History of Nephrology

Surprises from the 1994 Modification of Diet in Renal Disease (MDRD) study

2011-11-20T17:33:00.000Z

Low-protein disappoints; attention drawn to proteinuria and blood pressure

The MDRD study was a landmark trial set up to prove the importance of dietary protein in slowing the progression of kidney failure. This had been shown in animal models but human studies were not so clear. It was combined with using two different blood pressure targets, as again these seemed important in animal studies but it was not clear how much we should lower blood pressure in patients.

Patients were recruited from nephrologists and by advertisement; they were known to have a kidney diagnosis. They were not simply people found to have reduced kidney function by random testing. Diabetic nephropathy was excluded but diagnoses were varied. 25% had glomerulonephritis. Almost as many had the genetic condition polycystic kidney disease (PKD, a group you might think whose outcome would not be altered so much by control of diet or blood pressure.

The patients were divided into these groups with higher or lower protein intake, and higher or lower blood pressure:

Study	GFR	Protein intake	Blood pressure
1 (n = 585)	25-55	Usual protein (1.3 g/kg/d) or Low protein (0.58 g/kg/d)	140/90 or 130/80
2 (n = 255)	13-24	Low protein (0.58 g/kg/d) or Very low (0.28 g/kg/d)	140/90 or 130/80

The very low protein diet was supplemented with essential keto acids and amino acids. Glomerular filtration rate (GFR) was measured every 4 months by iothalamate clearance and normalised for surface area (/1.73m2). Follow up was for an average of 2.2 years.

The Results were surprising
Diet had no impact on rate of loss of GFR or on the number of patients starting dialysis or dying, in either the low or the high GFR groups.
Blood pressure control had no overall effect, but there was a striking benefit from the lower blood pressure target for those with over 1g of proteinuria per day. The benefits increased further as the amount of proteinuria rose.

Decline in GFR in study 1. Usual protein group is the dashed
line and low-protein the solid line. No significant difference.
There was an early fall then slower gradient in the low-protein
group but no overall benefit.

Deaths and ESRD in study 2. Very low protein is the solid

line, low protein is the dashed line. Figures from Klahr et
al as below, with permission from NEJM.

Diet enthusiasts have hoped that there might be a silver lining, but one has not emerged. If there is any long term effect, it seems to be slight. Worse, a 10 year analysis of what happened in the low-GFR group (Study 2) showed that those who had been allocated to the very low protein diet started dialysis no later than the low protein group, but were twice as likely to have died (Menon 2008). The effect seemed to persist long after the study had finished. Surely the last nail in the coffin of very low protein diets, and confirming Thomas Addis's caution about low protein diets in 1949, 'We are trying to do something dangerous'.
What else did the trial achieve? Well scores of other studies have come from analysing the details of the rich data collected in the MDRD study. The best known is the MDRD equation, a formula for estimating GFR from serum creatinine which is now in near universal use.
A couple of interesting subgroup analyses were mentioned in the original paper. Patients with polycystic kidney disease did not appear to benefit from blood pressure control. The 53 black patients had a higher rate of loss of GFR than other patients, but it was half the rate in those allocated to the lower blood pressure target group.

Why were the diet results so negative? The conclusion should be qualified: it was not that diet is useless. It was that lowered protein diets are not helpful in well supervised patients with good blood pressure control. Even the higher blood pressure group in MDRD had pretty good blood pressure control. Animals with renal failure probably have comparatively much higher pressures.

How high can protein intake safely be? With those animal experiments in mind, plus a number of concerning anecdotes about the effects of protein supplementation on kidney disease in some individuals, few dare to recommend much higher than 'moderate' protein intake.
Personal view: If blood pressure control is poor or supervision difficult, you might argue for lower intakes. If you cannot or do not want to use dialysis to control symptoms in advanced uraemia, targets could be lower still.

Further reading
Diets for chronic uraemia - on this blog
Klahr S et al. The effects of dietary protein restriction and blood-pressure control on the progression of chronic renal disease. New Engl J Med 1994 330:877-84
Menon V et al. Effect of a very low protein diet on outcomes: long-term follow-up of the MDRD study. Am J Kidney Dis 2009 53:208-17.

Twins in transplantation

2011-11-13T17:16:00.000Z

Groundbreaking - and lucky to have one

John Merrill shows the Herrick twins an early dialysis machine

On December 23rd 1954, 24 year-old Richard Herrick became the first successful kidney transplant recipient in Boston, Massachusetts. He was lucky both to be in Boston, and to have an identical twin brother Ronald who was prepared to take the risk to help him, as at that time the problems of rejection were known but not soluble.
Joseph Murray, the surgeon, had perfected the surgical technique in dogs. The kidney was anastamosed onto the iliac blood vessels in the pelvis outside the peritoneum, as originally developed in France. Much the same operation is used today. Murray had already undertaken 20 transplants of cadaver kidneys into dying patients, usually into the groin and with admission to patients of their experimental nature, but none of them successfully.
The recovery of Richard Herrick's health, anaemia and nutritional state were remarkable. He died of a heart attack 8 years later, while his genetically identical brother lived 56 years longer until December 2010, perhaps an early pointer to the cardiovascular consequences of kidney disease.

Edith Helm was 20 and just married in Oklahoma in 1956 when she was told she was dying of renal failure. However she had a twin, Wanda, and later that year travelled to Boston to become the first woman to receive a successful transplant. Before the operation the sisters were visited by Richard Herrick. As she was leaving the hospital in August 1956, she said 'Ive never been operated on before, never been east before, never been on a plane before. This has really been an experience' She lived 54 more years until April 2011, going to work as a school cook, and becoming the first transplant patient to give birth, having a son and a daughter.

A total of 12 identical twin grafts had been carried out in Boston by 1961, 35 around the world by 1965. In long term follow-up, 4 of the first 7 died later of renal failure following the recurrence of nephritis in their grafts, in the absence of immunosuppression.

The UK's first successful transplant was between 49 year old identical twins in October 1960. Means to prove that they were identical are described in detail in Woodruff's 1961 paper, and were essentially the same as used by Murray and Merrill in Boston, based on appearance, fingerprint patterns (undertaken by local police in Boston), detailed blood grouping, haptoglobin variants, and finally on skin grafting. A square of skin was taken from each twin and transplanted to the other. This proof of immunological identity and tolerance between identical twins was first demonstrated in 1937.

Reciprocal skin grafts between the
Edinburgh identical twin brothers

Skin grafts like this were used to prove tolerance between a pair of non-identical (male and female) twins who had exchanged some bone marrow in utero. Very unusually their blood showed two blood types: the man had 86% group A red cells and 14% group O, while the woman had 99% O and 1% A. The skin grafts were not rejected (Woodruff 1959). This provided evidence that tolerance might be achievable without drugs one day. Experience in twins suggests it could be at the expense of a higher incidence of disease recurrence.

Many different approaches to suppressing rejection were investigated in these early days and modern regimens were arrived at step by step, with azathioprine being the first key success after the failure of irradiation treatment.

Further reading
Murray JE, MP Merrill, JH Harrison. Renal homotransplantation in identical twins. J Am Soc Nephrol 12:201-4 (reprinted from Surg Forum 1955 VI: 432-6)
Woodruff MFA, JS Robson, JA Ross, B Nolan, AT Lambie. Transplantation of a kidney from an identical twin. Lancet 1961 ii 1245-9
Murray JE. Human organ transplantation: background and consequences. (from Nobel Prize Lecture 1990). Science 1992 256:1411-15
Woodruff MFA, B Lennox. Reciprocal skin grafts in a pari of twins showing blood chimaerism. Lancet 1959 ii 476-8
Tilney NL. Renal transplantation between identical twins: a review. World J Surg 1986 10:381-8

Diets for chronic uraemia

2011-11-06T15:26:00.001Z

1949-1993: Addis to Giovannetti

It didn’t work for her: a 46 year old female patient who stopped

her diet. Note that it was lowering urea but not creatinine.

From Shaw et al 1965, by kind permission of OUP.

Low protein diets were shown to prolong the life of uraemic rats in experiments in the 1930s, and it was long held that the products of protein metabolism (which included Urea) were major contributors to the symptoms and signs of uraemia. In the late 1940s, no-protein no-electrolyte diets, the Borst and Bull regimens, were introduced for conservative management of acute renal failure.

Thomas Addis was a strong proponent of low protein intake for chronic uraemia too. In his classic 1949 book Glomerular Nephritis he talked of ‘resting the kidney’, perhaps now interpreted as reducing hyperfiltration, and carefully explained how to achieve it in partnership with patients, dietitians and nurses in the real world. However he also commented

“We are trying to do something dangerous. We are always on the edge of a possible deficiency”.

Referring back to data from the 1920s, when the minimum protein intake compatible with neutral nitrogen (protein) balance was estimated, he prescribed 0.5g of protein per kg weight per day. This was increased by any amount lost in urine, and a bit more was alllowed for growing children. These principles became widely accepted and followed.

Giordano in 1961 was probably the first to advocate a much lower protein intake, 18g, with supplementation of essential amino acids, but this idea became more widely associated with the name of Giovannetti after a 1964 paper in The Lancet. It is interesting that this more extreme management came into vogue just at the time that dialysis and transplantation were beginning to develop. Perhaps there was increased awareness of end stage renal disease, and it was all too obvious who could not be eligible for these new experimental and expensive treatments. The aim was to reduce the symptoms and prolong the life of patients with advanced and terminal uraemia, when symptoms could be severe on more moderate protein restriction.

Giovannetti’s patients were 27-52 years old and had creatinine levels of 900-1600 micromol/l (10-18 mg/dl) on admission. Some of them needed temporary dialysis (the only kind available most likely) to stop vomiting before they could start their diet, but then symptoms improved. The severity of renal failure in their patients is apparent from their report. Two of 8 died but the others remained alive at 10 months.

