|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Early History of the Treatment of Renal Failure Before 1960 there was virtually no treatment for the common problem of end-stage renal failure in the United Kingdom. By 1970 every region had a unit capable of treating it by haemodialysis and transplantation, which have continued as complementary treatments to the present time. This development, a notable and rapid advance in clinical practice, deserves historical record. There are differences between dialysis and transplantation: dialysis is a medical treatment based on physical, chemical and engineering principles, and is applicable to acute and chronic renal failure. Transplantation emerged from surgical and immunological concepts, and is applicable only to chronic or end-stage renal failure. It would not be surprising if they had developed somewhat remotely from each other, and such an assertion has occasionally been made. It may well have been true for their earliest origins worldwide. It was not so for their emergence in the United Kingdom, where they took place predominantly in some half-dozen centres, albeit not at the same pace in each, to become complementary therapies. I believe that the intertwined stories of their origins have not been adequately recorded and should be told as a single narrative. I write this memoir in the knowledge of omissions, hoping it may serve as a framework for a definitive history. To describe the relationship of these origins, it is necessary to go back to the beginning of clinical haemodialysis in the UK, which will be familiar to many, and to proceed to the history of transplantation and of maintenance dialysis. This timetable may help to clarify the order of events:-
The laborious task of setting up and using the machine seems to have been undertaken in great part by Joekes, by this time a senior lecturer at Hammersmith together with his colleague, Ken Lowe. 2 Early results however did not establish its superiority over the dietary and electrolytic treatment then being refined and advocated by Bull and Borst, despite the nausea and mouth ulcers occasioned by their regimen. Joekes himself, although continuing to devote his experience to the development of dialysis as consultant to the renal units at RAF Halton and St Phillips (the Institute of Urology), has always said that at the time he was unconvinced that the artificial kidney would continue to play a major role in treatment. The one at Hammersmith was virtually abandoned until later in 1957 when Prof. Ralph Shackman started using it again in his department of urology. The next renal unit, established in 1956/57, was that at the RAF at Halton.5 It was led by Wing-Commander (Sir) Ralph Jackson and Jo Joekes was appointed as a consultant, and it was he who recommended the adoption of the Baxter Twin-Coil Kidney for the unit. This machine proved to be simpler to use. It became generally recognised that dialysis was needed for the more severe cases. Impatient at not being able to refer their patients for dialysis, several centres decided to start their own units. It is often remarked that many renal units were started by urological surgeons, and this was so in roughly half those under consideration here. Notable among these was Victor Dix, urological surgeon at the London Hospital. Having referred a patient elsewhere for dialysis, to find that he had been treated only by renal decapsulation, Dix resolved to set up his own unit. (Prof.Mary) Mollie McGeown, in an account of events in Belfast and Dublin, describes how the urological surgeon in Belfast, JM Megaw, had not accepted the decision that the population of Northern Ireland was not big enough to need a renal unit, and so enlisted her to set one up for him, which she did with such notable distinction.6 Leslie Pyrah (Leeds), Ralph Shackman (Hammersmith), J Cosbie Ross (Liverpool) and the author (Royal Free) are mentioned elsewhere. In 1958/59, there was something of a rush to establish renal units, almost exclusively using the twin coil kidney - a decision largely based on the Halton experience. This model was ordered for Dublin, Belfast, Edinburgh, Glasgow, the London and Royal Free Hospitals. Of these new units, that at the Royal Free, planned from the time of my appointment in 1957, was unique in being set up for the development of transplantation and maintenance dialysis to treat end-stage renal failure. This purpose was fulfilled at an early date by the fortuitous addition to the team of Roy Calne and Stanley Shaldon, respectively to set up these two services, which are both described below in the appropriate sections. The exception to the choice of the twin-coil dialyser was made in Newcastle by Prof. (Sir) George Smart, supported by John Swinney, who was later to become urological surgeon, and a pioneer of transplantation in the north of England. Smart, who had a most distinguished career, was perhaps best known for his interest in the reform of medical education. As Professor of Medicine in Newcastle he was determined to bring standards up to the forefront of modern practice and saw the need for