Aluminium poisoning

Draws attention to the importance of water quality in the 1970s

Your dialysis team on the verge of the 1970s (Kings College Hospital 1969)

Just as the outbreak of dialysis-associated hepatitis was dying down, a report (Alfrey et al) from Denver in 1972 described the first of many worldwide clusters of dialysis patients with an alarming degenerative neurological disease.  The name 'dialysis dementia' was coined by George Dunea in Chicago.  The disease started after more than 15 months of dialysis with disordered speech (dysarthria, dysphasia).  Jerking movements followed, there were often fits, and then a progressive dementia that was often fatal within months to a year.  By 1976 Denver was reporting that this was their leading cause of death.  It was responsible for 8 out of 12 deaths after more than a year of dialysis. 

This experience was repeated at various units around the world while many others were spared, and initially no clear pattern could be discerned.  Many possible causes were considered, but aluminium was an early candidate.  High blood levels of aluminium had been demonstrated in patients in Manchester in 1970, and it had been suspected of causing neurological syndromes.  The source was assumed to be the aluminium hydroxide (Alucaps) that was taken in large quantities by dialysis patients as the standard phosphate binder of the day.  However the epidemic affected only certain renal units, while just about all used aluminium hydroxide. 

The proof came in 1976 from an observation at Eindhoven in the Netherlands, where dialysis dementia developed within three years of establishment of a new unit while patients at another unit across town were unaffected.  Very high levels of aluminium were detected and it was noted that 32kg of aluminium had been eroded from the anode of a dialysis water heater in two years. 

It was quickly discovered that high levels of aluminium in the water was a common feature of centres experiencing dialysis dementia.  Aluminium levels in water vary naturally, but the high levels found were most commonly associated not with dialysis apparatus, but with Aluminium added to the water supply to 'flocculate' it (bring small particles out of the water to make it clear).  In hard water areas, the methods used to remove calcium from water (ion exchange or reverse osmosis) also removed most aluminium.  However in many soft water areas dialysate was often still made with tap water, just as it was when dialysis was new.  Each time the patients were dialysed, more aluminium passed into their body, with no escape route (it would normally be excreted by the kidneys). 

Other features of aluminium toxicity were a microcytic anaemia unresponsive to iron therapy, and a fracturing, vitamin D-resistant osteomalacia.  In Edinburgh in 1980, 12 patients with high blood aluminium levels had microcytic anaemia, 7 developed fracturing osteomalacia, and one fatal encephalopathy. 

Aluminium sulphate for water purification

With this realisation, affected units improved their water purification and it was realised that comprehensive quality standards were needed.  It was found that dialysis against low-aluminium dialysate slowly improved less severely affected patients.  From Manchester Peter Ackrill and colleagues described in 1980 that desferrioxamine infusions, previously used for iron overload, could speed removal of aluminium too. 

Numerous other examples of aluminium toxicity have been recorded since, due not only to impurity of dialysate, but also of intravenous or peritoneal dialysis fluids.  Close monitoring of blood aluminium levels since these episodes has shown that examples of serious aluminium toxicity from oral aluminium hydroxide intake must be very rare.

However aluminium turns out to be only one of the hazards of dialysis water, and dialysis dementia is just one of a number of diseases unique to dialysis patients. 


Further info
Cameron JS 2002. A history of the treatment of renal failure by dialysis. Oxford University Press, Oxford
Alfrey AC et al.  1976.  Dialysis encephalopathy syndrome.  Possible aluminum intoxication.  N Engl J Med 294: 184-8 
Flendrig JA et al.  1976.  Aluminium and dialysis dementia.  Lancet Jun 5: 1235.

Proteinuria: a bad thing since 400 B.C.

Indicates risk of renal failure and death

 Isaac Sarrabat 1600; Physician examining a urine flask.  (US National Library of Medicine) 

Hippocrates (400 B.C.) described bubbles on the surface of the urine as indicating kidney disease and a long illness. Inspection of the urine (uroscopy, Fig 1) was a major part of the art of the physician for many centuries, often going way beyond any evidence. A Dr Thomas Brian railed against this in a 1655 tract ‘The Pisse Prophet’:

Or certain Pisse-Pot lectures, wherein are newly discovered the old fallacies, deceit, and jugling of the piss-pot science, used by all those (whether quacks, and empiricks, or other methodical physicians) who pretend knowledg of diseases, by the urine.

The analysis became more scientific only in the latter part of the 1700s, with the observation by that acidification or heating caused the urine of some patients with dropsy (oedema) to coagulate. This was an exciting time in science and medicine, but Stewart Cameron singles out Domenico Cotugno’s 1764 observations in a patient with nephrotic syndrome, and those of early clinical chemist William Cruickshank. Then in an outstanding set of clinical and autopsy observations Richard Bright conclusively demonstrated the association between proteinuria, dropsy and fatal kidney disease in 1827, and in doing so laid the ground for the specialty of nephrology. Glomerulonephritis was known as Bright’s Disease for over a century.

