100 years ago

100 Years Ago: Ullmann’s Pioneering Operation—Autotransplantation of the Kidney R.M. Langer and B.D. Kahan LIFE AND WORK

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N MARCH 7, 1902, at a meeting of the Vienna Medical Society, 41-year-old Hungarian-born surgeon Emerich (Imre) Ullmann presented a paper entitled “Experimental Kidney Transplantation,”1 which reported canine renal autotransplantation (Figs 1 and 2). Within the same year he also successfully performed renal allotransplantation in canines and xenotransplantation from a dog to a goat. But who was this Hungarian-born surgeon? His contributions to the field of transplantation are almost unknown in English medical literature.2– 4 Emerich (the German equivalent of the Hungarian name Imre) Ullmann was born in the town of Pe´cs, Hungary, in 1861, the son of Moritz Ullmann, a local physician, and Elise Pollak. Original documents from Pe´cs4,5 describe an excellent pupil who gained admission to the world-renown University of Vienna Medical School. After graduating in 1884, his exemplary scholarship merited an invitation to work in the Surgical Department under the leadership of Theodor Billroth’s successor Professor Eduard Albert. After a year of special postgraduate surgical training in the Surgical Operations Institute, he undertook sabbatical studies in Go ¨ttingen, Leipzig, and Berlin with Robert Koch.6 Subsequently in Paris working with Louis Pasteur, he was one of the first volunteers for the study of human rabies vaccination. In 1886 he returned to Austria to pursue a surgical career: serving as an assistant professor until 1892, when he was appointed Chief of Surgery at The Vienna Hospital of the Clement Sisters. He published Evolution of Surgery in Recent Years* in 1902, a book based on his experimental work that presents innovative techniques for gut anastomoses, gastrostomy, liver resection and the surgery of the bile duct, as well as the treatment of osteomyelitis.7 In 1919 he became a full professor at The University of Vienna, where he was known for his lively personality and dynamic teaching style. His lectures for foreign students were especially popular and always ensured a packed auditorium. Already as Chief of Surgery at the Viennese Hospital of the Clement Sisters, Ullmann conducted kidney transplan-

* Originally published as Die Fortschritte der Chirurgie in den letzten Jahren. © 2002 by Elsevier Science Inc. 655 Avenue of the Americas, New York, NY 10010 Transplantation Proceedings, 34, 429–433 (2002)

Fig 1. Emerich (Imre) Ullmann 1861-1937 (courtesy of The University of Vienna, Institute for the History of Medicine).

tation experiments, using first rabbit and later canine models at The Physiological Institute of The University of Vienna, headed by Professor Sigmund Exner. Employing aseptic techniques and modifying the location from the inguinal vessels (where the dogs could access the wound) to the neck, he succeeded where two other scientists had failed

From the Division of Immunology and Organ Transplantation, University of Texas-Houston, Houston, Texas. Address reprint requests to Barry D. Kahan, PhD, MD, Division of Immunology and Organ Transplantation, The University of Texas Medical School at Houston, 6431 Fannin, Suite 6.240, Houston, TX 77030. E-mail: [email protected] 0041-1345/0⫺2000/$–see front matter PII S0041-1345(02)02642-8 429

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Fig 2. Ullmann’s original article from 1902 (reprinted by permission from Wiener Klinische Wochenschrift).

before him7: Alfred Exner, a surgeon and son of Professor Sigmund Exner, and Alfred Decastello-Rechtwehr, a physician. Ullmann performed a series of canine renal autotransplants using the following technique. After the carotid artery and the jugular vein were ligated cranially, magnesium tubes were utilized to construct the Payr-anastomoses (named after Erwin Payr, at that time working in Graz, later he became Professor of Surgery in Leipzig). After the native kidney was removed without flushing (no description is available about from which side), it was wrapped in warm, saline-soaked gauze. Its vessels were connected to the tubes. Upon removal of the clamps, the circulation to the kidney was reestablished, and immediate urine output was observed. Finally, the skin was closed except for the ureterostomy over a subcutaneous niche created for the graft. On May 1, 1902, Ullmann demonstrated an allotransplantation procedure in which the graft produced urine output for 5 days. He also demonstrated xenotransplantation on June 27, 1902, implanting a canine kidney into the neck of a goat. It produced urine only for a short time.5 A clinical experience was also reported: Ullmann attempted to transplant a pig kidney to the antecubital fossa of a young woman afflicted with uremia; the operation failed due to technical difficulties.4

