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BACKGROUND: Kidney transplantation is the preferred standard of care for patients who have both end stage renal disease (ESRD) and human immunodeficiency virus (HIV) infection. The first successful kidney transplant was done in 1954 and the first case of HIV/AIDS occurred in 1981. Until recently, HIV-positive patients who required an organ transplant received an HIV-negative organ because it was illegal to use HIV-positive organs in transplants in the United States. The HIV Organ Policy Equity (HOPE) Act was signed in 2013 and legalized the use of HIV-positive donor organs in organ transplants. The first of these transplants was completed in March 2016 with good results. LITERATURE REVIEW: Renal transplants have lower mortality than dialysis. HIV damages the kidney in multiple ways, including HIV associated nephropathy and HIV immune complex kidney disease, putting HIV patients at higher risk of ESRD. Studies from before the utilization of anti-retroviral therapy show that transplantation of HIV infected blood or organs do not cause failure of the transplanted organ. However, in 1997 most surgeons would not transplant kidneys to HIV-infected individuals. Success of antiretroviral therapy has allowed HIV patients to live longer, but patients experience complications including end organ damage. Providing transplants to ESRD patients with HIV infection has been preferred treatment since 2010. Due to improvements in both HIV and transplant science, transplant specialists today are likely to accept HIV-positive organs to HIV-positive transplant recipients. PROPOSED PROJECT: The proposed study is a survey of United States transplant professionals to determine their perceptions about these transplants. Researchers will collect data in the form of Likert scales as well as open-ended responses. The survey will also collect demographic information about surveyors. Investigators will then analyze the collected data for professional knowledge of the legal change, perceptions of efficacy and safety, and concerns. Researchers will analyze the data both as a whole and divided by demographic subgroups. CONCLUSIONS: To date, there has been no study that has assessed at the attitudes of the medical community involved in these transplants. This study is unique in that it attempts to obtain the perceptions and concerns the transplant specialists have about HIV-positive donor organs to HIV-positive transplant recipients. SIGNIFICANCE: The data from this study will help to establish what opinions are at this time, to determine if there are any regional discrepancies that may affect patient access to care, and to determine the concerns of transplant specialists at this time.

Kidney transplantation is the gold standard treatment for end-stage renal disease. Renal ischemia-reperfusion injury is an unavoidable consequence of the transplantation procedure and is responsible for delayed graft function and poorer long-term outcomes. Pharmacological inhibition of heat shock protein 90 is a preconditioning strategy that has previously been shown to reduce renal ischemia-reperfusion injury. However, the clinical application of heat shock protein 90 inhibitors is limited by their toxicity profile and the exact mechanisms of protection conferred are unknown. The aims of this thesis were to establish mechanisms of protection offered by these drugs and investigate a less toxic analogue that has the potential to be safely translated into human studies. AT13387 is a novel small molecule heat shock protein 90 inhibitor with a low toxicity profile, which is being evaluated in phase II studies in oncology and therefore has excellent translational potential in the context of transplantation. Heat shock protein 90 inhibition up-regulates protective heat shock proteins (especially heat shock protein 70) and potentially down-regulates NF-ҡB activity by disruption of the IҡB kinase complex. Toll-like receptor 4 is a further regulator of NF-ҡB activity and studies have suggested that Toll-like receptor 4 plays a dominant role in mediating kidney damage following ischemia-reperfusion injury. To explore potential molecular mechanisms of protection, human embryonic kidney cells were pre-treated with AT13387 and exposed to endotoxin-free hyaluronan to stimulate sterile Toll-like receptor 4-specific NF-ҡB activation. AT13387-treatment resulted in breakdown of IҡB kinase, which abolished Toll-like receptor 4-mediated NF-ҡB activation by hyaluronan. Inhibition of autophagy prevented IҡB kinase-α degradation by heat shock protein 90 inhibition and resulted in regain of NF-ҡB activity by hyaluronan. In subsequent investigations, AT13387 decreased pro-inflammatory cytokine release following hyaluronan stimulation and increased cell viability in an in vitro model of oxidative stress. In mice, AT13387 induced heat shock protein 70 expression in the kidney. AT13387 pre-treatment then significantly reduced kidney injury following renal ischemia-reperfusion injury. In contrast, in severe combined immunodeficient mice, AT13387 no longer reduced kidney injury from renal ischemia-reperfusion injury. This emphasises the potential importance of the adaptive immune system in the protective effect of this agent. This resonates with reports of heat shock protein 70 up-regulation in the context of heat preconditioning, which leads to renal protection from renal ischemia-reperfusion injury that is lymphocyte-dependent. Secondary lung injury is an additional consequence of renal ischemia-reperfusion injury. In further experiments, pre-treatment with AT13387 again did not reduce kidney injury following renal ischemia-reperfusion injury in severe combined immunodeficient mice. However, AT13387 did reduce secondary lung injury. This lung protective effect may have been related to heat shock protein 70 up-regulation in the lungs by AT13387. A rationale for enhancing recovery, following renal ischemia-reperfusion injury, by inhibiting heat shock protein 90 was then sought. This investigation was undertaken in order to broaden the range of the available therapies to a wider group of patients including renal transplant recipients. AT13387 pre-treatment of the recipient mice preceded an isograft renal transplantation with a kidney harvested from a treatment naive mouse and cold stored for 4 hours. Although a significant reduction in tubular necrosis was not demonstrated following AT13387 treatment, the feasibility of the treatment strategy was demonstrated and interestingly lung injury secondary to transplantation was reduced. This thesis therefore highlights AT13387 as a new agent with the potential of reducing kidney injury and secondary lung injury following renal ischemia-reperfusion injury. The findings also demonstrate that the mechanisms of protection offered by this drug may involve the adaptive immune system. In addition to the induction of heat shock protein 70 expression in the kidney and repression of Toll-like receptor 4-mediated NF-ҡB signalling through breakdown of IҡB kinase.