Proteinuria and mortality
Measuring proteinuria became a regular part of clinical assessment, and was subsequently taken up by insurance companies. At the first meeting of the Assurance Medical Society in 1894, the importance of measing albuminuria in assessing insurance risk was discussed. In 1912, increased mortality was described in 396 New york men who had been found to have proteinuria, but otherwise normal health, 10 years previously. Barringer also cited insurance company data from larger numbers of patients that suggested that mortality was more than doubled in individuals with a small amount of albuminuria and urinary casts. It is interesting in the light of later observations that there was not much evidence that the excess deaths were from renal failure, though this was probably easier to miss then.

In the last decade modern physicians have re-learned this message from a large number of epidemiological studies, which have shown that proteinuria is not only a renal risk factor, but also a powerful risk factor for cardiovascular events and death.

Proteinuria and kidney disease
The ability to undertake renal biopsies in the 1950s and to study them by immunofluorescence in the 1960s led to nephrologists spending the next 20 years largely studying the differences between different histological entities. However by the late 1970s it was realised that regardless of the underlying histology, greater proteinuria indicated greater long-term risk of renal failure.

The Modification of Diet in Renal Disease study (1994) showed again that higher levels of proteinuria were associated with faster decline in kidney function. However it also found that blood pressure control could dramatically reduce the rate of decline in patients with proteinuria. At the same time, Lewis’ equally famous trial of the ACE (angiotensin converting enzyme) inhibitor Captopril in diabetic nephropathy showed that it was significantly more protective than other drugs that lowered blood pressure to the same extent. And they lowered proteinuria too.

Since then studies in different diseases have confirmed that in patients with significant proteinuria (usually more than 1g/day or protein:creatinine ratio over 100 mg/mmol), a reduction in proteinuria brought about by ACE inhibitors or angiotensin receptor blockers (ARBs) is associated with lower risk of progressive loss of kidney function. There are at least two ways to explain this but the argument is not yet resolved. Why proteinuria is associated with cardiovascular events is unknown, but it is not clear that proteinuria-lowering treatments is necessarily beneficial in patients with lower levels of proteinuria who do not have a primary renal diagnosis.

Testing for proteinuria today

Great efforts are currently going into searches for particular ‘biomarker’ molecules in urine that could be valuable in tracking inflammation, predicting transplant rejection, or diagnosing reversible/irreversible acute kidney injury. But just simple measurement of proteinuria remains an extremely valuable, cheap and simple test that is hard to beat.

The dry reagent dipsticks that we still use were invented by Alfred Free and Helen Free Murray, working at Miles Laboratories.  Starting with dry chemistries in 1946, the first dipstick, Clinistix for glucose, was developed in 1956.  More on this another time.

Further info

Cameron JS. 2003. Milk or albumin? The history of proteinuria before Richard Bright. Nephrol Dial Transplant 18:1281-5
Barringer TB. 1912. The prognosis of albuminuria with or without casts. Arch Int Med 9: 657-64
A brief history of the Assurance Medical Society
Brian, T. 1655. The Pisse-Prophet. Published in London; from Wellcome Images
Cameron JS. 2005. The patient with proteinuria. In The Oxford Textbook of Clinical Nephrology, 3rd ed. OUP, Oxford.
Alfred Free and Helen Free Murray from the Chemical Heritage Foundation
A primer on proteinuria (edren Textbook)

This post, and many others from this series, are printed in sometimes shorter form in the Journal of Renal Nursing

The renal data revolution from 1980

Renal units pioneer electronic records 

In the UK through the 1970s and 1980s renal units found themselves responsible for increasing numbers of patients, and services were stretched to capacity and beyond in seeking to cope with pressure of new starts.  Managing their complex treatments and monitoring frequent test results was a major problem for understaffed services.  At Fulham hospital in West London in the late 1970s, doctors collaborated with computer programmers to simplify and speed storage and access to numerical data, presenting it both in tables and graphs.  However as needs changed, they realised that a system that could be configured without involvement of skilled programmers would be more versatile.  The principles spelled out in their 1983 paper should be read by today's IT system designers. 

Proton, as it became known, ran from a central server with interactions through terminals.  As it antedated the computer mouse, navigation used the numeric keypad.  Flipping from one patient to another was nearly instantaneous, and presentation of results was in time-ordered tables and graphs quickly allowing trends to be identified.  This was one of the earliest electronic patient records in the world. 

