Works of Napoleon Cybulski (1859-1919) and Władysław Szymonowicz (1869-1939) on Adrenal Function

Abstract

It is well recognized by the historian of medicine, that the discovery of the effect of adrenal medullary hormones on the peripheral and central control of circulation occurred independently by Szymonowicz and Cybulski at the Jagiellonian University in Cracow, and by Georg Oliver and Edward A. Schäffer, University College London, England.

Napoleon Cybulski was born to a Polish gentry family in 1885 at Krzywonosy, close to Vilnius. He studied (1875-1880) medicine at Military Surgical-Medical Academy in St. Petersburg, Russia. In 1885 Cybulski was appointed the Chair of Physiology at Jagiellonian University, Cracow. In 1893 he encouraged his younger colleague Dr. W. Szymonowicz to verify the already published studies on adrenal gland and to conduct new experiments on the effects of the extracts from adrenal tissue on physiological parameters in normal animals, and in animals post adrenalectomy. Extracts from the adrenal medulla had stronger effects, than those from the adrenal cortex, on blood pressure, heart rate and respiration of the dogs. Cybulski and Szymonowicz call the extract “nadnerczyna”, which can be translated as supranephrine/epinephrine. They noted: “Blood of the suprarenal vein contained the active principle of the gland in sufficient amount to mimic effect of adrenal extract.” These studies were published in March 1895 in Centralblatt fur Physiologie volume 9, page 173-175 and Gazeta Lekarska 1895: 15, page 300-308.

The studies of Oliver and Schäffer, published in Journal of Physiology 1895: 17; 230-276 came to similar conclusions. There were some discrepancies between the observed effects of adrenal medullary extracts between Polish and British physiologist, especially regarding direct action of the substance on the vascular tone and the effects modulated through the central nervous system.

In subsequent years, Napoleon Cybulski pioneered world research on the electrical activity of the brain cortex and heart, and on electrical currents in the muscle. He published the first Polish handbook of physiology with interesting observations on kidney function. He was great advocate of woman’s education and admission to medical schools. Napoleon Cybulski died of stroke on April 24, 1919 in Cracow.

Keywords: History, adrenal glands, nadnerczyna, epinephrine

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Introduction

The end of the 19th century was a time of rapid acceleration in scientific discoveries overall, but particularly in the field of chemistry, biology and medicine. Still, the understanding of the physiological role of many organs was lacking (1). The following is a good example of that.

Napoleon Cybulski, 40 years old professor of physiology at the Jagiellonian University in Cracow was working in 1893 on his Human Physiology part III (2) and “concluded after careful readings, that handful of studies on thyroid and adrenals suggested that these puzzling glandule can be part of the system through which the body is controlling various organs” but “he did not come across even single work which was devoted solely to explain the function of adrenals” (3).

He was aware of the studies of Charles-Édouard Brown-Sequard (1817-1894). The year after Thomas Addison’s description in 1855 of damaged adrenal glands associated with hyperpigmentation and death, Brown-Sequard showed that experimental animals died within few hours after bilateral adrenalectomy.

Finally Cybulski complained that over previous three years he could not find a single collaborator to pick up a research project to explain the function of adrenals /suprarenals. Finally near the end of 1893, Dr. Szymonowicz decided to study systematically the development of adrenal, its histology, and physiological response to adrenal ablation and to the injections of the extracts from adrenal glands.

 

Napoleon Cybulski – Biography and Scientific Works

Napoleon Nikodem Cybulski was born on September 14, 1854, in Krzywonosy, which was then in Polish/Lithuania territory under Russian rule (4) (Table 1 and Figure 1). He finished high school at Minsk (currently capital of the Belarus), and in 1875 he was admitted for medical studies at the prominent Imperial Medical and Surgical Academy in St. Petersburg. As a second year student he started working at the Institute of Physiology under mentorship of Professor Trachanov. Despite their age difference they became friends. Later (1901) when Trachanov was demoted by a group of reactionaries in administration of Academy, he was helped by Cybulski and continued to work and live in Cracow, Poland. Cybulski’s student work on “The effect of body posture on blood pressure, pulse and respiration in animals” was awarded a first-class gold medal. He collaborated with another future star of physiology, Ivan Pavlov. In 1880 he finished the Academy cum eximia laude (with the highest distinction) and obtained a doctorate in 1885 (5), with a thesis on the velocity of blood flow as detected by an apparatus called photohemotachometer, of his own construction.

In 1885 he was offered the position of chairman at the Department of Physiology at the Jagiellonian University, Cracow (then part of the Austro-Hungarian Empire). He was dean of the Medical Faculty, and subsequently rector of the University.

Napoleon Cybulski published more than 100 articles and dissertations. His research interest was broad and deep at the same time. His main contribution was in the field of cardiovascular system. He was the first who presented graphically the variation of blood flow velocity with various phases of heart cycles with the use of photohemotachometer and explained “dicrotic acceleration” in carotid artery, in contrast to the lack of it in femoral artery. Together with his pupils he demonstrated that blood velocity was attenuated in pregnant women with jaundice, and accelerated in working muscles. The fifth edition of Starling’s Principles of Human Physiology, 1930 provides description of the use of Cybulski’s photohemotachometer for measuring the velocity of the blood. The last studies on blood flow with the use of his apparatus were conducted in the1970s.

Cybulski had impressive neurophysiological research such as recordings of sensory potentials in cerebral cortex (1890), studies of cortical activity (1914), and muscular and nervous excitability (1890-1916). He define the “resting current (potential) as a property of the membrane, and “action current” as consisted with the movement of positive ion along the muscle fiber.

His “Fizjologia Czlowieka”, the first Polish physiology textbook, was published (1891-1896) in 4 volumes. Volume 3 contains a chapter on body fluid excretion, and a comprehensive discussion on kidney function. He presented in detail the use of onkometer methodology for measuring changes in blood volume going through the isolated kidney and its impact on urinary flow.

 

Władysław Szymonowicz: Biography and Scientific Works

He was born on March 21, 1869 at Tarnopol/Ternopil, Western Ukraine/Galicia, to a Polish/ Armenian family. He finished high school in Lemberg/Lwow, Galicia, and then studied at Medical School at Jagiellonian University in Cracow (1887-1893). He became assistant to Napoleon Cybulski in the 1893. Szymonowicz had chosen laboratories of Rudolf Virchow (pathology) and O. Hertwig (embriology/histology) in Berlin as a place for postgraduate studies (1893-1895). At the same time he was working on morphology and on the physiological role of adrenals in Cracow. These studies led to the new discoveries and allowed him to finish habilitation thesis, important step in academic development. He was invited to establish and to chair the Department of Histology and Embryology Medical School at Lwow (1897-1937). Other than his adrenal work, major scientific achievements were studies the development of nerve endings in skin of human and other animals.

Szymonowicz was also recognized for his Textbook of Histology and Microscopic Anatomy. This work reached 12 editions between 1901 and 1931 and was published in many languages including German, English, Italian, Spanish and Polish

He died in March 10, 1939 and was buried at Lyczakowski Cemetery in Lwow.

 

Work on adrenal gland by Cybulski and Szymonowicz

Szymonowicz conducted the first experiments on seven dogs with adrenal extirpation between May 1894 and December 21, 1894. On December 17, 1894 he started experiments with eleven control dogs and 1 cat to evaluate the physiological effect of adrenal gland extracts. In two more dogs, he injected extracts after aderenalectomy. His last experiment was on September 20, 1895. Starting January 1895 Szymonowicz was intermittently absent in the laboratory, and Professor Cybulski carried himself experiments on dogs, rabbits and cats with water, glycerin and alcohol adrenal extracts (3, 6).

Experiments with bilateral ablation of adrenals confirmed previous reports of animal death within day with shock. Injection of one cc of 10% water solution of adrenal extract to those dogs caused within seconds improvement in BP, heart rate, and respiration. Cybulski observed that adrenal extract did not affect BP and heart rate in animals after section of the spinal cord and emphasize the effect of the extract on cardio-inhibitory center in medulla oblongata rather than direct effect of it on peripheral vessels.

Extract from the adrenal medulla had much stronger effect than that from the cortex. The findings that blood from the suprarenal vein contains the active substance were also unique at that time. Cybulski noted, “Blood of the suprarenal vein contained the active principle of the gland in sufficient amount to mimic effect of adrenal extract.” They call the active, stimulating substance (Greek: hormao) from adrenal medulla “NADNERCZYNA”. Nadnerczyna can be translated into English as epinephrine/ supranephrine.

Some of the experiments were consistent with hypothesis that extreme stress conditions in dogs are inducing the generation of nadnerczyna in blood of those animals enough to cause similar effects on the circulation in normal dogs (although milder) to the ijection of the isolated extracts,.

In his lecture to the members of the Cracow Society of Physician on March 6, 1895, Cybulski stated that “this substance (nadnerczyna), without which the function of nervous system is impossible change the way we understand interaction between different organs”.

 

Oliver and Schäfer Work on Adrenal Function (1893/1894)

George Oliver (spa practicing physician in N. Yorkshire, England) and Edward A Schäfer (Professor of Physiology at University College, London presented in March 1894 to the Physiological Society studies on adrenal extracts. Their final paper was published in The Journal of Physiology, in 1894. This was a very well conducted study with extensive documentation of physiological effect of suprarenal extracts of various strength prepared with water, alcohol and glycerin. Experiments were done on rabbits, cats and dogs, and on isolated frog’s heart (7).

Authors concluded “It appears to be established… the suprarenal capsules are to be regarded although ductless, as strictly secreting glands. The material which they form and which is found, at least in its fully active condition, only in the medulla of the gland, produces striking physiological effects upon the muscular tissue generally, and especially upon that of the heart and the arteries. Its action is to increase the tone of all muscular tissue, and this result is produced mainly if not entirely by direct action. On the other hand the removal of the suprarenal capsules produces extreme weakness of the heart and muscular system generally, and great want of tone in the vascular system. A similar result is known to be characteristic of advanced disease of these organs (Addison’s disease). It may fairly be concluded therefore that one of the main functions, if not the main function, of the suprarenal capsules is to produce a material which is added in some way or another to the blood, and the effect of which is to assist by its direct action upon the various kinds of muscular tissue in maintaining that amount of tonic contraction which appears to be essential to the physiological activity of the tissue” (7).

In the addendum to their paper they acknowledged independent work of Cybulski/Szymonowicz, which was in major part in agreement with their results. They complimented the observation that venous outflow from adrenals had similar effect as extract and that blood does not destroyed the active substance.

The main point of difference was that according to Cybulski/Szymonowicz the extract acts not directly upon blood vasculature but rather through a vasomotor center. Oliver and Schäfer conducted additional experiments with section of the cord and nerves going to the limb, but still observed a constrictive effect of their adrenal extracts on blood vessels.

Soon, in 1897, John Abel, professor of Pharmacology at J Hopkins University purified the adrenal extract and call it epinephrine. Japanese chemist Iokichi Yakamine working in New York obtained pure crystal form in 1901 and marked it “Adrenalin”.

 

Legacy of Napoleon Cybulski

The legacy of Napoleon Cybulski was multidimensional (8). In the opinion of his contemporaries he was a very loving and humble person, full of scientific enthusiasm.

His pivotal work on the hormone of adrenal medulla is well recognized. He developed the Polish School of Physiology, conducted studies on the circulatory system and pioneered neurophysiological research. Cybulski was socially conscious, a propagator of medical science, and a strong proponent of women’s admission to medical school.