After the fall of the Hapsburg monarchy in 1920, Ullmann chose to accept Austrian citizenship5 and remained in Vienna, where he spent his remaining years as a beloved and successful surgeon who had a special interest in the arts, particularly in collecting miniatures.7 Ullmann died of apoplexy in 1937 at the age of 76. His last publication commemorated the 50th anniversary of the introduction of Pasteur’s vaccination for rabies in Vienna.8 In the same volume of Wiener Klinische Wochenschrift, which 35 years earlier had published Ullmann’s pioneering experiments, can be found an honorary obituary written by Professor Anton von Eiselsberg who presided over the 1902 Vienna Medical Society meeting.9 Another Vienna weekly also published an obituary by Professor Julius Schnitzler.10 EARLY ADVANCES IN TRANSPLANTATION

Alexis Carrel, the 1912 Nobel laureate who developed the technique of vascular anastomosis11 and used it to transplant blood vessels, heart, spleen, kidney, and extremities, had recognized the problem of rejection. He repeated Ullmann’s experiments citing the latter surgeon’s contributions in his early papers.2 Following the subsequent experimental work of Jaboulay, Unger, as well as Carrel and

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Fig 3.

Timeline of experimental and clinical kidney transplantation.

Guthrie, the Ukrainian surgeon Voronoy performed human kidney allotransplantations from 1933 to 1949 using the thigh vessels for anastomoses.12 None of the grafts functioned. In 1946, Landsteiner, Hufnagel, and Hume employed the arm vessels to connect a human kidney transplant, which produced transient life-saving function.2 Between 1950 and 1953 other attempts were made in Paris,13–15 an orthotopic attempt in Chicago by Lawler,16 and also in Boston by David Hume using a heterotopic approach.17 Probably because these early transplants were performed without the use of immunosuppressive regimens, only a few grafts displayed even temporary function. Finally in Boston in 1954 —a little more than 50 years after Ullmann’s experiments—Joseph Murray performed the first successful renal transplantation between identical twins.18 Figure 3 timeline of key dates in kidney transplantation. AUTOTRANSPLANTATION

Schackman and Dempster performed in 1961 the first reported case of human renal autotransplantation seeking to preserve the renal mass for treatment of renal artery stenosis,19 a condition generally believed to be either inoperable or optimally treated by nephrectomy. The first renal autotransplant performed in the United States was reported in 1963 by Professor James Hardy20 who reimplanted a right kidney into the iliac fossa to treat a stricture following a ureteroureteral anastomosis constructed after a previous injury. It was important to preserve renal mass and avoid a nephrostomy, because the patient also presented with a hydronephrotic left kidney. Hardy used moderate whole body hypothermia (32°C to 36°C), but not perfusion of the autograft, to minimize hypoxic damage to the organ. A 1966 report summarizing the results of renal autotransplantation in humans estimated a 5% to 10% failure rate.21 The authors suggested that the indications for autotransplantation were inadvertent total nephrectomy, renovascular hypertension, renal artery aneurysm, atherosclerotic aortic disease, and anomalies of or damage to the ureter. INDICATIONS FOR AUTOTRANSPLANTATION Renovascular Hypertension or Aneurysm

Autotransplantation rather than nephrectomy was documented22 for treatment of renal artery abnormalities result-

ing from fibromuscular hyperplasia, aneurysm, atherosclerosis, arteriovenous malformations, arteritis, or trauma.23 Autotransplantation became the treatment of choice in cases of bilateral arterial disease and for damage distal to the renal artery bifurcation. Increasingly, renal artery damages closer to the hilum of the kidney were also treated by bench surgery and autotransplantation. The ex vivo techniques facilitate repair of complex lesions.24 In one orthotopic technique25 the kidney was mobilized and perfused without transecting the renal vein or the ureter. Revascularization has been successful by using autologous hypogastric arteries, saphenous veins, or inferior epigastric arteries rather than synthetic material.26 Indeed, a series of 54 patients reported a 96% rate of satisfactory reconstruction and successful clinical outcome.27 Repair of diseased renal arteries currently remains the most frequent indication for autotransplantation as a complementary approach to percutaneous transluminal angioplasty and the older method of aortorenal bypass.26 Injuries of the Ureter

For replacing various portions of or the entire ureter, autotransplantation provides similar success rates as those for treating lesions of the renal artery.27 Other techniques used for ureteral repair include ileal interposition or construction of a Boari flap versus ureterostomy, pyeloureterostomy, uretero-ureterostomy, or ureterosigmoidostomy. In addition to iatrogenic and traumatic injuries, the ureter may be damaged by malignancy, tuberculosis, or cholesteatoma. However, current advances in endourology and the widespread use of the extracorporeal shock wave lithotripsy have reduced the number of ureteral injuries caused by renal calculi. Malignancy