Proton spread to serve most of the renal units in the UK, with a local server for each.  Remarkably, in 2005 it still served 40% of UK renal units, and it still serves many thousands of renal patients today.  The key to its longevity was its local configurability, so it could be adapted to local needs and new functions.  The quality and accessibility of this data was also invaluable politically, it was used to draw attention to provision rates of dialysis and transplantation in different regions of the country.  Renal registries went on to compare performance of different units in death rate, transplantation, anaemia, and an increasing number of other markers of quality of service, well in advance of such systematic evaluation of performance being implemented in most other specialties. 

This relatively advanced level of electronic information provision became the norm in renal units in the UK, with several other IT companies offering renal systems over the next 20 years. 

Renal PatientView was launched in 2005 as the online version of the data in units, showing live test results with information links to patients via a secure login.  The data came from that stored in electronic systems in units.  By the end of 2012 it had over 25,000 registered users from over 80% of UK renal units.  Take-up has reached over 50% of dialysis/transplant patients in a number of units and there is enthusiasm for it from patients and staff. 

The design of Renal PatientView is remarkably similar to Proton screens.  It gives data to patients via the web in the same way as it was designed to give data to clinicians 30 years earlier. 

Further info

Gordon M, JC Venn, PE Gower and HE deWardener.  1983.  Experience in the computer handling of clinical data for dialysis and transplantation units.  Kidney Int 24:455-63

About 
Renal PatientView
,  www.renal.org/rpv

Bartlett C, K Simpson, AN Turner 2012 Patient access to complex chronic disease records on the Internet.   BMC Medical Informatics and Decision Making 12:87.

Obstetric renal failure

Alarming emergency and important public health marker 

Methodist Hospital, Dallas, 1966 (credit at foot of post)

 In the early days of dialysis obstetric renal failure was a major part of the work of a renal unit.  Acute renal failure was estimated to occur in 1 in 1400 to 1 in 5000 pregnancies in the UK (in 2010 there were 13,400 births per million population in the UK, if you want to calculate how many referrals that would mean in your region).  Over the next 20-30 years medical complications of pregnancy remained a regular and frightening reason for acute renal referrals. Frightening because patients are young and healthy till days before, with unfamiliar and rapidly changing physiology.

Hammersmith Hospital in West London had a special interest in acute renal failure from the 1940s, and attracted many referrals. In their 1965 report (Kinsey Smith et al) obstetric renal failure accounted for 15% of cases requiring dialysis between 1957 and 1965.  However an estimate from Washington DC 10 years earlier (Schreiner and Berman 1955) was twice as high. 

The 1965 London report came two years before the Abortion Act legalised abortion in England, Wales and Scotland.  40 of the 70 patients (Figure 2) presented in the first half of pregnancy, when most were associated with illegal abortion.  These patients often presented late to hospital with sepsis or haemorrhage. 

Fig 1 from Smith's West London series 1965
(Lancet, with permission)

The 30 patients who developed acute renal failure in late pregnancy mostly had variants of eclampsia/pre-eclampsia or obstetric haemorrhage.  Eight failed to recover kidney function because of cortical necrosis, at this time a death sentence as long term dialysis and transplantation were not established. 

The Hammersmith group had by this time moved from conservative treatment by strict management of fluid and dietary intake, through the use of haemodialysis, to routinely adopting peritoneal dialysis for the management of obstetric renal failure.  The overall mortality was 35% with the late-onset group having worse outcomes.  Obstetric and medical renal failure were regarded as lower-risk than surgical or traumatic renal failure. 

Rates of obstetric renal failure have come down dramatically in the developed world, in line with falling maternal and infant mortality.  So much so that renal trainees now see few cases.  Abortion-associated renal failure is exceptionally rare.  Early identification and management of pre-eclampsia have dramatically reduced the size of the late pregnancy group.  Haemorrhage is more effectively managed and antibiotics have reduced the threat from infections.   Much of obstetric-renal practice is now pregnancy in renal patients, rather than obstetric complications. 

In other parts of the world many of these benefits of modern medicine and politics have yet to be felt.  Obstetric renal failure remains a frightening part of acute nephrological practice in many developing countries.  It is an indicator of levels of maternal morbidity and mortality, and influenced by the effective resource put into community-level healthcare and family planning.  The profile of causes often closely resembles that described in London in 1965. 

Further reading
Statistics on UK childbirth and mortality from the Royal College of Obstetricians and Gynaecologists (RCOG)
Gulshun Rehman. 2012. Malawi: reducing abortion-related deaths. Save the Children blog. 
Smith K, JC McClure Browne, R Shackman, OM Wrong. 1965.  Acute renal failure of obstetric origin.  Lancet 286:351-4 (Pubmed)
Schreiner GE LB Berman. 1955. The clinical spectrum of postpartum acute renal insufficiency.  Ann Intern Med 43:1230-40 (Pubmed)
Header image from US National Library of Medicine, Images of the History of Medicine. 

