History of Nephrology Am J Nephrol 1992;12:442-450
Klaus Hierholzera RolfW inaub
Pioneer Nephrologists of Berlin
Departments of a Clinical Physiology and b History of Medicine. Free University of Berlin, FRG
Celebration lecture delivered at the Joint Meeting of the German Society of Nephrology and the Israel Nephrology Society. Jerusalem. November 2-4. 1988.
Table 1. Pioneer nephrologists of Berlin
Participated in the development of
Cystoscopy M. Nitze, !.. Casper, F. Joseph Kidney transplantation E. Unger X-ray contrast media A. Binz, C. Rath. A.v. Lichtenberg, M. Swick
Development of Cystoscopy
Until late in the 19th century it was impossible to gain direct access to the bladder and the ureters by means other than surgery. This changed rapidly when in 1876 Maximilian Nitze [7, 11], a young Berlin-born physician, attended the demonstration of a diaphanoscope, i.e. an instrument which was introduced for the examination of accessory nasal sinuses. This stimulated Nitze to start with experiments aimed at designing an endoscope which would allow inspection of the urinary bladder of humans [11], First he was assisted by the engineer Deicke in Dres den. later by the instrument maker Leiter in Vienna and the optician Beneche in Berlin. On October 2, 1877, he demonstrated his ‘cystoscope’ in Dresden in human corpses and in May 9, 1879, he succeeded in using the improved cystoscope in living humans. The time of suprapubic catheterization of the bladder was over. In 1880 Nitze opened a private practice in Berlin and con tinued with further technical developments. For example he designed and built an ‘irrigation cystoscope’. In 1889
Professor Klaus Hierholzcr Freie Universität Berlin. Universitätsklinikum Steglitz Institut für Klinische Physiologie Hindenburgdamm 30 D-1000 Berlin 45 (FRG)
© 1992 S. Karger AG. Basel 0250-8095/92/0126-0442 $2.75/0
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The year 1988 marked the 40th anniversary of the foundation of the State of Israel. This prompted the Nephrological Societies of Germany and Israel to organ ize a joint meeting. At the same time the year 1988 marked the 50th anniversary of the death, near Berlin, of Ernst Unger [1], a man whose name has largely been for gotten although in his days he was a leading nephrologist as we will discuss later. The year 1988 also marked the 60th anniversary of the publication of a milestone paper by Binz and Räth [2] on the biochemistry of pyridine derivatives. These substances were developed in Berlin and their use as X-ray contrast media spread throughout the world. They were the first compounds which allowed adequate X-ray imaging not only of the lower urinary tract but also of the kidney, as it turned out later. Finally, 1988 marked the 90th anniversary of the foundation of the first Roentgenological Society (the ‘Berliner Röntgen gesellschaft’) which was founded in Berlin 2 years after Röntgen first presented his discovery of X-rays. We thought it would be appropriate on this occasion to con centrate on some of the roots of nephrology in Berlin and to focus on pioneer nephrologists including several pio neer urologists [3-8] who, from a historial point of view, are of particular importance. As shown in table 1, pioneer nephrologists of Berlin contributed to the development of cystoscopy, kidney transplantation and X-ray contrast media. Further aspects of the development of urology in Berlin have been discussed recently [9. 10], Other pioneer nephrologists who contributed landmark concepts in the 19th century and around the turn of the century such as J. Israel. J.L. Schönlein, E.H. Henoch. J. Henle. M. Löhlein and O. Heubner will be discussed in a subsequent paper.
Fig. 1. Cystoscopes developed in Berlin by M. Nitze and others, a Three different cystoscopes including a ‘lithotriptor'. b Instruments with Mignon lamps, built by W.H. Hirschmann, Berlin, c Cystoscope by Louis & H. Loewenstein. Berlin [from 33].
Development of Kidney Transplant
Experimental transplantation of kidneys started, to our knowledge, in Vienna [12-14], Arfred v. DecastelloRechtwehr, Alfred v. Exner and Emerich Ullmann de signed and carried out appropriate animal experiments. Ullmann [15] in 1902 reported his first successful autolo gous kidney transplantation of a kidney to the neck of a dog. The first attempt to transplant heterologous tissue to the human was carried out by Mathieu Jaboulay (Lyon) [16] in 1906. who used pig and goat as donors. At about the same time a young medical doctor in Berlin entered the stage and was bound to make a remarkable contribu tion to experimental and clinical nephrology: Ernst Unger (born 1875 in Berlin) had been trained at the Medical Faculty in Berlin. After his final examination in 1896 he started to work in gynaecology and wrote a thesis on the concept that the mammary gland could be considered as analogous to the sweat gland [ 1, 17], Later he entered the Department of Surgery, where he was trained under the notable surgeon Ernst von Bergmann. Aside from his clin ical work, he carried out pathophysiological experiments and founded a private hospital (in Derfflinger-Strasse, Berlin, the building still exists today) with several modern wards, operating theaters and laboratories in which he practiced medicine. Very stimulating for Unger was the fact that several outstanding surgeons, particularly Ernst v. Bergmann and H. Kehr. used his hospital for their pri vate patients. Thus. Unger was always in contact with the Medical Faculty and had the advantage of assisting expe rienced surgeons in his own hospital. He apparently met Alexis Carrel [18,19], who had moved from Lyon to New York, and it is possible that this contact stimulated Unger to focus his interest on kidney transplantation and even tually to test its therapeutic usefulness.
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he published the first Lehrbuch der Kystoskopie, which was reprinted in 1978 [7], He died in his office in Berlin in 1906. Another pioneer in the field of cystoscopy was Leopold Casper [5], also a Berliner, who went for some time to London, Paris and Vienna, where he was attracted by the noted urologist Leopold von Dittel and where he met Maximilian Nitze. Back in Berlin he participated in the development of cystoscopes. with the special aim of catheterizing not only the bladder but also the ureters. Direct access to the ureters had previously only been possible in females after digital or instrumental dilatation of the ure thra. With the instrument maker W.A. Hirschmann in Berlin he designed a 'ureter cystoscope’ which permitted the bending of the ureteral catheter under visual inspec tion in such a way that the tip could be directed into the ureteral ostium, thus permitting retrograde catheteriza tion in male humans. This was achieved in 1894. This is not the time and place to enter into the conflict over priorities between Nitze and Casper, which drew on for years. But attention should be drawn to another lead ing urologist and nephrologist who participated in the field of developing cystoscopy, Eugen Joseph [6], A few examples of cystoscopes developed in Berlin at the turn of the century are shown in figure 1. Cystoscopes of M. Nitze and others, designed and built before 1896 by W.A. Hirschmann and Louis and H. Loewenstein in Berlin 1897, included a cystoscope with electrical equipment and a Mignon lamp at the tip and other instruments, e.g. a 'cystoscopic lithotriptor’.
a
b
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c
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Fig. 2a-e. Surgical procedure of early renal transplantation carried out by E. Un ger. Original illustrations of various steps from the original paper [26]; for details see text.