a renal unit. An Alwall artificial kidney was chosen there for interesting reasons: the long-standing sea trade links between Newcastle and Scandinavia, and Prof. Smart’s personal friendship with many physicians there, resulted in his knowing of Alwall’s pioneering work at an early date. The artificial kidney arrived and first used in February 1959 7, a few months before David Kerr was appointed as a senior registrar in Newcastle. Previously a hepatologist with Sheila Sherlock at Hammersmith, Kerr was told that he would be in charge of the new unit “in his spare time”. The Alwall kidney functioned reasonably well, but after a few months Kerr persuaded his chief that a twin-coil machine was needed and the change was made In a history of research on organ transplantation, reference must be made to (Prof. Sir) Michael Woodruff who started thinking about its problems while he was in a Japanese prisoner of war camp after the fall of Singapore in 1942. He found an old copy of Rodney Maingot’s “Postgraduate Surgery” and, after reading about the fate of skin allografts he decided that if he survived he would investigate the phenomenon. On taking up the Chair of Surgical Science in Edinburgh (1956) he listed immunological tolerance and the effects of antilymphocytic globulin as his top two priorities for research as quoted in his autobiography. 10 His clinical transplant programme is mentioned below. Perhaps the most important experimental work, which led to successful clinical transplantation was made by (Professor Sir) Roy Calne. He had been appointed as surgical registrar to the Royal Free Hospital in1958, when the renal unit there was already being set up to undertake long term dialysis and transplantation, without any clear idea of how this was to be done. His interest in transplantation had been inspired by a lecture by Prof. Peter Medawar. It was arranged with Professor Slome for him to carry out research work at the Buckston Browne Farm.11 Hitherto the rejection reaction had either been left untreated or managed by the fearsome measure of total body irradiation (TBI), a relic of the early animal studies such as those of Lennox(pathologist) and Boag (radiologist), researching the fate of skin grafts in rabbits. 12 This was also used by Calne in his first trials. Ken Porter (St.Mary’s) then drew his attention to the recent paper by Swartz and Dameshek13 demonstrating the effect of 6 mercaptopurine on preventing antibody formation after the injection of human serum in the rabbit. Calne decided to see if it was equally effective for whole organ allografts and confirmed that it was indeed so in a successful series of canine renal allografts.14 This subsequent application of his findings is described under the section on clinical transplantation Clinical Unsurprisingly the operation was not a success, but it started a tradition of transplantation at St. Mary’s, where later Prof (Sir) Stanley Peart inspired the formation of an impressive team with Ken Owen (Urology), John Kenyon (Vascular Surgery), Ken Porter (Pathology) and Leslie Brent and James Mowbray (immunology). Barry Hulme, who had trained in Birmingham, established a haemodialysis unit there in 197116, thus completing the resources for treatment of chronic renal failure, which has continued and developed to the present times. Their first transplant was performed in August 1959. Peritoneal dialysis was used in the preparation for operation in 4 of 17 early cases. The five longest survivors were from 31 to 85 days postoperatively. They described four cases of obliterative arteritis in these 17 cases. 17 F.Peter Raper, surgeon and urologist at Leeds General Infirmary (LGI), is described in “Lives of the Fellows” (Royal College of Surgeons of England) as having “latterly become deeply involved with FM Parsons in the problems of renal transplantation….” It appears that his “involvement” went very much deeper than this. Philip Clark (ibid, above) described a series of nine cadaveric transplants carried out by Raper between July 13th 1959 up to his untimely death in 1966. In view of his outstanding surgical technique and his experience in treating renal artery stenosis, he had been a natural choice for Frank Parsons to enlist in a programme of transplantation. His first case received total body irradiation pre-operatively; the next two had cyclophosphamide alone, and in the remainder a combination of cyclophosphamide and steroids. His results were perhaps as good as could be expected without effective immunosuppressant chemotherapy, or, as in his earlier cases, the back-up of maintenance dialysis. One patient survived for eight months with a functional graft, sadly to die of a viral infection. This work was undertaken to test the effectiveness of cyclophosphamide as an immunosuppressive agent, and despite its negative finding it must earn Peter Raper a more prominent place in transplantation than he is currently accorded.18 From 1964, Philip Clark, Bob Williams, Philip Smith, David Pratt and Geoffrey Wilson carried out fourteen transplants up to 1972, using immuran with steroids. Eight grafts failed