 

References
    1. Medvei VC: The History of Clinical Endocrinology: A Comprehensive Account of Endocrinology from Earliest Times to the Present Day CRC Press,1993, p 179-181.
    2. Cybulski N: Fizjologia Czlowieka in four volumes (1891-1896).
    3. Cybulski N: O funkcyi nadnercza. Gazeta Lekarska 1895:12; 299–308.
    4. Beck A: Prof. Napoleon Cybulski: Wspomnienia posmiertne i ocena dzialalnosci naukowej. Gazeta Lekarska 1919: 22-23; 1-17.
    5. Cybulski N Isljedowanija nadj skorostju dwizenija krowi posredstwomj fotogemotachometra. Dissertacija na stepenj doktora mediciny Napoleona Cybulskiego. (1885) S. Peterburg, Tipografija. N. A. Lebedewa.
    6. Szymonowicz L: Die Funktion der Nebenniere. Pflueger’s Archiv für die gesamte Physiologie des Menschen und der Tiere 1895:64; 97–164
    7. Oliver G and Schaffer EA: The physiological effects of extracts of the suprarenal capsules The Journal of Physiology 18941:8; 230-276
    8. Rola R: Napoleon Cybulski – a pioneer of neurophysiology in Poland. Neurologia Neurochirurgia Polska 2011:45; 88-91.

History of kidney transplantation in Poland

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The first successful cadaveric kidney transplantation in Poland was performed in Medical University in Warsaw on January 26th 1966 by professor Jan Nielubowicz and his team (Waldemar Olszewski, Jerzy Szczerbań i Wojciech Rowiński). The recipient 18 year-old nursing school student had been prepared and taken care afterwards by nephrologists Professor Tadeusz Orłowski and his team. The operation went well and the patient was discharged home 3 weeks after transplantation. The patient died 6 months later with well functioning graft due to acute pancreatitis (1, 2). Soon after Professor Wiktor Bross in Wrocław performed the first in Poland kidney transplantation from living related donor on March 31st 1966. At the time when the first cadaveric kidney transplantation was performed in Poland the World Registry organized by professor Joseph Murray recorded only 600 such procedures in the world. It was a great success of polish medicine. This was followed by some attempts in other centres which however were abandoned very soon and the program until eighties was continued in Warsaw only. The surgical team had been preparing to start the clinical transplantation program for over two preceding years in Surgical Research Laboratory headed by prof. Jan Nielubowicz. Prof. Wojciech Rowiński learned transplantation medicine as research fellow in Peter bent Brigham Hospital in Boston in 1965. 1967 laboratory In Warsaw Transplant Centre produced anti-dog, anti-rat, anti-human anti-lymphocytic sera (ALS) and purified globulins in horses, goats, pigs and rabbits. Evaluation of effect of administration of ALS on renal graft survival in dogs was preformed. The team one of the first in the world prepared rabbit-anti-thymocyte serum used in transplant patients (3, 4).
Up to 1976 some 80 cadaver (10-12 per year) and several living related donor kidney transplantations were performed. Since 1977 the number of kidney transplantations in Poland slowly increased to 40-46 per year (5, 6). The legal limitations were not helpful. Cadaveric kidneys procurement was considered as an element of post-mortem examinations. The diagnosis of brain death was well known but not legally permissible. Harvesting of the kidneys was done after cardiac arrest which resulted of high rate of ischemic injury of the organ. At early eighties revival of transplantation programs in other Medical School hospitals: Wrocław, Katowice, Gdańsk, Kraków, Szczecin was started. In Warsaw in addition to Department of Vascular Surgery and Transplantlogy (headed by prof. Nielubowicz, thereafter by prof. Jacek Szmidt) two other transplant centres were set up; Department of General and Transplantation Surgery (1983 headed by prof. Wojciech Rowiński) and Children’s Memorial Health Institute where the first cadaveric kidney transplantation was performed in 1984 by prof. Wojciech Kamiński and prof. Czesław Szymkiewicz. In 1985 the first kidney transplantation from living donor was done. The forth transplant centre in Warsaw was established in Hospital of Internal Affairs in 1990 headed by prof. Marek Durlik (7, 8).
Professor Tadeusz Orłowski created in 1975 the Transplantation Institute in Warsaw Medical University which consisted of two medical departments and department of experimental immunology with the tissue typing laboratory. The pretransplant assessment and the posttransplantation care including immunological monitoring were done in Institute. Both surgical transplant units closely cooperated with Institute. For several years Transplantation Institute was the leading transplant centre in Poland. In 1987 the new protocol originally developed in the Transplantation Institute showed that addition of promethazine to standard immunosuppression (befroe CsA era) resulted in better graft survival (9).
Regarding legal regulations of organ retrieval Transplant Act on Cells, Tissues and Organ Retrieval and Transplantation was issued by Parliament and signed by President in 1995. It was updated in 2005. The act approved presumed consent for organ retrieval, regulateed living donor organ donation, penalized commerce in organ transplantation. In 1993 National Transplantation Council was established by Ministry of Health, main tasks of this advisory body were to elaboration of strategy for development of tissue and organ transplantation, popularisation of the idea of organ donation and transplantation among general public, education of medical students and staff in organ donation and transplantation, active participation in creating legal regulations concerning organ and tissue transplantation. POLTRANSPLANT- Polish Organ Procurement and Sharing Organization was established in 1996 ( headed by prof. Janusz Wałaszewski), National Specialist in the Field of Clinical Transplantation (prof. Wojciech Rowiński) as executive body was appointed in 1996 (10, 11). In 1993 the Polish Transplantation Society was established, the first President was elected prof. Mieczysław Lao head of the Transplantation Institute in Warsaw.
In the early 80-ties kidney transplantation programs were started in a number of Medical School hospitals across the country.
In Wroclaw renewal of transplant program was started in 1983 by the surgeon prof. Klemens Skóra and nephrologist prof. Zenon Szewczyk. Since 1989 one hundred cadaveric kidney transplants were performed. In 1988 second transplant centre in Voivodship Hospital was created headed by prof. Wojciech Witkiewicz (12).
The first two kidney transplantations from living related donors in Upper Silesia region were performed in 1966 (September, November) by doctor Józef Gasiński in hospital in Bytom in cooperation with nephrologist prof. Zbylut Twardowski. Both recipients died due to sepsis after 28 and 136 days respectively. Renewal of transplant program was started in Department of General Surgery in Medical University in Katowice. In 1983 prof. Roman Kurzbauer performer 4 cadaveric kidney transplants, all of them failed due to infectious complications. Under new head of Department of General Surgery prof. Stanisława Kuśmierskiego with cooperation with Nephrology Department headed by prof. Franciszek Kokot in 1984-1990 more than 200 kidney transplantation were performed (12).
In Krakow 9 kidney transplantations (one from living donor) were performed by doctor Romuald Drop, first in march 1975. The responsible nephrologist was prof. Zygmunt Hanicki. In 1992 renewal of transplant program was reported by prof. Tadeusz Popiela and doctor Jerzy Bucki in cooperation with nephrologist prof. Władysław Sułowicz (12).
In Gdańsk the first kidney transplantation in Medical University was done on 31st August 1980 by prof. Wojciech Gacyk and prof. Jerzy Dybicki in cooperation with Department of Nephrology headed by Andrzej Manitius thereafter by prof. Bolesław Rutkowski (12).
In Szczecin the first kidney transplantation was performed in 1980 in II Department of Surgery in medical University by prof. Stansisław Zieliński. The second transplant centre in Szczecin was established in 1983 in Voivodship Hospital by doctor Marek Umiński, prof. Marek Ostrowski and doctor Janusz Lapis (12).
In the Białystok Medical University the first kidney transplantation was performed in 1989 by prof. Stanisław Głowiński with help of prof Jacek Szmidt from Warsaw in cooperation with Department of Nephrology headed by prof. Michał Myśliwiec (12).
In Poznan in Medical University the first kidney transplantation was performed in 1985 in Department of General Surgery and Gastroenterology by prof. Adam Deja in cooperation with prof. Maciej Krzymański and prof. Andrzej Oko from the Department of Nephrology. The second transplant centre was created in Poznań in 1994 in Voivodship Hospital by prof. Zbigniew Włodarczyk, Konstanty Tukałło, Adam Deja and Maciej Głyda (12).
In Łódź two transplant centres started their activity in 1996, first inthe Medical University in Department of Surgery heade by prof. Janusz Wasiak and prof. Janusz Strzelczyk in cooperation with prof. Witold Chrzanowski from Department of Nephrology, second in Pirogow Voivodship Hospital headed by prof. Józef Matych (12).
In Lublin transplant program was started in 1994 inthe Medical University by prof. M.Jesipowicz, prof. S.Stettner, and prof. S.Rudzki in cooperation with prof. Andrzej Książek, head of the Department of Nephrology (12).
In Bydgoszcz prof. Zbigniew Włodarczyk created new transplant centre in 2000 year.
The youngest transplant centre was established in Olsztyn in 2010 by prof. Wojciech Rowiński and doctor Andrzej Kobryń (12).
During the 51 years since first renal transplantation until December 31st 2016 the total number of 22,658 kidney from deceased donor and 766 kidney from living donor transplantations were performed in Poland. Currently there are 21 kidney transplant centres performing 1000 transplants per year in Poland (13).

References:

  1. Orlowski T, Nielubowicz J, Gradowska L, Rowiński W, Klopotowska E. (1966) Function of a transplanted kidney. Pol Arch Med Wewn. 37(1):47-54. Polish. PubMed PMID: 5330481
  2. Nielubowicz J, Orlowski T, Rowiński W, Szczerbań J, Szostek M, Kamiński B, Olszewski W, Ladygin J, Lao M, Gradowska L. (1966) Transplantation of kidney from cadaver. Pol Przegl Chir. 38(10):1030-4. Polish. PubMed PMID: 5341716
  3. Rowiński W, Szmidt J, Rosnowska M, Baraniewski H, Grupińska E, Tupalska B, Brühl A, Krawczyński K, Madaliński K, Nowoslawski A. (1970) Effect of long-term administration of horse antilymphocyte serum to healthy dogs. Pol Arch Med Wewn. 45(2):281-9. Polish. PubMed PMID: 5471505
  4. Rowiński W, Szmidt J, Brühl A, Dziedziul S, Tupalska B, Baraniewski H, Grupińska E, Opertowski A, Nielubowicz J. (1970) Production and titration of antilymphocyte serum for use in dogs. Pol Arch Med Wewn. 45(2):275-80. Polish. PubMed PMID: 4919365
  5. Nielubowicz J, Orlowski T, Wesolowski S, Falda Z, Gradowska L, Rowińska D, Rowiński W, Skośkiewicz M, Szostek M, Filipowicz Z, Glyda J, Goliszek Z, Jedrzejewski R, Kardasiewicz W, Klepacka J, Klopotowska E, Kossowska B, Koziak H, Krzywicka E, Lao M, Ladygin J, Marzinek B, Miller J, Michalowicz B, Machowski Z, Olszewski K. (1970) Results of kidney transplantation in the Warsaw center. Pol Arch Med Wewn. 45(2):175-8. Polish. PubMed PMID: 4919357
  6. Rowiński W. (1970) Results of kidney transplantation in Poland. Pol Arch Med Wewn. 45(2):267-73. Polish. PubMed PMID: 4919364
  7. Rowiński W. (1996) History of organ transplantation in Warsaw. A personal perspective. Ann Transplant. 1(1):5-8. PubMed PMID: 9869929
  8. Lao M, Gradowska L, Stryjecka-Rowińska D, Szmidt J, Rowiński W, Wałaszewski J. (1997) Kidney transplantation in Warsaw and Poland in the years 1966-1996. Pol Arch Med Wewn. 98(10):294-303. Polish. PubMed PMID: 9557082
  9. Orłowski T, Gaciong Z, Paczek L. Promethazine.(1987) results of triple-drug immunosuppression for kidney transplantation. Transplant Proc. 1987 Feb;19(1 Pt 3):2124-5. PubMed PMID: 3079074
  10. Rowiński W, Lao M, Wałaszewski J, Lisik W. (1996) Social, legal and medical limitations of organ transplantation in Poland. Ann Transplant. 1(3):36-40. PubMed PMID: 9869918
  11. Rowiński WA, Wałaszewski JE. (1996) Organizational aspects of organ procurement. Ann Transplant. 1(4):61-4. PubMed PMID: 9869909
  12. Book: Homo Homini, Dzieje wybranych ośrodków transplantologicznych w Polsce, 2012, Publicat.
  13. poltransplant.org.pl

