TX History Dec2008

7/30/2019 TX History Dec2008

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The history of renaltransplantation:

from imagination to

reality

Dr. Sandra M. Cockfield

University of Alberta



Myth and imagination

• stories of substituting or exchanging parts betweenanimals and humans exist in mythology and religion

Egyptions and Phoenicians – gods bearing heads of animals

Greek – the centaurs and minotaur

Hindu’s god of wisdom, Ganesha

angels and devils

http://upload.wikimedia.org/wikipedia/commons/5/5c/Michael_Pacher_004.jpg

http://upload.wikimedia.org/wikipedia/commons/f/f1/Minotauros_Myron_NAMA_1664_n1.jpg

http://en.wikipedia.org/wiki/Image:Centaur_nymph_Marqueste_Tuileries.jpg



Myth and imagination

• integrated into our literature

Homer’s chimera – part goat, lion, and serpent

mermaids

Pinocchio and Frankenstein

http://en.wikipedia.org/wiki/Image:Chimera_Apulia_Louvre_K362.jpg

http://nalts.files.wordpress.com/2006/07/frankenstein.jpg

http://upload.wikimedia.org/wikipedia/en/5/5e/525_Little_Mermaid.jpg



Transplantation as treatment

• Tsin Yue-jen (407-310 BC) exchanged heartsbetween 2 soldiers, one with a strong spirit but weakwill and the other the reverse, to cure thedisequilibrium in their energies

• many references to transplantation of body parts inthe miracles described in the Bible

• most famous example of saintly surgery performedby 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 AD303; failed stoning, arrows, burning at the stake, anddrowning 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 acustodian 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 byLandsteiner in 1900

species-specific blood system

ABO-compatibility applied to organ transplantation

• discovery of the anticoagulants, sodium citrate andheparin

• 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, 1920’s



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 reportedin 1902

Prof. Emerich Ullmann, the Chief of Surgery at the ViennaPhysiology 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 modernmethod 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 caninekidney to the neck in1902

experimented with transplantation of blood vessels, thyroid

tissue, ovary, testes, kidneys, limbs, and hearts in dogs




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.




• described that allografts, after “behaving satisfactorilyover 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 anearly generation mechanical heart




• the first kidney transplant in humans was performedin 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 withkidney failure

each kidney only worked for ~1 hour

• next attempt was in 1909 by Ernst Unger (Berlin) whoperformed a monkey-to-human kidney transplant to ayoung girl dying of renal failure due to mercurypoisoning; failed to function




• 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 wasperformed 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 chloridepoisoning

transplanted into the thigh after 6 hours of warm ischemia

despite “exchange transfusion”, the kidney never worked

patient died 2 days later; vesselspatent at autopsy

• 6 kidney transplants from humandeceased donors with kidneysstored 9-20 days (1933-1949)

• none functioned



The 20th century: barriers to kidney Tx

• important issues which required solutions beforekidney 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



1947: dialysis & transplantation in Boston

• the group at Peter Bent Brigham performed the firstkidney transplant in a patient with ARF; the transplantbridged the patient until recovery of native renalfunction

• Kolff presented his findings on hemodialysis

• by 1950, the Boston team had carried out 33 dialysisruns in 26 patients

• in 1951, they attempted the first kidney transplant in a

ESRD patient who had received dialysis support; thepatient died due to rejection 5 weeks later



A renewed interest: the early 1950’s

• several groups started to do human kidneytransplants – Paris (7 cases), Boston (9 cases), andToronto (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 drainageinto the urinary bladder (Dr. René Küss, Paris)



The modern

approach to kidneytransplantation

http://images.usatoday.com/news/_photos/2004/12/19/transplant.jpg



The first successful kidney Tx!

• performed on December 23, 1954 at Peter BentBrigham 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 themanagement of malignant hypertension post-transplant

recipient survived 9 yrs until he died of a myocardial infarction

http://images.usatoday.com/news/_photos/2004/12/19/transplant.jpg



Kidney transplantation as therapy

• other successful monozygotic twin kidney transplantsperformed 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 transplantsperformed 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” asapplied to living organ donation

• first recognition of recurrent glomerulonephritis as acause of graft failure

• BUT it was a treatment of limited applicability!

For transplantation to succeed as a realisticform of renal replacement therapy, the

immunologic barrier would have to be

overcome.



The immunological barrier

• recognition that the body could determine “self” from“non-self” from initial experiences with reconstructivesurgery in ancient India and Egypt

• techniques revived during the Renaissance when

attempts were made to correct amputations anddeformities of the nose, ears and lips arising fromswordplay, 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 Pasteur and protective



INFECTION

INFLAMMATION

19th c

Pasteur and protective

immunization

Ehrlich: description

of humoral immunity

Metchnikoff: phagocytosis

and cellular immunity

1937: Gorer and

murine MHC

20th c

1945: recognition of the

immunosuppressiveeffects of total body

radiation

Immunosuppressive effects of

corticosteroids (1950-1960) and 6-mercaptopurine (1959) described

1950’s: description of HLA by

Dausset (Nobel prize awarded )

