in cardiology and of course developed a major interest in hypertension and the relationship between kidney and hypertension.

TM: This may sound like a naive question in a nephrology context, but why was there no nephrology in those days?

PKS: The only treatment for kidneys was surgical treatment and there were urologists but there were no nephrologists. I had the great opportunity of working with some of the foremost renal pathologists, particularly Dr. Doniac? who was at Hammersmith Hospital. I saw in those days, Dr. Heptinstall from time to time. He worked at St. Maryís Hospital. I also worked with Malcolm Milne, who was a joint physician on the unit. He was probably one of Englandís first nephrologists. But there was no term "nephrology", there was no training in nephrology prior to 1960.

TM: Iíd just like to stay on that period for a little bit and Austin Doyle talks about the fact that for a time you were a bridge between pathology and medicine. Did you have a dual appointment?

PKS: Yes I did. When I worked in pathology, I liked medicine so much that I managed to persuade Professor McMichael that I should go on ward rounds so that right through my time in pathology there, I regularly went to the wards and, as you say, was a bridge doing the post mortems, which in those days were tended every day by all the top people like McMichael, Sheila Sherlock and so on and were really a highlight of Hammersmith which linked very much the patientís history with pathology and really did then, and still like pathology but my first love is for treating patients.

TM: This morning when I came to your office, there was the microscope and the slides and obviously youíd been at work still reporting pathology. I mean if thereís one thread to what happened from that point forward it is this joining together of pathology and medicine. Certainly thatís the dominant impression that I gained working with you for many years. So that had its origins at that time. Bob Muerhke was around was he?

PKS: Bob Muerhke came when I went back to the medical side and was working with Professor McMichael as a registrar. Bob Muerhke came over and taught us to do a renal biopsy which was an important step in my career. That was the first time we were able to look at living pathology and thatís whatís been so exciting about nephrology - that ability to monitor whatís happening on an ongoing basis - a sort of living pathology. I think thatís made an enormous contribution to nephrology and of course has been one of my major interests.

TM: And of course fate - whatever - had you in the position where you had that interest and the technique came right at the pivotal time. You of course brought that back to Melbourne. It would have been, I think, the introduction of Australia to closed renal biopsy.

PKS: That had been a few done previously. There had been a very small series done at Walker-Eliza Hall and unfortunately had a very bad record in terms of complications. One of the major difficulties in Melbourne in persuading people that renal biopsies were useful was to overcome what was always said about them and I think urologists have never liked renal biopsy much and their story was that anybody who has a renal biopsy has a pint of bleeding. So it was really difficult to persuade people in Melbourne that renal biopsy was useful and could be a perfectly safe technique if it was carefully done.

TM: Iíd like to trace the origins of another theme in a sense which is the interest in the vascular part of the kidney. It is true that you worked in cardiology to start with and in fact wrote several paper with Barlow. Do you want to tell us about that?

PKS: Well I did formal cardiology training and my major interest was phono cardiography at that time and John Barlow and I published a number of papers on phonocardiography. We worked very close together. He of course is a South African whom I knew well before I came to London.

TM: Mitral lesions now have got his name and not yours!

PKS: Oh no. It was certainly his work. We were interested in it. We were recording those prolonged late systolic murmurs which have been called benign by Willie Evans before him at that time. But he certainly was the one who followed it through and discovered what it was all about.

TM: Is it true to say that the first kidney paper, the first paper focusing really on the kidney, had to do with hypertension and infection?

PKS: It was a paper on vascular lesions in chronic pyelonephritis, as we then called it, which is now called reflux nephropathy.

TM: Who stirred your interest in that?

PKS: Well I did that work while I was in pathology at Hammersmith and I just became particularly interested in the relationship between hypertension and lesions in the kidney and went through all the kidneys in the 5000 odd autopsies that had been done at Hammersmith was particularly interested in the hypertensive ones and particularly in malignant hypertension and there was a small group of cases which had had malignant hypertension associated with reflux nephropathy in which I showed a relationship between, what I called an ischemic lesion, which I thought was due to the vascular lesions, and which again I thought might be due to the inflammation of the pyelonephritis. Now, exactly what the origin of that is Iím not sure. I am sure there is an association between those lesions and severe hypertension. That was my first interest in the kidney I guess - through malignant hypertension.

TM: Of course, that work is recognized as being one of the seminal papers in that area and the essential message, I think, has stood the test of time.

Itís true, one of my impressions of you which is echoed in Stewart Cameronís writings in the Festschrift document which was in KI a couple of years ago is, and I want to quote this, "you have an uncanny knack for picking out just the question which needed answering and equally an uncanny knack in obtaining, what in time, turned out to be the correct answer, despite a slender database on which often to base that opinion." Putting that another way round, I think that shows you have always had or tended to have remarkable instincts for honing in on the right question and then honing in on the right answer. Is that your perception? Would you agree with that observation?

PKS: I think itís quite fair to say that often the answer is based on relatively little data but then because it is difficult to obtain data in patients on biopsies, or at least it was in those days - I mean one of the areas which I think was possibly one of my most important contributions was the work on the involvement of platelets in coagulation in glomerular and vascular lesions in particular in work we did together at the Royal Melbourne Hospital on the progression of lesions in transplants and how they develop. It was based on relatively little data. It was based on perhaps 100 odd biopsies in transplant patients. But that was 100 more than anyone else had because in those days people frowned on doing biopsies in transplant. Of course it was difficult to prove that the fact that you saw endothelial damage, then you saw platelet adhesion, then you saw fibrin deposition, then you saw proliferation of myoepithelial cells, it was difficult to prove that that was the way in which the vascular lesions developed. But it was pretty easy on the observations to make that assumption and I always feel a little bit upset that I wrote that in the Lancet in 1967 but it is never really acknowledged that in fact that progression of things which I suggested at that time might be why atheroma developed was recognized outside the renal literature but yes, there was a small amount of data and Ross and Hanset in the NEJM in about 1972 put forward that proposition and discovered the platelet factor which was all important.

TM: Of course, itís pertinent to reflect on the enormous change which there has been in science and medicine in your time. Itís true that the very first ever published randomized controlled trial was in 1952 and you, in the late 50s and 60s, would have been in an environment in which progress was made, not by big controlled experiments in humans, but rather by shrewd observation. Nevertheless, it is, from my personal point of view, an accurate observation and itís one Iíd like to leave the audience with that your instincts have served you well and Iím not aware of any area in therapy where you have latched onto a path or suggested treatment that has not proved in time to have a genuine basis to it and a success to it which is remarkable I think.