English:
The first successful cadaveric kidney transplantation in Poland was performed in Medical University in Warsaw on January 26th 1966 by professor Jan Nielubowicz and his team (Waldemar Olszewski, Jerzy Szczerbań i Wojciech Rowiński). The recipient 18 year-old nursing school student had been prepared and taken care afterwards by nephrologists Professor Tadeusz Orłowski and his team. The operation went well and the patient was discharged home 3 weeks after transplantation. The patient died 6 months later with well functioning graft due to acute pancreatitis (1, 2). Soon after Professor Wiktor Bross in Wrocław performed the first in Poland kidney transplantation from living related donor on March 31st 1966. At the time when the first cadaveric kidney transplantation was performed in Poland the World Registry organized by professor Joseph Murray recorded only 600 such procedures in the world. It was a great success of polish medicine. This was followed by some attempts in other centres which however were abandoned very soon and the program until eighties was continued in Warsaw only. The surgical team had been preparing to start the clinical transplantation program for over two preceding years in Surgical Research Laboratory headed by prof. Jan Nielubowicz. Prof. Wojciech Rowiński learned transplantation medicine as research fellow in Peter bent Brigham Hospital in Boston in 1965. 1967 laboratory In Warsaw Transplant Centre produced anti-dog, anti-rat, anti-human anti-lymphocytic sera (ALS) and purified globulins in horses, goats, pigs and rabbits. Evaluation of effect of administration of ALS on renal graft survival in dogs was preformed. The team one of the first in the world prepared rabbit-anti-thymocyte serum used in transplant patients (3, 4).
Up to 1976 some 80 cadaver (10-12 per year) and several living related donor kidney transplantations were performed. Since 1977 the number of kidney transplantations in Poland slowly increased to 40-46 per year (5, 6). The legal limitations were not helpful. Cadaveric kidneys procurement was considered as an element of post-mortem examinations. The diagnosis of brain death was well known but not legally permissible. Harvesting of the kidneys was done after cardiac arrest which resulted of high rate of ischemic injury of the organ. At early eighties revival of transplantation programs in other Medical School hospitals: Wrocław, Katowice, Gdańsk, Kraków, Szczecin was started. In Warsaw in addition to Department of Vascular Surgery and Transplantlogy (headed by prof. Nielubowicz, thereafter by prof. Jacek Szmidt) two other transplant centres were set up; Department of General and Transplantation Surgery (1983 headed by prof. Wojciech Rowiński) and Children’s Memorial Health Institute where the first cadaveric kidney transplantation was performed in 1984 by prof. Wojciech Kamiński and prof. Czesław Szymkiewicz. In 1985 the first kidney transplantation from living donor was done. The forth transplant centre in Warsaw was established in Hospital of Internal Affairs in 1990 headed by prof. Marek Durlik (7, 8).
Professor Tadeusz Orłowski created in 1975 the Transplantation Institute in Warsaw Medical University which consisted of two medical departments and department of experimental immunology with the tissue typing laboratory. The pretransplant assessment and the posttransplantation care including immunological monitoring were done in Institute. Both surgical transplant units closely cooperated with Institute. For several years Transplantation Institute was the leading transplant centre in Poland. In 1987 the new protocol originally developed in the Transplantation Institute showed that addition of promethazine to standard immunosuppression (befroe CsA era) resulted in better graft survival (9).
Regarding legal regulations of organ retrieval Transplant Act on Cells, Tissues and Organ Retrieval and Transplantation was issued by Parliament and signed by President in 1995. It was updated in 2005. The act approved presumed consent for organ retrieval, regulateed living donor organ donation, penalized commerce in organ transplantation. In 1993 National Transplantation Council was established by Ministry of Health, main tasks of this advisory body were to elaboration of strategy for development of tissue and organ transplantation, popularisation of the idea of organ donation and transplantation among general public, education of medical students and staff in organ donation and transplantation, active participation in creating legal regulations concerning organ and tissue transplantation. POLTRANSPLANT- Polish Organ Procurement and Sharing Organization was established in 1996 ( headed by prof. Janusz Wałaszewski), National Specialist in the Field of Clinical Transplantation (prof. Wojciech Rowiński) as executive body was appointed in 1996 (10, 11). In 1993 the Polish Transplantation Society was established, the first President was elected prof. Mieczysław Lao head of the Transplantation Institute in Warsaw.
In the early 80-ties kidney transplantation programs were started in a number of Medical School hospitals across the country.
In Wroclaw renewal of transplant program was started in 1983 by the surgeon prof. Klemens Skóra and nephrologist prof. Zenon Szewczyk. Since 1989 one hundred cadaveric kidney transplants were performed. In 1988 second transplant centre in Voivodship Hospital was created headed by prof. Wojciech Witkiewicz (12).
The first two kidney transplantations from living related donors in Upper Silesia region were performed in 1966 (September, November) by doctor Józef Gasiński in hospital in Bytom in cooperation with nephrologist prof. Zbylut Twardowski. Both recipients died due to sepsis after 28 and 136 days respectively. Renewal of transplant program was started in Department of General Surgery in Medical University in Katowice. In 1983 prof. Roman Kurzbauer performer 4 cadaveric kidney transplants, all of them failed due to infectious complications. Under new head of Department of General Surgery prof. Stanisława Kuśmierskiego with cooperation with Nephrology Department headed by prof. Franciszek Kokot in 1984-1990 more than 200 kidney transplantation were performed (12).
In Krakow 9 kidney transplantations (one from living donor) were performed by doctor Romuald Drop, first in march 1975. The responsible nephrologist was prof. Zygmunt Hanicki. In 1992 renewal of transplant program was reported by prof. Tadeusz Popiela and doctor Jerzy Bucki in cooperation with nephrologist prof. Władysław Sułowicz (12).
In Gdańsk the first kidney transplantation in Medical University was done on 31st August 1980 by prof. Wojciech Gacyk and prof. Jerzy Dybicki in cooperation with Department of Nephrology headed by Andrzej Manitius thereafter by prof. Bolesław Rutkowski (12).
In Szczecin the first kidney transplantation was performed in 1980 in II Department of Surgery in medical University by prof. Stansisław Zieliński. The second transplant centre in Szczecin was established in 1983 in Voivodship Hospital by doctor Marek Umiński, prof. Marek Ostrowski and doctor Janusz Lapis (12).
In the Białystok Medical University the first kidney transplantation was performed in 1989 by prof. Stanisław Głowiński with help of prof Jacek Szmidt from Warsaw in cooperation with Department of Nephrology headed by prof. Michał Myśliwiec (12).
In Poznan in Medical University the first kidney transplantation was performed in 1985 in Department of General Surgery and Gastroenterology by prof. Adam Deja in cooperation with prof. Maciej Krzymański and prof. Andrzej Oko from the Department of Nephrology. The second transplant centre was created in Poznań in 1994 in Voivodship Hospital by prof. Zbigniew Włodarczyk, Konstanty Tukałło, Adam Deja and Maciej Głyda (12).
In Łódź two transplant centres started their activity in 1996, first inthe Medical University in Department of Surgery heade by prof. Janusz Wasiak and prof. Janusz Strzelczyk in cooperation with prof. Witold Chrzanowski from Department of Nephrology, second in Pirogow Voivodship Hospital headed by prof. Józef Matych (12).
In Lublin transplant program was started in 1994 inthe Medical University by prof. M.Jesipowicz, prof. S.Stettner, and prof. S.Rudzki in cooperation with prof. Andrzej Książek, head of the Department of Nephrology (12).
In Bydgoszcz prof. Zbigniew Włodarczyk created new transplant centre in 2000 year.
The youngest transplant centre was established in Olsztyn in 2010 by prof. Wojciech Rowiński and doctor Andrzej Kobryń (12).
During the 51 years since first renal transplantation until December 31st 2016 the total number of 22,658 kidney from deceased donor and 766 kidney from living donor transplantations were performed in Poland. Currently there are 21 kidney transplant centres performing 1000 transplants per year in Poland (13).

References:

  1. Orlowski T, Nielubowicz J, Gradowska L, Rowiński W, Klopotowska E. (1966) Function of a transplanted kidney. Pol Arch Med Wewn. 37(1):47-54. Polish. PubMed PMID: 5330481
  2. Nielubowicz J, Orlowski T, Rowiński W, Szczerbań J, Szostek M, Kamiński B, Olszewski W, Ladygin J, Lao M, Gradowska L. (1966) Transplantation of kidney from cadaver. Pol Przegl Chir. 38(10):1030-4. Polish. PubMed PMID: 5341716
  3. Rowiński W, Szmidt J, Rosnowska M, Baraniewski H, Grupińska E, Tupalska B, Brühl A, Krawczyński K, Madaliński K, Nowoslawski A. (1970) Effect of long-term administration of horse antilymphocyte serum to healthy dogs. Pol Arch Med Wewn. 45(2):281-9. Polish. PubMed PMID: 5471505
  4. Rowiński W, Szmidt J, Brühl A, Dziedziul S, Tupalska B, Baraniewski H, Grupińska E, Opertowski A, Nielubowicz J. (1970) Production and titration of antilymphocyte serum for use in dogs. Pol Arch Med Wewn. 45(2):275-80. Polish. PubMed PMID: 4919365
  5. Nielubowicz J, Orlowski T, Wesolowski S, Falda Z, Gradowska L, Rowińska D, Rowiński W, Skośkiewicz M, Szostek M, Filipowicz Z, Glyda J, Goliszek Z, Jedrzejewski R, Kardasiewicz W, Klepacka J, Klopotowska E, Kossowska B, Koziak H, Krzywicka E, Lao M, Ladygin J, Marzinek B, Miller J, Michalowicz B, Machowski Z, Olszewski K. (1970) Results of kidney transplantation in the Warsaw center. Pol Arch Med Wewn. 45(2):175-8. Polish. PubMed PMID: 4919357
  6. Rowiński W. (1970) Results of kidney transplantation in Poland. Pol Arch Med Wewn. 45(2):267-73. Polish. PubMed PMID: 4919364
  7. Rowiński W. (1996) History of organ transplantation in Warsaw. A personal perspective. Ann Transplant. 1(1):5-8. PubMed PMID: 9869929
  8. Lao M, Gradowska L, Stryjecka-Rowińska D, Szmidt J, Rowiński W, Wałaszewski J. (1997) Kidney transplantation in Warsaw and Poland in the years 1966-1996. Pol Arch Med Wewn. 98(10):294-303. Polish. PubMed PMID: 9557082
  9. Orłowski T, Gaciong Z, Paczek L. Promethazine.(1987) results of triple-drug immunosuppression for kidney transplantation. Transplant Proc. 1987 Feb;19(1 Pt 3):2124-5. PubMed PMID: 3079074
  10. Rowiński W, Lao M, Wałaszewski J, Lisik W. (1996) Social, legal and medical limitations of organ transplantation in Poland. Ann Transplant. 1(3):36-40. PubMed PMID: 9869918
  11. Rowiński WA, Wałaszewski JE. (1996) Organizational aspects of organ procurement. Ann Transplant. 1(4):61-4. PubMed PMID: 9869909
  12. Book: Homo Homini, Dzieje wybranych ośrodków transplantologicznych w Polsce, 2012, Publicat.
  13. poltransplant.org.pl

The application of philosophy and history of medicine in current medical practice. The Nephrotic Syndrome Example

Abstract

Current medicine has banished all philosophical theories and systems and preserves only the facts, the data and the results of experience. However, according the belief of authors medical history and philosophy still continue producing apparent results upon the treatment of dilemmas in current medical practice. As an evidence of this belief a peculiar approach of nephrotic syndrome (one of the most debated issues in nephrology) in parallel with the aspects of medical history and philosophy was attempted.

The first empirical references from the earliest times of medical art, follow more defined rational and methodic classifications such as the clinical-etiological of Bright, the current histological and probably the forthcoming omics classification, of medical science.