Heterologous Kidney Transplantation in a Human Encouraged by the promising results of homologous transplantations in animals, Unger asked himself whether or not heterologous transplantation could be used as a ther apeutic measure in humans. At that time, this seemed to be a revolutionary idea. Between 1905 and 1919 he conducted several animal experiments. In 1910 [21] he summarized his pilot experiments as follows: 'We tried to transplant the kidneys from a young pig to a dog (1 X), a large dog to a goat ( I X) , and large cats to little dogs (2 X) with negative
result’ and 'as expected’ as he stated, due to the 'different composition of blood’. It should be recalled that Landsteiner had described blood groups in 1901 [23]. Thus, the idea arose that tissues should be transplanted only between closely related species, perhaps such as man and ape. Let us follow the protocol of a representative experiment: (a) On December 10, 1909, both kidneys of a dead newborn human baby were excised; (b) a medium-sized male bear baboon was prepared as recipient, however, his own kid neys were left in place; (c) the human kidneys, after having been rinsed with Locke’s solution, were transplanted with the effect of immediately apparent blood perfusion of the left kidney; (d) no blood coagulation was observed in the renal arteries of the transplanted kidney. Unger stated that it was a most promising experience that blood of the ape did not coagulate in the vessels of the human. This stimu lated the next step which Unger was to take, i.e., the heter ologous therapeutic transplantation with an ape as donor and a human patient as recipient. Unger considered three possibilities in 1910; (a) trans plantation of a kidney from a healthy human donor; he rejected this possibility on ethical grounds; (b) transplan tation of a human cadaver kidney; this he rejected for practical reasons - such kidneys would not be available on demand and in due time, and (c) transplantation from an ape as a closely related species. He concentrated on the third concept. He was aware of the results of Friedenthal, who had shown that one could replace a sizeable propor tion of ape blood by human blood [21]. The strategy of Unger was a brillant example of interdisciplinary cooper ation between a surgeon, an internist (Dr. Bleichroeder) and a zoologist (Dr. Heimroth, Zoological Garden of Ber lin). Dr. Bleichroeder had a 21-year-old female patient with uremic symptoms, nephritic changes of the retina and fever, whose condition was rapidly deteriorating. Death was imminent. The patient was seen by Professor His and it was decided to try transplantation as a last resort. On January 9, 1910. Unger performed the operation after Dr. Heimroth had personally provided a Macacus nemestrimus from Borneo as a heterologous donor. The surgical procedure is shown in figure 3. The left femoral artery and vein of the human patient were prepared under light inhalation anesthesia and local anesthesia as shown schematically; thus, Unger did not follow the Jaboulay approach with the elbow as site of implantation. Then, the ape was prepared and mass transplantation was carried out into the left upper thigh of the human patient. Finally the posterior wall of the bladder was implanted caudally to this site. The kidneys seemed to be well perfused imme-
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Heterologous Kidney Transplantation in Experimental Animals In 1909, Unger addressed the Berlin Medical Society and presented a paper on kidney transplantation [20]. It is highly stimulating to go through some of his arguments and results. He described several animal experiments, some of which were carried out in the laboratory of Emil du Bois-Reymond, then professor of Physiology in Berlin. The surgical procedure is illustrated in figure 2. As shown, kidneys, ureters and bladder of a fox terrier were mobil ized and the large vessels were disconnected. In parallel a second dog of a different race (bulldog) was prepared by surgical procedures to receive the kidney in the orthotope position. Then, the donor preparation was removed, per fused with slightly warmed Locke’s solution, and im planted into the recipient by anastomizing the blood ves sels using the Carrel technique. After blood flow through the transplantation organ had been reestablished the do nor bladder was anastomized with the posterior wall of the recipient’s own bladder. Two days later the dog excreted urine, slightly acid and somewhat concentrated. Two weeks later the dog was presented before the Medical and Physiological Society of Berlin [20, 21]. The experiment was repeated some 100 times in dogs and cats. Unger concluded and foresaw that the prerequi sites for successful transplantation would be: ( 1) surgery as rapid as possible, but with due care not to disturb the intestine and mesentery; (2) shortening of the ischemic period of the donor kidney, which he lowered to some 60-30 min, and (3) measures to prevent or reduce infec tion in the postoperative period. The main conclusion which he derived from the gradual improvement of his animal experiments was that in principle mass transplan tation of kidneys was possible and the transplanted kid neys could function well and main the life of the recipient up to 4 weeks. Being a modest man he paid credit to Car rel an Guthrie who had laid the path by developing the techniques for anastomosing blood vessels and, thus, for kidney transplantation [22],
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Fig. 3a, b. Surgical procedure of E. Un ger's heterologous transplantations of the kidney of an ape to a human recipient. Origi nal illustrations of the procedure from Unger [21]; for details see text.
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Fig. 4. X-ray contrast media developed by A. Binz + C. Rath, pro duced by Schering-Kahlbaum AG. tested by M. Swick, L. Lichtwitz, A.v. Lichtenberg [see 2].
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Erstveröffentlichung über Uroselectan
Fig. 5. First publication o f‘Uroselectan’ [28],
Pioneer Nephrologists of Berlin
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•
DARSTELLUNG DER NIERE UND HARN WEGE IM RÖNTGENBILD DURCH INTRAVENÖSE EINBRINGUNG EINES NEUEN KONTRASTSTOFFES. DES UROSELECTANS Von Dr. M. SWICK, New York.
