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Title: Novel strategies to help overcome immunological and anatomical barriers in complex transplantation
Author: Chandak, Pankaj
ISNI:       0000 0004 9357 5187
Awarding Body: King's College London
Current Institution: King's College London (University of London)
Date of Award: 2020
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Patients may present with immunological and anatomical barriers to receiving a transplant. For example, a child may have complex vascular abnormalities making implantation feasibility uncertain and may also have an incompatible living donor as the only option for transplantation. Indeed, there are also increasing numbers of renal transplant patients requiring re-transplantation and an increasing number of patients with antibodies (both HLA and blood group ABO) against their donor. Despite current paradigms in systemic antibody removal to facilitate antibody incompatible transplantation, these patients are often at increased risk of developing severe graft rejection associated with much morbidity and even death due to antibody incompatibility. The work here, presented as a thesis incorporating published research papers, aims to address some of the challenges in this high-risk patient group from both an anatomical and immunological perspective. The two key aims that form the framework for this work include: 1) Can ex-vivo normothermic machine perfusion (EVNP) be used to establish a translational human model of antibody mediated rejection? Developing such a model could enable the testing of localised cytoprotective agents that target the kidney endothelium against the effects of antibody; hence offering a novel strategic approach in antibody incompatible transplantation that focuses on the organ. 2) Can feasibility of organ implantation in the presence of anatomical uncertainty be predicted preoperatively, especially in paediatric recipients (where we are implanting adult sized kidneys into small children)? Can we safely transplant small children? In addressing the first aim, I have established EVNP from the outset in our unit and defined implementation and learning pathways and achieved competency in the perfusion technique (Chapter 2). Following on from this, I have adapted the machine perfusion clinical protocol to develop a reproducible phenotype in an experimental ex-vivo normothermic perfusion human model of antibody mediated rejection using HLA and ABO antibodies and fresh frozen plasma (Chapter 3). In addressing the second aim, I analysed a retrospectively collected database of 453 paediatric recipients undergoing kidney transplantation over a 12-year period and showed comparable outcomes with respect to graft and patient outcomes in those children weighing < 20kg compared to > 20kg at the time of transplant. Following on from this, I undertook a study detailing unconventional surgical approaches in those children with complex vasculature and further developed a novel classification system of vascular abnormalities that could be used clinically (Chapter 4). Chapter 5 details the first reported use and value of novel 3d printing technology to as a clinical tool to help facilitate implantation and overcome complex anatomical issues such as locating anastomosis sites on abnormal vessels and implanting adult sized kidneys into small children. In summary, the experimental EVNP work in this thesis has formed a platform to further investigate the use of localised therapeutic agents in AMR that could be translated into clinical practice and lend into human trials, promoting access to transplantation in high-risk immunological recipients. In addition, I have shown that transplantation in small children <20kg is safe and feasible and non-conventional surgical techniques may be required with a multi-disciplinary team approach. Furthermore, to aid this process, the use of preoperative 3D printing is of value in select cases. The work in this thesis has been awarded The Royal Society of Medicine Norman Tanner Medal and The Cutler’s Clarke Medal. I have delivered invited lectures internationally and presented at The Royal Society,The Royal Institution, The Academy of Medical Sciences, Parliament, Women’s Institute and The Science Museum in London.
Supervisor: Dorling, Anthony ; Callaghan, Christopher ; Mamode, Nizam Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available