The diet

Attempts to simplify the regimen, and make it more acceptable in the Northern Europe of the time by replacing the starch-based spaghetti with bread recipes designed for patients with phenylketonuria, were described by Berlyne and colleagues in Manchester in 1965. Glomerular filtration rates varied from 1 to 5 ml/min. Those with values greater than 2.5 ml/min tended to do better. They reported lowered urea and phosphate and improved (but persistent) acidosis, and perhaps most importantly, reduced anorexia, nausea and vomiting. In a later paper they also described less drowsiness so that patients tended to die in a bleeding-agitation syndrome, which doesn’t sound such a great success. On this diet death occurred when creatinine was over 1800 micromol/l (20 mg/ml), urea a mean of 80 mmol/l (230 mg/dl) (see Figure). Urea:creatinine levels were generally lower on very low protein diets.
All groups commented on the unpalatability of these diets (click on the diet sheet image to the right) and how difficult patients found it to adhere to them, and to maintain adequate intake, although they seemed to achieve their purpose in the short term.

A number of mostly small and flawed human studies during the 1980s supported that low protein diets reduced the rate of loss of function in patients, a conclusion supported by further animal experiments. However it was not until the Modification of Diet in Renal Disease (MDRD) study in 1994 that the real value of low protein diets in human kidney disease became known. And the answer was not at all what was expected.

Further info
Conservative dietary management from edren (www.edren.org)
Addis T. Glomerular Nephritis. Macmillan (New York) 1949.
Shaw AB, FJ Bazzard, EM Booth, S Nilwarangkur, GM Berlyne. The treatment of chronic renal failure by a modified Giovannetti diet. Quart J Med 1965 34:237-53
Giordano C. Treatment of uraemia using essential amino acid and low protein diets. 1963 Proceedings of the 2nd International Congress of Nephrology 752-7
Giordano C. Protein restriction in chronic renal failure. Kidney Int 1982 22:401-8
Giovannetti S, Q Maggiore. A low-nitrogen diet with proteins of high biological value for severe chronic uraemia. 1964 Lancet 1964 i 1000-1003

The record holders

2011-09-19T13:18:00.001+01:00

A few patients have been on renal replacement therapy for over 45 years

The Royal Free programme
This photograph of 'The Lucky Thirteen' taken in 1965 shows patients treated at the UK's first centre for long-term dialysis at the Royal Free Hospital, London, with their consultant Dr Stanley Shaldon (centre, front row). Olga Hepple, left of Dr Shaldon, featured in a Pathe film of very early home haemodialysis in the UK. Three of them featured in the first episode of the BBC's Tomorrow's World in 1965, which you can see online, a remarkable historical record.

Ray Jones (extreme left of the front row; called 'Ronnie' in the TV prog) began haemodialysis at the age of 34 in 1963 using Stanley Shaldon's dual femoral catheter system, a tube in the artery and vein in the groin. The other three patients who started at this time did not survive the year, but Ray survived nearly 29 years until 1991 and was in the Guinness book of records in 1989 as the world's longest survivor sustained by only haemodialysis. He never had home dialysis, but continued to work until he was in his 60s. His wife Joan continues to campaign for Kidney Research UK.

Second from the right on the front row is Robin Eady, who is the world record holder. Robin began treatment in Seattle in February 1963, when he was taken ill as a 21 year-old medical student and found to have advanced renal failure. He was put on an extremely limited diet and expected to die. However Life and Paris Match magazines had featured the first dialysis for end stage renal failure undertaken in Seattle by the group led by Belding Scribner. Robin was allowed treatment as he was to be trained as a technician to take the technique elsewhere. After 4 months he went on to the very new programme in Edmonton, Canada, for 18 months before coming back to the Royal Free programme in December 1964. Subsequently he returned to medical school and moved to Guy's, where he met he met his future wife Ann who was one of the first dialysis nurses. During his training he returned to Seattle for a year in 1973. He had home haemodialysis for many years until finally accepting a kidney transplant in 1987. He became Professor of Dermatology, retiring only recently, and in September 2011 he and Sir Peter Morris, his transplant surgeon, both attended Kidney Research UK's 50th Anniversary meeting in Edinburgh. More on early dialysis in the UK

Robin Eady 1966

The Seattle Programme
Robin Eady received his twice weekly 12-hour treatments alongside Clyde Shields, the first long-term dialysis patient in the world, who had commenced treatment in 1960, and two other patients. He is the only survivor from these very early days. More on Seattle and the beginnings of long term HD. More about Seattle history from Seattle.

Peter Lundin became a medical student two years after starting dialysis in Seattle in 1966, giving himself home nocturnal haemodialysis for 10 hours three times a week throughout his time at Stanford. He was on haemodialysis for most of his remaining life apart from 6 years transplanted in the 1990s, and had the same arteriovenous fistula for over 30 years. There are many testaments to the inspiring example he gave to other patients facing end stage renal failure. He became a professor of medicine, and a member of the group developing the K/DOQI treatment standards. He died in 2001 after 35 years of treatment.

Nancy Spaeth was accepted by the Life and Death Committee in Seattle in 1966, and after two years of in-centre treatment embarked on home haemodialysis. She recalls attending fund-raising events for Dr Scribner, Dr Henry Tenchkhoff holding her first baby, and participation in Dr Joseph Eschbach's first study of erythropoietin treatment. She had 4 transplants and two children, so has experience of all the ups and downs, and most of the different peritoneal and haemodialysis regimens.

Others from the mid 1960s
There are of course many more remarkable stories. In Edinburgh two patients are at or close to their 45th anniversary of renal replacement therapy.

Brian Tocher began treatment at Fulham Hospital (subsequently Charing Cross) in 1966, briefly intermittent PD then HD, with a few years of transplantation. Patricia LeBlack came from Guyana to London to work and began treatment at the Royal Free Hospital shortly after, but never had a transplant.

Most patients with such long survival have spent long periods transplanted. However Stephen Rifkin listed several patients with over 33 years of haemodialysis experience in a Medscape article in 2008.
Omitted from that list was Jean who commenced treatment in Oxford in 1966, thirteen years after experiencing Henoch Schonlein purpura, so presumably because of IgA nephropathy. She refused a transplant because she feared the side effects of steroids, and by the time of her death after 35 years in 2001 had experienced about 5,000 dialysis sessions and over 50 surgical procedures. During her final illness it was observed that only one member of staff had been alive (as a schoolboy) when she started treatment.

What do they have in common?
All recognise that they have been lucky. In the early days, it wasn't easy to get dialysis but the struggle to get onto treatment was just the beginning. All are grateful for the opportunities that they did not expect to have, and to their families and the medical teams that shared these struggles.

All of the very long term survivors have spent long periods transplanted, but it is interesting that several of them waited years or decades before their first. This may have saved them, as the risks of transplantation in the early years were extremely high. None of the very early transplant recipients are still alive. Most longterm survivors have had long periods of very long-hours dialysis, and this may be important too.

Those I have met are remarkably tolerant of the young renal unit staff members who believe they know so much about the management of renal failure. It is difficult to know how much their personalities have been moulded by the circumstances, but all of them have been careful and have complied with the treatments suggested most of the time, without being so overtly obsessional that it has completely dominated their lives.

All of them have the most remarkable stories, many have had miraculous escapes, most have had very eventful lives. Many renal patients have extraordinary stories, but if you know patients with the longest histories, ask them about their early days. They have a lot to teach us.

We would be interested to hear any updates or additions. Please post in Comments below or send to renal@ed.ac.uk

Further info
On the historyofnephrology blog: Early HD; and early transplantation
Eady R Survival is not enough: reflections of a long-term renal patient. J Nephrol (2008) 21:S3-S6.
Friedman EA, J Bommer. Peter Lundin (1944-2001) the physician/patient role model. Nephrol Dial Transplant (2001) 16:2272
Rifkin SI Thirty-seven uninterrupted years of haemodialysis: a case report. http://www.medscape.com/viewarticle/580265
Spaeth N The nurse, mother of two and four transplants - Nancy Spaeth tells her story. Nephrol Dial Tranpslant (2007) 22:64-7
Winearls CG, CW Pugh. Staying one step ahead - one patient's dialysis experience. British Journal of Renal Medicine (2003) 6-9

A version of this article will appear in the Journal of Renal Nursing.

Transplantation takes off in the mid 1960s

2011-07-13T22:25:00.007+01:00

Years of experimentation finally pay off

Roy Calne (white coat) with dogs Tweedledee,

Titus and Lollipop, recipient of the first successful long-term

organ transplant, using azathioprine (Copyright of and with
permission from Sir Roy Calne - link to source)

Transplantation only began to be a real prospect for patients with chronic renal failure in the mid 1960s, after many, many unsuccessful attempts. Success with several pairs of identical twins (when one had kidney failure and the other didn’t) showed that the technical problems, largely worked out in dogs, had been solved. However the problems of rejection had not. (see First transplants post)

Frank Burnet and Peter Medawar won the 1960 Nobel Prize in Medicine for work that defined rejection and immune tolerance. Medawar worked in the Glasgow Burns Unit on skin grafting during the Second World War, and subsequently with Burnet. He came to believe that the problem of rejection could not be solved. Certainly in the early 1960s there was no way of suppressing rejection without usually killing the patient, as many attempts showed. Whole body irradiation was transiently adopted, then there were experiments with various drugs including corticosteroids, cyclophosphamide and thiopurine, sometimes with brief or isolated successes.

As long-term dialysis was scarcely available or even thought of before this time, the high risks of these early transplants were felt to be justified. Several of the UK’s early dialysis units were established by transplant surgeons to support the patient temporarily. After work by Roy Calne in dogs, an analogue of thiopurine, azathioprine, was first used in human transplantion 1962, in Boston and then in Edinburgh, both successfully. However toxicity was still high and further deaths followed.

As experience with these new drugs developed, lower doses of azathioprine were used in combination with steroids (prednisolone or prednisone). By 1965, 1 year survival rates of cadaver grafts were over 60%, with live related grafts higher still. Dr Molly McGeown in Belfast pioneered a highly successful regimen using lower doses of prednisolone, 20mg per day from day 1, and this was taken up widely in other centres during the 1970s. However the Belfast results remained strikingly good, much better than other centres, showing that it wasn’t just what you used, but how you did it – the elusive ‘centre effect’. The Belfast results reported in 1977 showed 82% two-year survival from 102 transplants in 93 patients 1958-77; a level of success that many units struggled to match until several years after the next major anti-rejection milestone, the introduction of Cyclosporin. This was first approved for use (and it took some getting used to) in 1983 after trials led by Roy Calne in Cambridge in 1978-9.

