History Of Renal Transplant
Reviewed by Raimund Margreiter
Transplantation is not new. In 4-5th Century BC, the Indian physician Sushruta and his medical students developed plastic surgical transplants for reconstructing noses, earlobes etc, that were amputated as religious, criminal, or military punishment. This was published in Sushruta samhita (ca. 500 BC), his medico–surgical compendium.
History 1902-1936: Xenotransplantation
Erwin Payr (1871-1946), an Austrian-German surgeon, developed the first workable methods of vascular suturing. This led to a widespread interest in organ transplantation in the late 19th and early 20th centuries. Many centres were involved, including Vienna, Bucharest, Berlin and Lyon.
Austro-Hungarian surgeon Emerich Ullmann (1861-1937; originally from Pecs, Hungary), briefly worked with Louis Pasteur in Paris, on rabies antisera. Then in 1902, in Vienna, he carried out the first kidney transplant, in which a dog’s kidney was implanted into another dog’s neck (Ullmann, 1902). The kidney lasted for 5 days. Ullman presented his work to the Viennese Medical Society, on 7th March 1902. The work was published only 7 days later in the Wiener Klinische Woxhenschrift. Soon after, he carried out (unsucessfully) the first renal xenotransplant (across species) between a goat and a dog. Following an unsuccessful attempt to transplant a pig kidney into a human patient, in the final stages of CKD, he ceased work in this area.
Also in 1902, French surgeon Alexis Carrel, apparently unaware of Ullmann’s work, published a paper in the journal Lyon Médecine entitled ‘The Operating Technique for Vascular Anastomosis and Organ Transplantation’. Carrel - a student of Mathieu Jaboulay - working in Lyon, France, developed the end-to-end vascular suture techniques that are still widely used in transplantation (Carrel, 1902). Carrel left Lyon for the United States in 1904.
In the 21 months from November 1904 to August 1906, when Carrel was at the University of Chicago, his research achievements were astounding. In close collaboration with Charles Guthrie, the American physiologist, he published 33 papers describing advances that remain the basis of modern transplantation surgery: the ability to sew blood vessels together, to reattach severed limbs, and to transplant organs (including kidneys and hearts) into dogs and cats.
Carrel’s earliest description of his work appeared in “The Transplantation of Organs: A Preliminary Communication” (Carrel, 1905); where he included the prophetic statement: “From a clinical standpoint, the transplantation of organs may become important .. and may open new fields in therapy and biology”. For this and his subsequent work on organ preservation, at the Rockefeller Institute in New York, he received the Nobel prize in 1912 (quoting the work of Payr in his acceptance speech).
In 1905 in Bordeaux (France), M Princeteau inserted slices of rabbit kidney into a nephrotomy in a child with renal insufficiency. “The immediate results were excellent,” he wrote. “The volume of the urine increased; vomiting stopped .. On the 16th the child died of pulmonary congestion” (Princeteau, 1905).
The French surgeon Mathieu Jaboulay (1860-1913), like Carrel in Lyon, documented kidney transplants from animals to humans. On 24th January, 1906, he transplanted the left kidney of a pig into the left elbow of a 48 year old female suffering from nephrotic syndrome (Jaboulay,1906). However, the graft failed because of early vascular thrombosis. On 9th April 1906, he transplanted a goat kidney into a 50 year old female. The first patient died after 3 days, and the second after 9 days.
Three years later, in 1909, Ernst Unger (1875-1938) in Berlin, transplanted a pair of monkey kidneys en-bloc into the thigh of a girl dying of renal failure (interposition vascular reconstruction) (Unger, 1909). No urine was produced, and Unger concluded that the biochemical barrier was insoluble (Unger, 1910). Unger's second paper in 1909, contained the first illustration of an experimental kidney transplant. His 1910 paper contained the first illustration of a human kidney transplant operation. Also, Unger may have been the first to place a long intravenous line, passing it from his own leg into the inferior vena cava.
In New York, in 1923, Harold Neuhof at Mount SInai Hospital, attempted treatment of a patient with mercury bichloride poisoning by renal heterotransplantation. When he was unable to obtain a human kidney, he transplanted the kidney of a lamb into the patient. The patient died 9 days later, but Neuhof was not totally discouraged. He wrote, “[This case] proves, however, that a heterografted kidney in a human being does not necessarily become gangrenous and the procedure is, therefore, not necessarily a dangerous one, as had been supposed. It also demonstrates that thrombosis or hemorrhage at the anastomosis is not inevitable. I believe that this case report should turn attention anew” (Neuhof, 1923). Neuhof was clearly more optimistic than Unger.
