Power of One A clinician with a passion for pathologyPriscilla Kincaid-Smith As a woman in medicine and as a scientist, Professor Kincaid-Smith has met and overcome some determined obstructionists
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Introduction | The early 1950s, when I graduated, were an exciting time in clinical medicine. Penicillin had only just become generally available and it revolutionised the treatment of infectious disease, particularly in a hospital like Baragwanath Hospital, where I spent my early years as a doctor. This 2000-bed hospital across the road from the now-infamous Soweto township outside Johannesburg was to absorb my full attention for the next two years. It was a very exciting place for the residents and registrars, as the wards were full of very ill patients many of whom could now be cured. A dose of penicillin which we would now consider homoeopathic transformed pneumonia into an illness lasting a few days and its mortality fell dramatically. In the same years chloramphenicol did for typhoid fever what penicillin had done for pneumonia, and chloroquine cured most patients with malignant cerebral malaria. The ward balconies were full of patients with advanced tuberculosis and this too became a curable disease after streptomycin became available. | ||||
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After three years of working like a galley slave but gaining a huge
experience in clinical medicine, I was lucky enough to be accepted at
Hammersmith Hospital, London. At that time Hammersmith Hospital was
a leader in many fields, notably in cardiology, where McMichael and
Sharply-Schafer had pioneered cardiac catheterisation and the
Australian, Paul Wood, certainly one of the world's top clinical
cardiologists, worked for a time.
At Hammersmith the whole attitude was to do research, and improve medical knowledge. It didn't give me the same satisfaction of saving lives, but it was certainly the academic centre of London in the 1950s. At that time the ancient traditions of the London teaching hospitals were a handicap to doing new things and research. Hammersmith was frowned upon as "that hospital next to HMP Wormwood Scrubs, that hospital where they did all those experiments!". I came into contact with some of the most famous names in medicine. Each day seemed more exciting than the last and the rate of learning was exponential. I spent two and a half years in anatomical pathology, but my research interest in hypertension and the kidney stood me in good stead for my future career in the then non-existent field of nephrology. Renal biopsy was in its infancy and Robert Heptinstall, perhaps the world's best renal pathologist, came over regularly from Mary's Hospital to look at renal biopsies with our expert in this field, "Do" Doniach, who was senior pathologist at Hammersmith Hospital. This exposure to living pathology has had a great influence on my career in nephrology, which, although unequivocally clinical, has always kept me close to a microscope and involved in pathology. As a pathology registrar, I spent the mornings doing autopsies, the highlights of which were the attendance at lunchtime of all the top clinicians for a presentation of the findings. This was a no-holds-barred school, with people like John McMichael (Head of Medicine at Hammersmith) and Sheila Sherlock (who published the first major book on hepatology and became a world leader in the field). Nothing was taken for granted: the questioners were a very erudite and exacting bunch of clinicians. Histological analyses of biopsies and surgical specimens were reported on the day they became available. This necessitated many late nights to prepare for the consultant pathologist's overview the next morning, but this one-on-one learning process was excellent. As an early riser I found that I could easily start work about two hours before anyone else arrived, which allowed me to do some research. My first "kidney" paper was published in The Lancet in 1955,1 and I managed quite a lot more in those extra two hours each day. Although I was fully immersed in pathology, I couldn't drag myself away from the wards. After attending ward rounds two or three times a week, my envy of the doctors looking after patients finally drew me back to clinical medicine in 1956. My training was in cardiology -- there was no specialty of nephrology --but, as hypertension was my main research interest and most of my previous research had involved hypertension and the kidney, I became a de facto nephrologist. Another great advantage was that Malcolm Milne was second in charge in the McMichael cardiology unit in which I worked, and he was truly one of the founding fathers of nephrology. Not only did I learn a lot from Malcolm, but we ran the dialysis service for southern England and collaborated with a string of clinical fellows with renal interests, among them Bob Muehrcke (who established renal biopsy as a safe procedure) and Belding Scribner (of dialysis fame). In 1958 Sir John McMichael called me into his office to offer me a junior consultant post at Hammersmith. I was overwhelmed and greatly honoured, but had that week become engaged to Ken Fairley (from Melbourne, who spent four years training at the National Heart Hospital in cardiology with Paul Wood), and neither of us really wanted to bring up a family in England. I sometimes wonder if, had I known what awaited me in Australia, I might not have tried to persuade Ken to stay in England after all. | |||||
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I had assumed that I would be eligible for a similar post in Melbourne to
that offered in what I regarded as the UK's top hospital, but I was very
wrong. In the 1950s, in Australia, when a woman married she
automatically lost her job. I was not considered for any significant
post in a hospital or university in Melbourne. My curriculum vitae was
not wanting: I had published several respectable articles, held a
postgraduate qualification in pathology, was a member of the Royal
College of Physicians, London, and had eight years of first class
postgraduate training. I had excellent references. But I was the
wrong sex!
