kidney transplantation from myth to reality , ajman meeting 2013 may
TRANSCRIPT
Kidney transplantation
myth and reality
Dr Ayman Seddik , M.sc , MD Assistant professor of nephrology , AIN SHAMS UNIVERSITY
Consultant Nephrologist , DUBAI HOSPITAL
OBJECTIVES :
1. ORGAN TRANSPLANTATION HISTORY.
2. KIDNEY TRANSPLANTATION AS AN
IDEAL METHOD OF RENAL
REPLACEMENT THERAPY.
3. DONOR SELECTION , TISSUE TYPING,
AND MATCHING.
4. FUTURE
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
Myth and imagination
integrated into our literature
Homer’s chimera – part goat, lion.
mermaids
Frankenstein
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
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
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)
The modern version of Cosmos and Damian
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 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.. All our efforts must now be directed toward the biological methods which will prevent the reaction of the body against foreign tissue and allow the adapting of homoplastic organs to their hosts.”
Alexis Carrell, 1914 at the Int. Surgical Association Mtg.
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 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
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
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
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 1940’s to support patients with ARF
1st dialysis machine: Kolff rotating drum, 1943
A renewed interest: the early 1950’s
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)
Sayegh M and Carpenter C. N Engl J Med 2004;351:2761-2766
The First Identical-Twin Kidney Transplantation,
Performed on December 23, 1954
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!
For transplantation to succeed as a realistic form of
renal replacement therapy, the immunologic barrier
would have to be overcome.
The laws of transplantation
Isografts succeed
Allografts fail
Xenografts fail
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
although the kidney transplants functioned longer, 10 of 11 recipients died of sepsis despite vigorous isolation strategies → concept of opportunistic infection
irradiation too unpredictable and unreliable
Immunosuppressive drug therapy
chemical immunosuppression appeared more promising
corticosteroids were being used as anti-inflammatory agents for autoimmune diseases during the 1950’s
6-mercaptopurine was identified as an immunosuppressive medication; a derivative (azathioprine, Imuran®) became available in 1961
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
N. Tilney Transplant:. Yale University Press, 2003
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)
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
The 1960’s: successes
important developments during the 1960’s
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 1970’s → reduction in the incidence of hyperacute rejection which occurred due to the presence of preformed anti-donor HLA antibodies
creation of transplant wait-lists
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
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 & BEYOND
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 kidney
transplantation offered superior patient survival
compared with dialysis
0
20
40
60
80
100
'60 '65 '70 '75 '80 '85 '90 '95 '00 '05Year
% o
f tr
anspla
nts
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
The Worldwide Transplant Directory
Organ Centers 2011 Total
● Kidney 520 28,857 752,481
● SPK 173 1151 21,867
● Pancreas 117 413 7,195
● Liver 239 10,477 171,288
● Heart 208 3,015 81,969
● Lung 100 2,056 25,456
● Intestine 15 81 774
World Transplant Records
Longest surviving kidney = 45 years
Liver = 38 years
Heart = 28 years
SPK = 25 years
Lung = 21 years
Recipients still alive with functioning graft
Patient Survival After Kidney
Transplantation VS haemodialysis
Annual mortality rates for patients under dialysis range
from 21%-25%, but <8% with cadaveric and <4% with
living-related transplant recepients.
Healthier patients generally are selected for
transplantation.
The benefit of transplantation is most notable in young
people and in those with diabetes mellitus.
Projected years of life for patients 20-39 years old:
Dialysis Transplant
Non diabetic 20 31 years
Diabetic 8 25years
.
Kidney Donor
Living related.
Living unrelated
Cadaveric (Brain-dead)
Beating and non-beating heart.
CRITERIA FOR LIVING
DONOR SELECTION
- Blood relative.
- Highly motivated.
- ABO blood group-compatible.
- HLA-identical or haploidentical with
negative cross-match.
- Excellent medical condition with
normal renal function.
CRITERIA FOR
CADAVER DONOR SELECTION
- Irreversible brain damage.
- Normal renal function appropriate for
age.
- No evidence of preexisting renal disease.
- No evidence of transmissible diseases.
- ABO blood group-compatible.
- Negative cross-match.
- Best HLA match possible, particularly at
the DR and B loci.
Principles Involved In
evaluating A Prospective Living
Kidney Donor
Whether there is a medical condition
that will put donor at increased risk for
complications for general anaesthesia
or surgery.
Wether the removal of one kidney will
increase the donor’s risk for
developing renal insufficiency.
Medical Conditions That Exclude
Living Kidney Donation
Renal parenchymal disease.
Conditions that may predispose to renal disease
History of stone disease
History of frequent UTI
Hypertension
D.M.
Conditions that increase the risks of anaesthesia and surgery.
Recent malignancy.
Steinbrook R. N Engl J Med 2005;353:441-444
Kidney Transplantations in the United States,
1988-2005
Does Donation Of A kidney
Pose A long-term Risk For The
Donor?
Following nephrectomy, compensatory
hypertrophy and increase in GFR occur in the
remaining kidney.
Slight risk of poteinuria and hypertension.
Meta-analysis of data from donors followed for
>20y confirmed safety of kidney donation.
Ibrahim H et al. N Engl J Med 2009;360:459-469
Survival of Kidney Donors and Controls from the General Population
Ibrahim H et al. N Engl J Med 2009;360:459-469
Quality-of-Life Scores for Kidney Donors
Ibrahim H et al. N Engl J Med 2009;360:459-469
Glomerular Filtration Rate (GFR) and Urinary Albumin Excretion According to Time since
Donation
Why living related donors
give better results?
What if my donor doesn't
match me?
Matching between Recepient And Donor
A- Tissue typing Determined by 6 antigens located on cell surface
encoded for by the HLA gen located on the short arm of chromosom 6.
Class I antigens (HLA-A and HLA-B) are expressed on the surface of most nucleated cells.
Class II antigen (HLA-DR) are expressed on surface of APC and activated lymphocytes.
These 6 antigens are refered to as major transplant antigens.
The match between donor and recepient can range from 0 to six.
Matching between Recepient And
Donor
B- Cross matching
A laboratory test that determines weather a potential transplant
recepient has preformed antibodies against the HLA antigens of the
potential donor. (Donor Lymphocytest +Recepient Serum)
A Final CM is mandatory
C- Compatible ABO blood group.
Effect Of HLA Matching On The
Graft Outcome
Data from large registries indicate that, the better the HLA-
match, the better the long-term survival of the allograft.
The benefits of matching are particularly notworthy in
recipients of kidneys from donors with zero missmatch.
The benefits of lesser degrees of matching have become
less obvious with the use of newer and more potent
immunosuppressive drugs.
Matching for DR antigens are more favorable than others.
Delmonico F. N Engl J Med 2004;350:1812-1814
An Exchange Performed because of a Cross-Match Incompatibility in One Pair and a Blood-Type
Incompatibility in the Other
CONCLUSION
Major challenges remain in providing
optimal treatment for ESRD worldwide and a
need, particularly in low-income economies,
to mandate more focus on community
screening and implementation of simple
measures to minimise progression of CKD.
CONCLUSION
HOWEVER early detection
and prevention programmes will never
prevent ESRD in everyone with CKD, and
kidney transplantation is an essential, viable,
cost-effective and life-saving therapy which
should be equally available to all people in
need.
CONCLUSION
Meta-analysis of data from donors
followed for >20y confirmed safety
of kidney donation.
