• David Hartell

Announcing the results of the 2017 CNTRP Research Innovation Grant Competition


The Canadian National Transplant Research Program (CNTRP), in partnership with Astellas Canada, the Alberta Transplant Innovation Fund (ATIF), and the University Health Network in Toronto (UHN) are pleased to share the results of the 2017 CNTRP Research Innovations Grant Competition. We received 32 applications to this competition and are excited about integrating the following 11 new funded studies into the project and core structure of the CNTRP (full lay abstracts listed at the end).

“These eleven projects are important new components of the CNTRP and will have a significant impact on donor families, as well as on solid organ and stem cell transplant patients,” says Dr. Lori West, Director of the CNTRP and Director of the Alberta Transplant Institute. “This important investment in new peer reviewed grant funding from our partners into the CNTRP ($330,000) will allow these investigators to integrate their research into the CNTRP structure, enabling them to leverage the full resources of the network to increase access to donation and improve outcomes for transplant recipients. We are very grateful for the ongoing support from Astellas and UHN Multi Organ Transplant Program, in addition to the Alberta Transplant Innovation Fund, which receives funding from Astellas, the University Hospital Foundation and Alberta Economic Development and Trade. We would also like to thank and acknowledge the hard work of the CNTRP New Initiatives Committee and all our volunteer Peer Reviewers for participating in the CNTRP review process and for upholding an excellent level of professionalism and quality.”

The CNTRP, along with our partners, will launch new grant competitions in 2018. Please visit www.cntrp.ca often for new information on upcoming grant competitions.

The recipients of the 2017 CNTRP Astellas Research Innovation Grants are:

Dr Sunita Mathur

University of Toronto, Toronto, ON

Study Title: Exploring user-centred design features for e-health applications to support physical activity behaviors in solid organ transplant recipients

New CNTRP study within Project 7

Dr Marie-Josée Hébert

Université de Montréal, Montréal, QC

Study Title: Shedding light on Apoptotic exosome like vesicles induced by photopheresis in treatment of chronic graft-versus-host-disease.

New CNTRP study within Project 3 and 4

Dr Gonzalo Sapisochin

University Health Network, Toronto, ON

Study Title: Relationship between 18F-Fluorodeoxyglucose positron emission tomography/magnetic resonance imaging patterns and circulating tumor DNA to predict hepatocellular carcinoma recurrence after liver transplantation

New CNTRP study within Project 7

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Dr Sonny Dhanani

University of Ottawa, Ottawa, ON

Study Title: Exploration of the impact of donor hemodynamics during donation after circulatory determination of death on patient and graft outcomes in kidney recipients

New CNTRP study within Project 2 and 7

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Dr Alp Sener

London Health Sciences Centre, London, ON

Study Title: The effect of a mitochondria targeting H2S donor molecules in euthermic (21°C) organ preservation using existing organ preservation solutions.

New CNTRP study within Project 1

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Dr Kevin Wen

University of Alberta, Edmonton, AB

Study Title: Phased implementation for feasibility and evaluation of an adherence monitoring, feedback, and individualized intervention system for improving immunosuppression medication adherence in kidney transplant recipients

New CNTRP study within Project 6 and 7

The recipients of the 2017 CNTRP Alberta Transplant Innovation Fund Research Innovation Grant are:

Dr Puneeta Tandon

University of Alberta, Edmonton, AB

Study Title: A personalized online pre-habilitation program to improve health outcomes in patients awaiting liver transplantation

New CNTRP study within Project 7

Dr Benjamin Adam

University of Alberta, Edmonton, AB

Study Title: The molecular phenotype of polyomarivus nephropathy and its distinction from T-cell mediated rejection

New CNTRP study within Project 5

Dr Steven Greenway

University of Calgary, Calgary, AB

Study Title: Mechanism of microbiome-mediated gastrointestinal toxicity of mycophenolate mofetil

New CNTRP study within Project 7

Dr Aldo Montano-Loza

University of Alberta, Edmonton, AB

Study Title: A prospective, longitudinal evaluation of skeletal muscle for prognosis of patients with cirrhosis evaluated for liver transplantation