Class of 2015 Abstract / Objectives: Assess the impact of hydralazine in contributing to the risk of heart transplant rejection. Our primary working hypothesis is that patients who have undergone heart transplantation and have taken hydralazine have an increased risk of transplant rejection and ultimately have worse outcomes. Methods: A retrospective cohort study on data extracted from a patient’s medical chart at a local hospital. Data was collected using a paper data extraction form consisting of gender, race, age, panel reactive antibody scores, co-morbidities, white blood cell count, type of immunosuppression therapy and any other medications. The proportion of patients with rejections will then be compared and analyzed using a chi square test. Results: This study obtained 340 patient cases that involved heart transplantation. From the 340 patients that were extracted, 42 of them were recorded as having taken hydralazine. Of the 42 patients, 7 had stopped hydralazine before transplantation. The mean +/- S.D. age of the 35 patients analyzed was 54 +/- 20.5 years, and 69% were men. Approximately 14% of the 42 patients were found to have had a heart transplant rejection. Conclusions: Heart transplant patients at this institution who received hydralazine post surgery were on it about an average of 21 months. Most patients were placed on ACE inhibitors. ACE inhibitors have a theoretical benefit of immunosuppression, and this therapy is usually pursued in transplant patients. Further research must be done to determine the clinical significance of hydralazine use in heart transplant rejection.

Lungs donated after cardiac death (DCD) are an underutilized resource for a dwindling donor lung transplant pool. Our study investigates the potential of a novel preservation solution, Somah, to better preserve statically stored DCD lungs, for an extended time period, when compared to low-potassium dextran solution (LPD). We hypothesize that Somah is a metabolically superior organ preservation solution for hypothermic statically stored porcine DCD lungs, possibly improving lung transplant outcomes. Porcine DCD lungs (n = 3 per group) were flushed with and submerged in cold preservation solution. The lungs were stored up to 12 h, and samples were taken from lung tissue and the preservation medium throughout. Metabolomic and redox potential were analyzed using high performance liquid chromatography, mass spectrometry, and RedoxSYS (R), comparing substrate and pathway utilization in both preservation solutions. Glutathione reduction was seen in Somah but not in LPD during preservation. Carnitine, carnosine, and n-acetylcarnosine levels were elevated in the Somah medium compared with LPD throughout. Biopsies of Somah exposed lungs demonstrated similar trends after 2 h, up to 12 h. Adenosine gradually decreased in Somah medium over 12 h, but not in LPD. An inversely proportional increase in inosine was found in Somah. Higher oxidative stress levels were measured in LPD. Our study suggests suboptimal metabolic preservation in lungs stored in LPD. LPD had poor antioxidant potential, cytoprotection, and an insufficient redox potential. These findings may have immediate clinical implications for human organs; however, further investigation is needed to evaluate DCD lung preservation in Somah as a viable option for transplant.