I was devastated. It seemed that almost all doors were closed to married women. After doing general practice locums to help pay the bills, Sir John McMichael arranged a part-time research position for me at the Baker Institute at the Alfred Hospital, Melbourne. However, Ken and I decided that if I was not wanted in Melbourne perhaps we could be of service in New Guinea, which had almost no specialists in its health service. We applied for and were offered appointments, Ken as a physician and I as a pathologist. We went up to New Guinea to inspect the new hospital in Rabaul and were thrilled with the facilities, but soon discovered that, as a married woman, my appointment could only be temporary. If any man, irrespective of qualifications, applied, he would get the position, and permanent to boot! So it was back to Melbourne, where I was appointed as an honorary physician at the Queen Victoria Hospital, a hospital run by women for women. I also had a part time research position at the Baker Institute and a part time research and teaching appointment in the University of Melbourne, Department of Medicine, at the Alfred Hospital. Eventually, in 1967, I was appointed as first Assistant in Medicine in the University of Melbourne. That was the year in which barriers to employing married women in universities were removed. | |||||
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It was on my very first day at the Alfred that I encountered my first case
of what was later called analgesic nephropathy. I went, as I always had
at Hammersmith Hospital, to review that day's postmortem findings.
There was no formal presentation and the pathologist seemed somewhat
surprised to see me. Demonstrated were the kidneys from three
patients. All showed the same lesion, a kind which I had never
encountered at the Hammersmith. These had very obvious features:
black necrotic papillae with overlying atrophy and with striking
hypertrophy in adjacent columns of Bertin (Box 1). On asking the
pathologist what this lesion was he replied that it was papillary
necrosis, a common complication of renal infection.
"Well, it doesn't occur in renal infection in London", I replied, but I don't think he believed me. Although I recognised the lesion as the sign of a specific disease process at that first-ever autopsy attendance in Melbourne early in 1959, it took a bit longer to connect it to analgesic abuse. I had, of course, seen acute renal papillary necrosis in an occasional kidney in England, but the Alfred cases were quite different and more chronic lesions. Phenacetin nephritis had been described in Switzerland as chronic interstitial nephritis in 1953, but there was almost no mention of papillary necrosis in the description, certainly none of pigmented papillae. When I was finally able to get a photograph of one of the Swiss kidneys it was clearly different: the kidney was small and there was a moth-eaten appearance of the papillae, which presumably represented areas from which necrotic tissue had been lost (Box 2). Ken Fairley was working in Bill King's unit at the Royal Melbourne Hospital and it was he who made the connection between the kidneys seen so frequently on the autopsy table in Melbourne and analgesics. Bill King was a busy gastroenterologist and when he encountered patients with renal disease he consulted Ken. Over a relatively short period of time Ken gathered a series of patients with peptic ulcers and impaired renal function who also had a history of a phenomenally high intake of analgesics. When one of these patients passed a small fragment of pigmented material which was processed and turned out to be a piece of renal papilla the puzzle was solved. These patients had analgesic nephropathy, even if the lesions were quite different from those described by Spühler and Zollinger in Switzerland.2 In 1963, at the International Society of Nephrology meeting in Prague, we had great difficulty in persuading our European colleagues to accept our evidence for this new form of analgesic nephropathy. They particularly did not like the large kidneys, which we demonstrated to reduce in size on radiological imaging as papillae were sloughed, with resulting cortical atrophy. This always seemed to me to be the likely pathogenesis of the so-called "chronic interstitial nephritis". They objected even more strenuously to the demonstration that this shrinkage in our cases was often followed by remarkable hypertrophy in Bertin's columns. They stressed the rarity of pigmented papillae and papillary necrosis, both major features of our cases. They argued that what we were describing was certainly not "phenacetin nephritis". We were already calling it "analgesic nephropathy" by then, because it continued unabated if patients ceased taking phenacetin and replaced it with paracetamol. There was strong opposition to this view and almost a denial of any connection between our Australian variety of analgesic nephropathy and their "phenacetin nephritis" with chronic interstitial nephritis. Later, years of careful clinical documentation and animal experimentation showed that it was not the phenacetin but the mixed analgesics that caused the renal papillary necrosis. Phenacetin alone or its immediate metabolite, paracetamol, could be fed to rats in huge quantities without causing apparent damage. But when we fed rats the analgesic powders and tablets then being sold in huge quantities in Australia we quickly reproduced the lesion of renal papillary necrosis, which closely resembled