New CNTRP study within Project 7

The recipient of the 2017 CNTRP UHN Research Innovation Grant is:

Dr Tereza Martinu

University Health Network, Toronto, ON

Study Title: Targeting the renin-angiotensin system to monitor and treat fibrosis in chronic lung allograft dysfunction

New CNTRP study within Project 3 and Core 2

LAY ABSTRACTS

Dr Sunita Mathur

University of Toronto, Toronto, ON

Study Title: Exploring user-centred design features for e-health applications to support physical activity behaviors in solid organ transplant recipients

New CNTRP study within Project 7

Abstract :

Low physical activity levels are common among solid organ transplant (SOT) recipients. However, there are many beneficial effects of leading a physically active lifestyle for these individuals, including improvements in cardiovascular risk factors (blood pressure, blood glucose), improved aerobic fitness and quality of life. Despite these benefits, SOT recipients face several barriers to engaging in physical activity. Leading a physically active lifestyle requires strategies to support and engage individuals in behavior change. Electronic-health (e-health) tools, such as web-based platforms and mobile health applications (“apps”), offer a large potential to support behavior change and may be effective in engaging SOT recipients in adopting and maintaining a physically active lifestyle. The objective of this study is to identify and prioritize the core features of an e-health tool that will address adoption and maintenance of healthy physical activity behavior among SOT recipients. We propose to use a “usercentred design” approach to the development of the e-health tool for physical activity. This approach directly involves the end-users of the technology in the design and development of the product, and leads to an end-product that has greater acceptability and satisfaction for the end-user. We will conduct a qualitative study to determine the core features and design qualities that are most appealing to SOT recipients for an e-health tool to support physical activity. We will conduct semi-structured interviews of SOT recipients, their caregivers and healthcare professionals that counsel SOT recipients on exercise and physical activity. Directed content analysis will be used to determine the key themes emerging from the interviews, and these will be coded based on the theoretical domains framework for behavior change. The results of the qualitative study will inform the next phase of work, which is to develop a prototype e-health tool for testing in the field and further refinement from user feedback. Future studies will include larger scale efficacy and effectiveness studies for the e-health tool.

Dr Marie-Josée Hébert

Université de Montréal, Montréal, QC

Study Title: Shedding light on Apoptotic exosome like vesicles induced by photopheresis in treatment of chronic graft-versus-host-disease.

New CNTRP study within Project 3 and 4

Abstract :

Graft-versus-Host Disease (GVHD) develops in almost 50% of the patients in the first year following hematopoietic stem cell (HSC) transplantation. The disease involves an immune response from donor-derived T cells to host intra- and extracellular proteins and leads in severe cases to scleroderma-like skin disease with crippling contractures and ulcers, or severe pulmonary failure. The exact mechanism underlying GVHD initiation and breaking of tolerance that occurs in only a fraction of the patients is not clear. Apoptosis is classically considered an anti-inflammatory and tolerogenic type of cell death. This idea has recently been revisited with the discovery of a novel type of membrane vesicle called the apoptotic exosome-like vesicle (ApoExo), which is released through a caspase-3–dependent pathway, but is strikingly different from apoptotic bodies in size, ultrastructure, and enzymatic activity. ApoExo are characterized by the presence of an active 20S proteasome, which plays a key role in triggering autoantibody production (such as anti-Perlecan/LG3 and antidsDNA) and acceleration of GVHD development in mouse. Based on these data, we hypothesize that ApoExo might play a role in the development of GVHD and propose to analyse plasma from patients with GVHD for the presence of ApoExo and autoantibodies. Within the CNTRP a clinical trial is ongoing to test a photodynamic therapy (PDT), using the rhodamine derivate TH9402, in the treatment of chronic GVHD. The photopheresis of autologous peripheral blood mononuclear cell (PBMC) induces apoptosis of the causal alloreactive T cells that have a higher propensity to retain the TH9402, while sparing regulatory T cells. Treatment consists of infusion with apoptotic and live PBMCs, but not all patients are responding. The question arises whether ApoExo are produced by PDT-treated PBMC that may neutralize the anti-inflammatory response. Here, we aim to investigate the vesicles released by the PDT-PBMC and monitor the peripheral presence of ApoExo and anti-LG3 antibodies.