The mystic period and the sacred numbers of Egyptians and Babylonians, the mathematical theories of Pythagoras have now been replaced by the sacred number of p<0,001 and the mystic of statistic values of random controlled clinical trials (RCT).

According to the mentioned above current doctors could be considered as “eclectic” ones: they adopt the reports of beneficial experience (clinical guidelines), carefully and methodically controlled by RCT and follow the modern dogmas such as the individualization of therapy and cost/effectiveness relation combined with the diachronic one “the beneficence of the patient”. The remains of medical antiquity may now have little interest, especially in a didactic point of view; but they will always interest the “erudite” doctor, indicating the route followed by the science where the past is “dogmatic” in present and the present will be “empirical” in the future.

 

Key words: History, medicine, philosophy, nephrotic syndrome

INTRODUCTION

The nephrotic syndrome (NS), the glomerular disease (GD) in generally, is one of the most debated and challenging issue for the clinical nephrology. The uncertainty concerning the GD is reflected by the low grade of the existed clinical guidelines, (only 2% of clinical guidelines are grade as A (1) and the unwilling of nephrologists, (15-46%) to adopted them as it was recorded from a Canadian study (2) two years after the KDIGO guidelines.

The clinical nephrologist stands uncertain in front of the GD, where the cause is unknown, the treatment unsafe and the future uncertain. This uncertainty was expressed in ancient Greek philosophy (the aphorism quotes the first two lines of the Aphorismi) (3) by the ancient Greek physician Hippocrates:

“Life is short, and art long, opportunity fleeting, experimentations perilous, and judgment difficult.”

The above mentioned observations were the trigger of wondering about the utility of medical history and philosophy in facing current dilemmas in daily medical practice. The belief that philosophy is a matter of great value when it can be redeemed in daily life and practice and additionally that philosophical theories still produce apparent results upon the current practice of medicine overarches the text below. In order to support this, a peculiar approach was attempted. The retrospection of history of medical science and philosophy in parallel with the history of NS and GD. This was an interesting challenge to consider: both continuity and change in the practices of medicine (what traditions did medical practitioners draw upon – even as they made radical innovations) and the relationship of medicine to its wider culture.

 

HISTORY OF SCIENCE, PHILOSOPHY SCIENCE AND HISTORY OF MEDICAL SCIENCE (4, 5)

Science represents the only robust and trustworthy way of knowing both the world and the Mankind and could be a part of “… a new humanism a project that could bridge social, national and intellectual divisions just as the humanist movement had done a millennium earlier…” (6). Anciently philosophy embraced the whole human knowledge (physics, natural history, medicine, morals, metaphysics, theology, mathematics etc). Gradually many of these branches have been detached from the main trunk and constituted separate sciences. Historians take also seriously the point that before the early 19th century there was no such a thing as science but instead there was something called, natural philosophy, with much broader ultimately religious aims.

The discipline of the history of science concerns the history of the way nature has been manipulated, modeled and understood by different societies. History of science constantly reattaches itself to other disciplines in the humanities and social sciences and embraces a wide range of approaches. These link history of science to history of philosophy, medical history, social history, history of technology and many other historical disciplines.

In Europe a number of scientists turned to history to support their theories of scientific method what called philosophy of science. The assumption that the method and object of scientific practice demarcates it from all other human activities drew history of science and philosophy of science closely together. One could best discover a particular world view at any period or culture by looking at the sorts of problems addressed by its philosophers. In addition the central concepts of philosophy at any given time may be determining element of the nature of the scientific thought of that age. In the history of medicine, most of the medical theories derived more or less directly from some system of philosophy; consequently in estimating the merits of any theory or method of practice it becomes prominent to know from which of these emanated.

History of science has also allied itself move closely with developments in sociology of science and other historical disciplines (imperial history, economic and global history). This approach has to balance the intellectual history of science first to its social context (social history of science) and secondly to the technical accomplishments by adopting a more materialist view, with the integration of scientific instruments and their use (science of technology).

It is obvious that science has never flourished and been cultivated in the highest degree in any place where it has had no legal recognition. Science was usually conditioned by its social and historical contexts. In Ancient world the condition of organized theoretical knowledge or “episteme” had been that members of “leisured” classes devoted themselves to theory. Science had developed in the West from this disengaged basis and not elsewhere where there were great “bureaucracies” that were always hostile to independent scientific thought. The signal contribution of history of science has been to show the significance of relations between philosophical, historical, religious, social values in the development of science.

 

History of philosophy and medical science (7, 8) versus history of NS and GD

Science has been held to have a unique capacity to progress by providing us with true statements about nature. Scientific progress began when knowledge became more abstract and freed itself from its craft origins and then from unnecessary remaining metaphysical elements. Gradually became distinctive from other forms of human activity and progressed through operations that elevated it above and extricated itself from the plethora of superstitious metaphysical occultist and religious opinions that always held back its advance. The tenacious obedience to authority was disputed and there was a shift of human mind from the domain of purely speculative vague conjectures and dogmas to the actual study and collation of facts. New doctrines and scientific discoveries disputed the “authority” of the former time and surpassed dogmas which were not eliminated but attempts were made to reconstruct medicine upon “scientific” basis. Dogmatics who devoted themselves to philosophical speculations and the formation of theories gave their place to Empirics who gave their attention to the observation; their reasoning did not go beyond the observation and experience and placed nothing in the rank of positive and certain knowledge but the sensations.

The “scientists” started to observe the “unknown” and report the experience. Observation and memory which constitute experience were the principal faculties put in exercise: reason entered very little into their considerations.

Reports about NS dating back to Hippocrates. Generalized edema, referred to as dropsy in the earlier literature, and its correlation with renal disease has been documented by his observation: “when bubbles settle on the surface of the urine, it indicates a disease of the kidney and that the disease will be protracted (9). A rich history of observations and interpretations followed over the course of centuries until finally in 1827, an English clinician, Richard Bright, published his first book “Diseased Kidney in Dropsy” where a causal relationship between dropsy and anatomic changes in the kidney was established and the triad of generalized edema, proteinuria and kidney disease were the dominant features that defined the disease which from that time was called “Bright’s disease” (10). In 1833 Bright gave the Goulstonian lectures and he first described the rising of blood urea with advancing renal impairment (11). The full description of the clinical and gross morbid anatomical features of all stages of glomerular disease in Bright’s paper of 1836 is regarded as one of the classics of medical literature (12). The impact of his work was remarkable. His observations were quickly repeated in several centers and widely extended over the next decade. This was the empirical era of NS constituted only by observations concerning macroscopic symptoms where suggestions about reason were very cautious.

As the observations multiplied it became necessary to arrange them after a method which would impress them upon the previous acquired memory and experience. This was the origin of the first pathological classification. Mere experience report by occasional instinctive observations taken at hazard and gathered generally without taste or method; without the luxury of harmonious thought and premeditated design is an Art. It’s the combination of intelligence that investigates beyond the phenomena, the reason and the systematically arrangement of observations that transforms Art into Science. The Empirics were succeeded by the Methodists and observations that tend towards a common end were arranged systematically; both signaled the passage from Art to the Science of Medicine. In accordance with the above mentioned, as the experience concerning GD increases and the information multiplies, it becomes more obvious the need of classify them under some system and method. The method used to classify GD was based on three axes: clinical observation, etio/pathogenesis and histological findings. The initial “rough” clinical classification based on Bright’s Reports described cases of chronic NS. Acute nephritic related cases were also reported later. Another classification based on etio/pathogenesis arises as our knowledge and information about the causes of GD accumulated. Other immunological, genetic, metabolic causes are also involved in the pathogenesis of GD. However the “unknown” pathogenesis still has a dominant place and gives trigger for development of new theories and raising of new dilemmas and controversies.

The entrance of renal biopsy in 1950 was a revolution in the area of kidney disease and led to the emergence of a new specialty of nephropathology. There was a shift from the clinical/etiopathogenetic approach to the analysis of histological patterns. A grade range of morphological features appeared from “gross” findings on light microscopy (minimal change lesions, focal or diffused hypercellularity) to more complex and enriched descriptions with the support of immunofluorescence techniques and high revolution electron microscopy. Consequently the field of glomerular diseases dramatically augmented. New data are added in old clinical-histological entities and new diseases emerge such as immunotactoid GD, hereditary forms of GD, C3 glomerular disease. One the other hand the histological classification has its limitations; the most prominent one is that we don’t classify diseases but histological patterns and indeed patterns of limited “repertoire” since kidneys respond in a limited way to kidney damage. Therefore, certain histological patterns may be the end result of many different renal diseases and molecular pathways of progress of kidney injury. In other words different clinical manifestations may have similar histological findings while different histopathologies may be present to the same clinical entity. Consequently it became obvious in Renal Consensuses (13) that although the histological patterns are the only “scientific, objective observation” criteria we need to go beyond that to a more comprehensive classification where new data will be incorporated on the etiology/pathogenesis basis. Observation and classification are not enough in treating the GD. They may not be related to either clinical severity or prognosis and they do not always guarantee a clinical utility by determining the course of treatment.

Going back to the past. The Empirics assumed that in any given case only such remedies as had appeared to be valuable in similar cases, should be employed without any regard to the proximate cause of which they nothing reveals to us the mode of action. It was sufficient enough to show that they were able to cure in order to feel authorized to apply the same treatment to analogous cases. It was naturally supposed that the same remedy would relieve of a similar trouble and all similar cases should be treated in a like manner. No inquiry was made as to the mode of cure by the remedy. This attitude «treating without knowing” does not sound unfamiliar in medical practice even in recent days, representative examples the “early” use of aspirin and corticosteroids. The initial treatment of NS included resting and lowering the protein uptake in order to reduce the renal load, a therapeutic strategy that is followed even in now days. In 1950 the Nobel Prize in Physiology or Medicine was awarded jointly to Edward Calvin Kendall, Tadeus Reichstein and Philip Showalter Hench “for their discoveries relating to the hormones of the adrenal cortex, their structure and biological effects”. The whole story began by an observation. Kendal in the course of his work he observed the favorable effects of jaundice on arthritic patients, causing remission of pain. Other bodily changes, for example pregnancy produced the same effect. These and other observations led him gradually to the conclusion that the pain-alleviating substance was steroid. In the period 1930-1938 Kendal and his collaborators had isolated several steroids from the adrenal gland cortex one of which was initially called Compound E. Working with physician Philip Showalter Hench, Compound E was used to treat rheumatoid arthritis. The compound was eventually named cortisone (14). The excellent response to new treatment mainly in cases of minimal change GD in pediatric patients and other types of GD had established corticosteroids as a corner stone not only for the treatment but also as a prognostic marker of the outcome of GD.

However, it was proved, once again that observation and empirical treatment is not enough. It has been several decades since then but there are still dilemmas that oscillate the clinicians. There is a need once again to go beyond the experience, behind the phenomena discovering new pathogenetic pathways. New players of humoral and cellular immunity are introduced in the field of renal injury. The recognition and understanding of their role has led to the introduction of new more specific, effective and targeted therapies (15). But the response to therapy is not always the desirable one. Except the cortico-resistant forms of GD, new forms of resistant nephrotic syndrome appear like cyclosporine, mycophenolate resistant forms. We could say that treatment strategies offer a picture of a republic delivered up to many rival factions which dominate but turns without ever obtaining lasting power. What exactly is going on? Maybe the past will help us to find the answer. A basic doctrine of the philosophy of causes says that the same factors placed under identical conditions will always produce the same result. But in medicine this is different: here nature and accidents ie. diseases, furnish us the opportunities of experimenting: but in the first place the elements (patients) of these experiments and the diseases (glomerulopathies with great heterogeneity) are never identical; and secondly it is impossible to isolate the patients from a multitude of influences that alter the therapeutical results. Another fundamental principal is expressed by the aphorism: contraria contrariis curantur. It was held that always exists a species of antagonism between the cause of the morbid phenomena and the active properties of the remedies that cured them; or rather between the pathological modification of the organism and the curative impulse given to the economy by the treatment.