The other thing that Stewart said in that article was that you were a "therapeutic optimist" and he was particularly impressed with your propensity for going down a "polypharmacy route" which meant combining various agents together with different modes of action, all aimed at treating the same disease. An approach which was not widely regarded at that time. Do you see it that way and what were the origins of that therapeutic optimism?

PKS: Yes, well I sometimes think back at Baragwanath with sort of therapeutic enthusiasm. I mean I hate not to be able to treat a patient and, as you know of course, although dialysis and transplantation are important treatments, my major emphasis has always been on preventing the need for dialysis and transplantation. So, thereís is nothing I like more, even still today, than to see somebody with, for example, glomerulonephritis, to make the diagnosis and to give them some effective treatment. It was really my interest in pathology that made me think we should be combining treatments and it seemed obvious to me that in looking at mesangial capillary glomerulonephritis, where platelets were clearly involved, and there was a lot of evidence for that, apart from my observational data. There was clearly an immunological process, where fibrin deposition was also involved, that one should not only be treating the immunological disease with cyclophosphamide but one should trying to do something about the platelet deposition and the fibrin. I think as time goes on and we get better platelet drugs, I think that will again come back to be a more important therapeutic methodology.

TM: Thatís jumping ahead a bit. I would like to take you back to London and the fact that you met Ken, your husband, there. Was it ever considered that you might take him back to South Africa rather than him take you back to Melbourne?

PKS: No, those things didnít happen in those days. It wasnít considered, it wasnít really discussed. I was of course very happy indeed to come to Australia.

TM: How did you view Melbourne from London?

PKS: I thought it was a lovely warm place with beaches and sunshine and of course it isnít at all. Itís cold most of the time. But my life in Melbourne has been very happy apart from the initial period when I found that having been offered a permanent job at Hammersmith just before I left, nobody wanted me and I was unemployable as a married woman, which in those days, if you got married as a woman, you lost your job in any sort of university or public service and I just found that, you know, I was virtually unwanted. I worked for years as an honorary physician at the Queen Victoria Hospital and did research from there and as a research assistant in the University. But nobody would really employ me in the ordinary sense, as a married woman, particularly as I had young children.

TM: I want to come back later and talk about women in medicine and your thoughts about that. Just on that specific issue of breaking into the Melbourne scene, what was it that eventually allowed you to enter Melbourne medicine?

PKS: I think the most important was that I had continued to work through those work when I had young children. I worked half-time for 7 years and I did continued to do studies. I did a big bacteria control trial and a number of other studies at the Queen Victoria Hospital and I owe a real debt of gratitude to the Queen Victoria Hospital for facilitating that work and I think it was the fact that I had a number of good publications from Hammersmith before I came to Australia and that I demonstrated that in spite of being a married woman with young children, I could continued to publish papers in journals like the Lancet. I am sure that that was why when finally women were liberated in Australia and allowed to work, I got a position at the Royal Melbourne Hospital as a first assistant in medicine and as, what was then called, physician in charge of the Department of Nephrology. I think there was certainly opposition to that at that time from certain people but I think it was my academic record that made it possible.

TM: I think that some of the audience would not necessarily appreciate that that was the time when you began to have children. You had two pregnancies with twins and a single one. I have memories of you biopysing a week or so before you had the twins. So you did work through pregnancy and returned quite soon after.

As you say, you persistence to continue perhaps singled you out from the others. That was the time in the early 1960s when you brought biopsy back with you. You set up your own biopsy service did you at Melbourne?

PKS: Well, I was at the Alfred? Hospital initially and one of the difficulties was to get biopsies processed in the way to which Iíd been accustomed, with multiple sections and multiple stains, which was not something that was done anywhere in Australia at that time. Indeed, I ended up setting it up within the University Department of Medicine because I couldnít really get the biopsies processed by the Pathology Department and I did the biopsies myself. I taught a couple of other people to do biopsies but I used to go to all the hospitals in Melbourne and do a biopsy here and there and then we got them processed within the University Department of Medicine initially and then subsequently the Royal Melbourne Hospital. But of course that led to the tradition, which continued from then until I left the Royal Melbourne Hospital, of doing the biopsy, preparation and interpretation within the Department of Nephrology and jointly with the Department of Medicine at the University of Melbourne. This of course has led to comments from various places but I think there is some truth in the fact that if you really want something done well, youíve sometimes got to make sure you do it yourself. I think we did set a precedent in terms of technology which is extremely important - doing all those special stains, doing immunofluorescence, doing electron microscopy which is now routinely done by everybody.

TM: Yes and you still have a biopsy service going in your current situation in, what some might call semi-retirement, but really just another phase of your career.

They of course were times when contributions from biopsy was just being realized. The first symposium, as I understand it, for pulling together collective renal biopsy experience, was in about 1960-61. Over the next ten years, it would be fair to say, that you contributed greatly to the aggregate of knowledge which led on eventually to a meeting in Melbourne in 1972 focusing on glomerulonephritis. Iíd like to come back to that shortly but they were years when therapy consisted of ... well you tell me? What were the therapeutic options for someone with nephritis?

PKS: Nothing very much really. About the only form of nephritis that was being regularly treated was minimal lesion nephrotic syndrome with prednisone and that treatment of course had been established a decade before. I became interested in cyclophosphamide, having seen some of the benefits in relapsing growth of the minimal lesion nephrotic syndrome, having seen the apparent non-toxicity of the drug, and having been impressed with some uncontrolled studies in terms of its leading to a disappearance of the clinical manifestations of glomerulonephritis and indeed demonstrated on biopsy that the lesions could disappear. I still think that cyclophosphamide is a very important drug in the treatment of glomerulonephritis. And I think itís true that we discovered some of the important side effects of cyclophosphamide and, as you know, my husband, Ken Fairley, was the one who first documented the sterility problems, both in men and women, from cyclophosphamide. But we were therapeutically destitute and there was no enthusiasm for therapy and I must say that I still think we are an extremely conservative group as nephrologists in terms of treatment. I think there have been very good studies demonstrating that we can treat things like membranous glomerulonephritis and yet there is an attitude of pessimism and we really shouldnít treat it because itís such a benign disease anyway, ignoring the enormous benefits in the individual patients and indeed in the work as a whole.