Four other developments were important before Cyclosporin came into general use.

A vial of anti-lymphocyte

globulin made in horses

in Edinburgh in 1972

(first used there late 1960s)

A new anti-rejection tool introduced in the 1960s was anti-lymphocyte serum, antibodies raised in rabbits or horses to kill human lymphocytes, which had been developed during the 1950s and 60s.

‘Cross-matching’ using white blood cells to prevent hyperacute rejection was described by Terasaki in 1965, and the basis of tissue typing and its impact on graft survival was mapped out from then. The benefits of tissue type matching with modern drugs are smaller but still detectable.

In 1974 Terasaki also reported that patients who had received blood transfusions were less likely to reject their transplants. There was understandable reluctance to introduce deliberate transfusion policies in the light of previous experience on dialysis units with hepatitis, and the risk of sensitisation to tissue type antigens, but in the azathioprine/prednisolone era the effect was quite substantial so it was adopted by most units. With modern drugs it is no longer a powerful effect and has been abandoned again.

The fourth and final developments were medicolegal, increasingly allowing the use of cadaver donors, which formed the great majority of transplants in this era.

It is striking that the core tools of transplantation in the 1960s, azathioprine and steroids and anti-lympocyte antibodies, and the basic surgical technique, are still in use today. The major pharmaceutical modification has been the addition of the calcineurin inhibitor Cyclosporin and later Tacrolimus. Azathioprine has been partially supplanted by an equivalent drug Mycophenolate. More specific and targeted antibodies of various kinds are also in use, though many of these have yet to find a firm place. The ambition of inducing tolerance so that the patient does not require long term immunosuppression is closer, but has still not been achieved for human transplantation.

In 1988 McGeown was reporting that Belfast’s 10 year graft survival was 55%, and patient survival was 67%. Death with a functioning graft was becoming an important issue, with most deaths occurring not from kidney disease, but from cardiovascular causes. With most units now using Cyclosporin and beginning to aspire to this sort of long-term success rate, the possibility of moving on to think about long-term problems marked the beginning of the modern transplant era.

Further info

Sir Peter Medawar's Nobel Prize lecture (Nobel Prize website)

History of transplantation (with a UK bias) from the BTS

Roy Calne. Recollections from the Laboratory to the Clinic. In: Terasaki PI (ed) History of Transplantation: thirty-five recollections. UCLA Press, 1991

Starzl TE. The development of clinical renal transplantation. Am J Kid Dis 1009 6:548-56

Murray JE. Human organ transplantation: background and consequences (from Nobel prize lecture 1990). Science 1992 256:1411-15
Transplantation in Edinburgh from www.edren.org
Dialysis and transplantation in Belfast by Mollie McGeown; and a 1998 interview with Dr McGeown (ISN videolegacy project)

An article based on this post will appear in the Journal of Renal Nursing in August 2011.

Diet for acute renal failure in the 1940s

2011-05-08T17:18:00.001+01:00

The beginning of the multidisciplinary renal team

In 1949 Thomas Addis described the anarchy that existed in recommendations for the management of acute glomerulonephritis. He argued for protein restriction, as was becoming accepted for chronic uraemia, but it was in acute renal failure (ARF, or AKI) that real progress was being made.

An Edinburgh diet prescription
in the 1960s. Borst, Bull and
Addis ushered in an era of
precise dietary prescription in
renal failure.

The year before, Geerd Borst, Professor of Medicine in Amsterdam, published a landmark paper on the management of renal failure. In ARF he argued for radical restriction of protein and electrolytes. 20 years before it had been shown that the greatest reduction in urea production in healthy people was achieved by giving excess calories and a protein-free diet. The excess calories reduced breakdown of endogenous protein, mostly muscle protein. It seemed desirable to reduce this in patients with renal failure, as protein metabolism seemed to be toxic in animals and from clinical experience. The toxin was not necessarily urea itself though Borst seemed to assume so.

It was difficult to give enough calories to patients with severe renal failure, as they become anorexic and vomit. However enough calories could not be given intravenously in these pre-central catheter days. Borst described a diet of butter and sugar for patients with ARF, and described the effects in one normal individual, 3 patients with acute renal failure (ARF) and 2 with severe chronic renal failure (CRF). Only one survived, his kidneys opening up after 5 days of anuria, but the biochemical effects were encouraging. To improve palatability they later added some custard powder to the mix. As recovery occurred they allowed more protein.

Two diets for acute renal failure:

Borst, 1948 (Amsterdam)

Custard powder 100g 
Sugar 150g 
Butter 100g
Water 1.5 litres

Given as a gruel by mouth; provided 1750 calories.  No electrolytes, almost no protein.

Bull, 1949

Glucose 400g 
Peanut oil 100g 
Vitamins optional 
Water to 1 litre

Dripped in through a nasogastric tube; 2500 calories. No electrolytes, no protein.

They had Kolff’s revolutionary dialysis machine at their disposal but found it very hard to use – “we tried to free him from some of his urea with Kolff’s artificial kidney but failed through technical difficulties and our lack of skill”.

Bull’s 1949 paper from Hammersmith, West London, changed management. They took Borst’s observations along with those of Lattimer and others on fluid balance, and used them to develop a highly structured approach to the management of ARF. Lattimer had noted ‘the body is not analogous to a tank into which water can be forced until it finally bursts out through he kidneys’, and described the risks of fluid excess.

So Bull and colleagues modified Borst's unpalatable diet for administration by nasogastric tube, restricted intake to one litre and did not give any electrolytes at all, but readministered any vomitus after filtering, to minimise electrolyte loss. They reported the outcome in 11 patients with ARF caused by illegal abortion, mercury poisoning, and transfusion mismatch. Seven survived oliguria of 7-20 days, a remarkable achievement.

Bull’s report came from the same institution that had described the results of using Kolff’s artificial kidney the year before. While the paper was positive, the feeling on the ground was not – there was no further use of haemodialysis there until Shackman re-established a programme to support transplantation, and it was only in 1956 that haemodialysis returned to the UK. Conservative therapy became the accepted mode of management. It is still effective, and it is still the only therapy available for many in developing countries.

Borst noted that failure of dietary therapy was likely in ARF where there was muscle necrosis as in the Crush Syndrome described in West London by Bywaters, in major trauma, and if infection occurred, all of which led to increased endogenous production of urea (i.e. muscle breakdown). These limitations of conservative management led to trials of dialysis in the Korean War.

There was to be a long wait before the role of dietary composition in chronic renal failure became as well understood.

Further info

Addis T 1949. Glomerular nephritis. Macmillan, New York

Borst JGG. Protein katabolism in uraemia. Lancet 1948 ii 824-8

Bull GM, Joekes, AM, Lowe KG. Conservative treatment of anuric uraemia. Lancet 1949 ii 229-34
History of diet from the Edren History pages (www.edren.org)
Diet for chronic uraemia from this blog

Who shall live? Patient selection for dialysis

2011-03-15T23:03:00.000Z

Dustman before Duke?

Title from the 1965 NBC documentary
about dialysis in Seattle

The first patient with end stage renal failure deliberately taken on for dialysis was Clyde Shields, who was started on treatment by Dr Belding Scribner in Seattle in 1960. A couple of years later several more patients were being kept alive in Seattle, and other centres were taking it seriously and attempting the same. By 1964, pressures were mounting on all units, so that it became increasingly necessary to turn patients away.

Efforts to reduce costs were introduced in attempts to treat more patients. Monitoring devices reduced the amount of supervision required. Dialysis became a treatment run without doctors by nurses and technicians. Subsequently, staffing was reduced further by getting patients to take on the work - even sending them home with machines to run the entire process themselves. These were truly empowered patients who became much more in control of their lives. But still dialysis was too expensive to take on all the potential patients, and different ways to manage this evolved.

In the UK, a common approach was simply to take on the next available patient if there was a space, while all others died - first come first served: ‘If the dustman comes before the duke, the dustman gets treated’ (Freda Ellis attributed this comment to Dr Victor Parsons in Leeds). So you just had to be lucky and develop end stage renal failure at the right time and place. Generally only young and otherwise fit patients were referred to renal units, although some did put in place official or unofficial age limits (such as age less than 40), or exclusion criteria such as diabetes or other comorbid conditions, or a simple test ‘can we get her/him back to work?’ or ‘can we get them onto home haemodialysis’.

Other centres adopted more formal criteria and processes. In Seattle an age range of 18-45 was accepted at first, but soon a series of medical, social and psychological assessments led to consideration by the 'Life and Death Committee'. This was made up of 7 anonymous individuals who were given the task of judging between the candidates put forward. This story is told in an outstanding NBC documentary from 1965. It tells of the transforming effect of dialysis on those who could get it, the brutal consequences for those who didn't, and describes the cost and political issues behind the policies. The essential medical criteria from the Mayo Clinic in 1964 are shown in the figure. The criteria in Seattle were identical except for the mention of a transplant donor, which was a common criterion in units where dialysis had been set up to support a developing transplant programme, which was common in these early years. The first diabetic patient was taken on in Seattle in 1969, nine years after Clyde Shields.

Mayo clinic criteria in 1964. From 1964 meeting in Seattle

It is tempting to think that these problems have gone away. However most of the world's population lives in countries which still do not have the capacity to provide dialysis for all who need it. Here are the 2010 Tier 1 criteria for dialysis in the public sector in South Africa - they are remarkably similar:

Tier 1 – should receive dialysis in the public sector

Age <50
BMI <30
HIV negative
HepBsAg negative
Suitable for transplantation
No other negative factors

Others can be considered if facilities permit (Tier 2) if

Home circumstances good (space, electricity, running water and sanitation)
Well motivated and supported
Able to afford transport
HIV excellently controlled for 6 months
HBV/HCV positivity without cirrhosis
Non-smokers with no drug dependency or abuse
No diabetes or other comorbid disease

Interestingly, the annual cost of dialysis in South Africa today is estimated at $10,000 per annum, which is exactly the same as the Seattle price in 1965. The estimated UK cost in 1965 was £2,000, equivalent to about $6,000 then. The 2010 price for centre-based haemodialysis in England is now £22,000, $35,000.