Freedom of thought and expression are necessary prerequisites for any science to flourish. The right of free choice is the most dominant one. The history of medicine teach us that in the face of dilemmas about theories and treatments there was a cast of physicians the Eclectics who professed to select such principles and modes of practice as appeared to them the most valuable and beneficial for the patient. Their object seemed to be a reconciliation of the tenets of Methodists (classification of knowledge) with those of the Dogmatics (dogmas, principles and theories) and Empirics (observation and experience). Current doctors could be considered as “eclectic” ones: they adopt the reports of beneficial experience (clinical guidelines), carefully and methodically controlled by random controlled trials (RCT) and follow the modern dogmas such as the individualization of therapy and cost/effectiveness relation combined with the diachronic one “the beneficence of the patient”.

As medical science gradually detached from philosophy and humanities was influenced and supported by other “applied” sciences such as physics, chemistry, mathematics. The first link was made at the time of Pythagoras, but the few fragments of this mathematical system that are left serve more as proof of its existence than for its understanding,. Those who wrote them use a “jargon” that is supposed to be known in the same way that modern scientists use algebraic, statistical characters etc. The language of the numbers used by the Pythagoreans is lost. Now days the sacred numbers 1, 2, 3 7 have been replaced by the sacred number of p<0.001 and the mystery of statistic values of randomized double blind studies. But in the case of GD they are “weak” due to: a) the few number of patients b)the slow progression of the disease c) the differences in data classification as well as in types of histological patterns. All these impede the reliable comparison of the data and the creation of a basic reliable multicenter study. Consequently the mathematically “evidence –based” well doing of treating GD has been limited by poor availability of large comprehensive registries.

The basic sciences, systems biology, molecular biology and omics are the rapidly advancing, innovating and promising fields in molecular mechanisms underlying the diverse etiologies of GD. It is the answer of now days offering a “storm” of new information and entirely new fields in its investigation. Large-scale gene, protein and metabolite measurements (‘omics’) have driven the resolution of biology to an unprecedented high definition. Passing from reductionism to a system-oriented perspective, medical research will take advantage of these high-throughput technologies unveiling their full potential. The omic cascade, from the potentiality of ‘what can happen’(genome) through ‘what appears to happen’ (transcriptome) and ‘what makes it happen’ ( proteome) to ‘what has happened’ (metabolome), embodies the paradigm of what needs to be modelled. Integration will unveil the full potential of these high-throughput technologies leading to a comprehensive decoding of the upper emergent level, the phenotype and the key to decoding the underlying principles that govern the complex functions of living systems. Systems biology is a novel field pitched at decoding -omic dynamic interactions and adding an additional dimension to that of a classical homeostatic model of physiology (16, 17). In the near future omics will improve the classification of GD (in addition to clinical, etio/pathogenesis, histological the omics one) to a more sophisticated model. Finally there will be a radical moving from empirical to stratified and individualized medicine which will depend on refined molecular fingerprints.

These modern sciences will modify the traditional deductive model of scientific knowledge (scientific knowledge is hypothesis established on valid rationally and after research proven true statements) or even the more radical one related to Popper’s philosophy of empirical falsification (A theory in the empirical sciences can never be proven, but it can be falsified) to an unbiased model without prior hypothesis but first gathering data and then generating hypothesis after analysis and modeling.

Churchill once said as he was “bombarding” by the claims of the Balkan nations that … “they produce more history than they can consume…” In analogy we now produce more information and data than we can incorporate into the daily clinical practice. This creating a demand for effective storage (data bases), management and exchange of rapidly generated data and research discoveries. Databases are divided into two categories: general databases with a broad information scope and kidney specific databases distinctively concentrated on kidney pathologies. In research, databases can be used as a rich source of information about pathophysiological mechanisms and molecular targets. In the future, databases will support clinicians with their decisions, providing better and faster diagnoses and setting the direction towards more preventive, personalized medicine.

It is a fact that modern medicine rejects from medical practice any kind of system and philosophical theories and insists on the value of pure scientific evidence based data alone. However this may sound utopian when the “philosophy of physician’s attitude” about the welfare, disease and health determines his attitude towards healing. A science that deals with the mystery of life cannot be complete if it deals only with its empirical/scientific part. A major part of individualization of treatment in medicine relies on the “holistic” view of life and disease.

The clinical nephrologist still wanders around in the labyrinth of NS resulting usually in “minotauric dead ends” searching for the ball of yam (mitos) in order to find his way out.

 

Epilogue

This retrospection does not allude that that the progress of the science and the acquisition of knowledge is a circular game incessantly repeating. From Aristotle and Kant to Popper and model of systems biology, each era has its own “cognitive” model of approaching knowledge. Nevertheless knowing the history and philosophy of the science that we practice, it is not only a privilege of an erudite man but also make us more broad minded in, understanding, individualizing and treating current unknown under research issues indicating the route followed by the science where the past is dogmatic in the present and the present will be empirical in the future so that every current generation will be the empirical candidate of the future.

 

References:

  1. KDIGO Clinical Practice Guideline for Glomerulonephritis. Kidney Int. VOL 2, SUPPLEMENT 2, JUNE 2012.
  2. Barbour S, Beaulieu M, Gill J et al The need for improved uptake of the KDIGO glomerulonephritis guidelines into clinical practice in Canada: a survey of nephrologists. Clin Kidney J. 2014 Dec; 7(6): 538–545.
  3. Hippocrates, Aphorismi
  4. Dictionary of the History of Science, W.F. Bynum, E.J. Browne and R. Porter (eds), (London, Macmillan, 1981).
  5. Companion to the History of Modern Science, R. Olby, G. Cantor, J. Christie and J. Hodge, (eds) (London, Macmillan 1990)
  6. Cantor G. Charles Singer and the early years of the British Society for the History of Science. Br J Hist Sci. 1997 Mar; 30 (104 Pt 1): 5-23.
  7. History of medicine: a brief outline of medical history and sects of physicians from the earliest historic period. Alexander Wilder 1823-1908.
  8. History of medicine: from its origin to the nineteenth century, with an appendix, containing a philosophical and historical review of medicine to the present time. P.V. Renouard 1856.
  9. Chawick J Mann WN. The medical works of Hippocrates. London: Oxford University Press, 1950:228 (Section 2, No 136), 240 (Section 13, No 266) 244 (Section 7, No 34).
  10. Bright R. Reports of Medical Cases, Vol. 1. Longmans Green, London, 1827.
  11. Bright R. London Medical Gazette, 1833, 12, 378.
  12. Bright R, Guy’s Hospital Reports, 1836, 1, 338, 380.
  13. Mayo Clinic/ RPS Consensus Report on Classification, Diagnosis, and Reporting of Glomerulonephritis RPS Satellite Meeting, Seattle, 2016.
  14. Edward C. Kendall. The Nobel Foundation. Retrieved 2011-07-04.
  15. Kitching RA and Hutton HL. The Players: Cells Involved in Glomerular Disease. Clin J Am Soc Nephrol 2016. doi: 10.2215/CJN.13791215.
  16. Pesce F, Pathan S and Schena FP. From -omics to personalized medicine in nephrology: integration is the key. Nephrol Dial Transplant (2013) 28: 24–28.
  17. Papadopoulos T, Krochmal M, Cisek K et al. Omics databases on kidney disease: where they can be found and how to benefit from them. Clinical Kidney Journal, 2016, 1–10.

Urolithiasis from the point of view of the head physician of Ottoman emperors: Ahi Ahmed Çelebi

Ci spiace, ma questo articolo è disponibile soltanto in Inglese Americano. Per ragioni di convenienza del visitatore, il contenuto è mostrato sotto nella lingua alternativa. Puoi cliccare sul link per cambiare la lingua attiva.

Introduction

Ahi Ahmed Çelebi was a famous Turkish physician in the 16th Century. He was the head physician of Bayazıd II, Yavuz Sultan Selim, and the Magnificent Suleiman who were Ottoman emperors in rising period. He worked extensively on urolithiasis since it was also common at that times, and wrote his experiences as a pamphlet in “Risala al-Kilya wa’l-Mathana“, and dedicated it to Bayazıd II (1-3). He has been explaining his own observations/experiences as well as mentioning from the works of local and foreign medical researchers.

This pamphlet contains ten headings. Interestingly, most of his observations regarding the etiology of calculus had great similarity to our present knowledge, especially about dietary habits. For example, in the introduction, he said that “Especially it is prevalent among the people of the upper class. The reason is the people of this class have much comfort and much eating,.. In the formation of calculus these are important factors”(1-3).

We will discuss Ahi Ahmed Çelebi’s work and recommendations about urolithiasis and compare some of them to our current knowledge.

 

Heading # 1 (Calculi may be seen in whom, and why?)

He explained main etiological factors in urolithiasis with details; in boys up to the time of adolescence, in obese, and also in asthenic types. It occurs in bladder of boys, and in the kidneys of adults, and fat type persons. It is rarely formed in the urinary bladder of women because of the free vesical neck and short urethra. The calculi is formed in persons eating too much (meat, raw fruits, bitter orange, large fish meat, all sea bird meat, all roast meats, garlic, onion, starchy sweeties, etc…) (1-3).

Today’s data also stress the male preponderance for kidney stone disease both for pediatric and adult cases (4). It has been well known that obesity is one of the common cause of kidney stone disease, mostly because of increased sodium and fructose intake, and decreased intake of calcium and water together with increasing use of antibiotics (4). Probably the similar eating habits were the responsible factors at that time too, except the use of antibiotics. The listed foods above are rich in protein and cause urinary acidification, therefore facilitates the calcium oxalate formation, while raw fruits and bitter orange are the source of fructose. This was a great observation during that period, without knowing the chemical ingredients of them.

One of the surprising data from today demonstrated that lower percentile body weight children had their first clinical stone events significantly earlier than upper percentile or normal body weight peers (5), that is similar to Ahi Ahmed Çelebi’s observation for asthenic types.

His observation for females as ‘rarely formed in the urinary bladder of women because of the free vesical neck and short urethra’, may be true for more easily passage of stone, while current data have shown the male–female ratio is now close to 1:1 (4), because of different variables including body mass index, hyperinsulinemia, and hypertension (6).

 

Heading #2 (where do lithiasis exist in the human body)

This heading contains informations about the organs in which stones may appear, mainly in kidneys and the urinary bladder. He also mentions from the discourses of Rhazes (calculus may be seen in large intestines, muscle, joints, and tumors), and Galen (observation of a person with pneumonia, splitting stone like particles, similar to bladder stone, while coughing) (1-3).

 

Heading #3 (Symptoms of kidney and bladder stones)

Symptoms and clinical findings of kidney and bladder stones have been described in detail under this heading. He stresses that pain or heaviness in the loins, or acute pain like bodkin piercing into the flesh is belong to renal calculi. He describes the location of calculi according to the pain types; if these pains spreads from the loins into the direction of thighs, this indicates that the calculi descended into the lower urinary tract. If the pains decrease for a while, this means that the calculi has fallen into the bladder (1-3).

It has been well-known that stone formation is the result of a complex interaction between genetic and environmental factors including different patways for various stones in urinary tract (4). Although environmental factors has changed during the centuries that may affect the incidence and also the chemical composition of urinary tract stones, calcium oxalate stone formation is still common in kidneys, followed by uric acid or struvite, while most of bladder stones are ammonium acid urate and uric acid stones (7). Each stone has a special color and consistency. Ahi Ahmed Çelebi mentions from a correlation between nature/color of urinary sands and location of calculi; the yellowish and dryish sands originate from the kidneys, while white and gray sands originate from the bladder. The sands coming from bladder show that the stone is soft, otherwise, it is hard. Although the color of stone/calculi may give some information to an experienced clinician about the type of stone, it is difficult to say its type exactly without analysis. Detailed notes mentined above demonstrate his great observation and experience.

He also refers to the relationship between clinical findings and stone size; bladder is a large organ and stones in it mostly do not cause pain. However, if urinary bladder calculi is large and tortous, the patient often feels pain in groins, urinates with difficulty and has feeling for urination after miction. Males with bladder stones feel pain in the penis neck during walking, and the pain goes away if they lie down. If bladder stone is small, it may move to the bladder neck, and prevents urination (1-3).

