A follow-up is provided for 64 patients treated with renal transplantation at the University of Colorado before 31 March 1964. The 25-year survival was 15/64 (23.4%) and 14 patients (22%) are still alive after 25 1/2 to 27 years. There are 9 other survivors in the world from this era, distributed in 4 American and 2 European centers. All of the 25-year survivors received their grafts from living related donors

Barfield, N

Hartmann, NJ

Mangan, TL

Schroter, GPJ

Starzl, TE

Taylor, P

PubMed

D-Scholarship@Pitt

-_ ... __ ._------_.-------------------------,I ;,) Long-Term (25-Year) Survival After Renal Homotransplantation-The World Experience T.E. Starzl, G.P.J. Schroter, N.J. Hartmann, N. Barfield, P. Taylor, and T.L. Mangan AT the beginning of 1962, renal transplantation, except with an identical twin donor, was not a promising means of treatment. Total body irradiation 1.2 6-mercapto-purineIP~ its analogue, azathioprine? and steroids8 had been shown in dogs and/or rodents to have immunosup-pressive qualities. but prolonged survival of skin or kidney grafts in experimental animals was a relatively uncommon achievement. Similarly, the first clinical trials with these agents, alone or in combination, had been almost univer-sally unsuccessful. Y- J4 METHODS It was known from our own unpublished canine experiments that steroids and azathioprine had synergistic immunosuppressive effects. As it turned out, this kind of multimodality therapy allowed the prevention or reversal of rejection of renal homografts in most clinical cases. 15 Consequently, an extensive and encour-aging clinical experience (Table 1) with 64 patients was quickly acquired at the University of Colorado. 16 Forty-six patients were given kidneys from blood relatives other than identical twins. The other 18 received kidneys from nonrelated volunteer donors. Fifteen of the recipients survived for 25 years and 14 are still living after 25Y, to 27 years. These long-surviving recipients are the principal basis of this report. In addition, with the help of colleagues at 6 other centers which were active in these early years, 9 more patients have been found who have survived to date after treatment with renal homotrans-plantation during this same time frame. RESULTS Forty-Six Recipients of Living Related Kidneys Fourteen (30%) of 46 recipients of living related kidneys in the original University of Colorado series are still alive after 25Yz to 27 years (Table 2). The 25-year survival rate in this group was 15/46 (33%), but one of the patients died after 25.3 years with function of his original maternal graft (Cr 2.0 mg %). Ten of the 14 survivors have their original grafts (Table 2), and all have serum creatinines less than 2 mg%. Recipients of Sibling Kidneys. Only 3 (13%) of the 23 recipients of sibling kidneys are alive (Table 1). They have good function of their original transplants, the first two of which are the longest surviving homografts in the world. These 3 patients are males. Their grafts were placed on 31 January 1963 (from a sister), 9 February 1963 (brother), and 15 January 1964 (sister) (Table 2). The first of these recipients was A blood type and received a B kidney, a blood group incompatibility that is generally avoided to-day. The last 2 of the 3 surviving recipients stopped all therapy 25 and 23 years ago because of mental illness and religious convictions respectively. Renal function has been perfect throughout. Why treatment could be stopped per-manently is not known. Noncompliance of this kind often has been described in the literature as an important cause of graft loss. Recipients of Parental Kidneys. Nine (45%) of the 20 recipients of parental kidneys are alive (Table 1) and 5 still have adequate function of their original grafts. Two more have undergone successful retransplant at ion with related donors and two are on dialysis (Table 2). From the Department of Surgery, University Health Center of Pittsburgh, University of