The history of renal transplantation:

from imagination to reality

Dr. Sandra M. Cockfield University of Alberta

Myth and imagination

stories of substituting or exchanging parts between animals and humans exist in mythology and religion
Egyptions and Phoenicians gods bearing heads of animals Greek the centaurs and minotaur Hindus god of wisdom, Ganesha angels and devils

Myth and imagination

integrated into our literature

Homers chimera part goat, lion, and serpent mermaids Pinocchio and Frankenstein

Transplantation as treatment

Tsin Yue-jen (407-310 BC) exchanged hearts between 2 soldiers, one with a strong spirit but weak will and the other the reverse, to cure the disequilibrium in their energies
many references to transplantation of body parts in the miracles described in the Bible most famous example of saintly surgery performed by Saints Cosmos and Damian, two identical twin physicians who carried out surgery pro bono in Arabia and Syria in the 4th century AD Roman proconsul condemned them to death in AD 303; failed stoning, arrows, burning at the stake, and drowning but succumbed to beheading!

Cosmos and Damian: the patron saints of transplantation

Their most famous surgical feat occurred when they appeared in human form and transplanted the lower extremity of an dead Ethiopian gladiator onto a custodian of a Roman basilica who had a gangrenous leg.
Altarpiece by an anonymous painter about 1490 (Wurttenbergisches Landes Museum in Stuttgart)

Advances in the early 20th century

the discovery of the ABO blood system by Landsteiner in 1900

species-specific blood system ABO-compatibility applied to organ transplantation

discovery of the anticoagulants, sodium citrate and heparin

development of modern vascular surgical techniques early experience with tissue transplantation
first successful corneal transplant, 1905 first successful permanent skin transplant, 1908 first successful cadaveric knee joint replacement, 1908

glandular xenotransplants, 1920s

Kidney failure: a likely candidate

the syndrome of kidney failure was first described by Richard Bright in 1836

he is suddenly seized by an acute attack of pericarditis, or with a still more acute attack of peritonitis which, without any renewed warning, deprives him in 8-40 hours, of his life. Should he escape this danger other perils await him; his headaches become more frequent; his stomach more deranged; his vision indistinct; his hearing depraved; he is suddenly seized by a convulsive fit and becomes blind. He struggles through the attack; but again and again it returns; and before a day or a week has elapsed, worn out by convulsions, or overwhelmed by coma, the painful history of his disease is closed.

Kidney failure: a likely candidate

the syndrome of kidney failure was first described by Richard Bright in 1836
no known therapy of established kidney failure uniformly fatal unless ARF with recovery replacement of failed kidneys appeared technically possible
kidneys are anatomically simple

placement of a transplanted kidney does not need to be in the native renal fossa
function is easily measured via urine output

The early 20th century

the first experimental organ transplants were reported in 1902

Prof. Emerich Ullmann, the Chief of Surgery at the Vienna Physiology Institute, auto-transplanted a dog kidney to the vessels in the neck

first dog-to-dog renal allograft was performed at the Institute of Experimental Pathology in Vienna

Alexis Carrel (1873-1944)

Alexis Carrel (Lyon, France) described the modern method of vascular suturing
exploited the availability of fine silk sutures from Lyon sewing lessons from an experience embroideress end-to-end anastomosis avoiding the vascular lumen amongst the first to report auto-transplantation of a canine kidney to the neck in1902 experimented with transplantation of blood vessels, thyroid tissue, ovary, testes, kidneys, limbs, and hearts in dogs

Alexis Carrel (1873-1944)

The modern version of Cosmos and Damian

The immunological barrier

The surgical side of the transplantation of organs is now completed, as we are now able to perform transplantation of organs with perfect ease and with excellent results from an anatomical standpoint. But as yet the methods can not be applied to human surgery, for the reason that homoplastic transplantations are almost always unsuccessful from the standpoint of the functioning of the organs. All our efforts must now be directed toward the biological methods which will prevent the reaction of the organism against foreign tissue and allow the adapting of homoplastic organs to their hosts. Alexis Carrell, 1914 at the Int. Surgical Association Mtg.