The standard treatment for renal cell carcinoma is radical nephrectomy; however, nephron-sparing autotransplantation may be indicated in certain circumstances. Sir Roy Calne reported a case of autotransplantation for a renal tumor in 1971, citing Gelin’s earlier application of the technique for treating cancer.28 Calne’s patient had previously undergone a unilateral nephrectomy; 11 years later the cancer recurred in the contralateral organ. The kidney was removed, flushed with dextran 40, then with fructose/

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bicarbonate, and chilled to 4°C. After resection of the tumor, the kidney was transplanted after a total cold ischemia time of 100 minutes. Autotransplantation for the treatment of renal cell carcinoma renders 37.5% (6/16) patients free from both dialysis and disease according to a 1992 study.29 The 62.5% of patients who experienced poor outcomes may be explained by the advanced stage of disease with its increased probability of local recurrence. Inadequate vein length and a high risk for thrombosis have been reported to lower the early postoperative success rate.29 Loin Pain/Hematuria Syndrome

A 1967 report described a syndrome associated with loin pain and unexplained hematuria, usually observed in female patients.30 This syndrome reflects abnormalities of the small renal arteries and arterioles as well as platelet malfunction.31 Immune complexes, as evidenced by deposition of complement component 3 (C3), were found in most of the cases; there was no evidence of a systemic autoimmune process.32 A cohort of patients who experienced extreme, incapacitating flank pain required surgical therapy.32,33 Unilateral or bilateral renal autotransplantation rendered 83% of patients pain-free compared to 36% of subjects undergoing renal denervation with capsulotomy.34 However, the pain syndrome recurred in 10% to 25% of patients, usually during the first two postoperative years.35 Even in the case of a nephrectomy, the syndrome has been reported to recur in the remaining kidney. Thus when medical treatment fails, autotransplantation may provide a long-term, effective treatment for carefully selected patients. Rare Indications

One case report described the successful treatment of a central echinococcosis cyst of the kidney by orthotopic autotransplantation using only one incision.36 Another indication is entrapment of the left renal vein between the superior mesenteric artery and the aorta resulting in varices of the renal and/or gonadal vein (nutcracker syndrome).37 The consequent hematuria and flank pain represent an indication for autotransplantation.38 Chronic indwelling stents may cause gross hematuria, fibrosis, and/or stricture (a rare condition often diagnosed only at the time of the operation). If a primary ureteral repair is not feasible, autotransplantation may be employed.39 Autotransplantation of an allograft can be effective when the transplanted kidney requires reconstruction. One case reports that a patient developed a large, symptomatic pseudoaneurysm of the renal artery requiring excision and subsequent autotransplantation, which was delayed for 24 hours because an operative injury required grafting of the external iliac artery and hemodynamic stabilization.40 Another patient required pelvic irradiation for treatment of squamous cell carcinoma of the vulva, which would have

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jeopardized a well-functioning kidney that had been transplanted 23 years prior. The graft was transplanted to the contralateral common iliac vessels, thereby preserving its function.41

LAPAROSCOPY FOR AUTOTRANSPLANTATION

An open procedure for autotransplantation requires two surgical incisions, one for the retroperitoneal or abdominal nephrectomy and a second for the transplantation into the iliac fossa. In the hands of an experienced surgeon laparoscopy yields outcomes similar to those of conservative open surgery; donor nephrectomies are increasingly being performed using this minimally invasive approach. Employing a laparoscopic technique for autotransplantation lessens postoperative pain and the extent of scarring. One method utilizes a retroperitoneal approach using a standard Gibson incision for renal extraction and splitting the muscle layers but leaving the transversus fascia intact; the transplant is performed through the same incision.42 Alternatively, using a transabdominal approach, the kidney can be harvested through a periumbilical incision43 or through the Gibson incision.44 In the experimental setting, investigators have demonstrated that the entire autotransplantation procedure can be performed laparoscopically.45 After nephrectomy, intracorporeal renal hypothermia was achieved with a balloon catheter inserted intraarterially with subsequent laparoscopic anastomoses to the ipsilateral common iliac vessels. Renal autotransplantation remains a unique operation for selected patients. While the procedure poses technical challenges, given the right indication, it can serve as a nephron-sparing and effective treatment in most cases. According to Novick, one of the enthusiastic supporters of this procedure, of more than 350 patients who underwent renal revascularization only 3.5% needed autotransplantation.26 Marshall expressed in 1966 that autotransplantation remains uncommon in the setting of urological or vascular surgery, mainly due to lack of familiarity with the surgical technique.21

LEGACY

The pioneering work of Ullmann revolutionized the field of transplantation. During the last 100 years, surgical techniques, including solid organ transplantation with its complex immunologic and medical issues, have undergone tremendous development. Everything has changed, including techniques, preservation solutions, and postoperative treatment. Thus, human auto- and allotransplantation have become routine, thanks to the work of innovative surgeons such as Ullmann, who successfully brought experimental techniques into clinical use. On the 100th anniversary of the first successful autotransplantation, it is appropriate to remember this milestone and its creator.

