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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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

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

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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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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

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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).

 

References

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