Alexis Carrel (1873-1944)

described that allografts, after behaving satisfactorily over the first few days, almost inevitably failed (rejection); left the field in frustration
Nobel prize in Medicine or Physiology in 1912

collaborated with Charles Lindbergh in creating an early generation mechanical heart

The early 20th century

the first kidney transplant in humans was performed in 1906 by Prof. Jaboulay in Lyon
xenotransplants using a pig and goat as the kidney donors acceptable choice of donor given reports claims of successful xenografting of skin, corneas, and bone transplanted the kidneys into the arm or thigh of patients with kidney failure

each kidney only worked for ~1 hour

next attempt was in 1909 by Ernst Unger (Berlin) who performed a monkey-to-human kidney transplant to a young girl dying of renal failure due to mercury poisoning; failed to function

The early 20th century

the immunologic barrier appeared insurmountable

interest waned in organ transplantation by 1915 surgical departments in Europe and North America were decimated by the two world wars

The 20th century: the early experience

the first human-to-human kidney transplant was performed in 1933 in the Ukraine by Prof. Voronoy
ABO-incompatible transplant; ABO-B into ABO-O recipient kidney obtained from a man dying of a head injury recipient had acute renal failure from mercuric chloride poisoning transplanted into the thigh after 6 hours of warm ischemia despite exchange transfusion, the kidney never worked patient died 2 days later; vessels patent at autopsy

6 kidney transplants from human deceased donors with kidneys stored 9-20 days (1933-1949) none functioned

The 20th century: barriers to kidney Tx

important issues which required solutions before kidney transplantation could become a reality
diagnosis of renal failure and monitoring of kidney function, both pre- and post-transplant medical support of patients with end stage kidney disease, especially hypertension renal replacement therapy (dialysis) establishment of a match ABO, tissue typing and crossmatching

retrieval and preservation of the donor kidney

overcoming the immunologic barrier

1947: dialysis & transplantation in Boston

the group at Peter Bent Brigham performed the first kidney transplant in a patient with ARF; the transplant bridged the patient until recovery of native renal function Kolff presented his findings on hemodialysis by 1950, the Boston team had carried out 33 dialysis runs in 26 patients

in 1951, they attempted the first kidney transplant in a ESRD patient who had received dialysis support; the patient died due to rejection 5 weeks later

A renewed interest: the early 1950s

several groups started to do human kidney transplants Paris (7 cases), Boston (9 cases), and Toronto (5 cases)
no immunosuppressive agents used all kidneys ultimately failed, usually within 30 days occasional patients survived if their native kidneys recovered clinical features of acute rejection described

medical community was enthusiastic; society was not

difficulties obtaining deceased donor organs technical improvements the modern approach of transplanting the kidney into the pelvis with drainage into the urinary bladder (Dr. Ren Kss, Paris)

The modern approach to kidney transplantation

The first successful kidney Tx!

performed on December 23, 1954 at Peter Bent Brigham Hospital in Boston by Dr. Joseph Murray (1990 Nobel prize in Physiology or Medicine)
monozygotic twin donor (the Herrick brothers) genetic identity confirmed by: o birth records reporting a shared placenta o sharing of all known blood groups o identical eye colour and iris structure o fingerprint analysis at the local police station o successful skin grafts between donor and recipient hypothesized that no immunosuppression would be required recipient required urgent native nephrectomies for the management of malignant hypertension post-transplant recipient survived 9 yrs until he died of a myocardial infarction

Kidney transplantation as therapy

other successful monozygotic twin kidney transplants performed in Paris and Montreal
permitted refinements of the surgical techniques, anesthesia, and dialysis support

formulated eligibility criteria for recipients and donors

developed living donor assessment policies developed the concept of informed consent as applied to living organ donation first recognition of recurrent glomerulonephritis as a cause of graft failure BUT it was a treatment of limited applicability!

Kidney transplantation as therapy

other successful monozygotic twin kidney transplants performed in Paris and Montreal permitted refinements of the surgical techniques, anesthesia, and dialysis support

For transplantation to succeed as a realistic form of renal replacement therapy, the developed living donor assessment policies immunologic barrier would have to be developed the concept of informed consent as overcome. applied to living organ donation

formulated eligibility criteria for recipients and donors

first recognition of recurrent glomerulonephritis as a cause of graft failure

BUT it was a treatment of limited applicability!

