Starzl, TE

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The landmark identical twin case

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Reprinted from the Journal of the American Medical Association May 18, 1984, Volume 251 Copyright 1984, American Medical Association Landmark Perspective The Landmark Identical Twin Case* Thomas E. Starzl, MD, PhD In the autumn of 1979, the 25th anniversary was observed in Boston of the kidney transplantation that was the subject of the LANDMARK ARTICLE by Merrill and co-workers 1 that is reproduced in this issue. All of the authors of the article were members of the Harvard Medical School Faculty serving at the Peter Bent Brigham Hospital, where research in renal transplantation had been an important activity for several preceding years and where such work has continued to the present time. The decision at these institutions to focus for a historkal celebration on the first identical twin transplantati6n rather than some earlier or subsequent event rev~aled an in-house perception of the importance of the case that has been shared by outside students of medical history such as Groth2 of Stockholm. Of the four authors, Merrill and Guild were internists. The specialty of nephrology was somewhere between nonexistent and fledgling. George Thorn had been given one of the first four artificial kidneys by Wilhelm Kolff, the Dutch physician-inventor. A Brigham version of this machine was built, and with this advantage the first renal dialysis center in the world was born under the direction of Merrill et al. 1 The use of hemodialysis to prepare the identical twin recipient for transplantation foreshadowed this practice for tens of thousands of patients in later years. The availability of dialysis in the eventuality of poor or absent initial graft function was an obvious factor in the decision to proceed with transplantation. Thus, the Peter Bent Brigham Hospital in 1954 had all the ingredients of a modern nephrology support unit years ahead of its time. In this unit, under Merrill's direction, were trained many of the leaders in nephrology of the next three genera-tions. The Twin Transplant The transplantation was performed two days before Christmas, 1954, by Murray and Harrison, who modified the ectopic extraperitoneal technique originally de-scribed by the French surgeons Dubost,4 KUSS,5 and Servelle6 and their associates. Merrill had seen the extraperitoneal operation while visiting in France several years previously, as was mentioned by Hume et aV in an From the Department of Surgery, School of Medicine, University of Pittsburgh. Reprint requests to Department of Surgery, University of Pittsburgh, 103 Falk Clinic, 3601 Fifth Ave, Pittsburgh, PA 15213 (Dr Starzl). *A commentary on Merrill )p, Murray JE, Harrison JH, et al: Successful homotransplantation of the human kidney between identical twins. lAMA 1956;160:277-282. 2572 JAMA, May 18, 1984-Vol 251, No. 19 earlier publication from the Boston group. On Hume's departure to take over the surgical chair in Richmond, Va, Murray had explored the use of the pelvic position of the transplanted kidney in the dog and had acquired extensive experience with that operation. A brief report of the identical twin case was given by Murray8 at the American College of Surgeons and published in the Surgical Forum of 1955. Murray's legendary contributions to transplantation surgery continued until 1968, when he left this field to return to his first love, plastic surgery. Living-donor nephrectomy was an unusual operation at that time, and, except for the mother-to-offspring transplantation reported by Michon et al,9it had been limited to the removal of "expendable" kidneys excised during creation of ventriculoureteric CSF shunts or for other reasons. No effort was made to preserve the excised identical twin kidney, which functioned promptly even though it underwent 82 minutes of warm ischemia time. Core-cooling techniques with cold solution were not introduced until the next decade. It is possible that some of the abnormalities of renal function reported in the early identical twin recipients could have been late manifestations of ischemic damage. In addition to the nephrology prototype and the operative procedures, the connection