Race, Kidney Transplants, Immunosuppression Research, and White Supremacy under Apartheid, 1960-80.

This paper uses the history of kidney transplantation in South Africa as a lens through which to write a racialized, micro history that illustrates the politics of medical discoveries and medical research at one of South Africa's most prestigious medical research universities, the University of the Witwatersrand (Wits) in Johannesburg. Between 1966 and the 1980s, the Wits team became the most advanced and prolific kidney transplant unit in the country. Yet the racist, oppressive Apartheid system fundamentally shaped these developments. Transplantation, as this paper shows, became an elite medical procedure, performed by a select group of white doctors on mostly white patients. For these doctors, transplantation showed their medical prowess and displayed the technical advancements they were able to make in research and clinical practice as they strove to position South Africa as a significant international player in medical research, despite academic boycotts and increasing sanctions. Transplantation became a symbol of white supremacy in a country where the black majority were excluded from anything but the most basic health care.

The Untold Story of the First Hand Transplant: Dedicated to the Memory of one of the Great Minds of the Ecuadorian Medical Community and the World.

BACKGROUND: In 1964, faced with the challenge of traumatic amputation, a team of surgeons at Clinica Guayaquil was convinced that the transplantation of a hand could significantly improve function and quality of life for the recipient. With a current but basic understanding of immunosuppression, the surgeons identified a recipient and waited for the correct donor. A human hand transplant had never been performed to date. METHODS: The surgeons' criteria for the recipient included a young healthy individual who had sustained a traumatic amputation at the distal forearm level with full motion of the proximal joints. Communication with receiving hospitals and military facilities identified what they perceived to be a feasible donor for an allograft transplantation. Consent was obtained from the family in conjunction with the local military medical authorities and the clergy. Iced saline solution and Heparin irrigation were to be used to prepare the donor extremity. The immunosuppression regimen, limited at the time, consisted only of intravenous cortisone, Imuran, and a single dose of radiation. RESULTS: A member of the Ecuadorian marine sustained a limited blast injury that amputated his dominant hand but spared the forearm. He was transferred to the emergency department of Clinica Guayaquil. A donor who had recently died in a nearby hospital was identified not long after. A successful technical surgical transplantation was achieved. Consultants from major hospitals around the world (including Peter Bent Brigham Hospital) convened at the patient's bedside to observe the results. Despite all efforts, the patient suffered an irreversible rejection at 21 days post-transplant. CONCLUSION: This was the first allograft transplantation of a hand. The surgeons embarked on an intervention never tried before, firmly believing that better function and quality of life would result. The bravery of this surgical team was commendable. This early surgical endeavor opened the way for future successes in transplant surgery today.

Treating MS without continuous immunosuppression: an interview with Luciano Rossetti.

Luciano Rossetti, MD, Executive Vice President, Global Head of R&D at Merck KGaA, Darmstadt, Germany speaks to Laura Dormer, Commissioning Editor Luciano Rossetti, MD, is Executive Vice President, Global Head of R&D at Merck KGaA, Darmstadt, Germany, and a member of the Healthcare Executive Committee. As Global Head of R&D, Rossetti leads the strategy for Merck KGaA, Darmstadt, Germany's discovery and development efforts in healthcare. He joined Merck KGaA in July 2014, and has since led the acceleration of several key programs through the pipeline and advanced the innovation of Merck KGaA's discovery teams into development. Under his leadership, R&D has been transformed, with significant potential to deliver the scientific, clinical, regulatory and medical excellence of its teams to patients in need. Before joining Merck KGaA, he served as Senior Vice President, responsible for Global Scientific Strategy and Late Stage Development at Merck Sharp & Dohme, or MSD. In the latter position, he was responsible for clinical development from Phase II to V across all therapeutic areas. Prior to joining MSD in 2006, he spent 18 years in academia during which he had considerable involvement with the pharmaceutical industry in both discovery and development. In his latest assignment, he was Professor of Medicine and led the Diabetes Research & Training Center at the Albert Einstein College of Medicine. He has authored more than 150 peer-reviewed scientific journal articles. He is a Post-Doctoral Fellow of Rome University Medical School and of Yale University Medical School. He holds a Doctorate in Medicine from the Trieste University Medical School, Italy.

Liver and Kidney Transplantation: A Half-Century Historical Perspective.

This article describes the evolution of solid organ kidney and liver transplantation and expounds on the challenges and successes that the early transplant researchers and clinicians encountered. The article highlights the surgical pioneers, delves into the milestones of enhanced immunosuppression protocols, discusses key federal legislative and policy changes, and expounds on the ongoing disparities of organ supply and demand and the need for extended criteria and live donor organs to combat these shortages. Finally, recent changes in organ allocation and distribution policies are discussed. The authors also spotlight novel interventions that will further revolutionize abdominal transplantation in the next 50 years.

How the creative use of analogies can shape medical practice.