TM: 9; This is a reasonable time to reflect on that issue. It is true, and I suspect youíd agree, intensely disappointing in 1994, to look back on the last 30 or 40 years. You were using steroids and cyclophosphamide then and there has not been the progress in the choice of agents and in many ways there is certainly a lack of acceptance of therapy in many types of nephritis, despite huge amounts of effort and research and your own contributions. Do you feel disappointed?

PKS: 9; I feel very disappointed at the attitude. I mean Iím delighted that Jim Donadio and his colleagues have recently published the controlled trial demonstrating benefit in IgA glomerulonephritis of fish oil. I always expected it to work and I think it works probably mainly through its effect on platelets. But we did a control trial and it didnít demonstrate benefit, probably because we didnít have enough patients but if you talk to people generally they say there is no treatment for mesangial IgA nephritis. Well, thatís absolutely incorrect. There are several studies showing that you can get rid of the major risk factors of IgA glomerulonephritis with a variety of drugs. For example, the high red cell count, which we found to be the strongest predictor of progression if it is continuing. You can reduce the red cell count with all sorts of thing - with steroids, with tetracycline as we showed in the control trial, with phenytoin as again showed in a control trial, a host of other things. But many nephrologists say, and I see it in letters all the time, "thereís no treatment for this condition." I guess now everybody will be very enthusiastic that fish oil that we saw for that number of years, that thatís one of the treatments. But itís this attitude that nothing can be done.

TM: 9; Your optimism is coming across and Iím pleased to see that because that it one of your main contributions to my own philosophy and I share that fundamental view. On the other hand, we are now both working in an environment where, in my own small role in drug approvals, one is thrust repeatedly into a situation where you canít market or advertise anything unless youíve got large numbers of patients in properly controlled trials and the outcome markers identified and the whole rigmarole gone through. You would agree that the therapies youíve mentioned havenít yet survived that rigorous a scientific assessment for a variety of reasons. That provides a sort of conundrum of sort doesnít it?

PKS: 9; It depends on what you mean by that being proven or not being proven. Thereís good scientific data that you can reduce the red cell count with those agents. Now what youíre saying is, "who knows if that does any good." And thatís true. it seems reasonable to me that if you know people with IgA disease who got a urinary red cell count of 500,000-800,00 or a million always progress and those with 10,000 or 20,000 never progress. It seems reasonable that reducing the red cell count must be good. But youíll never prove in a big control trial unless you do it over 20 years and nobody lives long enough for that.

TM: And I mean itís not unique to nephrology. Surrogate markers and the difficulty of long term trials abound in many other conditions.

PKS: Iíd like if I may, in that context, to come back to membranous glomerulonephritis because thatís a common form of nephritis where again people are incredibly pessimistic and keep saying that you shouldnít treat it because its benign anywhere. As you know the Australian control trial proved unequivocally in the paper that finally did get published in the Asian Pacific Society of Nephrology Report of a huge effort, that showed clear-cut benefit in terms of reduction of urinary protein, increase in serum albumin and change in creatinine clearance and yet that trial got buried. Itís never quoted and people almost imply that cyclophosphamide isnít of benefit.

Take Ponticelliís work that has been very well published in the NEJM using chlorambusil and methyl predisone. Excellent data, long term follow-up. Excellent data that the treated group did much better than the untreated group on follow-up in terms of mortality and morbidity but in the same journal you have an editorial saying that one canít treat membranous nephritis, effectively. I think Ed Lewis was the person who wrote that. But there is this incredible pessimism in spite of trials.

TM: Do you want to, at this point, reflect about America, because you sent me to America for three years with George Schreiner which was a most constructive and wonderful time for me. It was only after I came back to Melbourne and work with yourself that I realized the huge dominance at that time of the physiologists on the American scene, with micropuncture and tubular function dominating the meetings and the research activity and I came home to find that over in the other world how a number of things were going on which were more related to the clinical scene. It is my perception that America is just coming out of that era in the last five or more years and there are now some therapeutic enthusiasts. Do you agree with that observations and do you feel a lot more optimistic about the American contribution to therapy.

PKS: Iíve always admired their science and their physiologists were superb scientists but they did have a grip on nephrology in America that I think held back clinical nephrology. They were not interested in clinical nephrology. Their research was unrelated to it and it has been of very little value in terms of treating patients. I overheard a remark between the President of the International Society of Nephrology and one of Americaís top physiologists. After Iíd presented a paper on our data on transplants and platelets and fibrin and where the vascular lesions developed, saying "whatís all this nonsense about platelets and what theyíve got to do with .anything?" I mean that was the attitude and I think, as you say, they are now focusing more on clinical things and on the need to treat patients and, you know, the fact that dialysis and transplantation are not as wonderful as weíd like them to be and if we can treat people before we get there, thatís the way to go. I think they have changed and I think there is much more emphasis now on sort of things that interest me - the things you see looking down the microscope. Things like in vitro hybridization and immunological things, observing whatí s actually happening in the kidney and trying to do something about them.

TM: Focusing on one of these difficult issues which is the physicianís right and ability to try medicines which are not proven and where the particular use is not approved by the authorities, you hold high office in this country at this time in several institutions. Do you have any feelings about that at this time? Are you supportive of what you and I did back in the 60s which was to use drugs for new purposes, and if you are supportive of that, what riders would you put on it?

PKS: Well, weíll never make any advance if weíre not prepared to do it. I mean, weíll never get anywhere unless weíre prepared to bridge that gap between animals and man and somebodyís got to do it. Iím currently very interested in doing a trial in this country on a new drug which have been shown to be effective in animals in polycystic disease. And Iím having difficulty in getting any enthusiasm from anywhere. As you know, the regulatory authorities say itís not an approved use. The company see it as "letís walk more slowly". Iíve never really belonged in that category. I think unless those trials are done - Iím an absolute supporter of controlled trials, in spite of their difficulties - but weíve got to them. We got to be prepared to do them, we got to talked to the patients concerned, explain all the risks. But I certainly will proceed the study if I can get access to the drug and Iím sure 100% of my patients with that condition will participate and perhaps that reflects my attitude but they are all very keen to have something done.

TM: Itís true. I think in the Australian sphere we still have a population who listen to their physicians and are influenced by them.

PKS: Yes, they want to know all the information. I think we try very hard to give them the information and to be honest about it. Iím still beating my head up against a government brick wall as hard as I can to try and push it down.