The immunological barrier

recognition that the body could determine self from non-self from initial experiences with reconstructive surgery in ancient India and Egypt techniques revived during the Renaissance when attempts were made to correct amputations and deformities of the nose, ears and lips arising from swordplay, torture, and syphilis Tagliacozzi warned about the power and force of individuality in 1557 AD by the end of the 17th century, the basic laws of transplantation were recognized

The laws of transplantation

Isografts succeed

Allografts fail

Xenografts fail

INFECTION
19th c

Pasteur and protective immunization Ehrlich: description of humoral immunity Metchnikoff: phagocytosis and cellular immunity 20th c

INFLAMMATION

1908: Ehrlich and Metchnikoff awarded the Nobel prize 1937: Gorer and murine MHC

1950s: description of HLA by Dausset (Nobel prize awarded )

1945: recognition of the immunosuppressive effects of total body radiation

Immunosuppressive effects of corticosteroids (1950-1960) and 6mercaptopurine (1959) described

INFECTION
19th c

Pasteur and protective immunization Ehrlich: description of humoral immunity Metchnikoff: phagocytosis and cellular immunity 20th c

INFLAMMATION

1915-1930: description of fetal or neonatal tolerance models 1900-1930: importance of lymphocytes in immunity 1940s: description of the DTH response

1940-1960:Medawar, Brent, Billingham: description of AR, memory response, acquired immunologic tolerance 1960: Medawar and Burnet awarded Nobel prize

1949: Burnet published on self and non-self and suggested clonal selection to explain fetal/neonatal tolerance

1950s: lymphocyte circulation/migration and function

The nature of rejection

critical observations from skin grafting in burn victims during WWI and II where skin was used from multiple donors
tissue rejection first described by Gibson and Medawar in 1943-1945
skin grafts between genetically disparate humans undergo rapid necrosis histology revealed infiltrating lymphocytes reaction was remarkably donor-specific as it did not damage adjacent host skin characterized by memory; a repeat skin graft from the same donor would be rejected even more rapidly

The first attempts at immunomodulation

some form of immunosuppression would be necessary to allow successful allografting effects of large doses of irradiation on lymphocytes and the immune system were observed in victims of Hiroshima and Nagasaki animal transplant models revealed the immunosuppressive effect of total body irradiation

1959-1962: first attempts in 11 humans with total body irradiation donor bone marrow in Boston
the first 2 patients died of sepsis despite elaborate isolation procedures

Patient #3: John Riteris

26 yr old with kidney failure from glomerulonephritis fraternal twin was the donor smaller dose of radiation given kidney transplant functioned immediately; 32 L of urine output over 1st 36 hours! intermittent low-dose radiation and corticosteroids reversed several rejections survived 27 years with graft function

The era of immunosuppression

some form of immunosuppression would be necessary to allow successful allografting effects of large doses of irradiation on lymphocytes and the immune system after Hiroshima and Nagasaki transplant models evaluating total body irradiation 1959-1962: first attempts in 11 humans with total body irradiation in Boston although the kidney transplants functioned longer, 10 of 11 recipients died of sepsis despite vigorous isolation strategies concept of opportunistic infection

Immunosuppressive drug therapy

irradiation too unpredictable and unreliable chemical immunosuppression appeared more promising

corticosteroids were being used as anti-inflammatory agents for autoimmune diseases during the 1950s
6-mercaptopurine was identified as an immunosuppressive medication; a derivative (azathioprine, Imuran) became available in 1961 1st successful deceased donor kidney transplant was performed in 1961 at Peter Bent Brigham Hospital in Boston; treated with azathioprine/steroid and the patient survived 21 months (Drs. Murray and Calne)

Experiment of N=1: hyperacute rejection

brother to sister living donor renal transplant performed in Los Angeles in 1964 broadcast for those attending a transplant conference uncomplicated OR with technically perfect vascular anastomosis kidney pinked up, then rapidly turned blue, then black, then thrombosed first description of hyperacute rejection due to preformed donor-specific antibodies

development of donor-specific cytotoxic crossmatch technique by Paul Terasaki et al at UCLA

N. Tilney Transplant: from myth to reality. Yale University Press, 2003

Experiment of N=1: cross-circulation at Royal Victoria Hospital, Montreal, 1967

young woman with ESRD underwent intermittent cross-circulation with woman dying of liver failure rationale included mutual replacement of vital organ function AND liver failure patient was a potential organ donor for the ESRD patient exposure to large amount of donor antigens ?reduced rate of AR due to immunologic tolerance liver failure patient died of massive GI bleed after 2 weeks; kidney transplanted into ESRD patient DGF x 19 days, then 9 yrs of graft function without rejection before dying in 1977 of HTN complications
Dossetor JB. Beyond the Hippocratic Oath, 2005