Pittsburgh, Pittsburgh, PA (T.E.S., N.J.H., and T.L.M.), and Veterans Administration Hospital, Denver, CO, and the Department of Surgery, University of Colorado, Denver, CO (G.P.J.S., N.B., and P.T.). Supported by research grants from the Veterans Administration and Project Grant No. DK 29961 from the National Institutes of Health, Bethesda, MD. Address reprint requests to Thomas E. Starzl, MD, PhD, De-partment of Surgery, 3601 Fifth Avenue, Falk Clinic, Pittsburgh, PA 15213. © 1990 by Appleton & Lange 0041-1345/90/$3.00/+0 Table 1. Living Donor Renal Transplants From November 1962 to March 1964 Alive in Years Function Now Off Dialysis Number 5 10 20 25 Now of Original Graft Now Non-Twin Relatives 46 28 24 17 15 14 10 12 Sibling 23 11 8 4 3 3 3 3 Parental 20 14 13 11 10 9 5 7 Other- 3 3 3 2 2 2 2 2 Non Related 18 2 2 0 0 0 0 • Aunt, Uncle. or Cousin. Transplantation Proceedings, Vol 22, No 5 (October), 1990: pp 2361-2365 2361 2362 STARZL, SCHROTER, HARTMANN ET AL Table 2. Fourteen Surviving Patients From 1962 to 1964 Table 4. Outcome of Pediatric Recipients Treated From Novem-(March) Series ber 24,1962 to March 23, 1964, Follow-up to September 1,1989 Renal Function LD Tx Date Donor Age/Sex Function Dialysis Age Patient LD atTx Survival Donor Tx Dates CR BUN 11-24-62 Mother 121M 5-21-68 Father Since 1982 12 Alive Mother 11·24-62 Dialysis Father 5-21-68 Since 9-2-82 2 1-31-63 Sister 381M Good 13 15 Alive Mother 7-03-63 Failed 3 2-9-63 Brother 211M Good Brother 7-27-87 Normal 13 7-3-63 Mother 151M 17 15 Alive Mother 7-19-63 Normal 7-27-87 Brother Good 19 17 109d Mother' 7-26-63 17 7-19-63 Mother 15/F Good Unrel M 8-09-63 33 10-07-63 Mother 18/F Good 20 6 201d Mother' 7-29-63 34 10-11-63 Mother 8/F 22 15 l1y 169d Mother 8-12-63 9-14-82 Brother Good 26 16 ld Father 8-29-63 39 11-13-63 Mother 171M Good 33 18 Alive Mother 10-07-63 Normal 42 11-27-63 Father 19/F Good 34 8 Alive Mother 10-11-63 Failed 49 1-15-64 Sister 321M Good Brother 9-14-82 Normal 50 1-25-64 Father 16/F 39 17 Alive Mother 11-13-63 Normal 11-07-69 Mother 41 3 14y 16d Mother 11-23-63 10-30-85 Cadaver Since 1987 Cadaver M 1-22-70 Cadaver F 6-29-70 51 2-10-64 Aunt 181M Good Cadaver F 2-27-71 52 2-17-64 Father 15/F Good Cadaver F 12-29-72 50 16 Alive Father 1-25-64 Dialysis 53 2-22-64 Uncle 151M Good Mother 11-07-69 Since 1987 Cadaver 10-30-85 Recipients ofGrafis From an Aunt, Uncle, and Cousin. 51 18 Alive Aunt 2-10-64 Normal One graft from an aunt and one from an uncle are still 52 15 Alive Father 2-17-64 Normal functioning well (Tables 1 and 2). A kidney from a second cousin was chronically rejected after 15 years and the 53 15 Alive Uncle 2-22-64 Normal recipient died not long after. Pediatric Vs Adult Recipients of Related Grafts. Of 16 61 5 36d Mother 3-23-64 patients who were 18 years-old or younger at the time of Tx = transplantation; ReTx = retransplantation . transplantation, 10 (63%) are still alive, 8 are dialysis free, • A to 0 transplants. and 6 have good function of their original grafts (Table 3). In contrast, only 4 (13%) of 30 adults are alive, all with Because of the disproportionately high 25-year survival function of their original grafts of which 3 were from observed in infants and pediatric recipients, all 16 cases siblings, and the other from a parental donor. were examined retrospectively (Table 4). Four of the 6 deaths occurred early from 1 to 201 days after transplan-tation. Only 2 more deaths occurred in the next 25 years. Table 3. Pediatric Versus Adult Recipients in 46 Related Transplantations Eighteen Colorado Recipients of Nonrelated Original Dialysis Volunteer Kidneys Number Alive Graft Free 6(38%) 8(50%) None of these patients are alive (Table 1). The longest Pediatric (3-18 years) 16 10 (63%) kidney survival was 16;13 years (LD63) and the longest Adult (19-55 years) 30 4 (13%) 4 (13%) 4 (13%) patient survival (LD54) was 24.8 years (Table 5). RENAL HOMOTRANSPLANTATION 2363 Table 5. Causes of 12 Deaths That Occurred After 10 Years Date