In 1926, at the Mayo Foundation (Rochester, USA), Carl S Williamson, of the Division of Experimental Surgery and Pathology, grafted the kidneys from two goats into two dogs - both recipients died within minutes.
For all of these reasons, there was little further interest in this area for a nearly decade.
History 1936: First Human Transplants
Interest resumed in the 1930s. Working in some obscurity in Kherson (Ukraine), Yuri Yurijevich Voronoy (1895-1961) performed six human kidney allografts between 1933 and 1949 - the kidneys being transplanted into the thigh. The first 'successful' one, in 1933, was the first human-to-human kidney transplant (Voronoy, 1936; Hamilton, 1984). The recipient was a 26-year old woman who was admitted in a uraemic coma after swallowing mercury chloride in a suicide attempt. Voronoy retrieved the kidney from a 60-year-old man who had died from a fracture of the base of the skull. The donor had been dead for 6 hours. The kidney was ABO-incompatible (B to O), and was rejected. The recipient died 48 hours later without making urine but the vessels were patent at autopsy. In the six transplants he reported, no significant longterm renal function occurred in any of them. The first transplant happened on the 3rd of April in 1933, whereas 1936 was the year of its publication.
Voronoy's publication in El Siglio Medico, 1936
Sporadic further efforts at renal allotransplantation were made in the ensuing 15 years without effective immunosuppression, as documented by Groth (1972) and Hume and Merrill (1935).
Yuri Voronoy, Kherson, Ukraine
History 1943–1944: Immunological Advances
During World War II, the British Medical Research Council (MRC) focused on the problem of skin grafting for the treatment of burns. They asked Peter Medawar, an Anglo-Lebanese professor of zoology, to work with Thomas Gibson, a plastic surgeon, to attempt to perfect skin auto - and, if possible, allo - transplantation in humans.
First in human studies (Gibson, 1943) then in rabbit experiments (Medawar, 1944), Gibson and Medawar, showed that rejection of skin grafts was an immunological process analogous to the cell mediated hypersensitivity phenomenon that confers immunity to diseases such as tuberculosis. In the laboratory, they observed a persistent finding in experiments with mice or rabbits: if an initial skin graft was taken from animal A and placed on animal B, it survived for about seven days. Then, if a second skin graft was taken from animal A and placed on animal B in exactly the same fashion, it was destroyed in about half that period of time. This was an important observation.
Medawar characterised this finding as the ‘second set response’ (ie of immune origin). In other words, he found that graft recipients would form antibodies against a graft, unless they had been exposed to similar foreign tissue early in life. This work showed that the body's rejection of foreign tissue was indeed an immune response.
Gibson took most of the iniative and did the analysis, but Medawar stayed working in this field long term. Medawar, in collaboration with Brent and Billingham (who have been called 'The Holy Trinity'), proceeded to unravel many aspects of tissue immunology. Medawar’s historic achievements established the field of modern transplant immunology, and he shared the Nobel prize in medicine with Sir Frank Macfarlane Burnet in 1960.
Carrel’s description of graft destruction due to ‘biological incompatibility’ was now explained as rejection due to an immunological response.
History 1945-1953: First Successful Renal Transplants
It is difficult to state who did the first successful human renal transplant. That honour could go the following three pioneers in 1945, at the Peter Bent Brigham Hospital in Boston: Charles Hufnagel (staff surgeon), Ernest Landsteiner (chief resident in urology) and David Hume (1917-1973; assistant surgical resident) . Landsteiner was the son of Karl Lansteiner, Nobel prize winner, who developed the modern system of classification of blood groups.
A 29 year old woman presented with acute renal failure. As dialysis was not yet available, they wheeled the patient to the treatment room at the end of the hall. They decided to try to save her life by performing a kidney transplant; obtaining a kidney from an elderly patient who had just died during surgery. Using two gooseneck lamps for light, attached the donor kidney to the woman’s antecubital vessels, so that it rested outside the skin. They then covered the kidney with a plastic bag and watched as the patient’s urine drained into a jar. This primitive transplant lasted only four days, and she recovered renal function, surviving to be discharged. This may have been the first (albeit perhaps not entirely necessary) 'successful' deceased donor transplant, outside the abdomen.