of the Boston activities of late 1954 with many present-day policies is not hard to identify, including the important (and in the identical twin case, crucial) role of tissue matching. Tissue Matching, Heterotransplantation, Immunosuppression In the account by Merrill et ai, I credit for originally suggesting the transplantation was given to the recip-ient's physician, Dr David C. Miller of the Public Health Service Hospital, Boston. It had been known for almost two decades that skin grafts between identical twins were not rejected. ,o.11 The application of this information in the transplantation of a vital organ was a bold extension of the same principle and one that depended in the absence of immunosuppression on the perfect tissue match that could be obtained only with genetic identity of the donor and recipient. The efforts that were made to be sure of this condition were extraordinary and ultimately included skin grafting. It is no distortion of concept to say that the tissue matching of today between nontwin donors and recipients is an attempt to come as close as possible to the ideal circumstances of the landmark Boston Case. In their summary, Merrill et ai' wrote, "Tissue trans-plantation including that of a functioning kidney appears to be a feasible procedure in identical twins, but to date Identical Twin-Starzl successful permanently functioning homografts appear to be limited to such individuals." Thus, as an isolated event, this transplantation would have had little signifi-cance. The real meaning came from the continuity of effort at the Brigham that had begun earlier with the work of Hufnagel" and Hume et ai' that had as the ultimate objective the transplantation of kidneys from nonidentical donors including cadavers or even animals (heterotransplantation). Renal heterotransplantation was given a surprisingly extensive trial at the beginning of this century, as summarized elsewhere.'13 Renal homotrans-plantation was first attempted by Voronoy'4 of Russia in 1936. The first example of probable extended homograft function was in a patient of Lawler1516; the only other example of prolonged homograft function through 1954 was in a patient of Hume and Merrilf whose graft was placed in the thigh with function for five months. Immunosuppression was to be a necessary condition for the fulfillment of the dreams of early transplanters. The deliberate obtundation of recipient immunologic activity became theoretically feasible with the demon-stration that total-body irradiation was immunosup-pressive. 17.18 Pharmacologic immunosuppression with steroids 19 and cytotoxic drugs'o." provided the basis for the new era of renal transplantation that began in 1962 and 1963. The first demonstration of the possible value of cytotoxic drug therapy in large animals was by a young English surgeon, Roy Calne,22 who brought his subsequent animal investigations to the Harvard facility. Within a few years after the watershed identical twin case, Merrill, Murray, and Harrison became responsible for clinical trials with immunosuppression for renal homotransplantation using total-body irradiation 23 and drug therapy.'4 Almost all of these efforts failed, but they paved the way for the "cocktail" therapy with azathio-prine and prednisone that opened the modern era of renal transplantation a little more than 20 years ago and that made it possible for the first time to consider the transplantation of extrarenal organs. 13.25 When great deeds are performed, it is just to honor the heroes and especially those like the Harvard physi-cians and surgeons whose efforts were not transient; renal transplantation occupied much of their professional lifetimes, as Moore'6 has emphasized in his history of these events. The personal accolades for the members of the Boston team have been numerous. If gold medals and prizes were awarded to institutions instead of individuals, the Peter Bent Brigham Hospital of 30 years ago would have qualified. The ruling board and administrative structure of that hospital did not falter in their support of the quixotic objective of treating end-stage renal disease despite the long list of tragic failures that resulted from these early efforts, leavened only by occasional encouraging notations such as those in the identical twin case. Those who were there at the time have credited Dr George Thorn, chairman of medicine, and Dr Francis D. Moore, chairman of surgery, with the qualities of leadership, creativity, courage, and unselfishness that made the Peter Bent Brigham Hospital a unique world resource for that moment of history. This report was supported in part by research grants from the Veterans Administration and grant AM-29961 from the National Institutes of Health, Bethesda, Md. References 1. Merrill]p, Murray JE, Harrison JH, et al: Successful homotransplan-tation of human kidney between identical twins. /AMA 1956;160:277-282. 