Thanks to Dr Gavin Dreyer (Blantyre, Malawi), Prof Sarala Naicker (Johannesburg, South Africa), Prof Chris Blagg (Leeds, UK and Seattle, USA) and Prof John Feehally (Leicester, UK) for discussions and material for this article, which will also be published in the Journal of Renal Nursing

Further info

How South African doctors make life-and-death choices (BBC News link)
Moosa MR et al 2010. Guideline: Priority-setting approach in the selection of patients in the public sector with end-stage kidney failure for renal replacement therapy in the Western Cape Province.
Tomorrow's World 1st edition 1965: view online from the BBC
Proceedings of the Working Conference on Chronic Dialysis (Seattle, December 1964)
Wellcome Witness to the History of Medicine 2009. History of dialysis in the UK (large pdf).

The Korean War 1950-3: acute dialysis finds its place

2011-01-18T00:00:00.001Z

War medicine tests science and dialysis

In June 1950, North Korea invaded South Korea. After a rapid advance, their army was repulsed by American and Commonwealth reinforcements, but in November China joined the war and the battle lines moved back and forth until settling around the 38th parallel marking the border. Fighting continued until an armistice in July 1953.

Evacuation helicopter, early 1950s

Receiving ward in a MASH

(Photos from Walter Reed Army Medical Center, US Army Office of Medical History)
As is well known from the TV show and film MASH (Mobile Army Surgical Unit), the US forces established several forward MASH units near the front line. About half an hour's flying time to the South were Evacuation Hospitals for more complex cases.

The high rate of death in military casualties who developed acute renal failure (ARF, now termed Acute Kidney Injury, AKI) had been noted in the second World War (1939-45), and was seen again in the early part of the Korean War, when it was reported that 80-90% of soldiers with ARF died.

Because of this a specialist Renal Center was established under the auspices of the US Army Surgical Research Team at the 11th evacuation Hospital of the 8th Army. Dr Paul Teschan arrived from the Walter Reed Army Medical Centre in Washington DC to lead this group in 1952, and soon after an artificial kidney arrived from Washington. Patients who were oliguric despite reasonable blood pressure were evacuated from the MASH that was managing them to be treated by this specialist team.

Brochure illustration of the Kolff Brigham dialyser made by Edward Olson Company

The Kolff-Brigham dialyser used in Korea was a Boston-modified version of Kolff's rotating drum machine. A first account of experience with it was published in September 1952, so it was a technical marvel that the team were just learning to use. It had an open dialysate bath and therefore no means of adjusting ultrafiltration rate, other than by adding glucose to the bath to achieve a temporary osmotic effect. Techicians, doctors and nurses needed to be in attendance throughout each treatment of a single patient. It was used 72 times on 31 patients during the last eight months of 1952.

Careful conservative management was the mode of care of almost all patients with acute renal failure at this time, and conservative management had become so well understood that in good units, periods of oliguria of up to 2-3 weeks could be managed in this way without dialysis. The important principles were:
•    monitor fluid balance strictly
•    tightly restrict sodium intake to be no greater than losses
•    minimal or no potassium intake
•    protein-free high calorie intake to reduce muscle breakdown and urea generation

However the type of renal failure that occurred in victims of military trauma, as in crush injuries in the Blitz in 1940, did not do well with conservative management. Tissue trauma and catabolism led to rapidly rising potassium commonly leading to death within days. Blood transfusion, though often substantial, did not seem to be a major contributor to hyperkalaemia.

The mortality of acute renal failure after the introduction of this focused management, including dialysis, was reported to fall from 87% to 53%. The patients who required dialysis had a higher mortality, about 70%. The indications for dialysis were mostly life-threatening hyperkalaemia, or frighteningly high blood urea levels. Later, Teschan proposed 'prophylactic' dialysis in patients with blood urea over 200 mg/dl, 70 mmol/l. In the patients in Korea, urea values at the time of dialysis were often much higher than this.

Teschan reported 'Having controlled or eliminated the original causes of mortality by means of fluid restriction, electrolyte management, and dialysis, acute renal failure was then revealed as a wasting disease, often accompanied by infections, poor wound healing until diuresis occurred, anaemia and bleeding, and hypertension during dialysis and in early diuresis'.

Dialysis with this technology was a labour intensive, expensive and hazardous operation and it is understandable that it was reserved till the end of a long period of conservative management. Merrill (1955) aptly described it as an adjunct, not a replacement for good conservative management. Dialysis still has an adjunctive role in addition to conservative management, but where it is now readily available earlier dialysis enables us to be more generous with nutrition and to be more sloppy with our salt and fluid balance. The latter at least is not necessarily a good thing; and dialysis still has real risks – perhaps we now often step in too soon.

Importantly, the Korean experience convinced others that dialysis had a place after all. By the end of the decade physicians and surgeons around the world were gearing up use it not only to support acute renal failure, but also for their fledgling transplant programmes.

Further info

This excellent but tiny movie gives some colour to the story. This originally came from the Walter Reed site Army Medical Center site but it doesn't seem to be there any more. Or try running it from www.edrep.org

Teschan PE 1955. Haemodialysis in military casualties. ASAIO Journal 1:52-4
Smith LH et al 1955. Post-traumatic renal insufficiency in military casualties. II. Management, use of an artificial kidney, prognosis. Am J Med 18:187-98
Murphy WP, Merrill JP et al 1952. Use of an artificial kidney. J Lab Clin Med 40:436-44
Merrill JP 1955. The Treatment of Renal Failure. Grune and Stratton, New York.
Interview with Dr Paul Teschan in 2007 from the Oral History Project
Teschan PE 2011. Building an acute dialysis machine in Korea. Hemodialysis International 15:3-7.

Photos are from the Otis Historical Archives of the US National Museum of Health & Medicine (Army Medical Museum) in Washington DC, and from the Walter Reed Army Medical Center

A version of this article will be published in the Journal of Renal Nursing in Feb 2011.

Hepatitis outbreaks run through renal units: 1964-72

2010-11-06T22:17:00.000Z

Staff as well as patients die, and new patients are turned down in affected centres

From about 1964 there was increasing excitement that dialysis might become a major life-saving treatment for chronic renal failure, not just for acute renal failure. Transplantation was also in its infancy, but despite some promise, overall success rates at this time were very poor. A major frustration was the lack of resources to give dialysis to all who could benefit. Some remarkably bold approaches included self-dialysis and home dialysis, for reasons of space and economy as well as patient independence.

A notorious anonymous editorial in the Lancet in November 1965 railed against the expansion of dialysis, complaining that it was consuming resources and diverting the attention of nephrologists who ought to be spending time on developing transplantation and blood pressure treatments. In the following three weeks, 5 pages of letters of protest were published from the renal units at Charing Cross, Edinburgh, Exeter, Leeds, Newcastle and the Royal Free, and from patient and medical student Robin Eady from Guy’s.

Hepatitis outbreaks in the UK, 1964-71 (Marmion 1982)

One paragraph of the gloomy editorial mentioned a recent serious outbreak of hepatitis at Manchester Royal Infirmary which had already affected over 50 people, and killed a nurse and a hospital porter. It later extended to 14 members of staff, with a further death. “Clearly the risk of similar outbreaks in other dialysis centres cannot be discounted”. This turned out to be the article’s only accurate premonition.

This Manchester outbreak turned out to be just the beginning, similar outbreaks affecting multiple units in the UK and worldwide. Edinburgh had one of the worst experiences with a particularly high mortality. The outbreak began when a patient was given a blood transfusion from a donor who turned out to be incubating hepatitis. In just over a year from June 1969, 26 dialysis patients were affected and 7 died. 12 members of staff developed hepatitis, of whom 4 died, two transplant surgeons and two technicians. Renal units now caused fear not only because of the complexity of their diseases and treatments.

The ‘Australia antigen’ was linked to serum hepatitis in 1966, leading to the identification of hepatitis B, and testing became widely available in 1969. It became apparent how extraordinarily easy it was to transmit hepatitis B. The Rosenheim Report in 1972 made recommendations about prevention, and coincided with a decline in new cases and the end of outbreaks. However in the same year the European Renal Registry recorded that 499 members of staff contracted hepatitis across 568 reporting renal units in Europe, with 12 deaths (2.4%).

Further expansion of dialysis slowed markedly, and in some units no new patients were taken on for a prolonged period. In many centres, and notably in the UK, there was a strong move towards home treatments delivered by patients. Vaccination against hepatitis B only became available from 1979 and was widely implemented in the 1980s. Newcomers sometimes wonder why current protocols for hepatitis testing remain so strict given the availability of vaccination, but history makes this clear.

In Edinburgh, the experience was so powerful that the full story was not presented at an internal meeting for 35 years. The memories of carrying out exchange transfusions on a dying surgical colleague in his own unit are indelibly imprinted on the minds of those involved. At the time it was not clear who would develop the disease next or when the epidemic would end.

The 1975 novel by Colin Douglas ‘The Houseman’s Tale’ is an outrageous, sexist, darkly funny and eventually moving novel of junior doctor life with the epidemic of hepatitis in the background. It was written by a doctor who was a senior student and house physician in Edinburgh at the time of the outbreak. Essential reading for renal unit staff; out of print but available online.

Further info:
Cameron JS 2002. A History of the Treatment of Renal Failure by Dialysis (OUP)
Editorial. Hepatitis and the artificial kidney. Lancet 1965 ii 1000
Editorial. Hepatitis in dialysis units. Br Med J 1970 iv 255-6
Editorial. Profit and loss in intermittent haemodialysis. Lancet 1965 ii 1058-9; responses 1182-4, 1245-7
Marmion et al 1982. Dialysis-associated hepatitis in Edinburgh; 1969-78. Rev Infect Dis 4:619-37

Dropsy, nephrosis, nephrotic syndrome

2010-08-31T22:29:00.000+01:00

The first effective treatment for a kidney disease, 1950.

Dropsy is an ancient word (first recorded about 1290 AD) meaning oedema. Generalised oedema can be caused by heart or liver or kidney disease, or by malnutrition. In all of these it was a pretty bad sign in ancient medicine as it meant that the patient had advanced disease that was likely to kill them. By the early 1800s it was realised that some patients with dropsy had albumin in their urine.