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Fig. 6. Kinetics of excretion of 'Uroselectan’ under normal and abnormal (reduced concentration capacity) conditions: from Swick [28].----- = Weight (g) of précipitable acid excreted;------= weight (g) of iodine excreted. Fig. 7. Reproduction of a 'Urogram' performed by M. Swick in 1929 with 'Uroselectan' [28].
in the field of heterologous transplantation, since ‘a single positive result once obtained would outweigh decisively any series of setbacks and failures’. It would be interesting to concentrate more on this remarkable man who, in addition to his nephrological achievements, developed the continuous suction tech nique in brain surgery' (before Harvey Cushing) and who organized the first Central Blood Bank in Germany (Blutspendedienst) in 1932 [1],
Excretion Urography
For centuries pain and hematuria had been the main symptoms in the diagnosis of renal stones or tumors, and renal palpation and/or surgical procedures were about the only diagnostic maneuvers at hand. This changed to some extent when cystoscopy was introduced, but only as far as the evaluation of lower urinary tract disease was con cerned. In 1905 Fritz Voelcker and the young physician Alexander v. Lichtenberg in Heidelberg developed the technique of retrograde pyelography using colloidal silver (collargol) [24], which turned out to be toxic. Therefore thorium, strontium, Na and lithium salts were evaluated (e.g. Li iodide as Umbrenal, Kahlbaum Comp., Berlin [25], as well as iodinated oils (jodipin), all of them with unsatisfactory results). The situation changed when Os borne treated syphilic patients with large doses of iodides (oral and intravenous administration) and observed that
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diately after anastomosing the blood vessels. The patient rested in her bed but produced only little hématurie urine. Thirty-two hours after the operation the patient died. On autopsy blood coagulation was not detected, nei ther in the aorta and renal artery' of the implant, nor in the renal vein or vena cava. The renal pelvis was filled with a clear solution which could escape via the open ureters. Microscopically the kidneys displayed interstitial inflam mation and necroses. However, histologically the renal tissue seemed to be in better shape than that after heterol ogous transplantation in animals. Unger concluded that: (a) blood circulation and renal tissue could be preserved after ‘autologous’ transplantation, however, (b) he was not sure that the transplanted animal kidneys had started to produce urine. Most remarkably he discussed the possi bility that the poison, which had destroyed the recipient's kidneys, would in turn also destroy the transplanted kid ney. Therefore, surgical kidney diseases such as stones or cystic degeneration would be more suitable for kidney transplantation. Furthermore he hypothesized that with increasing time of survival the differences between blood types of donor and recipient might be a serious obstacle. He also considered various sites of implantation, the upper thigh, the elbow, the axilla and/or the abdomen (ileocolica, or superior mesenteric). Unger foresaw that implantation of heterologous tissue posed serious theoret ical problems, and he considered a ‘biochemical barrier’ which had to be overcome eventually. Therefore, he felt it would be worthwhile to continue experimental research
1909 1919 1933 1936 1938
Born in Berlin Private hospital for surgery Begins with animal experiments on kidney transplantation Transplantation of monkey kidney to human patient Professor of Surgery', organizes 1st blood bank in Germany Loss of university position Forced closure of private hospital Death in car accident near Berlin
Fig. 9. Maximilian Nitze
1848 1876
Born in Berlin Endoscopic experiments in Dresden 1877/9 Cystoscopy of human bladder 1889 Lehrbuch der Kystoskopie 1906 Death in Berlin
the compounds were rapidly excreted by the kidneys. In 1923 he reported - together with Rowntree - that in cer tain cases the contours of the ureters and bladder and even the outlines of the kidneys could be visualized [26]. Roseno [27] tried to detoxify Na iodide by coupling to urea (Pyelognost) and reported somewhat better results. An important development started in Berlin in 1928. when Binz and Rath developed a very suitable group of organic iodinated compounds, which are depicted in fig ure 4. A. Binz and C. Rath, working at the Department of Chemistry of the Agricultural School of Berlin, synthe sized several pyridine derivatives which might be useful as antisyphilitic and antistreptococcal chemotherapeutic agents [2], Iodinated ‘Selectan' proved to be useful in the treatment of cattle and pig infections.
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Fig. 10. Leopold Casper 1859 Born in Berlin 1883/4 Training in urology (Sir Henry Thompson - London, L.v. Dittel - Vienna) 1900 Private hospital in Berlin 1906/7 Foundation of German Urological Society and of Zeitschrift für Urologie until 1933 Cystoscopy, catheterization of ureter, transurethral surgery 1933 Loss of teaching licence at university, emigration to Zürich, Nizza, Martinique 1941 Arrival in New York 1959 Death in New York
The N-methylated substance ‘Selectan neutral’ was ap propriately soluble. It was handed over to the internist L. Lichtwitz in Hamburg for clinical evaluation in patients with infectious diseases of gallbladders and kidneys. A young physician, Moses Swick from New York, partici pated in these studies and observed in rabbits as well as in humans that the drug was selectively excreted by the kid neys. However, sufficient X-ray images of the kidneys still could not be obtained unless ureters were compressed. In close collaboration between Swick, Lichtwitz, Binz and Rath further derivatives were synthesized and tested. The breakthrough came when pyridone was N-acetylated (Uroselectan) (fig. 5) [28, 29]. This compound was pro duced by Schering-Kahlbaum Company and tested in the Urology Department of the St. Hedwigs-Hospital in Ber-
Pioneer Nephrologists of Berlin
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Fig. 8. Ernst Unger
1875 1905
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Born in Budapest, worked in Heidelberg/Strasbourg/Budapest/ Berlin Retrograde + i.v. pyelography (with F. Voelcker. M. Swick, P. Rosenstein) 1935 Loss of teaching licence 1936 Emigration to Budapest, Mexico City 1949 Death in Mexico City
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Fig. 12. Moses Swick
1900
Born in New York Mount Sinai Hospital, Libman Scholarship 1928/9 Works in Hamburg and Berlin: excretion urography (Uroselectan) 1929 Returns to New York (hippuran) 1988 Death in New York
lin by Moses Swick and under the supervision of the noted urologist v. Lichtenberg [28. 30-32], The excretion pattern of the organic iodine drug is shown in figure 6. Renal excretion of the substance by a normal kidney, measured as precipitable substance or as iodine, was rapid in contrast to that in kidneys with impaired excretory function. Most promising results were reported in 1929 [30] and the use of Uroselectan and other polyiodinated derivatives provided by the ScheringKahlbaum AG became a general therapeutic principle after 1930. Figure 7 gives reproductions of one of the first urograms obtained by Swick with Uroselectan. For the first time one could see not only the outlines of the renal pelvis but also quite clearly the images of renal paren chyma.