within the first year, of which one was re-transplanted and three returned to maintenance dialysis. Six grafts survived over a year, for varying periods up to twelve years, and five of these dying of causes other than graft failure.19 Frank Parsons had begun maintenance dialysis at the LGI in 1964, initially to prepare patients for transplantation.20 After 1973 maintenance dialysis and transplantation were centred on St.James’s Hospital by a decision of the Ministry of Health. This service became fully operational in 1973 following the appointment of Prof. Geoffrey Giles, with Stanley Rosen, who had been transplant nephrologist at the LGI and St.James’s Hospital since January,1967. The further history of maintenance dialysis at St. James’s Hospital is given in the relevant section. By the time I was appointed as a surgeon to the Royal Free Hospital in 1957, with a commitment to start a department of urology, I was familiar with Jim Dempster’s work, and had seen a Kolff machine in Stanford being used to help patients with polycystic disease. I realised that a new department of urology would need to have a renal unit equipped for haemodialysis and transplantation working in association with it. An objection to this was made on the grounds that London’s two existing renal units were enough for its needs. I explained that they were treating acute renal failure, whereas that this was planned for the treatment of chronic renal failure by long term dialysis and transplantation. The Board of Governors agreed to the project and set aside a sum of £2,500 for the artificial kidney and its installation. (Minutes of the Board of Governors, Royal Free Hospital. Jan:1959). The unit was functional in 1959 with the arrival of a Baxter twin coil artificial kidney: it was housed in a cubicle erected within a “Nightingale” ward. The first dialyses were performed on cases of acute renal failure resulting from septic abortion, mainly by Dr. Melvin Ramsey the superintendent of the department of infectious disease. The fortuitous arrival of Roy Calne on the scene has been described in the “Experimental” section above. His findings gave us the confidence to proceed with clinical transplantation of the cadaveric kidney. The first two cases we conducted together were prepared by haemodialysis but proved unsuccessful. On November 1st 1960 I carried out a live donor transplant using 6-mercaptopurine and predisolone as immunosuppressants. There was evidence that these drugs controlled the rejection reaction but the recipient died at seven weeks and was found to be suffering from miliary tuberculosis.21 This case can be described as the first clinical allograft conducted in a unit set up for the purpose, backed by preliminary research studies that had confirmed the effectiveness of the immunosuppressive used. Calne had left just before that case, to pursue further research in Francis Moore’s department of surgery at the Peter Bent Brigham Hospital in Boston. There he showed azathioprine to be best immunosuppressant agent then available, finally convincing Dr.Murray to use it in clinical transplantation. From then on, following Calne’s work with Dr.Murray in Boston, chemotherapy gradually became accepted worldwide as the key to successful immunosuppression, leading on to the whole field of organ transplantation. Roy Calne’s recognition of this, the conviction and energy with which he demonstrated, first by his experimental studies on the use of 6-MP, and later clinical studies, has already been described here. His role in the story is of such importance that a note must be made of his future career. On his return from Boston in !962 he worked at St. Mary’s Hospital before gaining a consultant appointment at Westminster Hospital, London where he setup a Transplantation unit in collaboration with Dr. Loughridge’s Renal unit in Prof. Milne’s Academic Department of Medicine. He moved from this appointment to the Chair of Surgery in Cambridge, where of course his major interest was in transplantation, notably of the liver and pancreas. He was elected FRS and received a knighthood, but even these honours scarcely conferred on him due recognition for his contribution to making organ transplantation a routine treatment. The success of chemotherapy as immunosuppressant seems to have been generally accepted after the visit of Dr. Murray described above, St Mary’s adopting it routinely from October 1963.25 At Hammersmith the first clinical transplant was performed in 1962. 