The history of renal transplantation: from imagination to reality

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 • Hindu’s god of wisdom, Ganesha • angels and devils

3. Myth and imagination • integrated into our literature • Homer’s 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, 1920’s

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 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)

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! For transplantation to succeed as a realistic form of renal replacement therapy, the immunologic barrier would have to be overcome.

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. Isografts succeed Allografts fail Xenografts fail 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 1950’s: 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 6-mercaptopurine (1959) described

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 1940’s: 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 1950’s: lymphocyte circulation/migration and function TRANSPLANT IMMUNOBIOLOGY

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 1950’s • 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 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. Tilney Transplant: from myth to reality. Yale University Press, 2003

34. 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

35. 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

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

37. Should there be a moratorium on kidney transplantation, particularly from living donors? The early 1960’s: 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 Alive Dead Alive Dead Alive Dead Totals 88 42 46 Murray et al, Transplantation 1964; 2: 147-155

38. The early 1960’s: 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

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 1940’s to support patients with ARF 1st dialysis machine: Kolff rotating drum, 1943

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. The Scribner shunt

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 < 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 (3rdTx in program); kidney failed after 18 months and patient died 3 months later

44. University of Alberta: 1967-1970 (N=37) 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 1960’s; 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 • >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

48. Adjunctive immunomodulation • other strategies were designed to suppress or destroy immunocompetent lymphocytes : • splenectomofimmunomodulationy 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 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 • 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