TM: Briefly, to two therapeutic areas in the 60s, fluid management and hypertension and Iíd like to just take you back to those times and tell us about what options there were and what the practical facts were about those.

PKS: Well obviously both areas have been very important in controlling patientsí renal disease, particularly prior to dialysis.

Letís take the fluid one initially because thatís the easiest one to deal with. The drug frusemide became available at stage and we were probably, again, one of the first units to recognize that you needed to use really large doses to be effective in patients who had advanced impaired renal function. As you know, we kept patients alive, who would normally have been on dialysis for years. We kept them alive off dialysis with the use of, what we used to call the Giovanetti? diet, which we modified and with the use of very large doses of frusemide, which were necessary to control their fluids. Otherwise, they would have to had dialysis.

TM: Before frusemide, what did you have?

PKS: Almost nothing really. We used to drain the fluid off the legs. We had really no diuretics prior to frusemide that were effective in people with impaired renal function. So in terms of fluid, I think that was a remarkable step forward and saved a lot of lives in the days when we had very limited dialysis facilities and people had to wait for a place on dialysis.

Hypertension, as you know, has always been a major interest of mine and I really do think that even going back to the 50s, and certainly in the early 60s, we could treat hypertension if we really tried hard enough. I think there were a lot of patients who were not adequately treated, but we had the drugs in the 50s that would do the job, provided the patient could tolerate the side effects. As you know, in the 50s, in Hammersmith, we did a trial in malignant hypertension of the old drugs, hexamethonium bromide - those people wouldnít have even heard of. That showed a dramatic difference in the survival of patients with malignant hypertension and we should recall that malignant hypertension used to kill in the mean time of between 6 and 8 weeks before treatment. Having had that previous experience, Iíve always been terribly convinced that treatment of hypertension is very important, and I think weíre coming back to that again now, in terms of the importance of not just half treating the blood pressure, but really treating it. I think we had the drugs then provided we had the stamina to make sure the patient took them.

TM: With partial treatment though, I remember you saying, people used to allow malignant hypertension to heal.

PKS: Yes. I was terribly impressed at Hammersmith that that sort of rapid death in weeks could be avoided altogether by a single night dose of hexamethonium bromide. When we knew that the patientís blood pressure was quite uncontrolled during the day - 280/180 - you know pressures that people never see these days, if they were controlled by that night dose, the lesions would heal and the progression of the renal lesion would stop. Of course they had other things. They were still likely to get strokes and later coronary artery disease but we could stop the renal disease. Nonetheless, I think in the ideal world, where we are not talking about saving beyond weeks but beyond years, it is terribly important to be meticulous about blood pressure control.

TM: Do you remember cardiac beds in the Royal Melbourne unit? Cardiac beds were one of the first things we struggled to get because they cost some money and you have them laying down and up night in a necessary position to let the ganglion blockers work. That would have been in the middle or early 60s. I guess these days, with the range of agents, the question of control of hypertension seldom arises.

PKS: You can really, almost always treat high blood pressure these days.

TM: Iíve got a page in my notes which is headed "chance associations or fortuitous events", and I thought that you, being interested in pathology when renal biopsies came along must be one of those. Another must be the fact that you won the battle to gain a position at the Department of Medicine at Royal Melbourne just about the same time that transplantation began there. Do you want to take us through those early days of transplantation and some of the heartache and the drama.

PKS: Yes well Tim. You and I were very much involved together in those days. I think one of the important things that Australia led the world in is something that is still not liked by many surgeons but I think that although it was terribly important for the surgeon to do a good operation in renal transplantation, it was also terribly important to have a physician or a nephrologist have the expertise with the drugs, looking after those patients after transplantation and I think that the fact that we published that paper in the Lancet in 1967 regarding the 79% two year graft survival which many people donít believe, and which you and I know is true. When the world survival at that time was 30%, I think that was the fact that we were able to control the drug treatment and that they were meticulously looked after. And here I must single out you, Tim. You were one of only two people who looked after those patients and made sure that nothing happened to them in terms of infection or hypertension or anything else. Again, it was an area in which I loved therapeutically because it was just so wonderful to have something different from dialysis and something that was also available in dialysis. As you know, once we transplanted a patient, we had another spot available in dialysis and transplantation has always been a favorite treatment of mine and Iíve maintained a long interest in it. Nothing was as exciting as those early years of demonstrating that you really could get very good survival in cadaver transplants and it was messed up for a few years after that by all this nonsense about transfusion. Anyway, I think weíve got back to it. Nowadays they regard that as a good result with all the new drugs. You and I know that you could achieve it in the old days with the old drugs. Some of those patients are coming up to 30 days.

TM: And of course the transplant group are very biopsible. They must rate highly among your own contributions. Do you remember the early views of transplantation, views of transplant biopsies, the appreciation that this was a condition that might have parallels in natural disease?

PKS: Yes. That has been one of my major interests over many years. I first became intrigued with vascular lesions when I was studying malignant hypertension at Hammersmith in the 50s and of course the vascular lesions in pyelonephritis and from those days and from experimental studies which I did, I had this concept that vascular lesions developing in the way I think is now accepted. They develop mainly endothelial damage, platelet deposition, fibrin deposition and migration and proliferation of myoepithelial cells. Of course, the human transplant biopsy provided the ideal situation to study it day by day and as you know we did. Again, not without a lot of criticism. Of course, you did most of those biopsies I think. Even in 1970, which was 3 years after we published the paper in the Lancet, I was really severely hauled over the coals for daring to do biopsies in transplant. Yet that same prominent and nephrologist who criticized me at that time, later wrote about how important renal biopsy was in the management of graft rejection. I think it was terribly exciting to watch those vascular lesions developing and of course to observe some of the effects of some of treatment on them. You really could prevent them with heparin. Again, nobody believed it and we still donít know why heparin works, but it has a multitude of actions and perhaps itís not an anticoagulation is important but what the action on endothelial or a number of other things but we were also able to show that the day the lesions occurred, or if they occurred, that you could prevent them. Of course, everybody said, "What about a control trial?" Well, we did one, as you know, and after a long hard effort published it. [TM: It wasnít big enough or long enough!] It might not have been big enough or long enough but it did show significant benefits and it was agony to do over five year and nonetheless didnít really influence management which is always disappointing but it allowed some of our patients to go on to presantin and some even on warfarin. I think it was a carefully conducted study - doubled blind, etc - it came out with a result.