of LD' Donor Date of Tx Age Death 6 Brother 4-17-63 23 9-24-87 12 Brother 6-07-63 48 7-15-80 14 Brother 7-05-63 42 4-06-82 22 Mother 8-12-63 15 1-28-75 25 Brother 8-21-63 33 5-09-81 37 Mother 10-18-63 21 2-10-89 41 Mother 11-23-63 3 12-08-77 Cadaver 1-22-70 Cadaver 6-29-70 Cadaver 2-27-71 Cadaver 12-29-72 54 Unrelated 2-24-64 21 11-25-88 Cadaver 9-26-66 Cadaver 11-17-74 55 Father 2-26-64 21 9-02-84 58 Sister 3-13-64 27 10-10-74 60 2nd Cousin 3-17-64 21 5-29-79 Causes of Late Death in the Colorado Series At the end of 10 years, 24 (52.2%) of the 46 patients given living related kidneys, and 2 (11.1%) of 18 recipients of nonrelated kidneys were still alive. Twelve of these 26 survivors died subsequently for reasons summarized in Table 5. Heart disease from coronary arteriosclerosis and cancer (4 examples each), were the principal reasons for the late deaths. Two patients stopped immunosuppression in what may have been covert suicides. They rejected their kidneys, and died of inadequately treated renal failure, Another patient with perfect renal function 17.7 years posttransplantation committed suicide with carbon mon-oxide inhalation. One patient developed chronic active hepatitis and died of liver failure 10.6 years posttransplan-tation. It was particularly distressing to have 3 patients die a few months before or just after the twenty-fifth anniver-sary of their transplantation. Two of these patients (LD6 and LD37) still had life supporting although subnormal renal function. One (LD6) was under consideration for heart transplantation and kidney retransplantation. Survivors From Other Centers Before 31 March 1964 Nine additional survivors from this early era of renal transplantation are being followed in 6 centers (Table 6), 4 Last Kidney Function Survival CR BUN Cause of Death 24.4 5.0 73 Coronary artery disease 17.1 1.7 16 Cancer of prostate 18 1.2 19 Coronary artery disease 11.6 Renal failure, stopped medications 17.7 1.6 18 Suicide 25.3 2.0 40 Coronary artery disease 14 Renal failure 24.8 1.2 20 Coronary artery disease 20.5 1.5 25 Cancer of lung 10.6 1.2 13 Liver failure from chronic active hepatitis 15.2 Renal failure, multiple skin cancers in the United States and 2 in Europe. All 9 were recipients of kidneys from blood relatives. In 7 of the 9 cases, the original grafts are still functioning. In the other 2, retrans-plantation many years later has made or kept the patients dialysis free; these patients who were treated in Paris (1962) and Edinburgh (1962) are the longest survivors in the world. DISCUSSION There are no patients left from the era preceding 1962 in which immunosuppression was with total body irradiation. However, the long survi val of two fraternal twin recipients from this earlier time provided an exceptional incentive for continuing efforts during an otherwise bleak period. The first of these twins whose operation was in Boston on 24 January 1959,11.12.17 died in August 1979 of arteriosclerotic heart disease (personal communication, Dr Robert Kirk-man, August 1989). The second fraternal twin underwent transplantation in Paris on 29 June 1959,18 and died on 13 July 1985 of carcinoma of the bladder (personal communi-cation, Dr Henri Kreis, August 1989). The subsequent wave of successes that began in 1962 was made possible by the availability of azathioprine and by its combination with prednisone. March of 1964 was a natural demarcation point defining the end of this remark-2364 STARZL, SCHROTER, HARTMANN ET AL Table 6. Nine Other Non-Twin Recipients From Before March 31, 1984 Earlier Principal Late Dialysis Free Now With 1 st With Number Date Tx Where Done" Donor Age/Sex Physician Reports Follow-up by On Dialysis Graft RTx 2·12-62 Paris Cousin 18 M J. Hamburger H. Kreis No Yes 3-28-77 Sister 2 7-27-62 Edinburgh Father 12 M M. Woodruff 22 M. Woodruff 1-83 to 1-86 No Yes 1-86 Cadaver 3 3-18-63 Richmond Brother 22 F D.Hume 25 G. Mendez-Picon, Yes H.M. Lee 4 5-06-63 Boston Father 30M J. Murray, 20,21 