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REFERENCES 1. Ullmann E: Wien Klin Wschr 15:281, 1902 2. Moore FD: The Give and Take of Tissue Transplantation. New York: Simon and Schuster, 1972 3. Largiader F: Eur Surg Res 6:197, 1974 4. Nagy J: Am J Nephrol 19:346, 1999 5. To ¨ro ¨k B: Orv Hetil 115:2069, 1974 6. Klimpel V: Z Exp Chir Transplant Ku ¨nstl Organe 20:177, 1987 7. Lesky E: MMW Mu ¨nch Med Wochenschr 116:1081, 1974 8. Ullmann E: Wien Klin Wschr 50:44, 1937 9. Eiselsberg A: Wien Klin Wschr 50:239, 1937 10. Schnitzler J: Wien Med Wschr 87:251, 1937 11. Carrel A: J Exp Med 10:97, 1908 12. Voronoy Y: El Siglo Med 97:296, 1936 13. Dubost C, Oeconomos N, Nenna A, et al: Bull Soc Med Hop Paris 67:1372, 1951 14. Ku ¨ss R, Teinturier J, Milliez P: Mem Acad Chir 77:755, 1951 15. Michon L, Hamburger J, Oeconomos N, et al: Presse Med 61:1953 16. Lawler RH, West JW, McNulty PH, et al: JAMA 147:45, 1951 17. Hume DM, Merrill JP, Miller BF, et al: J Clin Invest 34:327, 1955 18. Merrill JP, Murray JE, Harrison JH, et al: JAMA 160:277, 1956 19. Schackman R, Dempster WJ: Br Med J 2:1724, 1963 20. Hardy JD: JAMA 184:97, 1963 21. Marshall VF, Whitsell J, McGovern JH, et al: JAMA 196:1154, 1966 22. Clunie GJA, Hartley CJ, Collins GM, et al: Brit J Surg 60:562, 1973

433 23. Momose S, Ishisawa N, Nakayama H, et al: Urol Int 23:224, 1968 24. Novick AC: J Urol 126:150, 1981 25. Dean RH, Meacham PW, Weaver FA: J Vasc Surg 4:546, 1986 26. Novick AC, Stewart BH, Straffon RA: J Urol 123:806, 1980 27. Novick AC, Jackson CL, Straffon RA: J Urol 143:452, 1990 28. Calne RY: Lancet 2:761, 1971 29. Stormont TJ, Bilhartz DL, Zincke H: Mayo Clin Proc 67:621, 1992 30. Little PJ, Sloper JS, De Wardener HE: QJM 36:253, 1967 31. Aber GM, Higgins PM: Br J Urol 54:613, 1982 32. Spitz A, Huffman JL, Mendez R: J Urol 157:1554, 1997 33. Karvelas JP, Ramsey EW: CJS 39:121, 1996 34. Sheil AG, Chui AK, Verran DJ, et al: Am J Kidney Dis 32:215, 1998 35. Chin JL, Kloth D, Pautler SE, et al: J Urol 160:1235, 1998 36. Tscholl R, Ausfeld R: J Urol 133:456, 1985 37. de Schepper A: J Belg Rad 55:507, 1972 38. Chuang CK, Chu SH, Lai PC: J Urol 157:1833, 1997 39. Bullock A, Andriole GL, Neuman N, et al: J Vasc Surg 15:436, 1992 40. Campbell SC, Gill I, Novick AC: J Urol 149:361, 1993 41. DeRoover A, Verni MP, Taylor RJ: Transplantation 70:844, 2000 42. Gill IS, Uzzo RG, Hobart MG, et al: J Urol 164:1500, 2000 43. Fabrizio MD, Kavoussi LR, Jackman S, et al: Urology 55:145, 2000 44. Shekarriz B, Lu H, Duh Q, et al: Urology 58:540, 2001 45. Meraney AM, Gill IS, Kaouk JH, et al: J Endourol 15:143, 2001