Fig. 13. Eugen Joseph
1879 1904
Born in Ober-Thalheim, Schlesien Chromocystoscopy (indigocarmin) (with F. Voelcker). Pyelography with Umbrenal® 1907 Dept, of Surgery Berlin (with Bier) 1911 Dept, of Neurosurgery Baltimore (with Cushing) 1914 German army 1921 Private hospital (surgery + urology) 1933 Sends family to Switzerland, suicide on December 24, 1933 in Berlin
Concluding Remarks
We have to leave this brief discussion of the more or less forgotten roots of nephrology in Berlin at this point. V. Lichtenberg’s clinic was widely recognized as a center of urology. Swick returned to New York. We would like to finish this discussion with a few figures which briefly sum marize the biographies of some of the scientists discussed above (fig. 8-13).
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Fig. 11 . Alexander v. Lichtenberg
1 Winkler EA: Emst Unger (1875-1938). Eine Biobibliographie: Diss FU Berlin. Med Fach bereiche. 1975, Kap 2.3, pp 21-23. 2 Binz A, Rätli C: Über biochemische Eigen schaften von Derivaten des Pyridins und Chi nolins. BiochemZ 1928:203:218-222. 3 Bloch P. Israel J. Schultze-Seeman F: James Israel 1848-1926: in Winau R (ed): Wiesba den. Steiner, 1983. 4 Lehmann H: James Israel (1859-1959). Bio bibliographie eines Berliner Chirurgen und Urologen: Diss FU Berlin, Fachbereich Zahn-, Mund- und Kieferheilkunde. 1977. 5 Lern O: Leopold Casper (1859-1959). Biobi bliographie eines Berliner Urologen: Diss FU Berlin, Med Fachbereiche, 1973. 6 Mahrcnholz MA: Eugen Joseph (26.4.187924.12.1933). Biobibliographie eines Berliner Urologen: Diss FU Berlin. Med Fachbereiche. 1978. 7 Nitze M: Lehrbuch der Kystoskopie. Ihre Technik und klinische Bedeutung. Berlin, Springer. 1978. 8 Westermann B: Alexander von Lichtenberg ( 1880-1949). Biobibliographie eines Urologen; Diss FU Berlin. Med Fachbereiche. 1978 9 Winau R: Zur Geschichte der Berliner Urolo gie - Mitteilungen. Dtsch Ges Urol 1991:7:2330. 10 Winau R: Aspekte der Entwicklung der Urolo gie in Berlin. Urol Imaging 1991:1:120—124. 11 Nitze M: Demonstration zum Katheterisiercn der Harnleiter beim Manne. Verh Berl Med Ges 1895:26:21-22.
12 Decastcllo AV: Über experimentelle Nieren transplantation. Wien Klin Wochenschr 1902; 15:317. 13 Dreikorn K: Meilensteine in der Geschichte der Nierentransplantation. Nieren Hochdruck krankheiten 1986;7:297-308. 14 Lesky E: Die erste Nierentransplantation. Emerich Ullmann (1861-1937). Münch Med Wochenschr 1974:116:1081. 15 Ullmann E: Experimentelle Nierentransplanta tion. Wien Klin Wochenschr 1902:11:281. 16 JaboulayM: Greffe de reins au pli du coude par soudures artérielles et veineuses. Lyon Méd 1906; 107:575. 17 Linger E: Das Colostrum; Med Diss Berlin. 1898/Arch Pathol Anat ( Berlin) 1898:151:159175. 18 Carrel A: La technique opératoire des anasto moses vasculaires et la transplantation des vis cères. Lyon Méd I902;98:859. 19 Carrel A, Guthrie CC: Functions of a trans planted kidney. Science 1905:22:473. 20 Unger E: Über Nierentransplantation. Berl Klin Wochenschr 1909:1:1057-1060. 21 Unger E: Nierentransplantation. Berl Klin Wo chenschr 1910:1 •573-578. 22 Carrel A. Guthrie CC: Anastomosis of blood vessels by the patching method and transplan tation of the kidney. JAM A 1906;47:1648. 23 Landsteiner K: Über Agglutinationserschei nungen normalen menschlichen Blutes. Wien Klin Wochenschr 1901:14:1132-1134. 24 Voelcker F, Lichtenberg A v: Pyelographie (Rocntgcnographie des Nierenbeckens nach Kollargolfüllung). Münch Med Wochenschr 1906:53:105-107.
25 Taenzer V, Herms HJ: Roentgenkontrastmittel. Zum Deutschen Roentgenkongress 1966. Berlin. Berlin, Schering, 1966, pp 1-36. 26 Osborne ED. Shutherland CG, Scholl AJ. Rowntree LG Jr: Roentgenography of urinary tract duringexeretion ofsodium iodide. JAMA I923;80:368. 27 Roseno A: Studien zur intravenösen Pyelogra phie. 8. Kongr Dtsch Ges Urol. Berlin, 1928. Z Urol I929(suppl):431-433. 28 Swick M: Darstellung der Niere und Hamwege im Roentgenbild durch intravenöse Einbrin gung eines neuen Kontraststoffes, des Uroselectans. Verh Dtsch Ges Urol 1929:9:328-331. 29 Lichtwitz L: Über Uroselectan. Chirurg 1930: 2:357-361. 30 Lichtenberg A v, Swick M: Klinische Prüfung des Uroselectans. Klin Wochenschr 1929:8: 2089-2091. 31 Rathcrt P. Melchior H, Lutzcyer W: Ge schichte der Urologie. M. Swick (*1900) und J. Volkmann (*1889): Beiträge zur kontroversen Geschichte der Ausscheidungsurographie. Ur ologe 1975;15:21-28. 32 Swick M: Geschichte der Urologie. Die histori sche Entwicklung der organischen Jodpräpa rate zur Ausscheidungs-Urographie und An giographie. Urologe 1975:15:19 6 -201. 33 Schultze-Seeman F. Riedel-Hartwitch C (eds): Die Sammlung zur Geschichte der Urologie des Instituts für Geschichte der Medizin der Freien Universität Berlin. From: Archiv der Deutschen Gesellschaft für Urologie in Berlin. Berlin. Springer. 1984.