David Hume (1917-1973), Boston
Five years later, in 1950, the first success intra-abdoeminal cadaveric renal transplant occurred in a patient with CKD. It was carried out on 17th June, by Richard Lawler (1895-1982) in Chicago. He removed a kidney from a patient with cirrhosis who had died of liver disease, and placed it into his patient, Ruth Tucker (44 years), who had polycystic kidney disease (removing one of them at the same time) (Lawler, 1950). The operation occured at the Little Company of Mary Hospital, Chicago. Lawler said of the donor, “Not the most ideal patient, but the best we could find,” in an interview after the surgery.
Richard H Lawler (1896-1982), Chicago
To everyone's surprise, the kidney worked for at least 53 days. At ten months, it was found to be shrunken, discoloured and rejected, and was removed. The patient lived for another five years. Enduring both notoriety and sometimes vociferous censure by his peers, Lawler never performed another transplant. He was besieged with letters from doctors wanting to learn from him and from patients seeking his services. But he never performed another kidney transplant, saying in 1979, ''I just wanted to get it started''. Lawler was assisted by: James West, who later went on to study alcoholism as a disease and launch the Betty Ford Clinic (of which he later became Medical Director), and Raymond Murphy. They were assisted by nurses including: Mary Lou Zidek, who assisted the anesthesiologist during the surgery; and Nora O’Malley, who was the scrub nurse. This Health News website article descibed what happened.
In the 1950s and early 60s a group of French transplant surgeons (who became known as the 'French Transplantation Club') carried out a series of important achievements. In a historic 12 day period in January 1951, René Küss and Charles Dubost (in Paris) and Marceau Servelle (Strasbourg) performed the first renal transplants in France, and first used the extraperitoneal renal transplantation procedure which is in common use today - called the 'Küss Procedure'. Dubost and Servelle obtained their renal allografts from the same guillotined convict donor, whereas R. Küss used a kidney that had been removed from another patient for therapeutic purpose.
Rene Kuss Charles Dubost Marceau Servelle
A total of nine patients were transplanted, all nine patients rejected their grafts. In Rene Kuss' famous publication in Mem Acad Chir (1951) he stated "about some cases of renal allograft in human .. in the present state of knowledge, the only rational basis for kidney replacement would be between monozygotic twins". Clearly the concept of an immune related rejection was well established at this point.
in 1951, Gordon Murray (1894-1976) in Toronto, performed a series of 4 deceased donor kidney transplants using his heterotopic technique (Murray, 1954). The team included nurse Rita Smith, anaesthetist Stephen Evelyn, and resident William Lougheed. Both the deceased donor and the prospective recipient were operated on in the same room, Operating Room “C” at the Toronto General Hospital, separated by a screen. Of the first 3 recipients, the longest survivor lived 12 days, with urine production and improvement in serum biochemistry.
On May 2nd, 1952, Murray’s fourth patient was a 26-year-old woman who had been diagnosed with Bright’s disease, 18 months previously. The patient made a spectacular recovery with loss of oedema. The patient remained well for at least the next 21 years and the kidney was never removed. In his report to this journal, Murray admitted that while “this patient might have returned to this sort of good health independently,” he remained convinced of the importance of the transplant in achieving that state. This may have been the first long term success in renal transplantation.
Gordon Murray, Toronto
In December 1952, the French physician, Jean Hamburger, working with the urologist Louis Michon at the Hospital Necker (Paris), reported transplanting a kidney from a live volunteer donor (Michon, 1953). The kidney, which was donated to a 16 year carpenter Marius Renard from his mother, functioned well and for 3 weeks before being rejected by the non-immunosuppressed recipient. Her son was probably in ATN following blood loss, and had a (congenital) single kidney. This was the first successful living kidney transplant, albeit lasting for a short period. Hamburger probably also coined the term 'nephrology'.
Jean Hamburger Mrs Renaud Marius
Visitors flocked to France in the early 1950s to learn first hand from this experience; including John Merrill, who observed the extraperitoneal pelvic operation. This was described in the classic account by Hume and Merrill (1955) of their first clinical trials at the Peter Bent Brigham Hospital. In this paper, the Boston operations were described. All but one of the transplants were placed in the thigh and revascularised from the femoral vessels, with urine drainage by skin ureterostomies.
