Diagnosis and treatment of autoimmune hemolytic anemia in adults: Recommendations from the First International Consensus Meeting

Abstract Autoimmune hemolytic anemias (AIHAs) are rare and heterogeneous disorders characterized by the destruction of red blood cells through warm or cold antibodies. There is currently no licensed treatment for AIHA. Due to the paucity of clinical trials, recommendations on diagnosis and therapy have often been based on expert opinions and some national guidelines. Here we report the recommendations of the First International Consensus Group, who met with the aim to review currently available data and to provide standardized diagnostic criteria and therapeutic approaches as well as an overview of novel therapies. Exact diagnostic workup is important because symptoms, course of disease, and therapeutic management relate to the type of antibody involved. Monospecific direct antiglobulin test is considered mandatory in the diagnostic workup, and any causes of secondary AIHA have to be diagnosed. Corticosteroids remain first-line therapy for warm-AIHA, while the addition of rituximab should be considered early in severe cases and if no prompt response to steroids is achieved. Rituximab with or without bendamustine should be used in the first line for patients with cold agglutinin disease requiring therapy. We identified a need to establish an international AIHA network. Future recommendations should be based on prospective clinical trials whenever possible

Transplanting Organ Donors with Printers: The Legal and Ethical Implications of Manufacturing Organs

Three-dimensional (3D) printing is no longer restricted to simple inanimate objects; that conjecture is a thing of the past. With advancements in many areas of science, living tissues and organs can now be printed through a technique called 3D bioprinting. This technology could potentially save the lives of the 120,000 Americans in need of an organ transplant. However, whether or not a 3D bioprinted organ qualifies as a “human organ” under the National Organ Transplant Act (NOTA) and whether 3D bioprinted organs require federal approval could either delay or completely bar this technology’s promise. The Ninth Circuit’s Flynn v. Holder and Richards v. Holder and the federal approval requirement for lab-grown organs bolster the interpretation that a manufactured organ would be a “human organ.” The ethical ramifications of 3D bioprinting might also detract from the benefits it promises to offer. If and until the federal government approves it, private creation and selling of 3D bioprinted organs would exacerbate organ selling on the black market. With increasing progressive ventures in medicine, it may be an appropriate time for Congress to amend NOTA

The Tin Man Needs a Heart: A Proposed Framework for the Regulation of Bioprinted Organs

Each day, seventeen people die in the United States while waiting for an organ transplant. At least part of this need could be met by bioprinting, a technology that allows the on-demand production of custom-sized organs from a patient’s own cells. The field of bioprinting is progressing rapidly: the first bioprinted organs have already entered the clinic. Yet, developers of bioprinted organs face significant uncertainty as to how their potentially lifesaving products will be regulated—and by which government agency. Such regulatory uncertainty has the potential to decrease investment and stifle innovation in this promising technological field. This Note examines how the current framework for the regulation of medical products and human organs might be applied to bioprinted organs. This Note concludes that the existing regulatory schemes do not sufficiently address the specific regulatory needs created by bioprinted organs, which are uniquely interdisciplinary materials. Therefore, this Note proposes a new regulatory framework to reduce uncertainty for bioprinted organ developers and to promote patient access to these bioprinted materials that might soon serve as safe and effective replacements for donor organs

Selective Antibody Removal from Blood, Plasma, and Buffer Using Hollow Fiber-Based Specific Antibody Filters

Therapeutic antibody removal is performed to facilitate ABO-incompatible kidney transplants and heart and kidney xenotransplants, and to treat Goodpasture syndrome, myasthenia gravis, hemophilia with inhibitors, and thrombocytopenic purpura. Antibody removal is achieved non-selectively, via plasma exchange, or semi-selectively, via plasma perfusion through immunoadsorption columns containing immobilized protein A. We are developing hollow fiber-based specific antibody filters (SAFs) that selectively remove antibodies of a given specificity directly from whole blood, without separation of the plasma and cellular blood components and with minimal removal of plasma proteins other than the targeted antibodies. The working unit of the SAF is a hollow fiber dialysis membrane with antigens, specific for targeted antibodies, immobilized on the inner fiber wall. Several thousand SAF fibers are connected in parallel to produce a filter similar in construction to a hollow fiber hemodialyzer. A principal goal of our research is to identify the primary mechanisms that control antibody transport within the SAF, and to use this information to guide the choice of design and operational parameters that maximize the SAF-based antibody removal rate. We approached this goal by formulating a simple mathematical model of SAF-based antibody removal and performing in vitro antibody removal experiments to test key predictions of the model. Our model revealed three antibody transport regimes, defined by the magnitude of the Damköhler number Da (antibody-binding rate/antibody diffusion rate): reaction-limited (Da ≤ 0.1), intermediate (0.1 < Da < 10), and diffusion-limited (Da ≥ 10). For a given SAF geometry, blood flow rate, and antibody diffusivity, the highest antibody removal rate was predicted for diffusion-limited antibody transport. We performed in vitro antibody removal experiments in which SAFs containing immobilized bovine albumin (BSA) were used to remove anti-BSA antibodies from buffer. The measured anti-BSA removal rates were consistent with antibody transport in the intermediate regime. We concluded that initial SAF development work should focus on achieving diffusion-limited antibody transport by maximizing the SAF antibody-binding capacity. If diffusion-limited antibody transport is achieved, the antibody removal rate can be raised further by increasing the number and length of the SAF fibers and by increasing the blood flow rate through the SAF

New Advances in Kidney Transplantation

This Special Issue in renal transplantation covers a variety of clinical and research areas in kidney transplantation. The recent decade is associated with an ongoing shortage of organs for transplantation with efforts to increase the organ pool with DCDs and extended criteria donors. However, with the increasing success rate of kidney transplants, there is also a growth in the candidate list because of removal of the age barrier and transplantation of high risk patients with other comorbidities. The future seems promising with the development of innovative non-invasive technologies introducing biomarkers for diagnosis of rejection and ischemic reperfusion injury, use of cell therapy for tolerance induction, development of artificial organs, and overcoming immune and non-immune barriers in xenotransplantation. This Special Issue will touch some of these topics that are in the frontiers of the modern era of kidney transplantation

Expert statement on the ICU management of patients with thrombotic thrombocytopenic purpura

Thrombotic thrombocytopenic purpura (TTP) is fatal in 90% of patients if left untreated and must be diagnosed early to optimize patient outcomes. However, the very low incidence of TTP is an obstacle to the development of evidence-based clinical practice recommendations, and the very wide variability in survival rates across centers may be partly ascribable to differences in management strategies due to insufficient guidance. We therefore developed an expert statement to provide trustworthy guidance about the management of critically ill patients with TTP. As strong evidence was difficult to find in the literature, consensus building among experts could not be reported for most of the items. This expert statement is timely given the recent advances in the treatment of TTP, such as the use of rituximab and of the recently licensed drug caplacizumab, whose benefits will be maximized if the other components of the management strategy follow a standardized pattern. Finally, unanswered questions are identified as topics of future research on TTP