A woman with dropsy. From Albert
JLM; Nosologie naturelle; ou, Les
maladies du corps humain
distribuees par familles. Paris:
Carpelet, 1817.
(US National Library of Medicine)

Richard Bright, working at Guy’s Hospital in London, showed that kidney disease could cause dropsy. His studies were mostly post-mortem, and his patients had advanced renal failure, but he also realised that some patients had low levels of albumin in their blood because it was leaking from their kidneys. What we now call Glomerulonephritis was for over a century known as Bright’s Disease.

Only two years after Bright’s 1827 paper, Robert Christisson in Edinburgh described patients with episodes of dropsy and albuminuria who got better without treatment and without developing ‘uraemia’, and others who had proteinuria not severe enough to cause dropsy. Accounts of relapsing dropsy in children followed soon after – the condition we now call minimal change disease. 1827 was 12 years after the battle of Waterloo and 22 after Trafalgar. Beethoven died that year, Charles Dickens began work in a law office aged 15, and Charles Darwin, aged 18, dropped his medical studies after two years for science.

German pathologist Friedrich von Muller introduced the term ‘Nephrosis’ in 1905, meaning a non-inflammatory kidney disease, to be distinguished from Nephritis, the inflammatory type of Bright’s disease. This distinction is still useful, but Nephrosis soon became used also to describe the clinical picture of dropsy with proteinuria. Between 1930 and the 1950s the term Nephrotic Syndrome largely replaced it.

Because of lipid deposits in tubules (‘lipoid nephrosis’), for a long time it was suspected that the tubules, rather than the glomeruli, were the source of the protein leak. The changes in the tubules are in response to the protein leak, not the cause of it, but the glomeruli only became widely accepted as the source of the leak in the 1940s.

Treatment of nephrotic syndrome in a child in the 1950s.
Note the fall in weight from 15 to 10kg over about a week
as the protein leak responds to steroids. The oedema is lost
through natural diuresis as the disease recovers. (From de
Wardener 1958, with permission).

By 1949-50 the first exciting reports of a successful treatment for nephrotic syndrome were appearing, using the newly synthesised steroid hormones. This was probably the first effective treatment for any kidney disease. Very few other useful drugs were available. The mercurial diuretics, invented in the 1920s, were weak and toxic, and largely ineffective in nephrotic syndrome. Management consisted of salt restriction, with drainage of ascites by tube if abdominal swelling became intolerable, or by insertion of Southey’s tubes into the legs to drain massive oedema. Antibiotics were however reducing deaths from the severe infections which are common in nephrotic syndrome. Very high serum cholesterol was recognised to be a sign of the disease – plasma often white (lipaemic) from its fat content. A striking film from 1954 on Childhood Nephrosis ends on the upbeat note – ‘Childhood Nephrosis has by no means an invariably fatal prognosis … the outlook is heartening’, because with steroid treatment recovery could be expected in up to 50% of cases. The response rate in adults was much lower.

Today we have different treatments for over half a dozen common causes of the nephrotic syndrome, that we usually distinguish by renal biopsy. That technique was just developing in the 1950s, with many of the analytical techniques that we rely on coming still later.

Further information
Cameron, JS Hick J. 2002. The origins and development of the concept of a ‘nephrotic syndrome’ Am J Nephrol 22:240-7.
de Wardener HE. 1958. The Kidney (1st ed.). London, Churchill. The classic nephrology text.
Cooke RE. 1954. Nephrosis in chidren. Medicine Around the World, Vol 1 Film 4. Pfizer. Available from www.edina.ac.uk (with an academic login).

This post will be published in the Journal of Renal Nursing in September 2010.

The birth of home dialysis

2010-07-04T17:55:00.000+01:00

The first home haemodialysis, 1964

In the early 1960s dialysis was still a very new technology. It was high-tech, life-saving and dramatic. That you can run the the blood of conscious patients through a machine to replace a critical body function is still pretty amazing today. The idea of sending patients home to look after such a new, high-tech treatment themselves themselves must have seemed extraordinary. But dialysis was very expensive, and soon renal units were wrestling with how to stretch their resources to treat as many patients as possible.

The pressures led to changes on renal units. Nurses took on tasks that were originally the responsibility of doctors, technicians shared work on the team, even patients shared the work. Dialysis moved to become a nurse-led team treatment. Ann Eady recalls how the pressure of increasing numbers led to a transfer of the job of needling the fistula at Guy's hospital. These radical changes in renal units probably had much further reaching consequences in medicine than we generally appreciate.

Ray Jones started treatment in 1963 via indwelling arterial and venous femoral catheters, one of the 'Lucky 13' at London's Royal Free Hospital. When he died in 1991 after 29 years of treatment he was the longest surviving haemodialysis patient of his day. (Thanks to Joan Jones and Kidney Research UK).
Nancy Spaeth began treatment aged 18 in Seattle in 1966, switched to home dialysis in 1968 (pictured in 1969), and has experienced every modality of renal replacement therapy since. She is an active advocate for kidney patients today. (Courtesy of Nancy Spaeth)

However these changes were not enough. Staff salary costs still kept dialysis expensive, and units became physically full. Patients were mostly young, and had to be capable of working to be accepted for dialysis, but even then there was not capacity to treat those who needed it. For those lucky enough to be accepted, combining dialysis with work and family life were as difficult as they are now. However transplantation was a very high-risk gamble and if it failed you might not get back onto dialysis.

Haemodialysis carried out at home was introduced in three units thousands of miles apart in 1964, all responding to the same pressures. In Boston (Merrill) in July, Seattle (Scribner) in September, and in London (Shaldon) in October a patient received unattended overnight home dialysis for the first time. All used Scribner shunts. Some used machines made by patients families, and some of the early patients were healthcare professionals, but quickly the spread widened. In the same year, Boen reported visiting a patient at home in Seattle to carry out intermittent PD by repeated puncture using a rigid catheter. However it was to be two more decades before peritoneal dialysis could become established as a realistic medium to long term home option.

Some of the earliest UK home dialysis patients appear in the first episode of Tomorrow's World 45 years ago (7th July 1965), available on the BBC website, but that was filmed at the Royal Free Hospital's unit. A remarkable Pathe newsreel the same year shows Olga Heppell dialysing at home in Harlow. Her machine was in part manufactured by her husband.

MECHANICAL KIDNEY SAVES WIFE'S LIFE - British Pathe newsreel 1965 (click on photo to watch)

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In 1965 Stanley Shaldon reported that giving the work to patients in the unit, primarily as a cost-saving measure, led to an increase in quality of care and in patients' independence. By 1968 he was writing about the additional benefits in independence and quality of life from home haemodialysis. Has this changed? Probably not.

Now home haemodialysis is on the rise again. The blogosphere is filled with enthusiastic accounts from patients doing daily dialysis at home, reporting much better health and quality of life. Machines are moving toward supporting home haemodialysis better. Getting the numbers really high again is made challenging by the different profile of patients today: older, with more comorbidities and greater dependencies. But it was always the best long term treatment if you couldn't get a safe transplant, and it probably still is.

Further information
Cameron JS 2002. A history of the treatment of renal failure by dialysis. Oxford University Press, Oxford
Wellcome Witness to the History of Medicine 2009. History of dialysis in the UK.
Spaeth N 2007. The nurse, mother of two and four transplants - Nancy Spaeth tells her story. Nephrol Dial Transplant 22:64-7
First episode of the BBC TV programme Tomorrow's World in 1965

This post will be published in the Journal of Renal Nursing in July 2010.

Dialysis for endstage renal failure in the UK

2010-04-25T18:10:00.000+01:00

Good news travels quickly

In September 1960 Scribner recounted his first 6 months experience of dialysis via the new AV shunt at the first International Society of Nephrology meeting in Evian, which had just launched its mineral water. (If you haven't already, you might start by reading Dialysis for endstage renal failure in the world. It's the post below this one.) At that meeting was Stanley Shaldon, then Sheila Sherlock’s Lecturer at the Royal Free Hospital in London. He had come to present a paper on diuretics in liver disease, but was impressed by Scribner’s presentation, and by another by Nils Alwall from Sweden, which hinted at the feasbility of long-term dialysis. The Royal Free Hospital had a dialysis machine, set up by urologist John Hopewell specifically to support patients with end stage renal disease in preparation for transplantation, which he was developing there with the aid of Roy Calne. However at this stage the machine had mostly been used for acute renal failure.

Early the following year Shaldon tested the technique he had used to study liver blood flow – Seldinger insertion of vascular catheters into femoral vessels without a surgical procedure – to connect patients to the dialysis machine. He went on to develop maintenance dialysis using this technique and you can see a remarkable Movietone newsreel from 1963 describing this. The Royal Free became the first UK centre to treat chronic renal failure by dialysis.

In December 1963 Newcastle became the second unit in the UK to start treating end stage renal failure by dialysis.

At the second International Society of Nephrology meeting in Prague in 1963, Hugh de Wardener found that Scribner’s patients were still alive, so sent a team to Seattle to learn the technique. They returned to set up a unit specifically for long-term dialysis, the third unit providing it, which began work at Fulham Hospital (a branch of Charing Cross Hospital) in August 1964.

An accepted treatment

The speed of change was dramatic. In the first edition of deWardener’s book on the new specialty (The Kidney) in 1958, the treatment of terminal chronic renal failure was entirely palliative, involving use of chlorpromazine, morphine and paraldehyde. Only six years later in the second edition there was discussion of peritoneal as well as haemodialysis and of transplantation, with the prescient prediction that none of these would be able to meet the new demand for treatment. After the technical hurdles, and professional resistance, finance became the third barrier.

The first episode of the BBC TV programme Tomorrow's World in 1965 featured the Royal Free dialysis programme led by Stanley Shaldon and including some early home haemodialysis, and hospital footage of one of the remarkable long term patients, Robin Eady. Watch it online.

A committee established by the Department of Health, which included de Wardener and David Kerr (Newcastle) recommended the building of a renal unit in each health region throughout the UK to cope. 35 were built within 5 years – a great start, but indeed it did not prove enough, and it was probably only in the 1990s that the UK completely caught up with providing dialysis for all those who could benefit. This progress would probably have been impossible and unaffordable if the results of transplantation had not improved beyond all recognition across the same period. Photo - one of the 35 units - Edinburgh 1969

Further information

Cameron JS 2002. A history of the treatment of renal failure by dialysis. Oxford University Press, Oxford

Wellcome Witness to the History of Medicine 2009. History of dialysis in the UK.