Experiment of N=1: Joe Palazola deceased donor kidney transplant in 1964 in Boston arrested as a possible bank robber while masked 16 months post-Tx presented with an enlarging mass
in the kidney allograft which proved to be lung cancer

the donor who was thought to have died from a CNS tumor, actually had CNS metastases from lung cancer immunosuppression withdrawn kidney rejected large inoperable tumor surrounding the transplant with extensive invasion into adjacent lymph nodes

residual tumor spontaneously disappeared tumor surveillance by competent immune system

N. Tilney Transplant: from myth to reality. Yale University Press, 2003

The early1960s: success

conference was held in 1963 to review the data on the accumulated experience of 216 non-identical donor kidney transplants
results:
75% (21/28) of monozygotic twin Tx recipients were alive

Alive Dead Murray et al, Transplantation 1964; 2: 147-155

The early 1960s: success and failure

inferior results of non-identical LD kidney transplants

52% of recipients of LRD renal transplants had died only 1 patient had survived > 24 months

Should there be a moratorium on kidney Alive Dead transplantation, particularly from living donors?
Alive Dead Alive

Totals 88

42

46

Dead

Murray et al, Transplantation 1964; 2: 147-155

The early 1960s: success and failure

dismal results of deceased donor transplants:

85% of recipients of DD renal transplants had died 79.4% died within first 3 months post-Tx month single survivor beyond 1 year; no survivors beyond 24 months

Alive Dead

Murray et al, Transplantation 1964; 2: 147-155

Kidney transplantation in context

ARF due to acute tubular necrosis was first described by English physicians during the blitz in WW II dialysis was initially developed in the 1940s to support patients with ARF 1st dialysis machine: Kolff rotating drum, 1943

Dialysis becomes a short-term solution

Initially dialysis could only be performed several times as blood access could not be maintained. The first two patients successfully treated with long-term hemodialysis were reported in 1960 by Dr. Scribner in Seattle.
The Scribner shunt

Dialysis reaches the University of Alberta

first hemodialysis treatment for ESRD performed in 1962 17 year old female with reflux nephropathy spearheaded by Drs. Lionel McLeod and Ray Ulan (his research fellow)

University of Alberta: kidney Tx program

started in January 1967

performed 5 transplants during the first year; 2 from living donors and 3 from deceased donors dismal early results; 4/5 kidneys never worked or functioned for < 5 months

University of Alberta: the early years

3rd patient to be accepted into chronic HD program in March 1963

living unrelated donor kidney transplant in November 1967 (3rd Tx in program); kidney failed after 18 months and patient died 3 months later

University of Alberta: 1967-1970 (N=37)

Graft survival Patient survival

Dialysis or kidney transplantation

both developed in parallel both were flawed with multiple complications and poor patient survival both had limited availability only the best were considered a new field of medical bioethics was born in the 1960s; would guide discussions of candidate selection, informed consent re: treatment choices, living organ donation, and organ allocation

LIFE Magazine, November 9, 1962: Criteria for acceptance onto RRT included sex, marital status and number of dependents, income, net worth, emotional stability, occupation, past performance and future potential.

A glimpse into the future

preliminary report from Dr. Tom Starzl of Denver at the 1963 conference
27 kidney Tx (25 from non-identical living donors) performed in preceding 10 months

azathioprine as sole immunosuppression

almost all experienced a rejection episode >90% of rejection episodes were reversed with high doses of prednisone 67% of patients remained alive with graft function steroid and azathioprine remained as standard immunosuppressive agents into the cyclosporine era

Adjunctive immunomodulation

other strategies were designed to suppress or destroy immunocompetent lymphocytes :

splenectomof immunomodulation y and/or thymectomy ineffective thoracic duct drainage (up to 100 L removed from some patients over days or weeks) - ineffective local irradiation of the allograft - ineffective observation that multiple blood transfusions reduced the risk of graft failure mandatory time on dialysis; pre-transplant transfusion of donor blood prior to living donor transplant depleting antibodies (anti-lymphocyte serum, anti-thymocyte globulin) as maintenance therapy; effective but substantial side effects with risks of infection and lymphoma

The 1960s: successes

important developments during the 1960s

organ preservation techniques brain death defined and legislation generated to permit organ donation after neurological death tissue typing became available in 1962 cross-matching became available in the early 1970s reduction in the incidence of hyperacute rejection which occurred due to the presence of preformed anti-donor HLA antibodies creation of transplant wait-lists creation of kidney sharing arrangements (Eurotransplant was formed in 1967)