The immune response is a major barrier to the successful transplantation of organs and tissues required in the treatment of many human diseases. Although the field of tissue engineering was created to address the shortage of human organs and tissues, the immune response remains a substantial challenge, impeding the development of allogeneic biological substitutes to repair, replace and regenerate tissues. Specifically, the T cell mediated immune response initiated through the recognition of cell surface Major histocompatibility complex Class I (MHCI) molecules is the primary cause of acute allograft rejection. In nature, viruses have evolved many mechanisms to exploit weaknesses of the T cell response to evade detection. Viral mechanisms to modulate the MHCI molecule can be effectively applied to allogeneic cells in a tissue-engineered construct to evade detection by CD8+ Cytotoxic T Lympocytes (CTLs) and Natural Killer (NK) cells of the immune system. We demonstrate the successful application of a retroviral vector to over-express the Kaposi's sarcoma-associated herpesvirus (KSHV) immunomodulatory protein, MIR2, in human monocyte-like leukemia cells to differentially downregulate cell surface MHCI, ICAM-1 and B7-2 molecules. We also developed a novel flow cytometry-based cytotoxicity assay to demonstrate that this differential downregulation of immunoactive molecules has the functional effect of significantly reducing CTL-mediated cytotoxicity, without altering NK-mediated cytotoxicity. We believe that this approach provides a potential solution to circumvent the acute immune rejection of allografts in vivo, and can also lead to the development of "universal" donor cells for tissue engineering applications that will not require anti-rejection drugs. / Thesis / Master of Applied Science (MASc)

This qualitative study examines the experiences of patients who have undergone renal transplant surgery. Interviews were conducted with six patient informants who received renal transplants one to six months prior to the study. Participants’ narratives offered insight into: the variability of transplant preparation, hopes, experiences, and perspectives of recovery, meanings of recovery, significance of social and economic supports in recovery, and the role of professional staff in providing support and resources during the transplant journey. Their stories are explored in relation to literature on psychosocial aspects of renal transplant and through a critical disability studies lens. The nuances of the social work role in relation to patients’ pre- and post-operative renal transplant journey was explored in depth. Based on the findings and relevant literature, recommendations and suggestions are made on how to expand the social work role in the pre- and post-transplant clinic at St. Joseph’s Healthcare Hamilton. / Thesis / Master of Social Work (MSW)