R. Kirkman Yes J. Merrill 5 5-16-63 Richmond Mother 14 F D.Hume 25 G. Mendez-Picon. Yes H.M. Lee 6 7-16-63 Cleveland Brother 41 M W. Kolff 26 W. Braun Yes 7 8-14-63 Minneapolis Mother 12 M W.O. Kelly, 27 J. Najarian Yes R. Lillehei 8 12-27-63 Minneapolis Aunt 7F W.O. Kelly, 27 J. Najarian Yes R. Lillehei 9 2-03-64 Richmond Sister 35 F O.Hume 25 G. Mendez-Picon, Yes H.M. Lee -Paris-Hopital Necker; Edinburgh-Western General Hospital; Boston-Peter Bent Brigham; Richmond-Medical College of Virginia; Cleveland-Cleveland Clinic; Minneapolis-University of Minnesota. able new phase. The cases compiled to that time at the University of Colorado provided the basis for the first textbook on renal transplantation. 16 In addition, this same time frame was used for a collection of all 342 renal homotransplantations done in the world up to March 1964. 19 This latter extraordinary labor of love had been undertaken by the great transplantation pioneer, Dr Joseph E. Murray of Boston, following a meeting on 26 and 27 September 1963 in Washington DC of about 20 early workers (surgeons, physicians, and pathologists) in this embryonal new specialty. The meeting was sponsored by the National Research Council and the National Academy of Science. Almost all of the survivors in the world at the time of the September 1963 meeting and up through the following March were treated at the same centers in Boston, Cleve-land, Denver, Edinburgh, Minneapolis, Paris, and Rich-mond where more than 25 years later the residual group of patients can be found today. Late reports from most of these centers have been published2G-27 but not for a number of years. The presence of these survivors contin-ues to justify an effort which once was perceived by many as the height of folly. 28 Ever since 1964. there was a growing uneasiness in the University of Colorado team about our dependence on living related donors; this is a concern which continues to haunt us to the present day. In addition, the failure to do better at the end of our 24-month trial than at the beginning of it had already convinced us that fundamental improve-ments in tissue matching, in immunosuppression, or both would be necessary before renal transplantation would be truly practical. Consequently, a moratorium on renal transplantation was declared at the University of Colorado from March 1964 until the following October. When efforts were resumed, they included the first trial (with Dr Paul Terasaki at the University of California, Los Angeles) of prospective tissue matching.29 By 1964 it became evident that the quality of life provided by nonrelated kidneys was inferior to that pro-vided under the same conditions by living-related donor transplants. Furthermore, progress in the results of ca-daver donor renal allografts appeared to be a clear prereq-uisite to extension of clinical transplantation to nonrenal organs, which uniformly require cadaveric donors. It is worthy of note that none of the world's currently surviving 23 long-term recipients was given an unrelated donor kidney. The longest continuous function of an unrelated kidney allograft in the University of Colorado series was 16.7 years. There is no report, as yet, in the world of a 25-year survival of a cadaveric kidney allograft, although a recipient in Paris who has maintained perfect renal func-tion is expected to breach this barrier on 12 October 1989 RENAL HOMOTRANSPLANTATION (personal communication, Dr Henri Kreis, August 1989). This female recipient was 31 years-old at the time of her transplantation in 1964. A disquieting note in this series of patients is the continuing late mortality, which appears to bear no rela-tionship to the organ source. In the University of Colorado series. 12 of the 26 patients alive at 10 years24 died subsequently. The higher rate of cancer seems to be related to chronic immunosuppression as was predicted from the beginning of this experience. 