analgesic nephropathy in man, even to the detail of pigmented papillae. The stories of analgesic abuse extracted from patients at that time were incredible. The patients were truly addicted to the analgesics. They appeared to be seeking the mood-altering effects, not the analgesic effects, and it seemed that it was the phenacetin which they missed when taking different combinations. The patients were commonly heavy smokers and found it easier to give up cigarettes than analgesics! In the first group of patients that we studied, as many died of coronary artery disease as of renal failure.3 Extensive premature atheroma was a prominent feature, but we could never quite prove that it was the analgesic abuse and not the smoking that was linked to the atheroma. Renal artery stenosis was another common feature, perhaps also due to smoking, but we did postulate that the huge quantities of aspirin which these patients took may have destroyed the "good" as well as the "bad" prostaglandins and predisposed to severe atheroma. Our wards were full of patients with the analgesic syndrome. In addition to the characteristic renal disease, peptic ulceration, anaemia, premature atheroma and premature ageing, dementia was a frequent finding. Some blamed phenacetin for the impaired cognitive function. Severe and often malignant hypertension was another characteristic feature. Renal failure was of course a major cause of death, but if the patient could be persuaded to give up the analgesic abuse a remarkable degree of recovery could be expected. Nonetheless, when this condition started to feature on dialysis and transplant registries 10 years later, it was indeed a major cause of end-stage renal failure -- most common in Queensland and New South Wales and least common in Victoria, where our studies had been carried out. Gradually the message got across. Long before government regulations were introduced to control sales, people became aware of the dangers of analgesic abuse and the prevalence gradually declined. Analgesic powders and tablets, which were then available free in factories and other places, also disappeared, as did the cardboard boxes in which a gross of analgesic powders or tablets were sold. They had once been a very prominent item in the weekly family supermarket trolley. Over the next 10 years or so, the pharmaceutical companies lobbied long and hard against the evidence that analgesic abuse was a major cause of renal failure. In the late 1970s I happened to be flying interstate, seated in front of two senior executives from one of the many companies whose fortunes were founded on APC sales. From this vantage point, I overheard them vigorously attacking me and what I had said about analgesic nephropathy. I was of course delighted that they thought that I had had such an influence on analgesic sales. Later, the tenor of their discussion was that Australia was a lost cause for advertisement and sale of mixed analgesics, and they began to discuss plans to invade the markets of South East Asia, where there were no controls over either advertising or sales. They were targeting Malaysia in the first instance, and reports of analgesic nephropathy from Malaysia 10-20 years later confirm that their plans succeeded. Advertising had been one of the secrets of the success of analgesic sales and this dated back to the 1920s, when Nicholas in Melbourne commenced manufacture of aspirin after the defeat of Germany in World War I and the collapse of Bayer. History relates that a new manager from the United States had predicted that there were millions to be made from aggressive advertising of analgesics. Thirty years later one would still hear on television programs that "You will need Aspro today". It was not uncommon even in the 1960s and 1970s to see shop windows devoted to advertising a particular variety of analgesics (Box 3). Between 1979 and 1982 all Australian States legislated to control over-the-counter sales of mixed analgesics. This was 20 years after most nephrologists were convinced of the need to do this. The final success came from joint activities by the Australian Kidney Foundation and the Australasian Society of Nephrology, which managed to convince the National Health and Medical Research Council and, in turn, the Government. Progress was painfully slow to those of us struggling with the very common disease which resulted from analgesic abuse. The controls were sensible and effective. Regulations controlled the number of analgesics that could be sold in one pack and did not permit the sale of combinations of aspirin, phenacetin, paracetamol and caffeine. Analgesic nephropathy, which had been such a common clinical condition, gradually faded away. | |||||
| Although I now rarely visit the autopsy room, I still look down the microscope every day, peering at all the fascinating things which appear in the urine of patients with renal disease, or examining renal biopsies. I now have a collection of some 20 000 renal biopsies; in many I have known the clinical story as well as the pathology. Nephrology was at first dominated by physiologists and pathology was a very poor relation, but, in my view, pathology has contributed far more to clinical nephrology than physiology. Now pathology, in combination with various immunological techniques applied to biopsy tissue, is certainly at the forefront of advancing knowledge in nephrology. | |||||
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©MJA 2000
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