All of these detailed descriptions are typical examples of, “from symptoms to diagnosis“.

 

Heading #4 (Preventive and curative medicine for kidney and bladder stones)

Under this heading, he suggests firstly to avoid the main factors facilitating stone formation, and later describes the methods of elimination; avoid to eat the above mentioned foodstuffs, avoid overeating (he refers to the benefits of eating regular meals), and make exercise. For the expulsion of calculus; sedatives, laxatives (to eliminate the substance(s) helping the stone formation), moderate exercise before meals, massage on hands and feet, regular sitting baths… (1-3). All of them would help to remove the stone from its place and facilitates its excretion by muscle relaxation.

 

Heading #5 (What is the disease, the causes, symptoms, and its treatment)

He tried to explain the causes of diseases according to “Humoral Pathology Theory”, and stated that the deterioration of the humoral balance in the body by endogenous or exogeneous reasons may damage the organ. Therefore, the reason of stone formation is the bad temperament of kidney and bladder.

He especially emphasizes heat and cold exposures of kidney. Drinking hot wine, eating warming herbs and meals, wearing warm clothes warm the kidneys, and the urine of those persons is reddish, dark yellow and has a pungent smell. He notes that these patients may have thirsty feeling, frequent urination, burning during urination, and sometimes high body temperature. If the problem is warming of the kidneys; he suggests resting, drinking beverages (purslane/cucumber juice, yoghourt), eating cooked green grapes, barley meal prepared with green grapes and Tamaricus Indica, etc.), and some herbal mixtures to apply on the kidneys (1-3).

He says that if the problem is cold (because of sitting or sleeping in cold places, eating cold meals and cold fruits, drinking cold sherbets with empty stomach, etc); a mixture of cinnamon, essences of wallnut, sour almond, and pistachio together with the gravies of a lamb head and a pigeon would be beneficial. He also suggests to eat chickpeas gravy, chicken, a good sized two year old male mutton cooked with cumin and cinnamon, and also roasted sparrow, etc (1-3).

Under this heading, there are also brief suggestions for kidney disorders which may be caused by excessive blood, phlegm and bile, as the cause of disease.

 

Heading #6 (Treatment of stones caused by various constitutional disturbances)

Under this topic, there are detailed descriptions to eliminate the kidney stones, resulted of several constitutional disturbances, such as warm and cold. Treatment recommendations such as sitting baths prepared with violet leaves, several herbal drugs and correct dietary habits were mentioned. He suggested some exercise to heat the body, and horse riding, going up and down the stairs to throw out the calculus from the kidneys into the bladder. If the calculus stops in somewhere in the kidneys, hot and sharp medicaments had been suggested, such as increasing urine volume with herbs, and dissolvent solutions, and oils facilitating the movement of stones (1-3).

 

Heading #7 (The preparation and instructions of several drugs)

It has been seen that he preferred not only herbals, also a few animal products in the treatment of calculi. He mentions from the preparation of some remedies; scorpion oil and ash, and the drying method of goat blood, etc., and the use of them. He referred that they would be effective to expel the calculi from kidney and bladder (detailed in the 10th Heading) (1-3).

It seems difficult to explain the action mechanism(s) of these materials on calculi, since they mostly look like an observational experience.

 

Heading #8 (Medications to expel the calculi, and instruments for stucked calculi)

He says that if there is a wound in an organ because of passing and/or stucked stones, it would be painful. Interestingly, he describes the place of wound according to urine color; when the urine is bloody, the wound is at or below the kidney, but, if the blood comes first, the wound is in the bladder or below it. In this case, he suggests to take blood from vena basilica to prevent swelling of the organs (a solution for increased blood according to Humoral Pathology Theory). He mentions from the treatment of wound with a variety of medications that can be applied to bladder by a kind of tube, “a water throwing tool”as was told in Turkish (1-3).

If a large stone comes to the bladder neck and causes severe pain and obstruction, he describes a movement suggested by Sayyid Ismail Jorjani to push it back: someone holds the patient lying down with two feet up position, and shakes several times. Thus, the stone is attempted to fall into the bladder. If the stone does not go back, he suggests sitting baths with several herbs, medicines and some tools used for stucked stones in urinary tract. He describes the urinary catheter, used in Europe at that time, both for urination and application of some drugs into the bladder via this catheter. Interestingly, he mentioned from one of the Beys of the Sultan, named as Keyvan Bey, suffering from stucking bladder stone, and did not get any benefit from available treatment modalities, invented an apparatus, and used it on himself. Ahi Ahmed Çelebi described this apparatus with details. He noted that “it was a pivot like silver bore containing holes on it, like on flutes. When the sensation to urinate occurs, he inserted this apparatus from its thinner end through the urethra, and push the calculus a little behind. Then, he withdraw the apparatus after successful voiding conducted through holes”, like a urinary catheter used today. He also mentioned from an instrument, like a simple lithotripter; “He also ordered a pair of pincers in steel, with their ends like pivots and the rive of the pincers at the root of the pivot. The pincers could open considerably by a slight movement at the other end. One day he inserted the pincers through the urethra into bladder. When it touched the calculus they opened the pincers without giving much suffering to the patient. In this way the pincers got hold of the calculus and crushed it, so its pieces came out with urine. That was the end of the calculus trouble in the patient”(1-3).

As it has been known, Hippocrates was extremely cautious about surgical intervention for bladder stones and did not recommend surgery. Two centuries after Hippocrates, bladder stones were broken by open surgery (Ammonius and Alexandre). They were grabbing the stone and breaking it with a sharp-tipped tool (1). It is noteworthy that a catheter and a simple lithotriptor is firstly invented by a patient, Keyvan Bey, and applied on his own, 3 centuries before European had done. Because, Santorius mentioned from such a tool firstly in 1726, and Civiale used it as suggested by Fournier in 1824 (1).

 

Heading #9 (Removal of bladder calculus by surgery)

He explains that if the stone is too big and does not crumble with the applied treatments, there is no other way but, to extract it from bladder. A few surgical curative methods had been briefly described under this heading. He strongly suggests to consider mainly the size of the stone, the length of the stone (caution should be needed during manuplation) and the pain sensitivity of the person during the surgery (1-3).

It has been emphasized that special care should be taken in children under 10 years old, in young people (he stressed that phlegmonous swelling was common in that age group, and drugs used for phlegmonia are contradictory to drugs used for wounds), and people over 60 years of age. His notice about drug interactions is appreciable, and an important experience for that time. He also highlighted the pain stamina during surgery and said that “the more pain the patient has suffered, the greater the strength of pain resistance during surgery”(1-3).

 

Heading #10 (Therapeutic and preventive drugs for kidney and bladder calculi)

The precautions and other drugs had been discussed with details in previous headings. He says that rumex acetosa cooked with wine, seeds of Asparagus officinalis mixed with honey, boiled water of black chickpeas break up the stone into small pieces, while sitting bath of boiled daisies would help to remove the stone. He also mentions from Agropyrum repens, Althaea Officinalis L. to cure stones that the diuretic, antiinfective and antiinflammatory effects of them have been well known beginning from Hippocrates. He suggests the use of Althaea Officinalis L. and Linum Usitatissimum seeds and the extract of pistachio tree as sedatives (1-3).

Besides of herbs, he mentions from a few mines for bladder calculi, such as Hajar al-yahûd stone described as Sons of Israel’s olive (should be crushed and drunk with a little water), and diamond as described by İbn-i Sina (helps the fragmentation of stone in bladder) (1-3).

He suggests to eat full consistency cooked wheat bread (with Nigella sativa seeds), chickpeas, onion, and several meats cooked with almond or olive oils. He recommends to eat some fruits every morning, such as figs, peanuts, red grapes with extracted seeds, sugar cane, sugar cheese, sugar almonds, bitter almonds. He notes that mint, celery, cucumber, chickpea water, pickle/pickle vinegar, melon and water consumed on an empty stomach would be useful for prevention of stones (1-3).

Detailed analysis of these foods (the fruits mentioned above and onion) show that they are rich in potassium, and pickle/pickle vinegar, grape berries are one of the main sources of citric acid, while mint, wheat bread, Linum Usitatissimum, almond, pistacchio, sugar cane all rich in magnesium, that they are important factors in prevention of urinary tract stones.

Interesting ones from his experiences are camel blood for bladder stone, earthworm with wine for kidney stone, meat of a bird like a sparrow with gray color, manure of the pigeon feded with broad beans, scorpion ash, etc. (1-3).

Conclusion

This pamphlet that Ahi Ahmed Çelebi shared his experiences in detail and wrote it in Turkish, has guided the physicians over generations. Every symptom of calculi has been described step by step, with detailed prescriptions including the amount of used material and preparation methods. Although some treatment methods seem to be based entirely on experimental observations, it is noteworthy that detailed observations and experiences about the urinary system stones five hundred years ago resemble current knowledge. One of the most striking part of this pamphlet is; a catheter and a simple lithotriptor is firstly invented by a patient, Keyvan Bey, and used on his own, 3 centuries before European had done.

 

References

  1. Erkun S. Ahî Ahmed (1948) Son of Kemaleddin. A Pamphlet on Urinary Calculus in the Kidneys and the Bladder. İsmail Akgün Matbaası, Istanbul, pp 44-78
  2. Âkil Muhtar (Özden AM) (1916) Hekîm Âhî Çelebi ve Fâ’ide’i Hasât Risâlesi. Dârülfünûn Tıb Fakültesi Mecmûası 2(2-3):110-113; 184-188
  3. Kahya E (1996) Onbeşinci yüzyılda yaşamış hekimlerimizden Hekimbaşı Âhî Çelebi. Erdem 9(25):293-342
  4. Edvardsson V (2016) Urolithiasis in children. In: Avner ED, Niaudet P, Yoshikawa N, Emma F, Goldstein SL (eds) Pediatric Nephrology, Springer-Verlag Berlin Heidelberg, pp 1821-1868
  5. Kieran K, Giel DW, Morris BJ, Wan JY, Tidwell CD, Giem A, et al (2010) Pediatric urolithiasis–does body mass index influence stone presentation and treatment? J Urol 184(4 Suppl):1810–1815. doi:10.1016/j.juro.2010.03.111
  6. Seitz C, Fajkovic H (2013) Epidemiological gender-specific aspects in urolithiasis. World J Urol 31(5):1087-1092. doi: 10.1007/s00345-013-1140-1
  7. Ribeiro da Silva SF, Leite da Silva S, De Francesco Daher E, de Holanda Campos H, Bruno da Silva CA (2010) Composition of kidney stone fragments obtained after extracorporeal shock wave lithotripsy. Clin Chem Lab Med 48(3):403-404. doi:10.1515/CCLM.2010.079

History of the Polish Society of Nephrology

Abstract

Polish Society of Nephrology (PSN) was born during the Founding Congress organized in September 1983 in Bydgoszcz. The main propagator of this idea was prof. Franciszek Kokot (Katowice) – widely recognized in whole nephrological community. In Bydgoszcz the PSN by-laws was approved and first Executive Council of the Society was elected. First PSN president was elected Tadeusz Orłowski (Warszawa) and vicepresident Andrzej Manitius (Gdańsk) respectively. Subsequent Congresses were organizes each three years in following cities: Kraków (1986), Gdańsk (1989), Katowice (1992), Lublin (1995), Poznań (1998), Kraków (2001), Białystok (2004), Wisła (2007), Bydgoszcz (2010), Wrocław (2013) and Łódź (2016). During these meetings and annual conferences organized between congresses actual topics dedicated to pathophysiology, clinical nephrology, dialysis therapy and kidney transplantation were presented and discussed. Prof. Tadeusz Orłowski was the PSN president till 1986 and subsequently other known Polish nephrology leaders hold this function: Kazimierz Bączyk (Poznań: 1986-1989), Franciszek Kokot (Katowice: 1989-1998), Bolesław Rutkowski (Gdańsk: 1998-2004), Michał Myśliwiec (Białystok: 2004-2007), Andrzej Więcek (Katowice: 2007-2010), Jacek Manitius (Bydgoszcz: 2010-2013), Magdalena Durlik (Warszawa: 2013-2016) and Michał Nowicki (Łódź: 2016 – present). Number of PSN members has risen from 150 at the beginning to over 1000 nowadays. During this 34 years regional structure of PSN was established and today 9 regional divisions are actively working. In 2014 Young Nephrologists’ Club was organized in PSN which is collaborating with Young Nephrologists’ Platform existing in the ERA-EDTA structure. PSN is collaborating closely with international (ISN, ERA-EDTA, IAHN) and Polish (Polish Transplantation Society) scientific societies. Many well known scientists from whole the world were recognized as Honorary Members of PSN. Coming to the end of this short presentation of the PSN activity it is worth to mention also that two journals are officially recognized by our society: Nefrologia I Dializoterapia Polska (Polish Nephrology and Dialysis Therapy) edited from 1997 in Kraków and Forum Nefrologiczne (Nephrological Forum) edited from 2004 in Gdańsk.