TM: You touched there on physiciansí involvement in transplantation as opposed to surgeons. I guess we were working in an environment in Australia where the surgical ethos was very much to be focusing on operating and not necessarily much on post-operative care. That is a little different to the American scene, where there has been a tradition for surgeons to be more involved but it is interesting to watch the American scene now that the pendulumís swinging. The transplant physiciansí associations, I think, now outnumber the transplant surgeonsí and the two bodies still meet together although they are apart and they are really evolving through a situation like you describe. If one puts on a purely physicianly hat, I think one could say that the improving results in America perhaps mirror that change.

You mentioned before criticism in 1970 of a particular therapeutic approach or a therapeutic technique. You are a person who has incurred a considerable amount of criticism through the years. How have you handled that and what is your advice in retrospect about that?

PKS: Itís never bothered me very much. I suppose I grew up in a fairly tough school, at least in Melbourne in the early years, and criticism hasnít bothered me too much. I have a sort of conviction that Iím right and that helps.

TM: Those years we had together in the Ď60s and Ď70s we were in fact putting together a unit, although I guess at some stage we didnít realize that. As I remember the new Royal Melbourne Renal Unit opened in about 1972. Do you want to reflect on those years and what you may recall about the struggle to establish the Unit, which in many ways is the evolution of nephrology in a microcosm?

PKS: I suppose the main opposition to the Unit was not that we should have a unit but that it should be the sort of unit that we wanted and that it became. There are two or three aspects to that: one was the surgical question and who was really in charge of the transplant patients, and thatís a battle that has continued over the years. I didnít mind whose name was on the bed card provided we could decide what happened to the patients. But indeed there were struggles in relation to that.

The pathologists were anxious to get the biopsy material back down to the Pathology Department and that, of course, was one that I would defend with my life because that was the most important thing of all - that we could do a biopsy and within a few hours have the result, make a decision and do something about it. And also make sure that the technology was state of the art and perfect. So there were constant attempts to try and take sections out of the Unit and one laboratory was eventually removed from the Unit. The Tissue Typing Laboratory was to have been there. But we managed to defend having a Microbiology Laboratory, and a Renal Biopsy Processing Laboratory.

I suppose the thing that I had the major battle about was research. Everytime I wrote research into the unit planning document, it was taken out again and I had to come back, and back, and back. Finally it did get put back, thank goodness. And of course research has to be an integral part of any unit like that and it had to be formally recognized. It was the first time in Australia that a hospital unit had been recognized as having research. It was acknowledged that we did research.

That I think was the biggest battle and the battles were with various people but I suppose there was a lot of opposition from the Administration at that time. We managed to win through and get what we wanted.

TM: Iím trying, as we talk, to give you a chance to give messages and advice and let others benefit from your battles. How did you win those battles, what techniques did you use as you look back?

PKS: I think working very hard on papers is important. For example, I managed to sit on committees like the USA Committee on Dialysis and Transplantation and managed to write the document on what a renal unit should consists of and of course that helped, being able to quote that document. I think one has got to keep honest and not accept defeat. Iím sure thatís the way to go and if, in the final event, if youíre not succeeding with your hospital, you sometimes have to go outside it and, as you know, we did that and tried to persuade various health ministers of the importance of this. I think itís just a matter of battling away and being sure that what youíre doing is the right was to go and try and sway other people to that point of view.

TM: Not taking NO for an answer.

We havenít touched much on infection. You mentioned infection as an early interest and then you continued that at the Queen Victoria Hospital with the drug trials. You ran a Urinary Infection Clinic devoted to that for many years. In a way, did it not culminate in a meeting in 1970 which was the first of what you might call the Melbourne Meetings. Why donít you tell us about that?

PKS: I have, as you know, had a big interest in infection and this is something in which Ken and I have worked jointly over a number of years and in which many of the major contributions have been his and not mine. It was an interesting and exciting time. Again, some of my very good friends around the world - John Hodson, who has unfortunately since died, Tom Stamey, whom I saw just last week at Stanford, were other people who were involved in our interest in those areas.

There was a school of thought that said pyelonephritis or (infection) causes renal failure. Now I was pretty convinced from our bacteria studies that that wasnít so. We had very large numbers of women in those studies and we followed them meticulously over the years and half of them were treated, half of them were untreated. Iím pretty sure that the renal failure that was attributed to infection in the end turned out to be analgesic nephropathy in other countries as well as here.

We were very interested in the local infection and in bladder infection and kidney infection and I think one of the major achievements of the 1970 meeting was to try and separate out infection and what it did or didnít do from reflux nephropathy and what that did or didnít contribute to scarring and again renal papillary necrosis or analgesic nephropathy which in this country at that time was a very important cause of endstage renal failure. I think it was a landmark meeting. The book of the meeting was I think called "Renal Infection and Renal Scarring" and that is what it was all about.

Interestingly, we have quite recently done a trial in acute pyelonephritis, looking at what happens in pyelonephritis with new imaging techniques, and have demonstrated that if you take random patients who have entered the casualty department with acute pyelonephritis, most of whom are healthy young women, and you treat in the standard way as soon as you see them, with various drugs but state of the art treatment, over 50% of them develop parenchymal lesions which you can demonstrate on imaging in the acute phase. Seventy percent of those who have the lesions in the acute phase, develop scarring in the chronic phase. That was a concept which was quite foreign to me, that we hadnít really accepted previously. We thought only reflux nephropathy causes scarring. I think the thing is that the new imaging techniques are demonstrating this. We shouldnít ignore it. It doesnít produce radiographic damage. We followed that our women, after pyelonephritis in pregnancy for 7 years at the Queen Victoria Hospital. It doesnít produce changes in the IVP but it does on DMSA scan and CT scan so I think we need to visit acute pyelonephritis and take it more seriously, take bacteria in pregnancy more seriously and perhaps come back perhaps to some of those conclusions from that 1970 meeting in that regard.

TM: The other impression I had coming back to Melbourne after that meeting was that it set the concept of reflux as a contributing factor to scarring on its feet as well. Up to that point the Americans were particularly slow to accept reflux as a common denominator of that pattern of scarring.

PKS: It was at that meeting that Hodson first spoke of his concept of intra-renal reflux, which is the important thing that happens to determine the site of the scars and the final scarring. That was a major contribution and youíre absolutely right, it was the first publication that mentioned intra-renal reflux.

