Matthew J. Weiss

Mechanisms of chronic rejection in cardiothoracic transplantation.

Despite significant improvements in early post-transplantation survival rates, long-term patient and graft survival have remained poor, due in large part to the vexing problem of chronic allograft rejection. Attempts to combat this problem with intensification of immunosuppression have led to concomitant increases in the rates of fatal malignancies and infections. In cardiac transplantation, chronic rejection is manifested primarily by a disease entity known as cardiac allograft vasculopathy, an occlusive narrowing of the coronary vessels. In lung transplantation, chronic rejection is typified by obliterative bronchiolitis, an airflow limiting narrowing of the bronchioles. From an immunologic standpoint, chronic rejection is believed to be the end result of repeated immune and non-immune insults to the graft. This review examines the pathophysiology of heart and lung chronic, with emphasis on both immune and non-immune causes.

Repetitive Gastric Aspiration Leads to Augmented Indirect Allorecognition after Lung Transplantation in Miniature Swine

Introduction. Lung transplant recipients with documented gastroesophageal reflux disease (GERD) are at increased risk for graft dysfunction. Here, we present the first large-animal model of gastric aspiration after allogeneic lung transplantation and some preliminary data demonstrating the effect of chronic aspiration on the direct and indirect pathways of allorecognition. Methods. Left orthotopic lung transplants (n=3) were performed in miniature swine across a major histocompatibility complex class I disparity, followed by 12 days of high-dose cyclosporine A. At the time of transplantation, a transtracheal catheter was placed at the carina, above the bronchial anastomosis. A gastrostomy tube was placed for daily aspiration of gastric contents. Subsequently, graft lungs were instilled with gastric aspirate daily (3 mL/hr×8 hr/day) for 50 days. Recipients were followed up with daily complete blood count, scheduled chest radiographs, and biopsies. In vitro studies, including cell-mediated lympholysis, mixed lymphocyte reactions, and peptide proliferation assays, were performed. Results from these three recipients were compared with those of historical controls (n=6) who were treated identically, except for the tracheal cannulation and simulated gastric aspiration. Results. Two of the experimental animals were euthanized with nonviable lungs soon after the postoperative day 50 biopsy. In both cases the native lung was normal. The third animal survived over 180 days without the evidence of chronic rejection. After immunosuppressive treatment, all animals demonstrated donor-specific hyporesponsiveness by assays of direct alloresponse (cell-mediated lympholysis, mixed lymphocyte reaction). A significant response to synthetic donor-derived class I peptide, however, was seen in all animals. A more pronounced and diffuse response was seen in the animals rejecting their grafts. The historical controls showed medium-term graft survival with evidence of chronic rejection in the majority of animals, as previously reported. Conclusion. In a model of GERD after lung transplantation, a spectrum of clinical outcomes was observed. The in vitro data suggest that acid reflux enhances the indirect alloresponse to processed donor class I antigen, giving mechanistic insight into the manner in which GERD may be deleterious to the transplanted lung.

The Indirect Alloresponse Impairs the Induction but not Maintenance of Tolerance to MHC Class I-Disparate Allografts

We studied the effects of indirect allorecognition on the induction and maintenance phases of tolerance in miniature swine cotransplanted with heart and kidney allografts. MHC class I‐mismatched heart and kidney grafts were cotransplanted in recipients receiving CyA for 12 days. Recipients were unimmunized or immunized with a set of donor‐derived or control third‐party MHC class I peptides either 21 days prior to transplantation or over 100 days after transplantation. T‐cell proliferation, delayed type hypersensitivity reaction (DTH) and antibody production were assessed. All animals injected with donor MHC class I peptides developed potent indirect alloresponses specific to the immunizing peptides. While untreated recipients developed stable tolerance, all animals preimmunized with donor allopeptides rejected kidney–heart transplants acutely. In contrast, when peptide immunization was delayed until over 100 days after kidney–heart transplantation, no effects were observed on graft function or in vitro measures of alloimmunity. Donor peptide immunization prevented tolerance when administered to recipients pre transplantation but did not abrogate tolerance when administered to long‐term survivors post transplantation. This suggests that the presence of T cells activated via indirect allorecognition represent a barrier to the induction but not the maintenance of tolerance.

Response to Vileito et al. Literature review on Paediatric Deceased Donation Guidelines

We were pleased to read the recent literature review by Vileito and colleagues on the need for more well-developed protocols in the field of paediatric deceased organ donation (1). The authors highlighted the general lack of rigorous, trustworthy guidelines in this domain. Considering the infrequent nature of paediatric organ donors and the significant impact that each donation event can have, it is critical for health care teams to have clear guidance during these medically and emotionally demanding situations. This article is protected by copyright. All rights reserved.