Cameron JS 2000. The first half-century of the Renal Association, 1950-2000. www.renal.org/aboutus/History.aspx

Edren - early history of dialysis and transplantation

de Wardener HE. 1958, 1964. The Kidney. London, Churchill.

Hopewell J. 2009. The early history of the treatment of renal failure.

First episode of the BBC TV programme Tomorrow's World in 1965

Dialysis for endstage renal failure (ESRF, ESRD)

2010-04-25T17:56:00.000+01:00

The obstacles started to fall in 1960

On the 9th March 1960, Clyde Shields, a Boeing machinist in Seattle, was started on haemodialysis despite having chronic kidney failure. He was the first long-term dialysis patient and the beginning of a revolution. He survived with transplant until 1971, but he is unlikely to have suspected at the outset that he could have been beginning such a remarkable chapter of medical progress.

Belding Scribner, his renal physician, had brave ambitions. He was testing ways of using both peritoneal dialysis and haemodialysis to keep patients with permanent renal failure alive. Most other centres were not keen to follow his example. Probably they felt they had enough work to do already with expanding acceptance of a role for dialysis in acute renal failure. Plus they had bad experiences with attempts at prolonged dialysis in acute renal failure.

The barriers to the new technique were enormous. The first was technical. In the early days of haemodialysis, each treatment required a cut-down to cannulate an artery and a vein in the arm or leg. The tubes were removed afterwards and the use of that vessel lost. Attempts to leave short term tubing in place were met by frequent clotting and infection. Only glass had some limited success in preventing clotting until polytetrafluoroethylene tubing (PTFE, or Teflon – the non-stick coating on pans) was applied to the problem by Belding Scribner, the Seattle nephrologist, with engineer Wayne Quinton. Quinton’s name is commonly associated with the central venous catheters he developed later.

The first shunts were made of rigid tubing. Later, Quinton introduced a loop of flexible silicone rubber tubing between short PTFE tubes (see illustrations, which show Edinburgh adaptations of the Seattle innovations). The shunt quickly became the mainstay of vascular access for acute renal failure, and a troublesome method for long-term dialysis, because it was prone to clotting, stenosis and infection. The development of the subcutaneous Brescia-Cimino fistula in 1966 really made long term dialysis feasible, but it began without it.

Scribner took Clyde Shields with his mother to the American Society of Artificial Organs in Atlantic City in April 1960, when he had been on dialysis for only a month. At a breakfast meeting he showed him to Willem Kolff (the inventor of the first effective dialysis machine), John Merrill and George Schreiner. Although they didn’t present a paper at the meeting, Schreiner allowed a first report to be added to the published record of the meeting, of which he was the editor.

Robin Eady is the only survivor from this very first generation of patients, although there is now a series of remarkable accounts of patients who commenced dialysis in the mid to late 1960s. Eady was a medical student at Guy’s Hospital in London in 1962 when he became ill and was found to have very advanced, irreversible renal failure. Having been advised to let things take their natural course by several doctors, his parent were able to send him to Seattle where Scribner got round the prohibition on taking on new patients by explaining that Eady was to be trained as a renal technician. He dialysed there from February 1963 alongside Clyde Shields and two of the other pioneer patients, after 4 months moving on to Edmonton (Alberta, Canada), then to the Royal Free Unit in London. He married, became a home haemodialysis patient, a dermatologist, and eventually a transplant recipient and professor of dermatology.

Further information

Cameron JS 2002. A history of the treatment of renal failure by dialysis. Oxford University Press, Oxford

Wellcome Witnesses to the History of Medicine 2009. History of dialysis in the UK.
Blagg CR 2010. The first dialysis for chronic renal failure 50 years ago. Hemodialysis International 14:1-2

... and in the UK, continued in the next post.
Both posts published in the Journal of Renal Nursing in May 2010.

The first randomised controlled trial in dialysis

2010-03-08T21:16:00.000Z

In 1980 the NCDS led to the first minimum standards for dialysis

The National Cooperative Dialysis Study (NCDS) reported in March 1980. It led to the widespread acceptance of minimum standards for 'dialysis dose' worldwide. However few people have read the full study. It is hard to find in libraries, and you can't get it online.

Dialysis in the early 1980s

In the 1970s, 'Generally, any change in a patient's treatment was influenced more by the need to remove fluid than it was by the need to remove metabolic waste' wrote Ed Lowrie in his introduction to the NCDS report. The trial was designed to investigate whether the removal of waste products could be usefully measured. Urea clearance was chosen as the method to test.

Clearance by dialysis was not routinely estimated at the time. A standard prescription was usual. In 1967, the Charing Cross Hospital regimen was described as 10 hours 3 times weekly at home, or 14h twice weekly overnight in hospital. Times shortened as dialysers became more efficient, and as pressure of patient numbers encouraged higher throughput.

The NCDS was a collaborative randomized controlled trial (RCT) between 9 renal units, a rare event in nephrology in the 1970s, and new to dialysis. The patients' mean age was 49, and they had been on dialysis for an average of 4.2 years. Half were white, there were no diabetics, many were taking androgens in attempt to raise haemoglobin in the pre-erythropoietin era, and in these ways the population was probably fairly typical of the time.

151 patients were randomised to two different average urea concentrations (adjusted by varying dialyser size and flow rates), and to two different durations of dialysis (2.5-3.5h and 4.5-5h three times weekly), in all 4 possible combinations, for 6-12 months.

Patients in the groups with higher average ureas (predialysis urea 38 versus 26 mmol/l (107 versus 72 mg/dl)) were more likely to be withdrawn from the study or admitted to hospital, and this led to the study being stopped in 1980. There was no significant mortality difference - in fact there were only 3 deaths in the study, but two of these were in the high-urea, short-dialysis group, which also had the highest rate of cardiovascular events (44%) and hospitalisation. However at the end of the (prematurely finished) study, the effects of increased urea removal looked greater than the effects of longer dialysis, and only the urea difference reached conventional levels of statistical significance. The long vs. short dialysis results were suggestive, but were dismissed as not significant in the main report, and mostly overlooked in subsequent analysis.

Proportion of patients who had no hospital admisssions with time during the NCDS. I = higher Kt/V, longer dialysis; II = lower Kt/V, longer dialysis; III = higher Kt/V, shorter dialysis; IV = lower Kt/V, shorter dialysis. From Parker et al, fig 5, full NCDS report.

The major publication from the NCDS focused on the analysis of urea clearance, and it has become one of nephrology's classic papers. The follow-on (1985) publication by Gotch and Sargent introduced the measurement of Kt/V, and this used together with the NCDS headline results have been very influential. An equilibrated Kt/V of 1 was their recommended minimum. It is equivalent to a single-pool Kt/V, the usual one we measure, of about 1.21. Kt/V remains a central element haemodialysis in guidelines 30 years later.

However targeting a desired Kt/V had some unintended consequences. Increasingly efficient dialysers made it possible to reduce treatment times dramatically, likely to lead to cumulative fluid overload and cardiovascular complications. In that way overinterpretation of the NCDS may have led to some avoidable deaths.

By modern standards, the NCDS was very small, certainly too small to be confident that shorter treatments were safe. Further studies were certainly needed, but the NCDS was pioneering and important.

Dialysis dose has been tested further. After the NCDS helped set a minimum Kt/V, it was noted in many observational (non-randomized) studies that patients with higher Kt/V had better survival. People still believed that this was a causative relationship until the HEMO study of 1846 patients (more than 10 times the size of the NCDS) published in 2002 definitively showed that increasing single pool Kt/V from 1.3 to 1.7 gave no extra benefit in patients on fixed duration thrice weekly dialysis. (Equilibrated Kt/V rose from 1.16 to 1.53.)

Treatment time is receiving much greater attention again but we have still not had an adequate RCT comparing different dialysis durations or frequency. Nearly everyone believes more frequent or longer treatments are better, but these are expensive and difficult for patients, and as the HEMO study showed, we could be wrong. We really need a trial.

References

de Wardener HE, 1967. The Kidney. London, Churchill. The classic early nephrology textbook.

Lowrie EG et al, 1981. Effect of the hemodialysis prescription on patient morbidity. N Engl J Med 305:1176-81

Lowrie EG, NM Laird (eds), 1983. The Cooperative Dialysis Study. The full report was Supplement 13 to Kidney International

Gotch FA, JA Sargent, 1985. A mechanistic analysis to the National Cooperative Dialysis Study. Kidney Int 28:526-34

Eknoyan G et al, 2002 Effect of dialysis dose and membrane flux in maintenance hemodialysis. N Engl J Med 347:2010-9

This article will also be published in the Journal of Renal Nursing in March 2010.

Bombs, earthquakes and rhabdomyolysis

2010-01-12T22:57:00.000Z

Seventy years ago the Battle of Britain led to recognition of a new disease and to important discoveries about acute renal failure

(Haiti earthquake, January 2010)
In the Summer of 1940, the German Luftwaffe switched its bombing targets from English airfields and aircraft factories to cities, and in September 1940 large scale air raids on London began. Shortly afterwards, a new type of acute renal failure was noticed in some of those rescued from fallen buildings.
Case 6 from the BMJ March 22nd 1941 (Mayon-White and Solandt, pages 434-5). She died after 6 days of oliguria by which time her serum urea was 62 mmol/l (369 mg/dl)

Typically the patient had been buried for several hours with pressure on a limb. On admission they often looked in good condition except for local swelling. Shock developed as fluid was lost into the crush site, but despite measures to restore the circulation, only small amounts of dark smoky urine were seen. Potassium and urea rose briskly, leading to death within 3-7 days despite careful management.
At autopsy, brown pigmented casts were described in the renal tubules, along with changes of what we now call acute tubular necrosis.
Six cases were published in the British Medical Journal of March 22nd 1941, 5 by Dr Eric Bywaters from Hammersmith Hospital in West London. All of the patients died, as did most of the others that the authors had been told of. Dialysis was not available in 1940, but the team was clearly aware of the importance of correcting shock and other core principles of managing acute renal failure (management of potassium, sodium intake).