2. Groth CG: Landmarks in clinical renal transplantation. Surg GynecolObstet 1972;134:323-328. 3. Merrill JP, Smith S III, Callahan EJ III, et al: The use of an artificial kidney: II. Clinical experience. / Clin Invest 1950;29:425-438. 4. Dubost C, Oeconomos N, Nenna A, et al: Resultats d'une tentative de greffe renale. Bull Soc Med Hop Paris 1951;67:1372-1382. 5 KGss R, Teinturier L Milliez P: Quelques essais de greffe rein chez I'homme. Mem Acad Chir 1951;77:755-764. 6. Servelle M, Sou lie P, Rougeulle j, et al: Greffe d'un rein de supplicie a une malade avec rein unique congenital, atteinte de nehprite chronique hypertensive azotemique. Bull Soc Med Hop Paris 1951 ;67:99-104. 7. Hume DM, Merrill ]p, Miller BF, et al: Experiences with renal homotransplantation in the human: Report of nine cases. / Clin Invest 1955;34:327-382. 8. Murray JE, Merrill ]p, Harrison JH: Renal homotransplantation in identical twins. Surg Forum 1955;6:432-436. 9. Michon L, Hamburger I. Oeconomos N, et al: Une tentative de transplantation renale chez I'homme. Aspects Medicaux et Biologiques. Presse Med 1953;61:1419-1423. 10. Padgett EC: Is iso-skin grafting practicable? South Med / 1932;25:895-900. 11. Brown IB: Homografting of skin: With report of success in identical twins. Surgery 1937;1 :558-563. 12. Hufnagel C, cited by Hume DM, Merrill JP, Miller BF, et al: Experiences with renal homotransplantation in the human: Report of nine cases. / Clin Invest 1955;34:327-382. 13. Starzl TE: Experience in Renal Transplantation. Philadelphia, WB Saunders Co, 1964. 14. Voronoy U: Sobre el bloqueo del aparato reticuloendotelial del JAMA, May 18, 1984-Vol 251, No. 19 hombre en algunas formas de intoxicacion por el sublimado y sobre la transplantacion del rinon cadaverico como metodo de tratamiento de la anuaria consecutiva a aquella intoxicacion. Siglo Med 1936;97:296. 15. Lawler RH, West jW, McNulty PH, et al: Homotransplantation of the kidney in the human. /AMA 1950;144:844-845. 16. Lawler RH, West jW, McNulty PH, et al: Homotransplantation of the kidney in the human Supplemental report of a case. /AMA 1951;147:45-46. 17. Dempster WI, Lennox B, Boog jW: Prolongation of survival of skin homotransplants in the rabbit by irracliation of the host. Br / Exp Patho/1950;31:669-670. 18. Lindley DL, Odell TT Jr, Tausche FG: Implantation of functional erythropoietic elements following total body irradiation. Proc Soc Exp BioI NY 1955;90:512-515. 19. Billingham RE, Krohn PL, Medawar PB: Effect of cortisone on survival of skin homografts in rabbits. BrMed /1951;11157-1163. 20. Hitchings GH, Elion GB: Activity of heterocyclic derivatives of 6-mercaptopurine and 6-thioguanine in adenocarcinoma 755. Proc Am Assoc Cancer Res 1959;3:27. 21. Schwartz R, Dameshek W: Drug-induced immunological toler-ance. Nature 1959;183:1682-1683. 22. Caine RY: The rejection of renal homograft: Inhibition in dogs by 6-mercaptopurine. Lancet 1960;1:417-418. 23. Murray IE, Merrill ]p, Dammin GJ, et al: Study of transplantation immunity after total body irradiation: Clinical and experimental investi-gation. Surgery 1960;48:272-284. 24. Murray JE, Merrill ]p, Dammin Gj, et al: Kidney transplantation in modified recipients. Ann Surg 1962;156:337-355. 25. Starzl TE, Marchioro TL, Waddell WR: The reversal of rejection in human renal homografts with subsequent development of homo-graft tolerance. Surg Gynecol Obstet 1963;'117385-395. 26. Moore FD: Give and Take: The Development of Tissue Transplantation. Philadelphia, WB Saunders Co, Garden City, NY, Doubleday & Co, 1964. Identical Twin-Starzl 2573 Printed and Published in the United States of America 