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References
Klaus Hierholzera RolfW inaub
Pioneer Nephrologists of Berlin
Departments of a Clinical Physiology and b History of Medicine. Free University of Berlin, FRG
Celebration lecture delivered at the Joint Meeting of the German Society of Nephrology and the Israel Nephrology Society. Jerusalem. November 2-4. 1988.
Table 1. Pioneer nephrologists of Berlin
Participated in the development of
Cystoscopy M. Nitze, !.. Casper, F. Joseph Kidney transplantation E. Unger X-ray contrast media A. Binz, C. Rath. A.v. Lichtenberg, M. Swick
Development of Cystoscopy
Until late in the 19th century it was impossible to gain direct access to the bladder and the ureters by means other than surgery. This changed rapidly when in 1876 Maximilian Nitze [7, 11], a young Berlin-born physician, attended the demonstration of a diaphanoscope, i.e. an instrument which was introduced for the examination of accessory nasal sinuses. This stimulated Nitze to start with experiments aimed at designing an endoscope which would allow inspection of the urinary bladder of humans [11], First he was assisted by the engineer Deicke in Dres den. later by the instrument maker Leiter in Vienna and the optician Beneche in Berlin. On October 2, 1877, he demonstrated his ‘cystoscope’ in Dresden in human corpses and in May 9, 1879, he succeeded in using the improved cystoscope in living humans. The time of suprapubic catheterization of the bladder was over. In 1880 Nitze opened a private practice in Berlin and con tinued with further technical developments. For example he designed and built an ‘irrigation cystoscope’. In 1889
Professor Klaus Hierholzcr Freie Universität Berlin. Universitätsklinikum Steglitz Institut für Klinische Physiologie Hindenburgdamm 30 D-1000 Berlin 45 (FRG)
© 1992 S. Karger AG. Basel 0250-8095/92/0126-0442 $2.75/0
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The year 1988 marked the 40th anniversary of the foundation of the State of Israel. This prompted the Nephrological Societies of Germany and Israel to organ ize a joint meeting. At the same time the year 1988 marked the 50th anniversary of the death, near Berlin, of Ernst Unger [1], a man whose name has largely been for gotten although in his days he was a leading nephrologist as we will discuss later. The year 1988 also marked the 60th anniversary of the publication of a milestone paper by Binz and Räth [2] on the biochemistry of pyridine derivatives. These substances were developed in Berlin and their use as X-ray contrast media spread throughout the world. They were the first compounds which allowed adequate X-ray imaging not only of the lower urinary tract but also of the kidney, as it turned out later. Finally, 1988 marked the 90th anniversary of the foundation of the first Roentgenological Society (the ‘Berliner Röntgen gesellschaft’) which was founded in Berlin 2 years after Röntgen first presented his discovery of X-rays. We thought it would be appropriate on this occasion to con centrate on some of the roots of nephrology in Berlin and to focus on pioneer nephrologists including several pio neer urologists [3-8] who, from a historial point of view, are of particular importance. As shown in table 1, pioneer nephrologists of Berlin contributed to the development of cystoscopy, kidney transplantation and X-ray contrast media. Further aspects of the development of urology in Berlin have been discussed recently [9. 10], Other pioneer nephrologists who contributed landmark concepts in the 19th century and around the turn of the century such as J. Israel. J.L. Schönlein, E.H. Henoch. J. Henle. M. Löhlein and O. Heubner will be discussed in a subsequent paper.
Fig. 1. Cystoscopes developed in Berlin by M. Nitze and others, a Three different cystoscopes including a ‘lithotriptor'. b Instruments with Mignon lamps, built by W.H. Hirschmann, Berlin, c Cystoscope by Louis & H. Loewenstein. Berlin [from 33].
Development of Kidney Transplant
Experimental transplantation of kidneys started, to our knowledge, in Vienna [12-14], Arfred v. DecastelloRechtwehr, Alfred v. Exner and Emerich Ullmann de signed and carried out appropriate animal experiments. Ullmann [15] in 1902 reported his first successful autolo gous kidney transplantation of a kidney to the neck of a dog. The first attempt to transplant heterologous tissue to the human was carried out by Mathieu Jaboulay (Lyon) [16] in 1906. who used pig and goat as donors. At about the same time a young medical doctor in Berlin entered the stage and was bound to make a remarkable contribu tion to experimental and clinical nephrology: Ernst Unger (born 1875 in Berlin) had been trained at the Medical Faculty in Berlin. After his final examination in 1896 he started to work in gynaecology and wrote a thesis on the concept that the mammary gland could be considered as analogous to the sweat gland [ 1, 17], Later he entered the Department of Surgery, where he was trained under the notable surgeon Ernst von Bergmann. Aside from his clin ical work, he carried out pathophysiological experiments and founded a private hospital (in Derfflinger-Strasse, Berlin, the building still exists today) with several modern wards, operating theaters and laboratories in which he practiced medicine. Very stimulating for Unger was the fact that several outstanding surgeons, particularly Ernst v. Bergmann and H. Kehr. used his hospital for their pri vate patients. Thus. Unger was always in contact with the Medical Faculty and had the advantage of assisting expe rienced surgeons in his own hospital. He apparently met Alexis Carrel [18,19], who had moved from Lyon to New York, and it is possible that this contact stimulated Unger to focus his interest on kidney transplantation and even tually to test its therapeutic usefulness.
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he published the first Lehrbuch der Kystoskopie, which was reprinted in 1978 [7], He died in his office in Berlin in 1906. Another pioneer in the field of cystoscopy was Leopold Casper [5], also a Berliner, who went for some time to London, Paris and Vienna, where he was attracted by the noted urologist Leopold von Dittel and where he met Maximilian Nitze. Back in Berlin he participated in the development of cystoscopes. with the special aim of catheterizing not only the bladder but also the ureters. Direct access to the ureters had previously only been possible in females after digital or instrumental dilatation of the ure thra. With the instrument maker W.A. Hirschmann in Berlin he designed a 'ureter cystoscope’ which permitted the bending of the ureteral catheter under visual inspec tion in such a way that the tip could be directed into the ureteral ostium, thus permitting retrograde catheteriza tion in male humans. This was achieved in 1894. This is not the time and place to enter into the conflict over priorities between Nitze and Casper, which drew on for years. But attention should be drawn to another lead ing urologist and nephrologist who participated in the field of developing cystoscopy, Eugen Joseph [6], A few examples of cystoscopes developed in Berlin at the turn of the century are shown in figure 1. Cystoscopes of M. Nitze and others, designed and built before 1896 by W.A. Hirschmann and Louis and H. Loewenstein in Berlin 1897, included a cystoscope with electrical equipment and a Mignon lamp at the tip and other instruments, e.g. a 'cystoscopic lithotriptor’.
a
b
d
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c
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Fig. 2a-e. Surgical procedure of early renal transplantation carried out by E. Un ger. Original illustrations of various steps from the original paper [26]; for details see text.