Although the Peter Bent Brigham program postdated the early French efforts, the depth and serious intentions of the Harvard group were obvious in the report by Hume et al (1955). It contained observations on nine kidney allografts in non-immunosuppressed recipients. The first of these kidneys was transplanted into the normal location in the recipient after its removal for a lower ureteral carcinoma on March 30th 1951 by JH Doolittle of Springfield, Massachusetts. The kidney was inserted by Scola. The patient had been undergoing short-term dialysis care at the Brigham, where the first artificial kidney in the United States had been brought from Holland by Wilhelm Kollf and modified by Harvard engineers - as described in detail by Moore (1972).
The next eight renal allografts, all placed in the thigh location, were transplanted between April 23rd 1951, and December 3rd 1952. Hume's description of this experience stands as one of the great medical classics of the 20th century. It provides a nearly complete clinical and pathological description of renal allograft rejection in an untreated human recipient
Also in 1951, Rupert Billingham and Sir Peter Medawar published their landmark paper on immune tolerance
History 1954-60: Boston and Murray
The only examples of probable allograft function through 1954 were provided first by one of the non-immunosuppressed patients of Hume whose graft in the thigh location functioned for 5 months (Hume, 1955). Hume's career lasted well into the next era of transplantation, until his death in May, 1973, near Los Angeles in the crash of a private plane. John Merrill drowned off the beach of a Caribbean island in 1984.
The next important milestone in the history of renal transplantation, occurred two days before Christmas in 1954. Something happened at the Peter Bent Brigham Hospital that was to change the course of renal transplantation. Richard Herrick, a 24 year-old patient with chronic kidney disease and severe hypertension secondary to glomerulonephritis and an identical twin, Ronald, had been referred to the Brigham by his physician, David C Miller. On December 23rd 1954, a kidney was removed from Ronald by the urologist J Hartwell Harrison and transplanted by Joseph E Murray into the pelvic location of the donor's identical twin brother, Richard (Murray, 1955). The nephrologist was John P Merrill. The vascular anastamosis was completed at 11.15am, and the operation lasted 5 and half hours.
Assisting Murray were: Miss Rhodes (Scrub Nurse), Daniel Pugh (Assistant Surgeon), John Rowbotham (Assistant Surgeon), Edward B Gray (Assistant Surgeon), Miss Edith Comisky (Circulating Nurse), and Leroy D Vandam (Anaesthetist).
Joseph Murray, Boston surgeon. John Merrill, nephrologist (left) explains the workings of a then-new machine called an artificial kidney to Richard Herrick (middle), who was to be donated a kidney by his twin brother Ronald (right).
As in the earlier mother-to-son transplant in France, no effort was made to preserve the isograft; but nonetheless, it functioned promptly despite 82 minutes of warm ischaemia. The kidney lasted for 8 years, when Richard Herrick died of a myocardial infarction, his glomerulonephritis having recurred. According to Merrill, the bold step of exploiting the principle of genetic identity for whole organ transplantation had been suggested by the recipient's physician, David C Miller, of the Public Health Service Hospital, Boston (Merrill, 1956). This was the first longterm success in living renal transplantation.
Soon after the success in Boston, progress started in the UK. The first deceased donor transplant (unsuccessful) was performed in the UK in 1955, at St Marys Hospital. This was carried out by Charles Rob (1913-2001) and William James 'Jim' Dempster (1918 - 2008; from the Hammersmith) (Joekes, 1957).
In 1959, Gordon Murray (Toronto) carried out the first successful non-twin sibling transplant. Again in 1959, Joseph Murray demonstrated that sublethal total body irradiation (TBI) could be used successfully, in the first non-identical (fraternal) twin transplant in the USA (Merrill, 1960). In January 1960, the first successful living kidney transplant between non-twin siblings in France took place at the Foch Hospital in Surenes, France - performed by a team led by René Küss (Kuss, 1962).