TM: Iíd like to pick up the story, if we could, with analgesic nephropathy. What an extraordinary episode that has been for Australia. If I was to tell you that the incidence of renal failure in 1993 contributing to dialysis caused by analgesic nephropathy was down to 7%, that would bring joy to your heart?

PKS: Yes indeed, and I think those 7% might have been misdiagnosed! As you know at the Melbourne, we havenít seen it for years. We stopped, probably ten years ago, teaching the students about it because, for practical purposes, we didnít have the patients to show them.

TM: Do you remember when you first became aware of it and would you like to paint a picture of what it was all about?

PKS: I first saw the lesions within days of coming to Australia. I came here right at the end of 1958 and started work with at the Baker Institute as a Research Fellow at the beginning of 1959. Indeed, it was in January of 1959 which was a particularly hot summer as I recall. Just in the pattern of what Iíd done at Hammersmith, I went every day to the Autopsy Room and there was this extraordinary lesion on the autopsy table every day. Perhaps they were dying fast because of the hot weather or something, but every day there were tow or three of these kidneys on the autopsy table that I hadnít seen in six years in London.

When I said to the pathologists, "Whatís this extraordinary form of papillary necrosis? Iíve never seen it before." They said, "Oh thatís a very common result of infection. We see it very commonly." I said "Itís very strange. I never saw it in six years in London looking at autopsies every day and I found it difficult right at the start to accept that it could possibly be the result of infection. So I became interested very soon after I landed in Australia. It took some time to establish the association with analgesics and all I was aware of then was that there were these kidneys with pigmented necrotic papillae. I tried to look at the histories a bit but there didnít seem to be anything in them and of course nobody ever asked questions about whether they took analgesics at that stage.

In fact, the connection with analgesics came through Ken and his experience with private patients. Patients who went into renal failure after gastrectomy. He was working, as you may know, at that time, with Bill King on Bill Kingís unit and Bill King was seeing these people who were having gastrectomies for peptic ulceration and who went into renal failure. Ken saw them and it was an extraordinary recoverable form of renal failure often. They did a few biopsies and they showed interstitial changes in the cortex but nothing very much, surprisingly little for the degree of impairment. He of course, in his very meticulous way, took a very good history, established that these people got episodes of renal colic, and of course peptic ulcerations which led to the w hole thing and also discovered that they were taking large quantities of analgesics. He really should get the credit for recognizing that it was indeed analgesic nephropathy.

It had of course been described in Europe at that time as chronic interstitial nephritis in Sweden. One of the difficulties was making the connection between this cause of papillary necrosis that was so common in Australia which was obviously associated with chronic ingestion of large quantities of APC tablets - aspirin, phenacetin and caffeine - and the disease seen in Switzerland? which was largely associated with phenacetin mixtures which they called chronic interstitial nephritis. I wrote to them straight away to Zollinger and said "Did they see papillary necrosis?" and they said "No." In their paper they said in very small print somewhere that 9 of the cases had papillary necrosis which they regarded as secondary. It was really establishing that link which was really one of the important things I think. Looking at the kidney here, and I had a vast number of autopsies kidneys (we collected several hundred between 1959 and about 1961) it was perfectly clear to me that the primary event was the papillary necrosis. The kidney at the time the papillary necrosis first occurred was relatively normal and that when the papillae were lost, you then subsequently got atrophy in those areas and hypertrophy in the intervening areas which were largely the Bowmanís columns.

I presented this at Prague in 1963 and I was absolutely howled down by the European pathologists. They said itís a lot of rubbish, it has nothing to do with analgesics. This was obviously infection causing the papillary necrosis and yet some of these people might also have this chronic interstitial nephritis from phenacetin. So it was really overcoming that attitude that was important but nevertheless, I was convinced then and I am convinced now that the sequence of events was papillary necrosis and subsequent interstitial fibrosis in the cortex, then atrophy ending up with chronic interstitial nephritis.

But the phase in Switzerland is rather different. Instead of getting these great big black papillae that we see, they got tiny little nibbling of the papilla and that presumably reflects the difference between phenazone? and APC mixtures here.

It was a fascinating story to put together and I think we did put it together first. We werenít the first publication. Publications were always a problem in those days because one had a busy life with three young children and trying to write papers.

TM: Of course you identified, not just nephropathy, but the syndrome which is involved, I guess, most other organ systems. What Iíd like to hear then about is the campaign to get these combination analgesics off the markets and perhaps some further observation about the use of the word "analgesic" versus phenacetin.

PKS: I was pretty convinced in the early days that phenacetin was the major culprit. I presented some of our work at a meeting in Boston in 1964 and it was the first time that the doubt was raised in my mind as to whether phenacetin was the major or only culprit. I have no doubt now that it is a combined analgesic lesion where the aspirin and the phenacetin were both important and indeed of course, when phenacetin was replaced, as it was as early as 1962 in many of the mixtures by paracetamol, it didnít alter the picture at all. It continued unabated and really unchanged. As you may know, we subsequently did some work on caffeine and found that that potentiated the effect of NSAIDS on papillary necrosis. I think that all three were contributing.

It was really getting that message across and being joined very much by the Kidney Foundation, the MRC and the Nephrology Society in the campaign to have, not control of phenacetin, which had already virtually occurred. (By 1965 there was no phenacetin in Australia.) but the disease continued and in the late 1970sí as a result of campaigns from many people (I think John Stewart was in that), we managed to persuade government that there should be regulations. Between 1978 and Ď80 I think all the states legislated, not to stop the sale of any of ingredients but to stop their combination. I think, as you say, thatís led to their disappearance. I havenít seen a new case for years and years. Theyíve disappeared from Victoria.

TM: We see the odd one still coming from the Ď60s and Ď70s out of Port Augusta and somewhere in the north. Mostly, theyíve stopped abusing but we are seeing a very late expression I think of damage from those days. But this surely in your career and in a public health sense must represent a real triumph.

PKS: I think in a public health sense it was very important. More intriguing to me of course was putting the whole story together and the pathology...

TM: And the beautiful demonstration of the anatomy of the kidney that came out of understanding the blood supply and the bumpy appearance involved. Any student of the kidney should go back and read that and try and understand the evolution of papillary necrosis. I think thereís a very important message there. But it remains in public health, one of the few areas where a piece of paper has virtually taken away a disease from the community in the last 20 years or so and Iíd like to quote it to the politicians.