Dr Gonzalo Sapisochin

University Health Network, Toronto, ON

Study Title: Relationship between 18F-Fluorodeoxyglucose positron emission tomography/magnetic resonance imaging patterns and circulating tumor DNA to predict hepatocellular carcinoma recurrence after liver transplantation

New CNTRP study within Project 7

Abstract :

One of the greatest challenges in the field of liver transplantation (LT) for hepatocellular carcinoma (HCC) is to identify each patients’ tumor biological behavior. It is well known that HCC is a very complex disease with highly heterogeneous degree of cell differentiation. It is also well known that tumoral differentiation is one of the most important risk factors for HCC recurrence after LT. To date, there is no accurate, non-invasive method to assess tumor differentiation and to predict HCC recurrence. In these regards, there is growing knowledge concerning the use of 18F-Fluorodeoxyglucose Positron Emission Tomography/Magnetic Resonance (18F-FDG PET/MRI) which may be able to identify more aggressive HCC.1Liquid biopsy is becoming a key method in personalized medicine in the cancer field. Circulating DNA (ctDNA) measurements is thought to be a promising tool to predict outcomes in patients with cancer. Our group is conducting a CIHR-funded study to assess the relationship between ctDNA, genomic features of liver cancer and HCC recurrence in liver transplant recipients. The main goal is to move away from the classic “size and number” selection criteria to include patients with HCC in the waiting list and to instead apply genomic methods to predict tumor biology. As a correlative investigation, in this pilot study, we propose to investigate the role of 18F-FDG PET/MRI in predicting HCC biological behavior in liver transplant recipients. We will study whether the findings in the 18F-FDG PET/MRI are associated with level of ctDNA in plasma and/or to pathological findings and genomic features of HCC in the explanted liver. Furthermore, we will determine the role of 18F-FDG PET/MRI in predicting HCC recurrence after liver transplantation. Consented patients with HCC listed for LT at the University Health Network will have a 18F-FDG PET/MRI ~90 days before the LT. The day of the 18F-FDG PET/MRI blood will be also collected for ctDNA detection. Blood samples will be also collected the day of the transplant and the serial blood samples will be tested after the transplant for detection of ctDNA. Tumoral patterns on the 18F-FDG PET/MRI will be assessed by radiology and nuclear medicine experts to determine each tumors’ characteristics. The 18F-FDG PET/MRI patterns will be correlated to the presence of ctDNA. 18F-FDG PET/MRI is a novel and promising imaging tool. We hypothesize that the hybrid imaging features of HCC before liver transplantation on 18F-FDG PET/MRI will correlate with the presence of ctDNA, the pathological findings at the explant pathology and with a genomic signature in the tumors on the explanted livers. This study will be the first to correlate this novel non-invasive imaging technique with genomic features of liver cancer.

Dr Sonny Dhanani

University of Ottawa, Ottawa, ON

Study Title: Exploration of the impact of donor hemodynamics during donation after circulatory determination of death on patient and graft outcomes in kidney recipients

New CNTRP study within Project 2 and 7

Abstract :

In Canada, deceased organ donation traditionally occurred only after an individual was determined to have no neurologic function. Over the last 10 years, expansion in the practice of organ donation after circulatory determination of death (DCD) has occurred. Further improvement of the practice of DCD will increase access to donation for Canadians, resulting in more and better organs for those who desperately need them. One of the barriers to DCD is the concern from medical staff that organs donated by this method are of poorer quality. This study aims to begin to address this barrier. Identifying the right donor organ for the right recipient will help to realize the full potential of DCD to provide the maximum number of high quality organs, with excellent recipient outcomes. To do this, we will use information already collected from another ongoing study on how we die (DePPaRT, www.ddepict.com) to see if the way a potential organ donor dies (i.e. the pattern of change of key vital signs such as heart rate, blood pressure, and breathing) after withdrawal of life sustaining therapy (WLST) has an impact on transplant outcomes (i.e. survival, number of medical complications, failure of the transplanted organ, etc..). We will work with Trillium Gift of Life, the Ontario organ donation organization, to create a process to link the data we collected from DePPaRT DCD donors to data from the recipients who received their kidneys. This new process of linking data from donors to their recipients will allow us to investigate whether specific hemodynamic patterns exhibited by DCD donors during the dying process impact how well the organs function after transplantation. The process that we will develop for linking of organ donor and transplant recipient information will be indispensible for other researchers investigating how to improve transplant outcomes. The ultimate goal is to make organ donation by DCD available for all those who want access to it andtransplantation of organs obtained from this practice safer for recipients.

