The history of renal transplantation:

1
The history of renal transplantation from
imagination to reality
Dr. Sandra M. Cockfield University of Alberta
2
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

3
Myth and imagination

• integrated into our literature
• Homers chimera part goat, lion, and serpent
• mermaids
• Pinocchio and Frankenstein

4
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!

5
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)
6
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

7
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.
8
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

9
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

10
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

11
Alexis Carrel (1873-1944)
The modern version of Cosmos and Damian
12
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.
13
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

14
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

15
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

16
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

17
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 cross-matching
• retrieval and preservation of the donor kidney
• overcoming the immunologic barrier

18
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

19
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. René Küss,
  Paris)

20
The modern approach to kidney transplantation
21
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
• birth records reporting a shared placenta
• sharing of all known blood groups
• identical eye colour and iris structure
• fingerprint analysis at the local police station
• 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

22
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!

23
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!

24
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

25
The laws of transplantation
26
INFECTION
Pasteur and protective immunization
19th c
Metchnikoff phagocytosis and cellular immunity
INFLAMMATION
Ehrlich description of humoral immunity
20th c
1908 Ehrlich and Metchnikoff awarded the Nobel
prize
1937 Gorer and murine MHC
1950s description of HLA by Dausset (Nobel
prize awarded )
27
INFECTION
Pasteur and protective immunization
19th c
Metchnikoff phagocytosis and cellular immunity
INFLAMMATION
Ehrlich description of humoral immunity
20th c
1915-1930 description of fetal or neonatal
tolerance models
1900-1930 importance of lymphocytes in immunity
1949 Burnet published on self and non-self
and suggested clonal selection to explain
fetal/neonatal tolerance
1940s description of the DTH response
1950s lymphocyte circulation/migration and
function
28
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

29
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

30
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

31
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

32
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)

33
Experiment of N1 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
  pre-formed 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
34
Experiment of N1 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
35
Experiment of N1 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
36
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

Murray et al, Transplantation 1964 2 147-155
37
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 gt 24 months

Totals
88
42
46
Murray et al, Transplantation 1964 2 147-155
38
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

Murray et al, Transplantation 1964 2 147-155
39
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

40
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.
41
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)

42
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 lt 5 months

43
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

44
University of Alberta 1967-1970 (N37)
Patient survival
Graft survival

45
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

46
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.
47
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
• gt90 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

48
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

49
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)

50
Kidney donation

• first few human kidney transplants were
  xeno-transplants 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

51
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

52
Kidney transplant activity northern AB

of Tx
DD deceased donor (includes kidney-liver,
kidney-heart Tx) LD living donor (relative,
spouse, friend) K-P simultaneous
kidney-pancreas transplant
53
Significant trends in living donation

• increasing number of living donors who are
  genetically unrelated to the recipient living
  unrelated or emotionally-related donors
• novel strategies in living donor programs -
  ABOi and cross-match positive live donor Tx -
  anonymous donors - paired exchange -
  transplant tourism - matchingdonors.com

54
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 gt 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

55
Back to the future donation after cardiac death

• donation after cardiac death accounts for 9.2 of
  all deceased donor kidneys transplanted in the US

SRTR Annual Report, 2007
56
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)

57
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

58
The impact of immunosuppression

• Radiation
• Prednisone
• 6-mercaptopurine

• Anti-thymocyte globulin

• Azathioprine

Adapted from Stewart F, Organ Transplantation,
2003
59
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

60
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

61
What is better - dialysis or transplantation?

• kidney transplantation is the treatment of choice

Schold et al, Clin J Am Soc Nephrol 2006
1532-538
62
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

63
Impact of new immunosuppressive agents

• Radiation
• Prednisone
• 6-mercaptopurine

• Neoral cyclosporine

• Tacrolimus

• MMF

• Cyclosporine

• Dacluzimab
• Basiliximab

• OKT3

• Thymoglobulin
• Sirolimus

• Azathioprine

• ATGAM

Adapted from Stewart F, Organ Transplantation,
2003
64
University of Alberta results of 1st kidney
transplants (2000-2007)
Death with a functioning graft considered as
graft loss.
65
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