26 I have no record of the details of the immunosuppression used, but one must presume that it was similar. This is a history of events in the UK, but it may be said that the transplantation teams in France made the change at much the same time. Maintenance dialysis Effective vascular access was the key to success, and this is acknowledged to have been started by Nils Alwall, who introduced an arterio-venous shunt which afforded repeated access to the circulation. However its effective life was only about six weeks, and again the value of Aiwall’s work was slow in gaining wide recognition. The potential of the Teflon coated a-v shunt was generally appreciated in Europe only after Dr.Scribner, at the First Congress of Nephrology, in Evian (September 1960) described his success with the shunt that he had developed. His account inspired confidence that the problem of vascular access was on the way to being solved. Royal Free Newcastle Charing Cross Leeds Liverpool Hammersmith Discussion Of the two pre-eminent units, Hammersmith and Leeds, both with an early start in haemodialysis for acute failure, it may be thought surprising that they were not equally ahead in developing maintenance dialysis. I have also given Prof. Blagg’s little-known and interesting reason for how this came about in Leeds. It may well be that the Hammersmith unit found itself in the same position, namely having such a heavy burden in treating acute renal failure, by reason of its early start in this field. Another important point may be observed, that in two of the units where maintenance dialysis was established early as a routine service (Royal Free and Charing Cross), the introduction of transplantation tended to be delayed. At the Royal Free Hospital, transplantation had been started in 1959/1960, giving Roy Calne the opportunity to launch his work on chemotherapy which has opened up the whole field of organ transplantation. However, when reliable maintenance dialysis became available, I thought it offered a better chance of survival for the patient than transplantation at that time. Stanley Shaldon, too, did not then accept that the results of cadaveric transplantation were justifiable for its use at that time. We resumed transplantation in 1968, chiefly at the request of our patients. In the intervening years I was occupied by forming the London Transplant Group, which became an almost nationwide organization for the exchange of donor kidneys, ultimately to become the National Kidney Registry. Toward the end of the 1960’s, Leslie Brent of the British Society of Immunology, and I realised that both bodies were planning to become a British Transplantation Society and we had support from each to form a single society under that name. Its inaugural meting was held at the Royal Free Hospital on 12th April 1972, when Sir Peter Medawar was elected as the first president. At Charing Cross, a maintenance dialysis service was set up first, but transplantation was not developed until Grant Williams was appointed some five years later in 1969. Thus it is arguable that de Wardener at Charing Cross made the same judgement, finding maintenance dialysis to be a safer treatment than transplantation at that time. Mortality appears to have been significantly less than it was in units undertaking transplantation without maintenance dialysis available. More or less the same opinion is expressed by Roy Calne when he wrote that in the early 1960’s he did not consider transplants from live donors to be justifiable, and restricted his practice to cadaver kidneys at that time.37 I wrote above that Jim Dempster’s warning against clinical transplantation in the late 1950s was justified. I say no more than that he had a feeling that the stage was not yet set for safe transplantation, and in that view he was correct, before the introduction of maintenance dialysis and chemotherapy for rejection. It was not until these provisions were met that patient survival from transplantation could be regarded as completely acceptable. One final point might be recorded. The introduction of the artificial kidney was greeted with scepticism and even hostility by some members of the medical establishment- that experienced in Leeds is mentioned above. One London professor of medicine has been recorded as opining that it would never establish a permanent place in the treatment of renal failure. Sir Netar Mallick has described38 how Sir Robert Platt in Manchester, who had been presented with an artificial kidney, passed it over to the urologists, presumably under the leadership of Mr. Thomas Moore, for their use. I think no such adverse feeling resulted from the introduction of clinical transplantation - though it is wryly remarked that now, fifty years later, it would not enjoy so smooth a path. I hope I have given an account which helps to sort out the somewhat tangled story of the two modes of treatment as they developed together in the United Kingdom. I am well aware that there are omissions and probably inaccuracies in my record - for example I made only scant reference to the related immunological history, because I am not competent to do so, and their application to clinical work became particularly significant just after the events which I have described. They have been well summarised in the History of the BTS. I send my sincere gratitude to all the colleagues who have helped – their number can be gauged from the “Personal Communications” in the references, and also to my wife Dr Rosemary Radley-Smith, who has helped in all aspects of writing the memoir, but particularly with the references, which I could never have compiled by myself.
1. Joekes AM (2009) Personal communication
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||