Heterologous Kidney Transplantation in a Human Encouraged by the promising results of homologous transplantations in animals, Unger asked himself whether or not heterologous transplantation could be used as a ther apeutic measure in humans. At that time, this seemed to be a revolutionary idea. Between 1905 and 1919 he conducted several animal experiments. In 1910 [21] he summarized his pilot experiments as follows: 'We tried to transplant the kidneys from a young pig to a dog (1 X), a large dog to a goat ( I X) , and large cats to little dogs (2 X) with negative
result’ and 'as expected’ as he stated, due to the 'different composition of blood’. It should be recalled that Landsteiner had described blood groups in 1901 [23]. Thus, the idea arose that tissues should be transplanted only between closely related species, perhaps such as man and ape. Let us follow the protocol of a representative experiment: (a) On December 10, 1909, both kidneys of a dead newborn human baby were excised; (b) a medium-sized male bear baboon was prepared as recipient, however, his own kid neys were left in place; (c) the human kidneys, after having been rinsed with Locke’s solution, were transplanted with the effect of immediately apparent blood perfusion of the left kidney; (d) no blood coagulation was observed in the renal arteries of the transplanted kidney. Unger stated that it was a most promising experience that blood of the ape did not coagulate in the vessels of the human. This stimu lated the next step which Unger was to take, i.e., the heter ologous therapeutic transplantation with an ape as donor and a human patient as recipient. Unger considered three possibilities in 1910; (a) trans plantation of a kidney from a healthy human donor; he rejected this possibility on ethical grounds; (b) transplan tation of a human cadaver kidney; this he rejected for practical reasons - such kidneys would not be available on demand and in due time, and (c) transplantation from an ape as a closely related species. He concentrated on the third concept. He was aware of the results of Friedenthal, who had shown that one could replace a sizeable propor tion of ape blood by human blood [21]. The strategy of Unger was a brillant example of interdisciplinary cooper ation between a surgeon, an internist (Dr. Bleichroeder) and a zoologist (Dr. Heimroth, Zoological Garden of Ber lin). Dr. Bleichroeder had a 21-year-old female patient with uremic symptoms, nephritic changes of the retina and fever, whose condition was rapidly deteriorating. Death was imminent. The patient was seen by Professor His and it was decided to try transplantation as a last resort. On January 9, 1910. Unger performed the operation after Dr. Heimroth had personally provided a Macacus nemestrimus from Borneo as a heterologous donor. The surgical procedure is shown in figure 3. The left femoral artery and vein of the human patient were prepared under light inhalation anesthesia and local anesthesia as shown schematically; thus, Unger did not follow the Jaboulay approach with the elbow as site of implantation. Then, the ape was prepared and mass transplantation was carried out into the left upper thigh of the human patient. Finally the posterior wall of the bladder was implanted caudally to this site. The kidneys seemed to be well perfused imme-
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Heterologous Kidney Transplantation in Experimental Animals In 1909, Unger addressed the Berlin Medical Society and presented a paper on kidney transplantation [20]. It is highly stimulating to go through some of his arguments and results. He described several animal experiments, some of which were carried out in the laboratory of Emil du Bois-Reymond, then professor of Physiology in Berlin. The surgical procedure is illustrated in figure 2. As shown, kidneys, ureters and bladder of a fox terrier were mobil ized and the large vessels were disconnected. In parallel a second dog of a different race (bulldog) was prepared by surgical procedures to receive the kidney in the orthotope position. Then, the donor preparation was removed, per fused with slightly warmed Locke’s solution, and im planted into the recipient by anastomizing the blood ves sels using the Carrel technique. After blood flow through the transplantation organ had been reestablished the do nor bladder was anastomized with the posterior wall of the recipient’s own bladder. Two days later the dog excreted urine, slightly acid and somewhat concentrated. Two weeks later the dog was presented before the Medical and Physiological Society of Berlin [20, 21]. The experiment was repeated some 100 times in dogs and cats. Unger concluded and foresaw that the prerequi sites for successful transplantation would be: ( 1) surgery as rapid as possible, but with due care not to disturb the intestine and mesentery; (2) shortening of the ischemic period of the donor kidney, which he lowered to some 60-30 min, and (3) measures to prevent or reduce infec tion in the postoperative period. The main conclusion which he derived from the gradual improvement of his animal experiments was that in principle mass transplan tation of kidneys was possible and the transplanted kid neys could function well and main the life of the recipient up to 4 weeks. Being a modest man he paid credit to Car rel an Guthrie who had laid the path by developing the techniques for anastomosing blood vessels and, thus, for kidney transplantation [22],
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Fig. 3a, b. Surgical procedure of E. Un ger's heterologous transplantations of the kidney of an ape to a human recipient. Origi nal illustrations of the procedure from Unger [21]; for details see text.
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Fig. 4. X-ray contrast media developed by A. Binz + C. Rath, pro duced by Schering-Kahlbaum AG. tested by M. Swick, L. Lichtwitz, A.v. Lichtenberg [see 2].
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Erstveröffentlichung über Uroselectan
Fig. 5. First publication o f‘Uroselectan’ [28],
Pioneer Nephrologists of Berlin
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•
DARSTELLUNG DER NIERE UND HARN WEGE IM RÖNTGENBILD DURCH INTRAVENÖSE EINBRINGUNG EINES NEUEN KONTRASTSTOFFES. DES UROSELECTANS Von Dr. M. SWICK, New York.