PKS: There really was an extraordinary cult wasnít there in Australia at that time. I was aware of people wheeling their supermarket trolleys out with two big packets containing a gross of powders and that wasnít an occasional trolley, that was most of the trolleys. There was an extraordinary habit in the Australian community and I never understood that quite.

TM: No and it wasnít present in England and it certainly wasnít in America when I went there and looked hard for it. It did seem to be in large part an Australian ethos.

TM: Iíd like to turn to nephritis again and focus on the 1972 meeting. That came 12 years after the Ciba Symposium on Renal Biopsy. It was by invitation largely. I donít know, never did know how, but you raised a large amount of money to fly in 20 or 30 hand-picked people who contributed to nephritis and we sat in the Royal Melbourne Lecture Theatre for 4 or 5 days and to me created history. Did it seem like that to you?

PKS: Iím glad to hear that Tim. I loved the meeting and I thought it was a very important contribution. I think it was really the first time that people internationally started to focus on the importance of differentiating the different types of glomerulonephritis, characterizing them and said, if youíre going to set up clinical trials, doing it on the basis of the histology. I think Rene Habib is perhaps the person to me who has always been an outstanding person in that field and youíll recall her outstanding contributions at the meeting. She of course has remained a very good friend. But yes, it was an important meeting.

TM: Iím glad you mentioned Rene, because I was going to bring her up later. It seemed to me Rene was the one in those days tended to stay home and keep the fires burning while you took an occasional international trip. But whenever you touched base with Rene you came back with either a recharge or a new idea and she was, it seemed to me, a very important person to you in your thinking at this time.

PKS: Very important and Rene Habib, I think, is the worldís best renal pathologist. Iíve always had the greatest respect for her. Weíve always got on terribly well. We were both born in Africa. She was born in Morocco and I was born in South Africa and itís been a very interesting association. But sheís a very great friend of mine and an enormous contributor in the field. As you say, every time I had a chance to spend a day or so with her in Paris, and I never went away for long, it just seemed to find something that each of us gained from those discussions. I think she is a superb pathologist and made a huge contributions.

TM: In those days Paris, in my perception anyway, was several years in front of the rest of the world in certainly in pathology terms, if not in other ways.

PKS: I would certainly agree with that, yes. And transplantation too.

TM: I know you sent several of your fellows over to Paris to take advantage of that. Thatís changed a bit do you think?

PKS: Yes I think it probably has. Perhaps itís just that I donít know the new people. But I donít think people focus on Paris now as a sort of centre of pathology and I think it has perhaps slipped behind a bit.

TM: In part I guess thatís had an up and down with Reneís own contributions.

The Melbourne meeting then pulled together nephritis and sorted it out into a grouping of conditions that really stood the test of time until today. But Stewart Cameron reminded me and reading about that, that it introduced the concept of life table analysis to areas outside transplantation and that in its own way is a real contribution. The fact that we could look at diseases and their evolution in a much more sensible way. The same attempt to pull people together in 1978 - another Melbourne meeting on nephritis. Your memory of that?

PKS: I think that the interests had changed by then. The emphasis was immunological and of course some of the main contributors at that meeting, people like Keith Peters and many others, were much more interested in the immunological side of renal disease. I think that has come to the fore and is in fact the great area and the important area of the present. We were looking just at morphology and they were looking at immunological mechanisms anyway. We were looking of course at other mechanisms but I think of that second meeting mainly as one that where immunology was the major contributor and it was the beginning of that era of the greats of immunology and coming back of morphology at an immunological level in terms of nephrology.

TM: In those days we all had such high hopes that within the next decade would find the key and be able to turn that key to cure more nephritis than weíd been able.

Let us turn to more general issues. Itís my perception that whenever you have joined an organization like the College of Physicians or the AMA or the Society of Nephrology or others, that you have had a very rapid passage to the top, usually to the leadership position. I think that in each of those that I have mentioned thatís occurred. Iíd like to hear your account of that and perhaps words of advice to those others who join organizations as to why thatís happened and how to accomplish it.

PKS: Itís occurred for a number of reasons. It certainly wasnít rapid in the College of Physicians. I was on the Council for 12 years before I became President and it was a closely contested battle. As you probably know, 12 years is the maximum time you can sit on the Council. I deliberately joined the AMA because I believe that doctors need to be involved with government in trying to preserve the best in medicine and there is not much one can do in an organization like that without getting into an executive position and so I stood for election to the Executive and subsequently chairmanship of Council. I didnít really intend to get involved in the World Medical Association which I did recently. I really did that because I was a little bit put off at a meeting where they wouldnít let me speak because they assumed that I couldnít possibly be a Councillor because I was a woman! So I thought there was only one thing to do and that was stand for the top job. Now that I am President of the World Medical Association I intend to do something from that position in the short period of a year that Iíll be there.

I guess I had a sort of commitment that enables one to go to the top. I mean not every seeks to go to those positions. Itís work and some people are quite happy to sit around the table and discuss but Iíve always enjoyed trying to make changes and I think Iím supposed to be a figurehead in the World Medical Association.

TM: I would not regard you as a feminist. Would you regard yourself as a feminist?

PKS: Not really unless you define feminist as someone who thinks that women should have equal opportunities in all things to men. If thatís a feminist, then Iím a feminist but Iíve never been part of the "bra burning brigade". Iím certainly not on the extreme feminist group that, for example, say that you shouldnít use certain contraceptives in women because they might be harmful. Thatís doing more harm than good adopting that attitude. I just expect women to be given an equal go. I certainly think that women are quite different from men and I can see many reasons why women may might not wish to succeed or to go to the top in certain areas because of their commitment to their families. And thatís a very strong factor for women and I think that when people ask me what is my greatest achievement, I say, and I really believe it, that our family stayed together, it is a happy family with three successful, happily married children and thatís what lifeís about, for women anyway. But I donít regard myself as a feminist but I do think that women should have equal rights.

TM: Would you reflect back on your femininity in regard to your career. Has it been an advantage or disadvantage or at times both?

PKS: I think itís been an advantage in certain situations. I think it was a distinct disadvantage when I first came to Melbourne and when everybody but everybody except Ken expected me to give up medicine and look after my children. Well, I tried to look after my children but I certainly didnít want to give up medicine. I think it was a distinct disadvantage then with clear opposition to my getting hospital appointments, university appointments. Even at the time when I got my personal chair there was clear opposition to that, I think on the basis of gender.