Background Research on the optimal management of deceased organ donors poses unique challenges including the fact that one deceased donor may provide up to 8 organs for transplantation. Measuring the post-transplant function of these organs – good or bad – represents an attractive way of deciding whether treatment of deceased donors is working well, or not so well. Function, however, is organ-specific. Therefore, to conduct the most efficient and informative research on deceased donor management, we need an outcome measure that works well in all organs. The new outcome measure is called Generic Rating of Allograft Function post-Transplantation (GRAFT). Methods In this thesis, I highlight the methods for developing the cardiac-specific version of the GRAFT instrument. The same methods, however, have and will be applied to other organ-specific versions. The work comprised various study designs and developed novel research tools, all of which have advanced the development of the GRAFT instrument. At first, we developed a simple conceptualization for the instrument. Through regular consultation with research methodologists, biostatisticians and clinical experts, we refined the fundamental conceptualization and then refined the generic instrument, itself. One key concept is that GRAFT ratings should correlate with one-year graft function. To maximize its utility, I developed a heart--specific guide for applying GRAFT in future studies, and other organ-specific guides are underway. Specifically, we developed these guides by identifying the most robust predictors of one-year graft function through the conduct of organ-specific systematic reviews and meta-analyses of prognostic factors. The evidence from these reviews, in consultation with a focus group of organ-specific transplant physicians, lead to refinements of our guides. We subsequently conducted a mixed-methods user testing to assess reliability and usability of the organ-specific guides. In appraising the evidence informing the guides, we developed GRADE guidance and a novel absolute risk calculator to assess our certainty in the body of evidence on prognostic factors informing our guides. Results We developed a 6-point generic rating instrument for classification of graft function to be applied post-transplant across all major solid organs. We designed GRAFT to be applied at the time of discharge, 1-month post-transplant, or at the time of death (whichever occurs first). We classify function as 1) normal, 2A) impaired but likely to gain normal function, 2B) impaired and unlikely to gain normal function, 3A) severely impaired but likely to gain some function, 3B) severely impaired and unlikely to gain some function, and 4) irreversible graft failure. Clinical expert collaborators for each organ type confirmed face validity of the GRAFT instrument. For all organs, we identified a number of prognostic factors that can guide users in classifying organ function post-transplant. In consultation with clinical experts, we determined that the most important factor is graft function as measured by left ventricular ejection fraction (LVEF) or right atrial pressure (RAP). Due to limitations with the quality and quantity of the evidence, however, the heart transplant experts did not rely on the results of their organ group’s systematic review. In turn, we conducted a retrospective cohort study to calculate the best estimate of association between LVEF, RAP, and overall mortality post heart transplant. For the cardiac version of GRAFT, user testing demonstrated high reliability (Kappa of 0.87, 95% CI 0.62 – 1.00) and acceptable usability (system usability score of 75, inter-quartile range of 72.5 – 80). In the process, we developed and published GRADE guidance for assessing certainty in the body of evidence addressing prognostic factors and devised a calculator to transform relative effect of each prognostic factor to absolute risks (http://hiru.mcmaster.ca/AbsoluteRiskCalculator/). Conclusion In this thesis, I advanced the development of an innovative generic instrument for the classification of graft function specifically for the purpose of application in clinical trials of deceased donor interventions. This work is ongoing, but very advanced for heart-specific components, for which I have ensured face validity, and demonstrated reliability and usability. The GRAFT instrument may better facilitate the conduct of future research to improve care of deceased organ donors with a view to improving quality and quantity of organs for transplantation. / Thesis / Candidate in Philosophy

The purpose of this study was to evaluate liver transplant recipient factors associated with postoperative complications leading to longer intensive care unit (ICU) length of stay which in turn may increase hospital morbidity and mortality. A retrospective, correlational design was developed with a sample of 230 participants. Data were collected for liver transplant recipients over a four-year period (June 2007-December 2011) from the electronic medical record and the transplant database. T test and binary logistic regression were used to assess for the factors predictive of ICU complications, ICU length of stay (LOS), hospital length of stay (HLOS), and overall morbidity and mortality. Data were collected from three time periods: preoperatively, intraoperatively, and postoperatively. The factors identified as statistically significant were cold ischemic time, lowest intraoperative glucose, postoperative four-hour blood urea nitrogen (BUN), Postoperative Day 1 (POD 1) hematocrit, postoperative lowest systolic blood pressure, and fresh frozen plasma (FFP) transfusions. Mortality occurred in 1 recipient in the >9-day ICU stay group, and 7 deaths were noted in the >19-day hospital LOS group. Age of recipients who died was 48-59 (6 males, 2 females), with 7 Caucasian and 1 Other. Comorbidities of these deceased recipients were diabetes and obesity with MELD scores of 18-45. Complications experienced by recipients included: 6 with renal failure, 2 with sepsis, 3 with graft dysfunction, and 1 with cerebral edema. Findings from this study showed factors that impact ICU LOS, HLOS, and mortality, including BUN, glucose, and hematocrit. Implications for practice are that these factors should be closely monitored in the pre-, intra-, and postoperative time periods to reduce risks of complications to transplant recipients. Future research should include further evaluation of the factors associated with poor transplant outcomes, including glucose, continuous renal replacement therapy (CRRT) use, age, and gender. Nurse researchers must continue to strive to understand the pathophysiological mechanism of liver disease to reduce ICU complications ultimately to improve the care and outcomes of liver transplant recipients while reducing ICU LOS and HLOS.