Dr Alp Sener

London Health Sciences Centre, London, ON

Study Title: The effect of a mitochondria targeting H2S donor molecules in euthermic (21°C) organ preservation using existing organ preservation solutions.

New CNTRP study within Project 1

Abstract :

Organ preservation solutions have not been modified since their inception >50 years ago but, the organs they are preserving have become increasingly more damaged (ex: DCD) as we push the limits of organ donation to accommodate the rising number of patients being added to the growing transplant waiting list. Modification of these solutions with H2S donor molecules such as AP39 (as proposed in the current grant) may be a simple, inexpensive and non-toxic therapeutic strategy to modulate IRI in donor organs to ultimately improve transplant patient and graft outcomes. Although not the main focus of this proposal, its findings and the model it employs will be crucial in spring boarding patient specific and patient centered therapies in organ transplantation. For example, we have previously demonstrated that the H2S to organ preservation solutions activates various cellular regenerative and reparative pathways1. This important characteristic of H2S, in addition to its tissue preservation properties, will be of significant interest to the future of tissue and organ preservation, as it may enable us to evaluate potentially “unsuitable” grafts in an ex vivo setting (prior to transplantation) whereby genetic therapies could be further applied to the graft to make them more “suitable” for the recipient prior to transplantation. In fact, several lines of evidence suggest that siRNA and shRNA work best at room temperature, therefore, the H2S in the preservation solution at that point may allow for longer preservation times and enable more efficient protein manipulation. The results of the proposed study will be the first in a series of steps to determine efficacy and safety for the use of AP39 (or its derivatives) in future clinical trials and has the potential to make a significant impact to the growing field of “normothermic” organ preservation.

Dr Kevin Wen

University of Alberta, Edmonton, AB

Study Title: Phased implementation for feasibility and evaluation of an adherence monitoring, feedback, and individualized intervention system for improving immunosuppression medication adherence in kidney transplant recipients

New CNTRP study within Project 6 and 7

Abstract :

Poor adherence to immunosuppressive medications may be the single most important factor limiting long-term allograft survival in transplantation. Development of effective interventions to improve adherence has been identified as a priority by the transplant community. Both adherence intervention literature and Dr. Foster’s TAKE-IT clinical trial demonstrated that adherence monitoring, feedback, and personalized intervention is effective in improving immunosuppression adherence in kidney transplant recipients. We plan to implement a pragmatic program of adherence monitoring, feedback, and individualized intervention, by taking advantage of the ability to use pharmacy refill auditing to measure adherence at the University of Alberta Kidney Transplant Program. This project is modeled after the successful TAKE-IT trial to evaluate the feasibility and effectiveness of the real world translation of this efficacious intervention in improving immunosuppression adherence.

The immunosuppression adherence of kidney transplant recipients will be monitored via prescription auditing. Each recipient will receive feedback on his/her adherence, and will work with healthcare providers to identify individual barriers to adherence and collaboratively come up with a personalized action plan. This method of individualized care is consistent with personalized medicine.

Dr Puneeta Tandon

University of Alberta, Edmonton, AB

Study Title: A personalized online pre-habilitation program to improve health outcomes in patients awaiting liver transplantation

New CNTRP study within Project 7

Abstract :

Solid organ transplant is a costly albeit life-saving therapy made possible by continuous improvements in surgical techniques, medications, and matching of suitable donor organs with recipients. Prehabilitation (pre-hab) is a long-standing practice in cardiac and lung transplant associated with improved patient health outcomes; emerging data indicates it is also beneficial in other pre-transplant populations.