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Fig. 6. Kinetics of excretion of 'Uroselectan’ under normal and abnormal (reduced concentration capacity) conditions: from Swick [28].----- = Weight (g) of précipitable acid excreted;------= weight (g) of iodine excreted. Fig. 7. Reproduction of a 'Urogram' performed by M. Swick in 1929 with 'Uroselectan' [28].
in the field of heterologous transplantation, since ‘a single positive result once obtained would outweigh decisively any series of setbacks and failures’. It would be interesting to concentrate more on this remarkable man who, in addition to his nephrological achievements, developed the continuous suction tech nique in brain surgery' (before Harvey Cushing) and who organized the first Central Blood Bank in Germany (Blutspendedienst) in 1932 [1],
Excretion Urography
For centuries pain and hematuria had been the main symptoms in the diagnosis of renal stones or tumors, and renal palpation and/or surgical procedures were about the only diagnostic maneuvers at hand. This changed to some extent when cystoscopy was introduced, but only as far as the evaluation of lower urinary tract disease was con cerned. In 1905 Fritz Voelcker and the young physician Alexander v. Lichtenberg in Heidelberg developed the technique of retrograde pyelography using colloidal silver (collargol) [24], which turned out to be toxic. Therefore thorium, strontium, Na and lithium salts were evaluated (e.g. Li iodide as Umbrenal, Kahlbaum Comp., Berlin [25], as well as iodinated oils (jodipin), all of them with unsatisfactory results). The situation changed when Os borne treated syphilic patients with large doses of iodides (oral and intravenous administration) and observed that
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diately after anastomosing the blood vessels. The patient rested in her bed but produced only little hématurie urine. Thirty-two hours after the operation the patient died. On autopsy blood coagulation was not detected, nei ther in the aorta and renal artery' of the implant, nor in the renal vein or vena cava. The renal pelvis was filled with a clear solution which could escape via the open ureters. Microscopically the kidneys displayed interstitial inflam mation and necroses. However, histologically the renal tissue seemed to be in better shape than that after heterol ogous transplantation in animals. Unger concluded that: (a) blood circulation and renal tissue could be preserved after ‘autologous’ transplantation, however, (b) he was not sure that the transplanted animal kidneys had started to produce urine. Most remarkably he discussed the possi bility that the poison, which had destroyed the recipient's kidneys, would in turn also destroy the transplanted kid ney. Therefore, surgical kidney diseases such as stones or cystic degeneration would be more suitable for kidney transplantation. Furthermore he hypothesized that with increasing time of survival the differences between blood types of donor and recipient might be a serious obstacle. He also considered various sites of implantation, the upper thigh, the elbow, the axilla and/or the abdomen (ileocolica, or superior mesenteric). Unger foresaw that implantation of heterologous tissue posed serious theoret ical problems, and he considered a ‘biochemical barrier’ which had to be overcome eventually. Therefore, he felt it would be worthwhile to continue experimental research
1909 1919 1933 1936 1938
Born in Berlin Private hospital for surgery Begins with animal experiments on kidney transplantation Transplantation of monkey kidney to human patient Professor of Surgery', organizes 1st blood bank in Germany Loss of university position Forced closure of private hospital Death in car accident near Berlin
Fig. 9. Maximilian Nitze
1848 1876
Born in Berlin Endoscopic experiments in Dresden 1877/9 Cystoscopy of human bladder 1889 Lehrbuch der Kystoskopie 1906 Death in Berlin
the compounds were rapidly excreted by the kidneys. In 1923 he reported - together with Rowntree - that in cer tain cases the contours of the ureters and bladder and even the outlines of the kidneys could be visualized [26]. Roseno [27] tried to detoxify Na iodide by coupling to urea (Pyelognost) and reported somewhat better results. An important development started in Berlin in 1928. when Binz and Rath developed a very suitable group of organic iodinated compounds, which are depicted in fig ure 4. A. Binz and C. Rath, working at the Department of Chemistry of the Agricultural School of Berlin, synthe sized several pyridine derivatives which might be useful as antisyphilitic and antistreptococcal chemotherapeutic agents [2], Iodinated ‘Selectan' proved to be useful in the treatment of cattle and pig infections.
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Fig. 10. Leopold Casper 1859 Born in Berlin 1883/4 Training in urology (Sir Henry Thompson - London, L.v. Dittel - Vienna) 1900 Private hospital in Berlin 1906/7 Foundation of German Urological Society and of Zeitschrift für Urologie until 1933 Cystoscopy, catheterization of ureter, transurethral surgery 1933 Loss of teaching licence at university, emigration to Zürich, Nizza, Martinique 1941 Arrival in New York 1959 Death in New York
The N-methylated substance ‘Selectan neutral’ was ap propriately soluble. It was handed over to the internist L. Lichtwitz in Hamburg for clinical evaluation in patients with infectious diseases of gallbladders and kidneys. A young physician, Moses Swick from New York, partici pated in these studies and observed in rabbits as well as in humans that the drug was selectively excreted by the kid neys. However, sufficient X-ray images of the kidneys still could not be obtained unless ureters were compressed. In close collaboration between Swick, Lichtwitz, Binz and Rath further derivatives were synthesized and tested. The breakthrough came when pyridone was N-acetylated (Uroselectan) (fig. 5) [28, 29]. This compound was pro duced by Schering-Kahlbaum Company and tested in the Urology Department of the St. Hedwigs-Hospital in Ber-
Pioneer Nephrologists of Berlin
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Fig. 8. Ernst Unger
1875 1905
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Born in Budapest, worked in Heidelberg/Strasbourg/Budapest/ Berlin Retrograde + i.v. pyelography (with F. Voelcker. M. Swick, P. Rosenstein) 1935 Loss of teaching licence 1936 Emigration to Budapest, Mexico City 1949 Death in Mexico City
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Fig. 12. Moses Swick
1900
Born in New York Mount Sinai Hospital, Libman Scholarship 1928/9 Works in Hamburg and Berlin: excretion urography (Uroselectan) 1929 Returns to New York (hippuran) 1988 Death in New York
lin by Moses Swick and under the supervision of the noted urologist v. Lichtenberg [28. 30-32], The excretion pattern of the organic iodine drug is shown in figure 6. Renal excretion of the substance by a normal kidney, measured as precipitable substance or as iodine, was rapid in contrast to that in kidneys with impaired excretory function. Most promising results were reported in 1929 [30] and the use of Uroselectan and other polyiodinated derivatives provided by the ScheringKahlbaum AG became a general therapeutic principle after 1930. Figure 7 gives reproductions of one of the first urograms obtained by Swick with Uroselectan. For the first time one could see not only the outlines of the renal pelvis but also quite clearly the images of renal paren chyma.