Further pioneering work at Hammersmith on acute renal failure led to it becoming a referral centre for patients with acute renal failure of other causes. Soon after the war Bywaters obtained one of Kolff’s first haemodialysis machines to try out, and the Hammersmith team became the third in the world to use dialysis successfully. But it was high risk and very hard work with uncertain outcomes, and as medical management improved the machine was put on one side. Prof Kenneth Lowe, who later became a professor of medicine and cardiology, later described to Dr John Turney working with the Kolff rotating drum dialyzer in 1947 (see further reading below).

By 1942 Bywaters had proved that the brown pigment in the tubules was myoglobin from muscle, and was nearly convinced that this was the culprit in causing kidney damage. He proposed urinary alkalinisation (which had been tested for haemoglobinuria) and treatment of shock by fluid replacement as the emergency treatment most likely to prevent myoglobin precipitating in tubules and acute renal failure. This remains the recommended first line therapy today.
Bywaters later discovered similar cases in German literature from the 1914-1918 war, and references to it from accounts of the Messina earthquake of 1909. By 1942 the MRC had received notification of 70 cases, and Bywaters estimated that it may occur in 5% of air raid casualties in urban areas.

Rhabdomyolysis continues to occur today after bomb blasts during peace and war, and in devastatingly large numbers in earthquakes when getting the survivors to the needed treatment is most difficult. At the time of writing this there is breaking news of an earthquake in Haiti which is certain to create another surge in cases requiring urgent treatment. It is also seen after prolonged unconsciousness caused by epilepsy or drugs, and sometimes by sudden arterial occlusion by thrombosis or inadvertent arterial injection. The threshold for causing rhabdomyolysis may be low for inherited reasons, or by taking certain drugs.
Dialysis is often life-saving in rhabdomyolysis. Medical management would always struggle to cope with the rate of metabolite release in rhabdomyolysis and in other catabolic acute renal failure. Dialysis returned to the management of acute renal failure in the UK in 1956, some years after it had been tested severely in the Korean war.

Further information
Bywaters EGL, D Beall. Crushing injury. Br Med J 1942 ii 643-6
Wellcome Witnesses to the History of Medicine 2009. History of Dialysis in the UK. (p79-83 for Prof Lowe's account)
Rhabdomyolysis (edrep textbook)

The first successful transplants, 1960-70

2009-11-09T08:52:00.000Z

For patients, a last throw of the dice

The first human transplants were heroic operations undertaken at a time when dialysis was not a long term option. A few outstanding stories kept hopes high, but in general, the outcome of these early experiments were downheartening.

Photos: Linda Phillips in 1966, at the Western General Hospital, Edinburgh; and at BBC Radio Scotland for an interview in 2008. She had to be carried to this bench for the photo, and received brief dialysis before her transplant from her mother a few months later. 41 years after her transplant she was back on dialysis but well.

After many failed efforts since the first attempt in 1936, the first success was in Boston in 1954. It was between identical twins, so rejection was not a concern. However behind the scenes a great deal of experiment animal work was going on in Boston and elsewhere into surgical technique and possible ways to prevent rejection, with occasional successes.

The UK’s first successful transplant, also between identical twins, was done in Edinburgh by Michael Woodruff in September 1960. The hospital superintendent reported “I think the recipient has a sporting chance of getting away with it”. He did, and died of cancer 6 years later. A second, brother-sister transplant the following year led to death from sepsis after whole body radiation. A third in 1962, only the second transplant using azathioprine, lasted for 20 years.

Meanwhile from 1958 at the Royal Free Hospital in London, John Hopewell and Roy Calne were experimenting with mercaptopurine, the forerunner of azathioprine, and undertook their first attempted transplant in November 1959. Their first potential donor had died of a subarachnoid haemorrhage – they both recall their horror and disappointment at finding that their donor had the same kidney disease – polycystic kidneys – as the patient waiting for the transplant. A second donor’s kidney lasted only 3 days. However their third case, a live donor kidney recipient in November 1960 lived for 49 days, and was found at post mortem to have miliary tuberculosis.

However overall the results were poor. Kolff (the inventor of the first successful haemodialysis machine, now working in the USA) summarised the Cleveland Clinic’s figures and reported world experience to March 1964. He recorded 336 non-twin transplants, of whom 102 were living – but only 14 had been alive more than one year, and 2 for more than 2 years.

From the UK, Parsons and Clark wrote to every transplant unit in Europe in 1965. They learned of 258 transplants and gained information on 187. Two kidneys came from chimpanzees, 100 from deceased donors and 89 from living donors. 22 (maybe 10%?) lived for more than 10 months. 37% of living donor kidneys failed in the first month; 63% of cadaveric. Only 5 of 48 recipients of failed grafts were kept alive by intermittent haemodialysis, the long-term use of which remained a fairly experimental technique at this time.

Early anti-rejection protocols included whole body irradiation, invented as a technique to suppress the immune system in 1956, so new transplant units were built next to radiotherapy units. Mortality from infection after irradiation was extremely high, and this inflenced the design of transplant units. A common UK transplant unit design was a row of single rooms with a glass corridor for relatives to wave to the recipients through the window.

Roy Calne joined the Department of Surgery in Boston under Francis Moore in 1960 and brought the use of azathiopine to Dr Murray’s lab and developed its subsequent use. It was only when the use of azathioprine in combination with prednisolone (steroid) for suppressing the immune system became better understood that the statistics began to improve perceptibly. In Edinburgh by the end of 1974, since 1960 127 patients had renal transplants, of whom 37 (29%) remained alive with functioning grafts at 6 months or more. 28 patients had lived more than 2 years, 13 patients more than 5 years, 6 patients more than 8 years and 2 patients more than 12 years. 34 patients were employed, able to do housework, or in full-time education after transplant. 1 patient fathered a child, and 1 gave birth 3 years post-transplant (her photo is at the top of this post).

But by this time long-term haemodialysis was beginning to look more competitive, albeit arduous and expensive. This was a surprise to some, as in several centres it had been introduced by surgeons mainly as a technique to keep patients alive until a transplant could be attempted.

Further info:

Hopewell J, RY Calne, I Bewick, 1964. Three clinical cases of renal transplantation. Br Med J i 411-4
Murray JE. Human organ transplantation: background and consequences. Science 1992 256:1411-6
Kolff WJ, RA Straffon, S Nakamoto, 1965. Clinical experience with renal transplantation. Br J Urol 37:370-9
Murray JE. Human organ transplantation: background and consequences. Science 1992 256:1411-6
Parsons FM, Clark PB. Repon on renal transplantation in Europe, based on replies to questionnaire. EDTA Proc. 1965; 2: 157-60.
Woodruff MFA, Nolan B, Anderton JL, Abouna GM, Morton JB, Jenkins A McL. Long survival after renal transplantation in man. British Journal of Surgery. 1976; 63: 85-101.

Peritoneal dialysis becomes a treatment for endstage renal disease

2009-07-13T02:13:00.000+01:00

Many small improvements

Peritoneal dialysis (PD) for endstage renal failure was first given as intermittent intensive treatments (IPD) given continuously for 1-2 days once weekly. Patients would generally have a new rigid PD catheter inserted each week under local anaesthetic, be treated for up to 48h, then receive no dialysis for 5 days. Its first use this way is attributed to Richard Ruben in 1959, but the shortage of haemodialysis (HD) facilities led to it being widely used, despite its many problems, in the 1960s and 1970s. Even in the early 1980s some patients were being treated by intermittent puncture IPD in the UK.
Photo (Copyright reserved): Nora Kehoe with a newly implanted PD catheter, London 1987. It's the Maxwell system of 1959 with plastic fluid bags.

However the success of PD as a lasting treatment required better catheters that could be left in long term, and a reduction in the risk of introducing infection during fluid exchanges.
In 1959 Fred Boen published an impressive thesis in Amsterdam which helped to understand the capabilities of PD. The following year he went to Belding Scribner’s unit in Seattle to attempt to set up a chronic PD programme. An automated infusion and drainage system was developed, but maintaining peritoneal access without infection remained a key obstacle. For a time he tried home visits to insert a new PD catheter under local anaesthetic each week, an experience reported at the same time as the very first experiments were taking place with the even more revolutionary concept of home haemodialysis.

Henry Tenckhoff joined the Seattle group in 1963 and developed both home fluid production machines and the silicone Tenckhoff catheter, a modification of a design by Russell Palmer which was made by Wayne Quinton who had developed the Quinton haemodialysis catheter. Harold McDonald added a Dacron cuff, and Tenckhoff added the second one.
Dimitrios Oreopoulos encountered PD while training in Belfast in 1966, and in 1969 took on the 4-bed chronic IPD programme in Toronto. Coupling the Tenckhoff catheter with a cycling device made by Norman Lasker, who was sending patients home with these devices in Philadelphia, Oreopoulos developed a home IPD programme which had expanded to over 70 by 1974. Moncrieff and Popovich developed the continuous ambulatory (CAPD) technique in response to a patient with no vascular access in 1975, and Oreopoulos investigated this further in his patients in 1977, converting most to CAPD.

Further improvements in peritonitis rate were needed and the first commercial 2 litre bags and improved connection systems from Baxter in 1978 and 1979 made CAPD more generally possible.

When CAPD was introduced widely in the UK during the 1980s, haemodialysis places were very limited, and CAPD was seen as a way of broadening access to dialysis, for example by accepting patients with diseases such as diabetes who would otherwise have been excluded. The slow growth of HD capacity in the UK led to its PD programme burgeoning in the 1980s, so that by 1990 the UK had more patients on PD than on HD. 18 years later the total number of PD patients was about the same, but by now this was only 10% of endstage patients were on PD, with 43% on HD and 47% transplanted (UK Renal Registry).

Experience with CAPD proved that PD could work for years as a feasible treatment. Debate about its relative place as a longterm treatment will no doubt continue.