Analogical reasoning is central to medical progress, and is either creative or conservative. According to Hofmann et al., conservative analogy relates concepts from old technology to new technologies with emphasis on preservation of comprehension and conduct. Creative analogy however brings new understanding to new technology, brings similarities existing in the source domain to a target domain where they previously had no bearing, and imports something entirely different from the content of the analogy itself. I defend the claim that while conservative analogies are useful by virtue of being comfortable to use from familiarity and experience, and are more easily accepted by society, they only lead to incremental advances in medicine. However, creative analogies are more exciting and productive because they generate previously unexpected associations across widely separated domains, emphasize relations over physical similarities, and structure over superficiality. I use kidney transplantation and anti-rejection medication development as an exemplar of analogical reasoning used to improve medical practice. Anti-rejection medication has not helped highly sensitized patients because of their propensity to rejecting most organs. I outline how conservative analogical reasoning led to anti-rejection medication development, but creative analogical reasoning helped highly sensitized and blood type incompatible patients through domino transplants, by which they obtain a kidney to which they are not sensitized. Creative analogical reasoning is more likely than conservative analogical reasoning to lead to revolutionary progress. While these analogies overlap and creative analogies eventually become conservative, progress is best facilitated by combining conservative and creative analogical reasoning.

Historical perspectives in kidney transplantation: an updated review.

The present state of success in kidney transplantation, including its benefits to patients with end-stage renal failure, was achieved through relentless research, both in experimental animal models and human volunteers. Kidney transplantation has evolved during the past century thanks to various milestones in surgical techniques, immunology, immunosuppressive drugs, expansion of donor sources, organ preservation, transplant against immunological barriers (ABO blood group-incompatible and positive crossmatch transplants), and research on induction of tolerance, xenotransplants, and stem cell technology. Despite significant improvements in graft and patient survival, several issues still must be addressed to reduce the growing number of patients with kidney failure waiting to receive organs. This article provides an up-to-date review of the milestones in the history of kidney transplantation and highlights strategies to resolve current problems faced by patients and the transplant community.

An Overview of Transplant Immunosuppression--History, Principles, and Current Practices in Kidney Transplantation.

From the historical first transplant in 1954 to the current transplant era, tremendous strides have been made in transplant immunology and immunosuppression. The most common immunosuppressive regimens use a combination of agents with differing modes of action to maximize efficacy and minimize the toxicities associated with each class of agent. The general categories of immunosuppressives are glucocorticoids, antimetabolites, calcineurin inhibitors, anti-lymphocyte antibody therapies (monoclonal and polyclonal), costimulation blockers, and mTOR inhibitors. This article reviews immunosuppressant medications, their actions, and significant side effects; discusses clinical management issues of immunosuppression; and describes future directions for the development of immunosuppressive medications.

Historical overview of transplantation.

Except for legends and claims of miracles, most histories of transplantation cover only the last 60 years because there were no earlier successes. However, the story of even this era has been documented in such rich detail that a full account would fill several volumes. Thus, this brief summary must be limited to highly selected "landmarks." Some landmarks had an immediate impact, but the importance of others went unrecognized for decades. Some findings that deserved landmark status were overlooked or forgotten, whereas others of no biological significance had major impact. Placing these events in perspective is challenging. Several of transplantation's pioneers are still alive, and most of the others are within living memory. Virtually all of them have produced their own accounts. For the most part, they agree on what the "landmarks" are, but their differences in emphasis and perspective make an interesting story.

Ischemia-reperfusion injury in vascularized composite allotransplantation.

Vascularized composite allotransplantation may now be considered a viable treatment option in patients with complex craniofacial and limb defects. However, the field is still in its infancy, and challenges continue to exist. These challenges, most notably the adverse effects of lifelong immunosuppression, must be weighed against the benefits of the procedure. Improvements in this risk-benefit ratio can be achieved by achieving tolerance and preventing rejection. Five decades after Dr. Joseph E. Murray introduced the field of transplantation to the world, we now have a better understanding of the immunologic factors that may contribute to rejection and inhibit tolerance. In this article, we review emerging evidence that suggests that "danger signals" associated with ischemia-reperfusion injury contribute to innate immune activation, promoting rejection, and inhibiting tolerance. Based on this understanding, we also describe several strategies that may ameliorate the damaging effects of ischemia-reperfusion and the clinical implications of ischemia-reperfusion on the vascularized composite tissue allotransplantation outcome.

Organ transplantation: historical perspective and current practice.

Over the course of the last century, organ transplantation has overcome major technical limitations to become the success it is today. The breakthroughs include developing techniques for vascular anastomoses, managing the immune response (initially by avoiding it with the use of identical twins and subsequently controlling it with chemical immunosuppressants), and devising preservation solutions that enable prolonged periods of ex vivo storage while preserving function. One challenge that has remained from the outset is to overcome the shortage of suitable donor organs. The results of organ transplantation continue to improve, both as a consequence of the above innovations and the improvements in peri- and postoperative management. This review describes some of the achievements and challenges of organ transplantation.

Immunosuppressive therapies in the management of immune-mediated marrow failures in adults: where we stand and where we are going.

Immunosuppression is a key treatment strategy for aplastic anaemia (AA) and the related immune-mediated bone marrow failure syndromes (BMFS). For the last 20 years the standard immunosuppressive regimen for AA patients has been anti-thymocyte globulin (ATG) plus ciclosporin A (CyA), which results in response rates ranging between 50% and 70%, and even higher overall survival. However, primary and secondary failures after immunosuppressive therapy remain frequent, and to date all attempts aiming to overcome this problem have been unfruitful. This article reviews the state of the art of current immunosuppressive therapies for AA, focusing on open questions linked to standard immunosuppressive treatment, and on experimental immunosuppressive strategies which could lead to future improvement of current treatments. Specific immunosuppressive strategies employed for other BMFS, such as lineage-restricted marrow failures, myelodysplastic syndromes and large granular lymphocyte leukaemia-associated cytopenias, are also briefly discussed.