1908: Ehrlich and Metchnikoff

awarded the Nobel prize

INFECTION Pasteur and protective



INFECTION

INFLAMMATION

19th c

Pasteur and protective

immunization

Ehrlich: description

of humoral immunity

Metchnikoff: phagocytosis

and cellular immunity

1915-1930: descriptionof fetal or neonatal

tolerance models

1900-1930: importance of

lymphocytes in immunity

1940’s: description

of the DTH

response

1950’s: lymphocyte

circulation/migration

and function

20th c

1940-1960:Medawar, Brent,

Billingham: description of AR,

memory response, acquired

immunologic tolerance

1960: Medawar and Burnetawarded Nobel prize

1949: Burnet published

on “self” and “non-self”

and suggested clonal

selection to explain

fetal/neonatal tolerance



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 andMedawar 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 benecessary to allow successful allografting

• effects of large doses of irradiation on lymphocytesand 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 corticosteroidsreversed several rejections

• survived 27 years withgraft function



The era of immunosuppression

• some form of immunosuppression would benecessary to allow successful allografting

• effects of large doses of irradiation on lymphocytesand the immune system after Hiroshima and

Nagasaki• transplant models evaluating total body irradiation

• 1959-1962: first attempts in 11 humans with totalbody irradiation in Boston

• although the kidney transplants functioned longer, 10of 11 recipients died of sepsis despite vigorousisolation strategies → concept of opportunisticinfection



Immunosuppressive drug therapy

• irradiation too unpredictable and unreliable

• chemical immunosuppression appeared morepromising

• corticosteroids were being used as anti-inflammatoryagents for autoimmune diseases during the 1950’s

• 6-mercaptopurine was identified as animmunosuppressive medication; a derivative(azathioprine, Imuran®) became available in 1961

• 1st successful deceased donor kidney transplant wasperformed in 1961 at Peter Bent Brigham Hospital inBoston; treated with azathioprine/steroid and thepatient 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 pre-formed donor-specific antibodies

• development of donor-specific cytotoxic crossmatch

technique by Paul Terasaki et al at UCLA

N. Tilne Trans lant: from m th to realit . Yale Universit 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 organdonor 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 2weeks; 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. Tilne Trans lant: from m th to realit . Yale Universit Press 2003



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

The early1960’s: 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



The early 1960’s: success

• inferior results of non-identical LD kidney transplants

52% of recipients of LRD renal transplants had died

only 1 patient had survived > 24 months

and failure


Alive

Dead

Alive

Dead

Alive

Dead

88 42 46Totals

Should there be a moratorium on kidney

transplantation, particularly from living donors?



The early 1960’s: success

• 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

and failure


Alive

Dead



Kidney transplantation in context

• ARF due to acute tubular necrosis was first describedby English physicians during the “blitz” in WW II

• dialysis was initially developed in the 1940’s tosupport patients with ARF

1st dialysis machine: Kolff rotating drum, 1943

http://www.homedialysis.org/images/learn/museum/lg_kolff1.jpg



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 hemodialysiswere reported in 1960 by

Dr. Scribner in Seattle.The Scribner shunt



Dialysis reaches the University of Alberta

• first hemodialysis treatment for ESRD performed in1962

• 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

1960’s; 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-transplanttransfusion 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 1960’s: successes

• important developments during the 1960’s

organ preservation techniques

brain death defined and legislation generated to permitorgan donation after neurological death

tissue typing became available in 1962 cross-matching became available in the early 1970’s →

reduction in the incidence of hyperacute rejection whichoccurred due to the presence of preformed anti-donor HLAantibodies

creation of transplant wait-lists

creation of kidney sharing arrangements (Eurotransplant

was formed in 1967)



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



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 beendamaged in an accident; worked but rejected on day 22

• several attempts at unrelated donor kidneytransplants occurred in the early 1950’s

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-1990’s, it was clear that kidneytransplantation offered superior patient survival

compared with dialysis



What is better - dialysis or transplantation?

• kidney transplantation is the treatment of choice

Schold et al, Clin J Am Soc Nephrol 2006; 1:532-538

0

5

10

15

20

2530

35

40

45

18-39 40-54 55-64 >65Patient age (yrs)

P

r o j e c t e d l i f e - e x p

e c t a n c y

f r o m t h

e t i m e o f

E S R D

Living donor SCD transplant

Maintenance dialysis

Treatment after 2

years of dialysis



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-1990’s, it was clear that kidneytransplantation offered superior patient survival

compared with dialysis

• new immunosuppressive medications have further

reduced rejection rates and improved outcomes



0

20

40

60

80

100

'60 '65 '70 '75 '80 '85 '90 '95 '00 '05Year

% o

f t r a n s p l a

n t s

rejection in the first year

1 year graft survival

• Radiation

• Prednisone

• 6-mercaptopurine

• Azathioprine

• ATGAM

• Cyclosporine

• OKT3

• Neoral cyclosporine

• Tacrolimus

• MMF

• Dacluzimab

• Basiliximab

• Thymoglobulin

• Sirolimus

Impact of new immunosuppressive agents

Adapted from Stewart F, Organ Transplantation , 2003



University of Alberta: results of 1st kidney

transplants (2000-2007)

Graft survival

97.4%95.9%1 year 95.2%90.2%3 year

91.4%84.2%5 year

94.9%89.1%5 year

98.0%94.6%3 year

99.6%96.8%1 year

Patient survival

Living donor

(n=256)

Deceased donor

(n=372)

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

TX History Dec2008

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