Kidney transplantation from myth to reality

1. Kidney
transplantation
myth and reality
Dr Ayman Seddik , M.sc , MD
Assistant professor of nephrology , AIN SHAMS UNIVERSITY
Consultant Nephrologist , DUBAI HOSPITAL

2. 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

4. Myth and imagination
 stories of substituting or exchanging parts between
animals and humans exist in mythology and religion
 Egyptionsand Phoenicians– gods bearingheadsof animals
 Greek – the centaursand minotaur

5. Myth and imagination
 integrated into our literature
 Homer’s chimera – part goat, lion.
 mermaids
 Frankenstein

6. 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)

8. 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

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)
The modern version of
Cosmos and Damian

11. 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

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.. 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.

13. 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
 acceptablechoice of donor given reports claims of successful
xenograftingof 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

14. The 20th century: the early experience
 the first human-to-human kidneytransplantwas performedin
1933 in the Ukraineby 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

15. 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

17. 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

18. 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

19. 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 immunosuppressiveagents used
 all kidneys ultimatelyfailed, usually within 30 days
 occasional patientssurvived 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. Sayegh M and Carpenter C. N Engl J Med 2004;351:2761-2766
The First Identical-Twin Kidney
Transplantation,
Performed on December 23, 1954

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)
 monozygotictwin donor (the Herrick brothers)
 genetic identityconfirmed 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
 hypothesizedthat no immunosuppression would be required
 recipient required urgent native nephrectomiesfor the
management of malignant hypertensionpost-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!
For transplantation to succeed as a realistic form of
renal replacement therapy, the immunologic barrier
would have to be overcome.

23. The laws of transplantation
Isografts succeed
Allografts fail
Xenografts fail

24. 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

25. 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

26. 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

27. 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

28. 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

29. 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

31. 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)

32. 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

33. 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.

34. 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

35. 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

36. 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

37. 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

38. 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

39. 0
20
40
60
80
100
'60 '65 '70 '75 '80 '85 '90 '95 '00 '05
Year
%oftransplants
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

43. 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

44. 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


45. 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

46. .

47. Kidney Donor
 Living related.
 Living unrelated
 Cadaveric (Brain-dead)
Beating and non-beating heart.

48. 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.

49. 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.

50. 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.

51. 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.

52. Steinbrook R. N Engl J Med 2005;353:441-444
Kidney Transplantations in the
United States,
1988-2005

53. 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.

54. Ibrahim H et al. N Engl J Med 2009;360:459-469
Survival of Kidney Donors and Controls from
the General Population

55. Ibrahim H et al. N Engl J Med 2009;360:459-469
Quality-of-Life Scores for
Kidney Donors

56. 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

57. Why living related donors
give better results?
What if my donor doesn't
match me?

58. 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.

59. Matching between Recepient And
Donor
B- Cross matching
 A laboratory test that determines weather a potential transplant
recepienthas preformed antibodiesagainst the HLA antigens of the
potential donor. (Donor Lymphocytest+RecepientSerum)
 A Final CM is mandatory
C- Compatible ABO blood group.

60. 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.

61. 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

62. 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.

63. 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.

64. CONCLUSION
Meta-analysis of data from donors
followed for >20y confirmed safety
of kidney donation.