Last updated: Haemodialysis (HD)
on 11 Jul 2012

History Of Transplantation

Early History

Transplantation is not new. In 4-5th C BC, the Indian physician Sushruta and his medical students developed plastic surgical transplants for reconstructing noses, genitalia, earlobes, et cetera, 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

In 1902 Emerich Ullmann (1861-1937), in Vienna, attempted the first kidney transplant (from a pig) to a patient, but this was technically unsuccessful (Ullmann, 1902). Alexis Carrel (Carrel, 1902), a student of Mathieu Jaboulay, working in Lyon, France, developed the end-to-end vascular suture techniques in 1902 that are widely used in transplantation, and for this and his subsequent work on organ preservation at the Rockefeller Institute in New York, received the Nobel prize in 1912

In 1906, Mathieu Jaboulay (1860-1913), in Lyon, used Carrel's technique to transplant a xenograft kidney (pig or goat) to the limbs of two patients with chronic renal failure; both grafts failed within an hour (Jaboulay, 1906). Three years later, in 1909, Ernest Unger (1875-1938) in Berlin transplanted a monkey kidney to a girl dying of renal failure; no urine was produced, and Unger concluded that the biochemical barrier was insoluble (Unger, 1909)

History 1936-1954: First Human Transplants 

Working in some obscurity, Yu Yu Voronoy, in Kherson, Ukraine, performed six human kidney allografts between 1933 (CHECK) and 1949. The first one, in 1936, was the first transplanted human kidney (Voronoy, 1937; Hamilton, 1984). The donor died from a head injury, and the recipient had acute renal failure from mercuric chloride poisoning. The kidney was ABO-incompatible (B to O). The donor had been dead for 6 hours. The recipient died 48 hours later without making urine but the vessels were patent at autopsy 2 days later. 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)

Yu Yu Voronoy, Kiev 

While working as a surgical resident in Peter Bent Brigham Hospital, Boston, in 1947, David Hume (1917-1973) was caring for a 29-year-old woman dying from acute renal failure. He decided to try to save her life by performing a kidney transplant. One evening Hume obtained a kidney from an elderly patient who had just died during surgery. He and another resident wheeled the woman to the treatment room at the end of the hall, and, using two gooseneck lamps for light, they attached the donor kidney to the woman’s forearm 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, but that was long enough to allow the woman’s own kidneys to recover, and she survived to be discharged. It may have been the first successful kidney transplant

David Hume (1917-1973), Boston  

In Chicago, on 17th June 1950, Richard Lawler (1895-1982) (Lawler, 1950) 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). 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 (  - 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'' 

In 1951, Rene Kuss et al (1951) and Charles Dubost et al (1951) of Paris and Marceau Servelle et al (1951) of Strasbourg carried out a series of cadaveric renal transplantations from convict donors after execution by guillotine
 

Rene Kuss       Charles Dubost       Marceau Servelle 

Starting 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, anesthetist 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, even though urine excretion and serum biochemical improvement were observed

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 

Gordon Murray, Toronto

In Dec 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. This was the first successful living kidney transplant, although lasting for a short period. Hamburger probably also coined the term 'nephrology'

Jean Hamburger  Mrs Renaud  Marius

It has been performed hundreds of thousands of times since then, including for the celebrated identical (monozygotic) twin transplantation performed by Joseph Murray (Nobel Laureate, 1990) et al in Boston (Murray, 1955), in 1954

Visitors flocked to France in the early 1950s to learn first hand from this experience, including John Merrill; who observed the extraperitoneal pelvic operation (often called the 'Kuss Procedure' in Europe). 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 revascularized from the femoral vessels, with urine drainage by skin ureterostomies

The extensive discussion of the French experience by Hume et al included acknowledgment of the French source of the vascular surgical technology in the person of Alexis Carrel (1902) (Nobel Laureate, 1912), who had spent much of his professional life in the United States in transplantation research. Carrel understood that transplanted organ allografts were not permanently accepted. but he did not know why

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 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 23, 1951, and December 3, 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 pathologic profile 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. In this, their classic paper, they showed that when skin from the same donor is repetitively transplanted to a given recipient, graft survival becomes progressively shorter. This was convincing evidence that graft rejection is an immune response

History 1954-65

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'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 perception, if not the reality, of hopelessness was changed at the Peter Bent Brigham Hospital 2 days before Christmas 1954. 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 to the pelvic location of the donor's uraemic 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 - and is a landmark in renal transplantation

Assisting Murray were: L-R. Miss Rhodes (Scrub Nurse), Dr. Daniel Pugh (Assistant Surgeon), Dr. John Rowbotham (Assistant Surgeon), Dr. Edward B. Gray (Assistant Surgeon), Miss Edith Comisky (Circulating Nurse), Dr. 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, it functioned promptly despite 82 minutes of warm ischemia. The kidney lasted for 8 years, when Richard Herrick died of a myocardial infarction, his glomerulonephritis having recurred. According to Merrill et al (1956) the bold step of exploiting the principle of genetic identity for wholeorgan transplantation had been suggested by the recipient's physician, David C Miller, of the Public Health Service Hospital, Boston

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 dead end. Further progress in the presence of an immunologic barrier would require effective immunosuppression

The first deceased donor transplant (unsuccessful) performed in the UK was at St Marys Hospital, by Charles Rob and William Dempster (from the Hammersmith) in 1955 (Joekes, 1957). The first successful kidney transplant in UK was performed in Edinburgh by Sir Michael Woodruff (1911-2001) (on the patient) and Mr James A Ross (on the donor) on 30th October, 1960 (Woodruff, 1961). On 15th September, 1960, Dr R.F. Robertson referred a 49-year old man suffering from gross impairment of renal function from the Leith Hospital to the Royal Infirmary of Edinburgh. The impairment was suspected to be due to chronic pyelonephritis or chronic glomerulonephritis. The prognosis for either condition with conventional treatment was poor. It so happened that the patient had a twin brother, who was healthy, and was willing to donate one of his kidneys

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

Calne and Murray first used azathioprine as an immunosuppressant in 1962 (Calne, 1962). Murray's team, in Boston, started using azathioprine, initially with poor results. However, their third patient, transplanted in April 1962, was treated with azathioprine following a cadaveric renal allograft. He survived over one year and was the world's first successful unrelated renal allograft (Murray, 1963). That Murray considered a year of life a success is a useful background to a conference later on that year

Willard Goodwin, at the University of California in Los Angeles, almost immediately introduced the use of corticosteroids as a further adjunct to the treatment (Goodwin, 1963)

Keith Reemtsma (1925-2000) was the first to show that nonhuman organs could be transplanted to humans and function for a significant period of time. At Tulane University in New Orleans. Reemtsma in 1963 and 1964 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 buidling 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 pateints. 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)

None of the European and American efforts to this time, however, or all together, would have had any lasting impact on medical practice were it not for what lay ahead. The principal ingredients of organ transplantation-immunosuppression, tissue matching, and organ procurement (and preservation) were still unknown or undeveloped