Progress was also occurring in the UK. In July 1959 the first successful deceased donor renal transplant in the UK was performed by 'Fred' Peter Raper, a urologist, in Leeds. The team in Leeds used cyclophosphamide as an immunosuppression. The patient died, with a working transplant eight months later, of a viral infection. On 30th October, 1960, the first successful living kidney transplant in UK was performed on identical twins. Sir Michael Woodruff (1911-2001) operated on the patient, a 49 year old man; and Mr James A Ross, on the donor (Woodruff, 1961). The patient had been referred on 15th September, 1960, by Dr RF Robertson with advanced CKD, from Leith Hospital to the Royal Infirmary of Edinburgh. Following these successful operations, the donor resumed work 3 weeks after the operation; the patient returned to work after 15 weeks. The patient lived for a further 6 years before dying from an unrelated disease.
It already was well known that identical twins did not reject each others' skin grafts (Brown, 1937). To ensure identity, reciprocal skin grafting was performed on the Boston twins. Although the identical twin cases attracted worldwide attention, organ transplantation had reached a turning point. Even though research - both in dogs and humans - progressed using total body irradiation (TBI) to prevent rejection, real advances would require effective immunosuppression.
History 1960-65: Age of Imunosuppression
1960 was an important year in the history of transplantation, especially in terms of immunosuppression. In 1960, Willard Goodwin, at the University of California in Los Angeles, started using corticosteroids as a further adjunct to the treatment (Goodwin, 1963). Roy Calne first used 6 mercaptopurine (6MCP) in dogs (Calne,1960). The experiments were done in the UK at the Royal College of Surgeons research facility. In November 1960 the first successful non-twin sibling living transplant in the UK was carried out by Hopewell. This was also the first use of 6-MCP in humans, and the first use of prednisolone in the UK. 'Success' was difficult to define in these early transplants. This patient died after seven weeks.
The next big step occurred in 1962, when Calne and Murray first used azathioprine (a drug related to 6MCP) as an immunosuppressant (Calne, 1962). Murray's team, in Boston, started using azathioprine, initially with poor results. However, their third azathioprine-treated patient, who received a deceased donor transplant in April 1962, did significantly better. He survived over one year and was the USA's first deceased donor renal allograft (Murray, 1963) with long term survival. This followed Gordon Murray's original success in Canada in 1952. That Joseph Murray considered a year of life a success is a useful background to a conference later on that year. In 1963, Thomas Starzyl first used prednisolone and azathioprine from the start of a transplant, with success; ushering in a new era of effective 'dual therapy' in transplantation. Starzyl was to go on to carry out the world's first liver transplant in the same year. Calne also went on to pioneer the use of ciclosporin in renal transplantation (Calne, 1978).
Keith Reemtsma (1925-2000) was the first to show that non-human organs could be transplanted to humans and function for a significant period of time. In 1963 and 1964, at Tulane University in New Orleans, Reemtsma, gave chimpanzee kidneys to 5 patients in the first chimpanzee-to-human transplants. The recipients died (of infection) from 8 to 63 days after receiving a chimpanzee kidney. Then, in 1964, Reemtsma transplanted a kidney from a chimpanzee to a 23-year-old teacher. She lived with it for 9 months until succumbing to overwhelming infection.
Late in 1963, all available information was discussed at a conference near Washington DC (Murray, 1964). About twenty-five active participants gathered in a small, hot room, in an old building at the National Institutes of Health. Thirteen teams - two from France, five from the UK, and six from the USA - presented their overall findings from 216 recipients of renal allografts. The results were not good. 52% of all those receiving grafts from related donors had died, and 81% of those with kidneys from unrelated or cadaveric donors. Joseph Murray concluded, "Although the beginnings of clinical success are apparent, strong reservations must be kept in mind regarding the ultimate fate of these patients. Kidney transplantation is still highly experimental and not yet a therapeutic procedure".
Nonetheless, teams continued their research, and progress was rapid. By 1965, one year survival rates of allografted kidneys from living related donors were approaching 80%, and from cadavers 65% (Murray JE, Nobel Lecture, 1990); accepting that there was a substantial death rate and no return to dialysis. It is interesting that one year graft survival rates are not that different in the modern age (95% and 85% respectively). Surgical techniques are largely the same as in this pioneering period (1943-1965). So, indefinite functioning of transplanted organs with little/no immunosuppression (with all its complications) remains the target for future generations. In other words, the non-surgical components of organ transplantation - immunosuppression, tissue matching, and organ procurement (and preservation) - have not yet delivered excellence in the 21st Century.
An article written by Allan Lansing in 1974 describes the story of the development of renal transplantation (and dialysis) in Louisville during the 1960s. It is a nice summary of what it was like in the early pioneering days of transplantation.