Effect of the Diabetic State on Islet Engraftment and Function in a Large Animal Model of Islet–Kidney Transplantation

In islet transplantation, in addition to immunologic and ischemic factors, the diabetic/hyperglycemic state of the recipient has been proposed, although not yet validated, as a possible cause of islet toxicity, contributing to islet loss during the engraftment period. Using a miniature swine model of islet transplantation, we have now assessed the effect of a persistent state of hyperglycemia on islet engraftment and subsequent function. An islet–kidney (IK) model previously described by our laboratory was utilized. Three experimental donor animals underwent total pancreatectomy and autologous islet transplantation underneath the renal capsule to prepare an IK at a load of ≤1,000 islet equivalents (IE)/kg donor weight, leading to a chronic diabetic state during the engraftment period (fasting blood glucose >250 mg/dL). Three control donor animals underwent partial pancreatectomy (sufficient to maintain normoglycemia during islet engraftment period) and IK preparation. As in vivo functional readout for islet engraftment, the IKs were transplanted across an immunologic minor or class I mismatch barrier into diabetic, nephrectomized recipients at an islet load of ∼4,500 IE/kg recipient weight. A 12-d course of cyclosporine was administered for tolerance induction. All experimental donors became diabetic and showed signs of end organ injury, while control donors maintained normoglycemia. All recipients of IK from both experimental and control donors achieved glycemic control over long-term follow-up, with reversal of diabetic nephropathy and with similar glucose tolerance tests. In this preclinical, large animal model, neither islet engraftment nor subsequent long-term islet function after transplantation appear to be affected by the diabetic state.

Pediatric donation after circulatory determination of death (pDCD): A narrative review

Pediatric donation after circulatory death (pDCD) is an established pathway for organ donation. It remains, however, a relatively rare event worldwide, and most clinicians outside of the pediatric intensive care unit (PICU) are unfamiliar with it. The goal of this review is to introduce the processes and concepts of pDCD. While most children die in circumstances that would not allow pDCD, many children that die after withdrawal of life sustaining therapy (WLST) may be eligible for donation of some organs. The potential benefits of this practice to patients on the wait list are well known, but donation can also be an opportunity to honor a patients or familys desire to altruistically improve the lives of others. Offering the possibility of donation requires careful attention to ethical principles to ensure that conflicts of interest are avoided and that the family is free to make an independent, fully informed decision. Doing so allows families and decision makers the autonomy to decide if donation is something they wish to incorporate into end-of-life care.

GRADEing the un-GRADE-able: a description of challenges in applying GRADE methods to the ethical and implementation questions of pediatric organ donation guidelines

Good practice statements (GPSs) have been proposed by the GRADE working group as a way of avoiding the inappropriate characterization of evidence as low quality in support of strong recommendations justified by indirect evidence. This commentary examines how the GPS methodology was applied to the development of a recent guideline for pediatric deceased donation after circulatory determined death. This guideline was informed by a broad body of indirect literature and addressed a variety of social, legal, and ethical questions in addition to several implementation issues. While the resulting document contained a vast majority of GPS (63 as opposed to seven actionable GRADEd recommendations), we maintain that this application was appropriate to develop recommendations within the GRADE framework. This commentary explores how GPS may be applied in this context and explores whether a new classification of recommendations focused on these types of issues may be appropriate.

Development of Canadian National Guidelines for Pediatric Donation After Circulatory Determined Death (pDCD)

Introduction/Hypothesis pDCD uptake has been slow in Canada, where most pediatric hospitals do not have active programs and pDCD represents only 8% of pediatric deceased donation. This project generated national, pediatric specific clinical practice guidelines (CPGs) to inform the development of ethical and effective pDCD practice. Methods We followed a process of CPG development based on World Health Organization (WHO) and Canadian Medical Association (CMA) methods. These included application of the Appraisal of Guidelines, Research and Evaluation (AGREE II) tool, and Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology. Questions requiring recommendations were generated based on: 1) 2006 Canadian DCD guidelines (not pediatric specific), 2) a multidisciplinary symposium of national and international pDCD leaders, and 3) a scoping review of the pDCD literature (1). Input from these sources drove drafting of actionable questions and Good Practice Statements (GPSs), as defined by the GRADE group. We performed additional literature reviews for all actionable questions. Evidence was assessed for quality using GRADE, and then formulated into evidence profiles that informed recommendations through the Evidence-to-Decision framework. Recommendations were revised through consensus among the members of 7 topic specific working groups (WGs), and finalized during meetings of WG leads and the planning committee. External review was provided by pediatric, critical care, and critical care nursing professional societies as well as patient partners. Results 65 GPS recommendations and 7 GRADEd recommendations covering: 1) Ethics, Consent and Withdrawal of Life Sustaining Therapy (WLST) 2) Eligibility 3) WLST Practices 4) Ante and Post Mortem Interventions 5) Death Determination 6) Neonatal pDCD 7) Cardiac and Innovative pDCD 8) Implementation. Conclusions This process showed that rigorous, evidence based CPGs are possible in the domain of pediatric deceased donation. We hope that these CPGs will increase access to pDCD across Canada and serve as a model for international CPG development in deceased donation. Reference: 1. Weiss MJ, Hornby L, Witteman W, Shemie SD. Pediatric Donation After Circulatory Determination of Death. Pediatr Crit Care Med. 2016 Mar;17(3):e88–108.