The discovery of an effective treatment for renal anemia

In 1986 recombinant erythropoietin is the product of years of research

Anaemia was a major cause of morbidity in patients with end stage renal disease until recombinant erythropoietin became available at the end of  the 1980s. 
Before long-term dialysis was available, haemoglobin (Hb) levels fell to a mean of about 8 g/dl at a glomerular filtration rate (GFR) of 10ml/min, and about 7 g/dl at a GFR of 5, with a significant minority of patients running levels below 5 g/dl. 

The anaemia of renal failure in a pre-dialysis and pre-EPO
study.  Mishra and Kerr,  with permission.

Dialysis alone elevated Hb a little, but many patients were severely symptomatic and disabled by their anaemia.  Androgens and other treatments were in use but had only slight impact.  Blood transfusions raised Hb to relieve the worst symptoms or life-threatening crises, but were problematic for long term use because:

• Weekly or alternate weekly treatment was commonly required
• Iron overload was a serious consequence of regular transfusions 
• Antibody formation made blood increasingly difficult to match
• Sensitization to transplant antigens could preclude later transplantation
• Risks of transmission of viral infections (hepatitis devastated renal units 1964-72)

For these reasons, transfusion to near-normal haemoglobin values was not feasible and many patients lived with chronic severe anaemia. 

The full explanation for renal anaemia was controversial.  It was known that red cells had shortened survival in renal failure.  Regular blood loss was an additional factor for haemodialysis patients.  However the more severe anaemia of patients who had had bilateral nephrectomies suggested that something produced by the kidneys was important. 
Many pieces of scientific work led to the discovery of Erythropoietin (EPO), which was purified from urine in 1977.  Assays to measure it were developed in the 1980s, and showed that although renal patients produced some erythropoietin, levels failed to rise as they did in patients with anaemia of other causes.

EPO was a revolutionary treatment for these relatively young patients.  Recombinant EPO became the first blockbuster of a new generation of genetically engineered protein drugs.  But it was extremely expensive, adding about £5000 per annum, over 30% of the cost of dialysis in 1990.  Subcutaneous administration and increased iron therapy were subsequently found to be ways to reduce the amounts needed and minimize cost.

Recommendations from the UK Renal Association in 1990 were that EPO should be given to patients with Hb below 8g/dl, or who were transfusion dependent or had their lives threatened by anaemia, or were at risk of sensitization to transplant antigens because of their transfusion requirement.  It was hoped that this would note extend to more than 20% of dialysis patients. 

Today's patients are older and have more comorbid disease than the patients treated 15-20 years ago.   They tolerate low haemoglobins less well and arguably have more to gain from successful treatment of anaemia.  This led to an edging up of target haemoglobins, supported by mostly pharma-sponsored research that showed improved activity and well-being in patients whose Hb was lifted over 10. ‘Minimum acceptable’ haemoglobin levels were identified in guidelines.  The proportion of haemodialysis patients receiving EPO or similar agents rose to 90%.

Testing of whether these higher targets were safe came late, and wasn’t so encouraging.  Beginning with the Normal Haematocrit Study in 1998, and culminating in the CHOIR and CREATE studies in 2006, it became apparent that although having normal haemoglobins seemed to make patients feel better, it might be at the cost of increased thrombotic events, death, and cancer.  No safe dose of EPO, or safe Hb limit that can completely prevent these adverse effects has been established. 

ESAs (meaning Erythropoiesis Stimulating Agents of all types, including recombinant EPO) are now a core part of the management of advanced CKD. They have been hugely beneficial, and national and international guidelines assume their use.  But how to balance the benefits with the potential long-term risks is still not solved. 


Further reading

Cotes PM 1982 Immunoreactive erythropoietin in serum. I. Evidence for the validity of the assay method and the physiological relevance of estimates  Br J Haematol 50:427-38
Eschbach JW, Egrie JC, Downing MR, Browne JK, Adamson JW. 1987. Correction of the anemia of end-stage renal disease with recombinant human erythropoietin. Results of a combined phase I and II clinical trial. N Engl J Med. 316:73-8.
Winearls CG, Oliver DO, Pippard MJ, Reid C, Downing MR, Cotes PM. 1986. Effect of human erythropoietin derived from recombinant DNA on the anaemia of patients maintained by chronic haemodialysis. Lancet. 1986 328:1175-8.
Goldsmith DJA, CG Winearls.  2008.  EPO – taken for granted now, but 20 years ago a new era was dawning.  UK Renal Association.  (not available online)

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

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 exceeding '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

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