Fig. 13. Eugen Joseph
1879 1904
Born in Ober-Thalheim, Schlesien Chromocystoscopy (indigocarmin) (with F. Voelcker). Pyelography with Umbrenal® 1907 Dept, of Surgery Berlin (with Bier) 1911 Dept, of Neurosurgery Baltimore (with Cushing) 1914 German army 1921 Private hospital (surgery + urology) 1933 Sends family to Switzerland, suicide on December 24, 1933 in Berlin
Concluding Remarks
We have to leave this brief discussion of the more or less forgotten roots of nephrology in Berlin at this point. V. Lichtenberg’s clinic was widely recognized as a center of urology. Swick returned to New York. We would like to finish this discussion with a few figures which briefly sum marize the biographies of some of the scientists discussed above (fig. 8-13).
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Fig. 11 . Alexander v. Lichtenberg
1 Winkler EA: Emst Unger (1875-1938). Eine Biobibliographie: Diss FU Berlin. Med Fach bereiche. 1975, Kap 2.3, pp 21-23. 2 Binz A, Rätli C: Über biochemische Eigen schaften von Derivaten des Pyridins und Chi nolins. BiochemZ 1928:203:218-222. 3 Bloch P. Israel J. Schultze-Seeman F: James Israel 1848-1926: in Winau R (ed): Wiesba den. Steiner, 1983. 4 Lehmann H: James Israel (1859-1959). Bio bibliographie eines Berliner Chirurgen und Urologen: Diss FU Berlin, Fachbereich Zahn-, Mund- und Kieferheilkunde. 1977. 5 Lern O: Leopold Casper (1859-1959). Biobi bliographie eines Berliner Urologen: Diss FU Berlin, Med Fachbereiche, 1973. 6 Mahrcnholz MA: Eugen Joseph (26.4.187924.12.1933). Biobibliographie eines Berliner Urologen: Diss FU Berlin. Med Fachbereiche. 1978. 7 Nitze M: Lehrbuch der Kystoskopie. Ihre Technik und klinische Bedeutung. Berlin, Springer. 1978. 8 Westermann B: Alexander von Lichtenberg ( 1880-1949). Biobibliographie eines Urologen; Diss FU Berlin. Med Fachbereiche. 1978 9 Winau R: Zur Geschichte der Berliner Urolo gie - Mitteilungen. Dtsch Ges Urol 1991:7:2330. 10 Winau R: Aspekte der Entwicklung der Urolo gie in Berlin. Urol Imaging 1991:1:120—124. 11 Nitze M: Demonstration zum Katheterisiercn der Harnleiter beim Manne. Verh Berl Med Ges 1895:26:21-22.
12 Decastcllo AV: Über experimentelle Nieren transplantation. Wien Klin Wochenschr 1902; 15:317. 13 Dreikorn K: Meilensteine in der Geschichte der Nierentransplantation. Nieren Hochdruck krankheiten 1986;7:297-308. 14 Lesky E: Die erste Nierentransplantation. Emerich Ullmann (1861-1937). Münch Med Wochenschr 1974:116:1081. 15 Ullmann E: Experimentelle Nierentransplanta tion. Wien Klin Wochenschr 1902:11:281. 16 JaboulayM: Greffe de reins au pli du coude par soudures artérielles et veineuses. Lyon Méd 1906; 107:575. 17 Linger E: Das Colostrum; Med Diss Berlin. 1898/Arch Pathol Anat ( Berlin) 1898:151:159175. 18 Carrel A: La technique opératoire des anasto moses vasculaires et la transplantation des vis cères. Lyon Méd I902;98:859. 19 Carrel A, Guthrie CC: Functions of a trans planted kidney. Science 1905:22:473. 20 Unger E: Über Nierentransplantation. Berl Klin Wochenschr 1909:1:1057-1060. 21 Unger E: Nierentransplantation. Berl Klin Wo chenschr 1910:1 •573-578. 22 Carrel A. Guthrie CC: Anastomosis of blood vessels by the patching method and transplan tation of the kidney. JAM A 1906;47:1648. 23 Landsteiner K: Über Agglutinationserschei nungen normalen menschlichen Blutes. Wien Klin Wochenschr 1901:14:1132-1134. 24 Voelcker F, Lichtenberg A v: Pyelographie (Rocntgcnographie des Nierenbeckens nach Kollargolfüllung). Münch Med Wochenschr 1906:53:105-107.
25 Taenzer V, Herms HJ: Roentgenkontrastmittel. Zum Deutschen Roentgenkongress 1966. Berlin. Berlin, Schering, 1966, pp 1-36. 26 Osborne ED. Shutherland CG, Scholl AJ. Rowntree LG Jr: Roentgenography of urinary tract duringexeretion ofsodium iodide. JAMA I923;80:368. 27 Roseno A: Studien zur intravenösen Pyelogra phie. 8. Kongr Dtsch Ges Urol. Berlin, 1928. Z Urol I929(suppl):431-433. 28 Swick M: Darstellung der Niere und Hamwege im Roentgenbild durch intravenöse Einbrin gung eines neuen Kontraststoffes, des Uroselectans. Verh Dtsch Ges Urol 1929:9:328-331. 29 Lichtwitz L: Über Uroselectan. Chirurg 1930: 2:357-361. 30 Lichtenberg A v, Swick M: Klinische Prüfung des Uroselectans. Klin Wochenschr 1929:8: 2089-2091. 31 Rathcrt P. Melchior H, Lutzcyer W: Ge schichte der Urologie. M. Swick (*1900) und J. Volkmann (*1889): Beiträge zur kontroversen Geschichte der Ausscheidungsurographie. Ur ologe 1975;15:21-28. 32 Swick M: Geschichte der Urologie. Die histori sche Entwicklung der organischen Jodpräpa rate zur Ausscheidungs-Urographie und An giographie. Urologe 1975:15:19 6 -201. 33 Schultze-Seeman F. Riedel-Hartwitch C (eds): Die Sammlung zur Geschichte der Urologie des Instituts für Geschichte der Medizin der Freien Universität Berlin. From: Archiv der Deutschen Gesellschaft für Urologie in Berlin. Berlin. Springer. 1984.
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References