Keywords: Poland, nephrology, society, history

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Introduction

Polish Society of Nephrology (PSN) was founded during its First Founding Congress organized in September 1983 in Bydgoszcz. At this time two structures connected with nephrology existed in Poland: Nephrological Committee of the Polish Academy of Science chaired by prof. Tadeusz Orłowski (Warsaw) and Nephrological Section of the Polish Society of Internal Medicine chaired by prof. Kazimierz Trznadel (Łódź). The main initiator and propagator of the PSN was prof. Franciszek Kokot (Katowice) who was then member of the European Dialysis and Transplant Association Board (1, 2). One has to remember that it was time when other National Nephrological Societies were founded in whole Europe. Prof. Kokot was supported strongly by the group of other known Polish nephrologists like prof. Kazimierz Bączyk (Poznań), prof. Zenon Szewczyk (Wrocław) and prof. Zygmunt Hanicki (Kraków) and great part of the younger colleagues. All of them worked hard to persuade this idea to other nephrological leaders. In Bydgoszcz last official Conference of the Nephrological Section of Polish Society of Internal Medicine was transformed to the PSN Founding Congress. It is necessary to mention that local organizer of this event was prof. Edmund Nartowicz, Head of Nephrology Department in Bydgoszcz and all necessary documents were prepared by prof. Kazimierz Trznadel (Head of Nephrology Department in Military Hospital in Łódź). During this Founding Congress rules and regulations of the new Society were established and first Executive Council was elected. First PSN president for three years term prof. Tadeusz Orłowski (Figure 1) prominent nephrologist form Warsaw was elected and Vicepresident prof. Andrzej Manitius – Head of Nephrology Department in Gdańsk Medical University (3, 4). Prof. Tadeusz Orłowski was the PSN president till 1986 and subsequently other known Polish nephrology leaders hold this function. Prof. Kazimierz Bączyk from Poznań (Figure 2) was the second and prof. Franciszek Kokot from Katowice (Figure 3) the third PSN president. Whole list of PSN presidents and period of their activity on this position was presented in Table 1, Figure 4, Figure 5 and Figure 6. Subsequent Congresses were organized every three years in following cities: Kraków (1986), Gdańsk (1989), Katowice (1992), Lublin (1995), Poznań (1998), Kraków (2001), Białystok (2004), Wisła (2007), Bydgoszcz (2010), Wrocław (2013) and Łódź (2016). There were also annual scientific and educational conferences organized under the auspices of PSN like:

  1. “Advances in peritoneal dialysis” organized from 1996 in different nephrological centers – prof. B. Rutkowski and currently prof. M. Lichodziejewska-Niemierko (Gdańsk).
  2. “Advances in Nephrology and Hypertension” Polish-German-Czech conferences organized from 1994 by turns in Poland (mainly in Wisła – prof. F. Kokot and Wrocław – prof. M. Klinger), Germany (mainly Gorlitz) and Czech Republic (mainly Liberec).
  3. Post ASN Meetings – Gdańsk Repetitory in Nephrology organized from 2002 by prof. B. Rutkowski
  4. Katowice Seminar – Advances in Nephrology and Hypertension organized from 2001 by prof. A. Więcek
  5. Top Nephrological Trends organized in Poznań currently by prof. A. Oko, earlier from 2002 as Great Poland Spring Nephrological Actualities by prof. S. Czekalski
  6. Nephrocardiology – conference organized from 2005 in Białowieża by prof. M. Myśliwiec (Białystok) and currently by his successor prof. B. Naumnik (Białystok)
  7. Płock Nephrology Days organized between 1995 and 2005 by dr M. Świtalski in Płock
  8. Cracovian Dialysis Days – very special meeting organized on the biennial mode from 1994 until 2014 this meetings which is uniting all parties involved in dialysis – physicians, nurses, technicians, dietitians and patients was organized by prof. O. Smoleński. After his sudden death in 2015 this important meeting is organized by his successors dr A. Smoleńska, mgr M. Liber and prof. J. Pietrzyk.
  9. Nephrological Conference in Włocławek organized from 1992 by doc. J. Ostrowski.

It is worth to mention that also Regional PSN divisions are organizing educational conferences at least 2–3 times during a year. Lectures during all these events were delivered not only by Polish speakers but also very often by eminent nephrologists from Europe and United States. It is worth to mention that many well-known scientists from whole the world were recognized as Honorary Members of PSN. Whole list of foreign PSN Honorary Members is shown in Table 2. One may recognize that among them are also active IAHN members like: G. Richet, S. Massry, G. Eknoyan, R. Ardaillou, A. Heidland and M. Mydlik. There are also twenty six eminent Polish nephrologists who were recognized as PSN Honorary Members (Table 3). Number of PSN members has risen from 150 at the beginning to over 1000 nowadays (Figure 6). During this 34 years regional structure of PSN was established and today 9 regional divisions are actively working. There are also several sections in the PSN central structure eg. historical, rehabilitation in chronic kidney disease, Polish Renal Registry and Polish Registry of Kidney Biopsy. In 2014 Young Nephrologists’ Club was organized in PSN which is collaborating with Young Nephrologists’ Platform existing in the ERA-EDTA structure. PSN is collaborating closely with international (ISN, ERA-EDTA, IAHN) and Polish (Polish Transplantation Society) scientific societies. It is worth to mention that Polish nephrologists played active role in these organizations. Prof. J. Roguski (Poznań) and prof. Stefan Angielski were members of the ISN Board in sixties and seventies. Later on prof. F. Kokot was a member of Nominating Committee and prof. A. Więcek – Head of the section organizing COMGAN CME courses and prof. B. Rutkowski member of the Historical Committee. Even closer is collaboration with ERA-EDTA where several Polish representatives were elected as members of the Council like: prof. T. Orłowski, prof. F. Kokot (3 times), prof. A. Więcek, prof. M. Klinger, prof. J. Małyszko. One have to remember that prof. A. Więcek after accomplishing his second term as Council member was elected as a Secretary-Treasurer and later hold most important position of ERA-EDTA President during last three years (2014-2017). Additionally prof. B. Rutkowski was a member of the Scientific Board of ERA-EDTA Registry and prof. R. Gellert director of the Registry Office. It is worth to mention that three Polish nephrologists were among founders of the International Society of Peritoneal Dialysis: prof. K. Bączyk (Poznań), prof. Z. Twardowski (Lublin), prof. P. Hirszel (Kraków) (4). Currently prof. M. Lichodziejewska-Niemierko is member of the Council in this Society. Very successful EuroPD Meeting was organised in 2015 in Kraków coordinated by prof. W. Sułowicz (Kraków) and prof. Lichodziejewska-Niemierko (Gdańsk). Another scientific collaboration was maintained between PSN and International Society of Uremic Research and Toxicity (ISURT). B. Rutkowski was member of the Council, president elect, president and past president in this Society. He organized also very successful ISURT Congress in Sopot in 2007. Special attention has to be paid to collaboration with the International Association for the History of Nephrology (IAHN). Prof. B. Rutkowski spent in the IAHN Council four terms as member, president elect, president and past president of the Association. Doc. Janusz Ostrowski from Włocławek was Council member, president elect and currently he is holding position of IAHN president. Dr Marek Muszytowski from Toruń was Council member and currently is secretary treasurer. Three IAHN Congresses were organized in Poland: in 2004 in Gdańsk in 2010 in Toruń and in 2016 in Wieniec near Włocławek. All these events were organized in collaboration with PSN.

Coming to the end of this short presentation of the PSN activity it is worth to mention also that two journals are officially recognized by our society: Nefrologia i Dializoterapia Polska (Polish Nephrology and Dialysis Therapy) edited from 1997 in Kraków (Chief editor – prof. W. Sułowicz) and Forum Nefrologiczne (Nephrological Forum) edited from 2004 in Gdańsk (Chief editor – prof. B. Rutkowski).

In summary we like to underline that during almost 35 years of PSN activity our Society help to establish high position of Polish nephrology among European countries both from scientific and practical point of view (5). This fact is the result of hard work of many people mentioned in this article and many other anonymous PSN members. We do hope that young generations of Polish nephrologists will keep this high level and also will remember about their mentors who established and developed PSN.

 

References:

  1. Rutkowski B.: Professor Franciszek Kokot – his contribution in the development of Polish nephrology: Pol Arch Med Wewn 1994, 9: 1 11-13.
  2. Rutkowski B.: Leader and promotor of the of the polish nephrology. In: Franciszek Kokot, Ed. Medical University of Silesia, Main Library, Katowice 1999.
  3. Heidland A., Pączek L. Professor Tadeusz Orłowski – in memory of a pioneer in European Nephrology and Transplantation. Kidney Blood Press. Res. 2009; 32: 304-306.
  4. Ostrowski J., Rutkowski B.: Honorary member of the Polish Society of Nephrology. Part One: Tadeusz Orłowski. Forum Nefrol. 2013; 1: 71-75.
  5. Czekalski S. Kazimierz Bączyk, Poznań, Poland. Nephrol. Dial. Transplant. 1996; 11:1656.
  6. Czekalski S., Rutkowski B. The History of nephrology in Poland. J. Nephrol. 2006; 19 (supl. 10): S150-S158.

The history of renal transplantation in France

Abstract

The history of renal transplantation in France began with 2 surgeons from Lyon, M. Jaboulay and A. Carrel. The latter initiated the proper techniques of vascular suture, performed the first experiments in animals, initially in Lyon, then in Chicago with C. Guthrie and demonstrated that failure in obtaining a prolonged success was due to an immunological rejection of the graft. Trials in humans began in France in the 1950s with transplants from healthy donors. All ended in failure, although in 1953 the conjunction of a donor mother and a previous irradiation of the recipient allowed a survival of 3 weeks in the patient. J. Hamburger in France and J. Murray in the USA tried transplantations in monozygotic twins, then dizygotic ones, which represented the first successes. A decisive jump occurred with the arrival of immunosuppressors (combination of azathioprine and prednisone) which allowed R. Küss to win the first success in recipients that were unrelated to their donors. At the same time, J. Dausset described the Human Leucocyte Antigen (HLA) groups, markers of tissular immunogenicity, thus allowing the most appropriate donors to be selected. To the living donors were added soon the patients in irreversible coma, which made it possible to increase the number of grafts. Despite obstacles and doubts, kidney transplantation developed rapidly and was accepted as the most efficient treatment of chronic renal failure. The role of French and American physicians was decisive in this success.