There have been occasions when itís been an advantage. Iíd like to think of it as something that is not particularly relevant. That itís how good one is doing a job that should enable you to achieve.

TM: I canít and wonít attempt to rattle off all the firsts but you undoubtedly have been the first woman this or that in about 25 different ways. In particular, I think Iím right in saying the first woman Professor of the University of Melbourne, an institution that has been going 150 odd years. Certainly the first woman President of the College of Physicians of Australia and first woman President of the World Medical Association. Thatís the context in which I wanted you to give an account of whether being a woman having mattered.

PKS: Iíd just like to say one word there because poor old South Africa gets such a rough time from many people and of course it is the country I grew up in and a country I love. But I really came out of South Africa without any sense at all of the fact that being a woman was a disadvantage whereas it clearly was at that time in England and much more clearly so in Australia. So I think at least South Africa got that right. A third of my class graduating in medicine were women. At that stage everywhere else in the world it was 10% or less. So for some reason or other South Africa gave women a good go. I expected automatically when I got the top marks in medicine in Johannesburg to get the jobs I wanted. I would never have done that in Melbourne University just because I got the top marks. I wouldnít have been given the jobs I wanted in the Royal Melbourne Hospital and I think that sort of typifies the attitudes at that time and I think that that perhaps was one reason why I was not frightened off.

TM: You mentioned your proudest achievement or your best achievement was that of your family. If you put the family achievement aside, which within the medical context, what achievement do you look back on with most pride and joy.

PKS: I donít have any single one I don't think. In terms of my observational pathology, I think in the long term, the observation of the vascular lesion and its evolution in terms of platelets and endothelial cells and proliferation and so on which leads to the common lesion of atheroma but also described in the context of graft rejection. I think thatís probably one of the most important ones. I donít look on any saying that was my proudest moment in the medical community.

TM: What about disappointments. Do you look back on any particular medical disappointments?

PKS: I suppose I was really disappointed when I came to Australia and found that I wasnít wanted. I didnít really believe it at first. I hadnít had that concept. And Ken hadnít, to himself, that was likely to happen. He was obviously unaware of the attitude about women in Australia. That was my major disappointment, that coming here and finding that I thought I had something to offer and nobody seemed to want it and indeed everybody seemed to think I should give up medicine.

I really was bitterly disappointed to find when I was compulsorily retired from the University and the Royal Melbourne Hospital at the age of 65 that suddenly I had a sort of a vacuum for some time and I really felt that I was in my full stride. I think I had a most successful final year in my Department and with more Ph.D. students, more papers, more everything really than Iíd had in any other years and then suddenly it all came to an end and I think that was a disappointing time for me and Iíve managed to build up areas of other interests that I think was disappointed at that time.

I canít remember any other particular disappointments.

TM: Do you know how many fellows or students you had through?

PKS: No Iíve never really kept count Iím afraid. We really should have done that better than we did. But as you know, we always worked with very little infrastructure.

TM: Yes, but it must number a hundred.

PKS: Yes, Iím sure.

TM: And they would, of course, come from many parts of the world. Do they keep in touch with you at this time.

PKS: Yes. I see them from time to time if I happen to visit that particular country, I would usually see the fellows from that country and thatís the time I particularly keep in touch. Every so often I see a patient who comes to Melbourne to see me from somewhere round the Southeast Asian area and indeed when I go to other countries I keep in touch with them but itís been a great joy. One of the worst things about retiring is the loss of contact with students and fellows and residents and registrars and you know people where one feels oneís contributing to their development and thatís the sad part of the time.

TM: Priscilla, just before I ask you about the future because Iíd like you to gaze into the crystal ball in nephrological terms, I would just like to go back as a personal contribution and say that the lingering impression that I have of you is of that persistence, is that therapeutic optimism and that ability to say, "Yes, letís try it." Never "No, letís not try it" and above all, the fact that you had that uncanny knack of being right. I think with those excellent bedside instincts combined with that knack of being right, you reinforced the message that it was appropriate to try new therapies and to try new things but what about the future? As you look back from 1994 to 1960 or thereabouts, enormous things have happened. Nephrology has been born and is now reasonably mature. Perhaps completing its teenage days. Various diseases have been identified and some have come and gone. You have been right in the middle of most of all that. Where do you see it going? What does the next decade have? What about molecular biology and its contribution to therapy?

PKS: Difficult questions Tim! I suppose, as you said earlier, itís disappointing to think that dialysis and transplantation have changed so little in that time. One had thought that dialysis would become at least a suitcase kidney with something that could be easily transported around and not the process it still is. Transplantationís progress again has been disappointing. There is always this or that newer drug. As we said before, there are not that much better than they were 30 years ago. So I would hope that in terms of clinical nephrology, the future must be early diagnosis and treatment and surely there must be, out of all the huge science thatís going on at present to identify the underlying mechanisms of disease and all the cytokines and things, some new treatments that come out of that. But in order to apply those treatments, the clinicians have got to be bold. Theyíve got to be prepared to make diagnoses. People are so conservative out there in renal biopsies. They say they don't biopsy microscopic hematuria alone. Well, why not? Weíve shown quite clearly there are two major diagnoses. One is basement membrane disease. We can send the patient away if they donít worry that something is going to happen to them. The other one is mesangial IgA glomerulonephritis where, if the red cell count remains high, they are going to progress and they certainly need to be followed if not treated. So of course you should do biopsies to diagnose the underlying renal disease and itís only by being clinically bold and then applying treatments as they become available, that we are going to progress. And as I say, thatís been disappointing and I think the pessimism is disappointing. Weíve got to grasp onto any new treatment and be prepared to wear the consequences if there are consequences. But Iím sure there must be new treatments becoming available out of molecular biology, out of our huge increase in understanding of the mechanisms going on in glomerular damage and its largely glomerular damage we are talking about - glomerular and vascular. Although the interstitium plays an important part, itís the same sort of mechanism there. if you can shut off the proteinuria, you can easily shut off the interstitial component. I hope that clinicians will continue to try treatments as they become available and I hope weíll get onto some much more effective treatment than those we use at present. I do see new things coming along even although weíve had a rather slow progress in the 30 years that nephrology existed or 35 perhaps.

TM: Priscilla, I think that may have been an appropriate time to conclude. I would like to, in doing so, thank you very much for your time and for, what I hope has been an interesting account of the fighting years during which nephrology grew up. Thank you very much.