Kidney donation

first few human kidney transplants were xenotransplants using pigs, goats, and monkeys; all failed
first human-to-human kidney transplants were from deceased donors
used kidneys from beheaded prisoners or those dying in hospital of acute illness/injury
donation after cardiac death substantial warm ischemia high rate of initial non-function and never function death of the recipient due to ongoing kidney failure

Living donation

the first living-related donor kidney transplant was performed in Paris on December 24th, 1952
mother donated to her son whose solitary kidney had been damaged in an accident; worked but rejected on day 22

several attempts at unrelated donor kidney transplants occurred in the early 1950s
kidneys were removed electively for cause due to irreversible ureteric abnormalities or from infants from hydrocephalus

worked initially but all rejected

led to discussions of the ethics of living donation; primum non nocere or first, do no harm vs. the desire to assist a loved one

Deceased donation: brain death

concept of brain death first discussed in 1965; to prevent pointless ventilation

Harvard Committee drafted criteria to define brain death in 1968 Uniform Anatomical Gift Act in the United States in 1968

donation after cardiac death abandoned for > 20 yrs first donation after cardiac death program was started in 1993 (Pittsburgh) may occur in either uncontrolled or controlled settings similar results compared to organs from equivalent brain dead donors

Organ preservation

Belzer (UCSF) began to evaluate strategies to store organs

developed home-grown pulsatile perfusion apparatus Collins and Terasaki introduced cold storage simplicity of this approach cold storage grew in popularity; by 1980, 75% of kidneys were cold-stored renewed interest in pulsatile perfusion due to ECD and DCD kidney transplants (Lifeport)

Developments up to 1980

1-yr graft survival remained relatively poor (~70% in living donor; 45% in deceased donor Tx)
many kidneys were lost to refractory rejection

Developments up to 1980

1-yr graft survival remained relatively poor (~70% in living donor; 45% in deceased donor Tx)
many kidneys were lost to refractory rejection increasing concerns about the burden of therapy
opportunistic infections avascular necrosis and other steroid complications pancytopenia, enteritis.. with high-dose azathioprine

transplant-associated malignancies (donor transmitted, de novo tumours)

understanding of the importance of quality of life in survivors on long-term immunosuppression

The cyclosporine era

first clinical use of cyclosporine in 1978

FDA approval for the indication of kidney transplantation in 1983 revolutionalized organ transplantation
reduced the rate of rejection and improved early graft survival rates finally permitted successful non-renal transplantation

by the mid-1990s, it was clear that kidney transplantation offered superior patient survival compared with dialysis

What is better - dialysis or transplantation?

kidney transplantation is the treatment of choice

45 40 35 30 25 20 15 10 5 0 18-39 Living donor Maintenance dialysis
Schold et al, Clin J Am Soc Nephrol 2006; 1:532-538

Projected life-expectancy from the time of ESRD

Treatment after 2 years of dialysis

40-54 55-64 Patient age (yrs)

>65

SCD transplant

The cyclosporine era

first clinical use of cyclosporine in 1978

FDA approval for the indication of kidney transplantation in 1983 revolutionalized organ transplantation
reduced the rate of rejection and improved graft early graft survival rates finally permitted successful non-renal transplantation

by the mid-1990s, it was clear that kidney transplantation offered superior patient survival compared with dialysis
new immunosuppressive medications have further reduced rejection rates and improved outcomes

Impact of new immunosuppressive agents

100 80
Radiation Prednisone 6-mercaptopurine

% of transplants

60 40 20 0 '60 '65 '70 '75

Azathioprine ATGAM

Neoral cyclosporine Tacrolimus MMF Dacluzimab Cyclosporine Basiliximab OKT3 Thymoglobulin Sirolimus

rejection in the first year 1 year graft survival

'80 '85 Year '90 '95 '00 '05

Adapted from Stewart F, Organ Transplantation, 2003

University of Alberta: results of 1st kidney transplants (2000-2007)

Deceased donor (n=372) Living donor (n=256) 99.6% 98.0% 94.9% 97.4% 95.2% 91.4%

Patient survival 1 year 3 year 5 year Graft survival 1 year 3 year 5 year

96.8% 94.6% 89.1% 95.9% 90.2% 84.2%

Death with a functioning graft considered as graft loss.

The remaining challenges

closing the gap between supply and demand maximizing long-term graft function and survival diagnosis and management of chronic rejection

new immunosuppressive strategies to reduce the burden of toxicities; ?development of tolerance

premature cardiovascular disease new onset diabetes post-transplant and dyslipidemia infections malignancies