Keywords: transplantation, kidney, history

The early beginnings

Organ transplantation is an old idea. It is not easy to say with precision where and by whom the first trials were realized. It is reported that Saint Cosmo and Saint Damian grafted a Moorish leg to replace the necrotic leg of a patient, an event that was considered to be a miracle. In the sixteenth century, Gaspare Tagliacozzi successfully performed autografts of the nose but failed in the allografts (1). The eighteenth century saw the development of unsuccessful animal graft experiments. The pioneers of renal transplantation in France were two surgeons in Lyon: Mathieu Jaboulay (1860-1913) and Alexis Carrel (1873-1944). Mathieu Jaboulay implemented on the dog an original process of non-stenosing arterial suture with separate U-shaped points after interposition or not of an arterial fragment (2). He tried in 1906 the xenograft of a pig kidney and then of a goat kidney to the bend of the elbow of two women with renal insufficiency (3). It was a failure, but it showed the feasibility of the technique. Alexis Carrel developed the end-to-end vascular suture techniques that are still widely used in transplantation. This was published in the “Journal de médecine de Lyon” (4, 5). In 1906, he moved to the USA where he worked with Charles Guthrie in Chicago. Both of them realized organ transplantations in animals and published a number of scientific articles where they described the successive improvements of their techniques of vascular anastomoses. They demonstrated for the first time that a vein could be substituted to an artery and reported their experiments of organ transplantations (6, 7). Their main conclusion was that using appropriate techniques of vascular suture, autografts were most of the time successful in animals whereas homografts never were. Alexis Carrel wrote at this time: “From a clinical standpoint, the transplantation of organs may become important and may open new fields in biology and therapy” (8). He was awarded the Nobel prize in 1912 “in recognition of his work on the vascular suture and the transplantation of blood cells and organs”, He accepted in 1908 a position at the Rockfeller Institute in New York where he stayed until 1939. He realized the first fully functional renal self-transplantation on a bitch and was the first to study the chemical composition of the urine from the transplant, to describe the histology of the rejected kidney showing “an important infiltration of small round cells around the vessels and the collecting ducts”, to hypothesize the responsibility of the spleen and the bone marrow in the production of antibodies and to suggest utilization of irradiation to diminish the immune capacity of the leukocytes (6, 9). He concluded that: “an animal which has undergone a double nephrectomy and the grafting of both kidneys from another animal can secrete almost normal urine with his new organs, and live in good health, at least for a few weeks. This demonstrates that it is possible to reestablish efficiently the functions of transplanted kidneys” (9). Alexis Carrel can be considered as the main pioneer of renal transplantation. He was also at the origin of tissue culture. He returned to France in 1939. Unfortunately, the end of his life was clouded by the defense of eugenism in his book “L’Homme, cet inconnu (Man, this unknown)”.

 

Unsuccessful attempts of renal transplantation in man in France (1950-1952)

The first homograft of a human kidney in man was performed by Yuri Voronoy (1895-1961) in 1936 in Kiev (10). He transplanted in the thigh of a uremic patient a kidney from a healthy man who had died in an accident. The transplant did not function and the recipient died 2 days later. Human kidney transplantations started in France in the fifties. From 1950 to 1952 almost ten renal transplantations were performed after removal of a kidney from guillotined criminals immediately after their execution or from patients in whom a kidney had to be removed for therapeutic reasons. Several teams were active: René Küss (Paris), Charles Dubost (Paris), Marcel Servelle (Strasbourg). Early failures occurred in each case, but these trials allowed progress in the surgical technique to be realized. In particular, René Küss described the ideal heterotopic position of the grafted kidney in the iliac fossa with anastomosis of the renal vein to the iliac vein, of the renal artery to the hypogastric artery and of the ureter to the bladder. These unsuccessful trials were published in the “Mémoires de l’Académie de Chirurgie” in 1951 (11-13). These failures did not discourage French surgeons and nephrologists, and in 1952, Jean Hamburger and Louis Michon performed the graft of one kidney of his mother in a young man whose the only kidney had been removed after a fall from a ladder. For the first time a survival of 3 weeks was observed (14). This intervention was widely reported by the media and had a worldwide impact. It showed that the main problem to be solved remained the immunological rejection of the graft as written by the authors: “After the 17th day of the transplant, no complication disturbed evolution; but the satisfaction that was derived from this observation was followed by the most intense anxiety six days later due to the sudden arrest of the transplanted kidney”. The challenge did not seem achievable at that time as evidenced by this 1955 citation of David Hume: “In the present state of our knowledge, renal homotransplatation does not seem to be justified in the treatment of human diseases” (15). There were two approaches to address this difficult issue: to find a donor the most genetically related to the recipient, to treat the recipient so as to attenuate and, if possible, control the reject of the graft.

 

The first successes

The three main pioneers of successful renal transplantation in France were a nephrologist, Jean Hamburger, an urologist, René Küss and an immunologist, Jean Dausset. They addressed the main problem still unresolved that was the immunological rejection of the graft.

 

Jean Hamburger (1909-1992), after having been the assistant of Louis Pasteur Vallery-Radot at Broussais Hospital, created the first department of nephrology in France at Necker Hospital in Paris (Figure 1). His main collaborators were Gabriel Richet, Jean Crosnier and Jean-Louis Funck-Brentano. He was the first president of the International Society of Nephrology and chaired the first International Congress of Nephrology (Evian and Geneva, 1960). In addition to his scientific achievements, he was a writer and published several books on the human fate, in particular “La Puissance et la fragilité: Essai sur les métamorphoses de la médecine et de l’homme (Power and fragility: An essay on the metamorphoses of medicine and man)”. His achievements in the progress of renal transplantation are numerous and were inspired by his conviction that “The great destiny of man is to refuse his destiny”. He succeeded in diminishing the immune rejection with total body irradiation of the recipient and matching the HLA characteristics of the donor and of the recipient. As mentioned above, he was the first to realize a transplant from a mother to her son with a survival of 3 weeks and was the second (5 months after Joseph Murray) to obtain a successful transplant between dizygotic twins genetically different (rejection of a skin graft from the donor by the recipient, dissimilar blood groups) after sub-lethal irradiation and isolation in a sterile room (16). The recipient died 26 years later from a bladder carcinoma. This was followed by a successful transplant from a cousin that was rejected 18 years later, which necessitated a second transplant. The recipient was still living 32 years after the first transplant. In 1964, he transplanted a cadaver kidney in a patient who lived more than 25 years. He also demonstrated the successful treatment of acute rejection (15 days after surgery) with prednisone. In 1965, Jean Hamburger drew conclusions from the review of his first 45 transplantations (17). He found that 29 of them were in a satisfactory condition after 6 months with a normal blood pressure and a mean glomerular filtration rate of 73 ml/min. Cellular infiltration was visible in all renal biopsy specimens, but tended to diminish later. Glomerular lesions and progressive interstitial fibrosis were observed more rarely. In late crises, even if biopsy specimens showed gross oedema and cellular infiltration, a satisfactory reversal could be obtained. As a whole, one could be optimistic on the future of renal transplantation.

 

René Küss (1913-2006) was head of the department of urology in “La Pitié” Hospital in Paris (Figure 2). His main collaborator was Marcel Legrain, head of the department of nephrology in the same hospital. Their purpose was to realize successful transplantation between unrelated persons. The results obtained by Joseph Murray and Jean Hamburger in dizygotic twins left a persistent doubt about the possible role of an induction of this tolerance by an exchange of cells during the intra-uterine life. The answer to this question was given by René Küss and Marcel Legrain who realized in 1960 at Foch Hospital, for the first time, three successful renal grafts outside of gemellarity, once between brother and sister and twice without any kinship. These successes were due to the efficacy of the conditioning with an immunosuppressive treatment including 6-mercaptopurine and prednisone (18). The grafts functioned for 5, 17 and 18 months, respectively, and were followed by other successful grafts between unrelated donors and recipients (19). Therefore, total body irradiation was no longer needed. René Küss was awarded the Medawar Prize in 2002 for his contribution to kidney transplantation. This prize was simultaneously attributed to Georges Mathé who was the first to realize bone marrow transplantations and participated in the first successful attempts by René Küss.

 

Jean Dausset (1916-2009) was head of the department of hemato-immunology at St Louis Hospital in Paris (Figure 3). He was appointed later professor at the “Collège de France”, which represents the highest distinction for researchers working in all fields of knowledge. He was the first to describe the HLA system of leucocyte and tissue groups which enables the selection of donors, in a series of publications between 1952 and 1963 (20, 21). His main collaborator was Jean Colombani. He was awarded the Nobel prize in 1980 for the discovery of the HLA groups. He created «France transplant»  in 1970 allowing the rapid transfer of a kidney from a donor with a compatible HLA group. Before him, Peter Medawar in UK had performed a series of skin homografts in rabbits in 1944. If he recognized the immunological nature of the rejections, he limited his observations to histological morphology (22). However, some years later, he inoculated intrauterine fetuses with spleen cells of a donor mouse to induce chimerism, which resulted in the acceptance of grafts of the donor by the chimeric mice. Therefore, he could conclude that homograft rejection was not obligatory. This discovery earned Peter Medawar the Nobel prize in 1966 (22).

Progresses in renal transplantation have also to be attributed in France to other researchers than Jean Hamburger, René Küss and Jean Dausset and the teams working with them. In 1959, Pierre Mollaret and Maurice Goulon defined a new entity, the irreversible coma, (“le coma dépassé”) in patients without any cerebral activity who were maintained in artificial survival by artificial breathing and whose hearts were still beating. Kidneys were removed from these patients after agreement of their family and successfully transplanted with results similar to those obtained with transplantations from related donors. Their studies were at the origin of a new stage in renal transplantation allowing their number to be greatly increased (23). To diminish the immune reaction was also the preoccupation of French teams. Jules Traeger and Jean Perrin proposed lymphocyte depletion by cannulation of the thoracic duct. The collected lymphocytes were utilized to prepare an anti-lymphocyte serum which found a place next to the couple azathioprine – prednisone (24). This treatment was quickly abandoned because of its side effects. It is the precursor of the use of monoclonal antibodies.

 

What did occur simultaneously in USA?

In parallel with the studies carried out in France, the United States were actively participating in this race towards the development of effective and well-tolerated renal transplants. In 1950, Richard Lawler (1896-1982) working in Chicago performed an intra-abdominal cadaveric renal transplant in a patient with polycystic renal disease after removal of one of his kidneys that functioned for 53 days (25). David Hume (1917-1973) working in Boston realized nine kidney transplantations between 1951 and 1953. The donors were patients who had died after surgery. Except in one case, the grafted kidneys were placed in the thigh and the ureter brought to the skin. Four kidneys only functioned, briefly for three of them, but for almost 6 months for the latter (26).The first real success was obtained in 1954 by Joseph Murray (1917-2012) with a graft between monozygotic twins. The recipient died 25 years later (27). This was followed in 1959 by 2 successful grafts between dizygotic twins after radiotherapy that were performed in collaboration with John Merrill (1917-1984) (28), but grafts between unrelated persons were rejected (29). Success was soon obtained by conditioning the recipient with azathioprine. Using this drug alone allowed Joseph Murray to win a first long-term success in 1962 (30). Chemical immunosuppression, then used by the different teams, too happy to abandon irradiation, contributed greatly to the development of renal transplantation. One year later, Thoma Starzl exhibited previously unmatched results relating the efficacy of azathioprine and cortisone (31).

 

Conclusion

In spite of all these progresses, everybody was not convinced of the future of renal transplantation at that time, even the most famous immunologists. Frank Macfarlane Burnett (Australia) was awarded the Nobel prize in 1960 for his works on immune tolerance and clonal selection. In a review entitled “The new approach to immunology” he wrote: “Much thought has been given to ways by which tissues or organs not genetically and antigenically identical with the patient might to be made to survive and function in the alien environment. On the whole, the present outlook is highly unfavorable to success…” (32). For this reason, we must be particularly grateful to the French and American medical doctors who persisted despite their failures in pursuing their quest for a successful renal transplant. The best conclusion is given by Thomas Starzl, who wrote in 1990: “These events and subsequent ones could not have transpired in the way they did without French pioneers, Hamburger the physician and Küss the surgeon, and their friends in Boston whose vision was greater than that given to most men and women. Workers in the two cities founded a clinical discipline where none existed before and then persisted despite allegations of folly or worse. The French successes with kidney transplantation over the three-year period from 1959 through early 1962 kept the flames alive when all other efforts were failing” (33).

 

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