30 Cardiovascular disease seen in these patients may also have been a consequence of chronic immunosuppression. and particu-larly of the use of steroids. It is of interest in this regard that the two patients who stopped their own immunosup-pression more than 20 years ago remain free of these complications. These recipients have behaved almost as identical twin recipients studied during this era. Less than complete satisfaction with the outcome of transplantation may be inferred from the suicide of one patient and the occult suicide of2 other subjects. who refused to return to chronic dialysis after their kidney grafts had failed. At the time, the results observed during this era ending in March 1964 were considered revolutionary. A new field was deemed to have been opened with staggering scientific and social ramifications. The follow-up provided in this report is less of a justification of the technology then available than a sobering description of its limitations. The treatment options available today continue to have many of the same risk factors for truly long survival as the methods of 25 years ago. The results provide a stark warning against complacency regarding what we have to offer to transplant recipients today. SUMMARY A follow-up is provided for 64 patients treated with renal transplantation at the University of Colorado before 31 March 1964. The 25-year survival was 15/64 (23.4%) and 14 patients (22%) are still alive after 251/2 to 27 years. There are 9 other survivors in the world from this era, distributed in 4 American and 2 European centers. All of the 25-year survivors received their grafts from living related donors. REFERENCES I. Dempster WJ, Lennox B. BoagJW: Br J Exp PathoI31:670, 1950 2365 2. Lindsley DL, Odell TT Jr, Tausche FG: Proc Soc Exp Bioi 90:512, 1955 3. Schwartz R, Dameshek W: Nature 183:168, 1959 4. Caine RY: Lancet 1:417, 1960 5. Zukoski CF, Lee HM, Hume DM: Surg Forum 11:470, 1960 6. Pierce JC, Varco RL: Lancet 1:781, 1962 7. Caine RY, Murray JE: Surg Forum 12:118, 1961 8. Billingham RE, Krohn PL, Medawar PB: Br Med J 1: 1157, 1951 9. Goodwin WE, Martin DC: Urol Survey 13:229, 1963 10. Groth CG: Surg Gynecol Obstet 134:323, 1972 11. Murray JE, Merrill JP, Dammin GJ, et al: Surgery 48:272, 1960 12. Murray JE, Merrill JP, Dammin GJ, et al: Ann Surg 156:337, 1962 13. Murray JE, Merrill JP, Harrison JH, et al: N Engl J Med 268:1315, 1963 14. Woodruff MFA, Robson JS, Nolan B, et al: Lancet 2:675, 1963 15. Starzl TE, Marchioro TL, Waddell WR: Surg Gynecol Obstet 117:385, 1963 16. Starzl TE: Experience in Renal Transplantation. Philadel-phia: WB Saunders Company, 1964 17. Merrill JP, Murray JE, Harrison JH, et a1: New Engl J Med 262: 1251, 1960 18. Hamburger J, Vaysse J, Crosnier J, et al: Presse Med 67:1771,1959 19. Murray JE, Gleason R, Bartholomay A: Transplantation 2:660, 1964 20. Murray JE, Wilson RE, O'Connor NE: Surg Gynecol Obstet 124: 124, 1967 21. Kirkman RL, Strom TB, Weir MR, Tilney NL: Transplan-tation 34:347, 1982 22. Woodruff MFA, Nolan B, Anderton JL, et al: Br J Surg 63:85, 1976 23. Starzl TE, Porter KA, Halgrimson CG, et al: Ann Surg 180:606, 1974 24. Starzl TE, Wei1 R, Putnam CW, Koep LJ: Transplant Proc 9:1,1977 25. Thomas F, Lee HM. Wolf JS, et al: Transplant Proc 7:707, 1975 26. Braun WE, Crile G Jr, Straffon RA, et al: Transplant Proc 12(Suppl 1):715, 1975 27. Kelly WD, Lillehei R, Aust JB, et al: Surgery 62:704, 1967 28. Elkinton JR: Ann Int Med 60:309, 1964 29. Terasaki PI, Vredevoe DL, Mickey MR, et al: Ann NY Acad Sci 129:500, 1966 30. Starzl TB, Penn I, Putnam CW, et al: Transplantation Review 7:112, 1971 

Long-term (25-year) survival after renal homotransplantation - The world experience

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Long term (25 year) survival after renal homotransplantation - the world experience

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Long-term (25-year) survival after renal homotransplantation - The world experience

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