Further info:

International Society of Peritoneal Dialysis. The history of peritoneal dialysis. Only published online, and no longer available, unfortunately.
Boen ST. Peritoneal dialysis – a clinical study of factors governing its effectiveness. PhD thesis 1959 University of Amsterdam
Boen ST et al. Periodic peritoneal dialysis using repeated puncture technique and automatic cycling machine. Trans Am Soc Artif Intern Organs 1964 10:409-14
J. Stewart Cameron 2002. A History of the Treatment of Renal Failure by Dialysis (OUP)

The unsung story of early peritoneal dialysis

2009-06-11T22:26:00.000+01:00

The first successful mode of dialysis for acute renal failure and still not replaced

The beginnings of haemodialysis have been described many times, but the first successful peritoneal dialysis probably antedated the first successful haemodialysis by 7 years. Peritoneal dialysis was undertaken alongside haemodialysis in most renal units from the early 1960s, but also in many hospitals without renal units, and numbers are poorly recorded.

The first successfully treated patient was probably a patient with obstructive acute renal failure (ARF) at Wisconsin General Hospital, reported in 1938, and further success was reported from Boston by Fine, Frank and Seligman in 1945, about the same time as Kolff’s first successful haemodialysis. In the UK a 36 year old woman with ARF caused by mismatched blood transfusion was successfully treated by urologist Ronnie Reid in 1946.

These results followed years of research into the use of the peritoneum for dialysis, particularly by individuals and groups in Germany and the USA. Its use in patients with renal failure was reported by Ganter in 1923, but the familiar problems of peritonitis, leakage, drainage difficulty, and learning curve with electrolyte correction and fluid balance made early experiences discouraging.

In 1959, the year haemodialysis began to catch on in the UK, Morton Maxwell and his team in Los Angeles described a simplified and improved closed infusion/drainage system joined to a rigid catheter introduced in the midline through a trochar. They were responding to the difficulties of using the Kolff twin coil artificial kidney machine, which they described as a ‘formidable and costly procedure’. Their case histories reveal how much of a last resort dialysis was at the time. It was often not introduced before the patient was in extremis.

Paul Doolan, writing the same year from a naval unit which had used HD since 1950, described similar value (and problems) with a closed technique but with improved catheters that were the forerunners of modern PD catheters.

Maxwell’s technique has lasted and is in use in many parts of the world still - except that the use of pharmacy-mixed dialysate in glass bottles has mostly been superseded. Some centres continue to use rigid catheters rather than soft ‘Tenckhoff’ types, probably for reasons of cost. It remains important as a treatment for acute renal failure worldwide. Rigid catheter design was improved by the ‘Trocath’ introduced by Weston and Roberts in Los Angeles in 1964, which was inserted around a sharp stylet instead of through a hollow trochar, so reducing leakage.

However successful longterm use of PD for end stage renal failure required further technical progress.

Further info:
J. Stewart Cameron 2002. A History of the Treatment of Renal Failure by Dialysis (OUP)
Doolan PD et al. An evaluation of intermittent peritoneal lavage. Am J Med 1959 26:831-44
Maxwell MH, RE Rockney, CR Kleeman, MR Twiss. Peritoneal dialysis 1: technique and applications. 1959 JAMA 170:917-24
ISPD. The history of peritoneal dialysis. Originally published by the ISPD, now available here.
Boen ST 1959. Peritoneal dialysis – a clinical study of factors governing its effectiveness. PhD thesis, University of Amsterdam
The early history of dialysis (Edren)

Illustrations from Boen as above, and from Maxwell 1959 as above (all rights reserved by JAMA). This article will be published in the Journal of Renal Nursing in August 2009

Haemodialysis was first used successfully in 1945

2009-06-11T22:15:00.000+01:00

Willem (‘Pim’) Kolff’s remarkable achievement

Kolff is famously the man who first put the developing theory of therapeutic dialysis into successful practice in the most unlikely circumstances, in Kampen in the occupied Netherlands during World War 2. Influenced by a patient he had seen die in 1938, and in a remote hospital to avoid the Nazi sympathisers who had been put in charge in Groningen, he undertook experiments with cellulose tubing and chemicals and then went straight on to make a machine to treat patients from 1943.

His first 15 patients died, but the 16th, a 67 year old woman with acute renal failure caused by septicaemia, recovered after 11 hours of dialysis.
His rotating-drum kidney was a fearsome beast. Blood ran around cellulose (sausage skin) tubing which was wound round a drum made of wooden slats, dipping into the ‘bath’ of dialysate at the bottom of its turn. The movement of blood was powered by the rotation of the drum rather than a blood pump. The surface area of the dialyzer was respectable by modern standards at over 2m2, but it required up to two units of blood to prime the tubing before each dialysis, and ultrafiltration control was inaccurate and unreliable – achieved by adding variable amounts of glucose to the ‘bath’. Dialysate was made by stirring weighed salts into the tapwater bath. A water pump from a model T Ford powered rotation.

Kolff subsequently moved to the USA and went on to more remarkable things. His design was modified in Boston to make the Kolff-Brigham machine, which was widely used in the early 1950s and which through its use in the Korean war (1950-3) helped to establish the role of dialysis in acute renal failure. The Watschinger-Kolff twin coil kidney introduced the concept of the disposable dialyser, enabled more controllable ultrafiltration, and the Travenol machine that used it became the most widely used machine in the early days of dialysis. Kolff went on to found the ‘Maytag’ programme of dialysis using a coil in a washing machine at the Cleveland clinic, and to design artificial hearts and other bioengineering challenges.

His success with dialysis was dependent on the work of many who investigated its potential since Thomas Graham first described dialysis (and distinguished crystalloids and colloids) in 1861, and on technical developments, notably the development of cellulose tubing, and of heparin (instead of hirudin from leeches) as an anticoagulant. All of his practical experiments were on humans – he recounted that there was only his conscience as a brake. In the 1940s he investigated alternatives too, testing peritoneal dialysis and ‘intestinal dialysis’ too.

Nils Alwall (Sweden) and Gordon Murray (Canada) independently developed haemodialysis techniques and put them into practice shortly afterwards.

Willem Kolff died in 2009 aged 97.

Further info:
Sheldon T. Willem Kolff. BMJ 2009 338:b2027
Henderson LW. A tribute to Willem Kolff MD, 1912-2009. JASN 2009 20:923-4.
J. Stewart Cameron 2002. A History of the Treatment of Renal Failure by Dialysis (OUP)
The early history of dialysis (Edren)

The origin of our photo of one of Kolff's original rotating drum kidneys is not known. The photo of dialysis in Cleveland in the 1960s is courtesy of (and copyright of) Dr Y Nose.

Dialysis in the UK in 1959

2009-02-23T13:55:00.000Z

50 years ago dialysis suddenly caught on in the UK

In 1958 there were only 3 renal units operating in the UK, at Leeds, Hammersmith, and RAF Halton. The Leeds unit had been the first, using a modified version of the original Kolff dialysis machine, but the other two units had newer technology made by Travenol with Kolff's help - a machine that looked rather like a washing machine, but was more controllable and used disposable artificial kidneys (coils), a first. 1959 was the beginning of a boom, with new units opening in Edinburgh, Glasgow, Newcastle, Belfast and the London hospital. You can read a 1958 Report on the United Kingdom Artificial Kidney Units at www.edren.org. This led to the purchase of a Kolff-Travenol device.

Dr Frank Parsons had worked in Boston and in 1956 managed to persuade his Leeds hospital managers, and the Medical Research Council, to give dialysis a second go using the Brigham (Boston) Hospital modified version of the Kolff dialysis machine.

There was considerable resistance. Early experience in the UK with one of Kolff's unmodified machines at Hammersmith had been widely regarded as unsuccessful, despite the positive spin put on it in the 1948 paper by Bywaters and Joekes. Eminent physicians believed that it was a barbaric treatment with results no better than could be achieved by conservative fluid and dietary management, the 'Bull' regimen. However the experience in the Korean war with Kolff-Brigham machines had been more positive, and in Scandinavia Nils Alwall had an even more effective machine in use since 1946. Newcastle chose his machine. An English pathologist and clinician Michael Darmady made his own improvements to the basic Kolff design and treated a number of patients in Wiltshire from 1947-48, but there was no haemodialysis in the UK between 1948 and 1956.

However by 1959 dialysis was becoming accepted as a treatment for acute renal failure in a number of countries, and Britain was playing catch up. Perhaps one of the reasons for its slow uptake becomes clear from the Edinburgh report on their recommended machine:

"The Kolff-Travenol Artificial Kidney with disposable coils and incorporating ultra filtration and dialysis is the machine which combines the most advantages. Its simplicity of preparation and operation and its intrinsic safety are outstanding. It has the additional advantage of relative cheapness. For the operation of dialysis two doctors and two nurses are required. One of the nurses should be senior and preferably have operating theatre experience. One other member of the medical staff should be able to run the machine. A full time biochemical technician is necessary. The room in the Clinical Laboratory suggested for the artificial kidney when suitably equipped, would be adequate for the purpose."

So a single dialysis on one patient involved two doctors, two nurses, and a biochemistry technician. It began with a cut-down onto an artery and vein, which were tied off after a single treatment lasting 6-8 hours. Such treatment was not cheap or simple - and the disposable coils were very expensive for the era.

Edinburgh's first patient was treated in May 1959, then again 3 days later, and survived. In the first year 65 dialyses were undertaken on 50 patients. Early reviews of results showed mortality of about 50%, similar to today, but these were a very different group of patients. They were young, they did not have multi-organ failure, and their diagnoses were mismatched blood transfusions, antibiotic toxicity (often crystallization), poisoning, post-surgical renal failure, and sepsis following illegal abortions.

What of acute peritoneal dialysis? And of dialysis for chronic renal failure? Stories for another time.

Further info:
J. Stewart Cameron 2002. A History of the Treatment of Renal Failure by Dialysis (OUP)
The early history of dialysis (Edren)

This article is due to appear in the Journal of Renal Nursing in May 2009.

.........................................

Welcome and Introduction

2009-02-19T17:40:00.001Z

Once people thought that the kidney was run by little people ...

The aim here is to tell the story of nephrology and transplantation in random bite-sized chunks. So out of sequence, an eclectic selection, and perhaps it will all make sense in the end. The tags (labels) should help. Must remember to use them.

The Kidney Factory is by Beth Shortt. Ask us about it.