We propose PHiT, a personalized home-based interactive therapy comprised of exercise and nutrition education and programming. Study patients on the liver transplant wait list will be assessed at baseline regarding their muscle mass, endurance, strength, and physical frailty. A personalized activity program will be developed by a certified personal trainer supervised by Alberta Transplant Institute Physiotherapist, Ms J Holman and NAIT rehabilitation specialist Dr K Riess. At the randomization visit, the trainer will demonstrate and watch the patient complete the exercises. During weekly Skype based

video interfaces, the trainer can modify the exercise program based upon patient feedback and step counter measures. Our website will host exercise demonstration videos and educational material on both exercise and nutrition. The trainer will refer the patient to a physician if alarm signals are mentioned. All patients will receive nutrition counselling as standard of care. As part of the study, each will receive a hard copy and online access to the “Nutrition in Cirrhosis Guide” developed by our program to support liver-friendly nutrition and prevent sarcopenia. All patients will receive monthly virtual interactions with the Registered Dietitian outside of usual care to reinforce liver-friendly nutrition, answer questions, and provide support as needed.

Physical deconditioning is a major issue in liver transplant populations, with a significant impact on pre- and post-transplant outcomes. Only one liver transplant program across Canada currently offers structured pre-hab to wait-listed patients. A virtual and yet personalized and interactive platform such as PHiT is an innovative, easy-to-use solution to this care gap, combining the benefits of home-based and supervised programs. We forsee that this novel intervention will have the capacity to increase the accessibility and availability of programming to all wait-list participants, irrespective of their distance from the facility and provide evidence that a trainer can safely supervise multiple patients from a distance. We anticipate improvements in physical condition, nutritional intake, and health outcomes as well as patient empowerment, shared decision-making, quality of life, and reduced health care use in both the pre- and post-transplant settings.

Dr Benjamin Adam

University of Alberta, Edmonton, AB

Study Title: The molecular phenotype of polyomarivus nephropathy and its distinction from T-cell mediated rejection

New CNTRP study within Project 5

Abstract :

Improved immunosuppression protocols have reduced the incidence of T-cell mediated rejection (TCMR) in renal allograft recipients but carry a significant risk of polyomavirus nephropathy (PVN). Despite requiring opposite treatments, PVN and TCMR often have overlapping clinical and histological presentations. Molecular analysis represents an opportunity for more precise diagnosis and treatment, but previous work has been hampered by the dependency of traditional gene expression platforms on fresh, prospectively-collected tissue specifically preserved for RNA testing. Furthermore, biopsies from native kidneys with ‘pure’ PVN or tumors with polyomavirus (PV) are rare and prospective collection is essentially impossible. NanoString® nSolver® is a game-changer in the field of gene expression testing because it works reliably on formalin-fixed paraffin-embedded (FFPE) tissue, thus allowing the retrieval and retrospective molecular testing of rare cases from pathology archives. This innovative technology also affords the opportunity for direct translation of research findings into clinical use, evidenced by its recent approval by Health Canada for clinical diagnostic purposes in the setting of breast cancer.

In preliminary work, we utilized the NanoString® platform to measure the expression of 800 immune and PV-related genes in 40 FFPE human samples, including pure PVN and TCMR. We found all five PV genes that were tested to have significantly increased expression in pure PVN versus pure TMCR, while no human immune genes were differentially expressed. The PV genes demonstrated near-perfect diagnostic performance in the detection of PVN (AUC 0.99) with improved sensitivity (0.96) over histology alone (0.87). These preliminary findings suggest that PV gene expression is more sensitive than histology and can more precisely discriminate PVN and TCMR. However, at the molecular level, no significant difference between the rejection and anti-virus immune response was identified.

We propose to further validate this molecular diagnostic approach in a retrospective study design in which we will compare index biopsies from PVN patients with known outcomes. The aim of this translational study is to use the molecular phenotype of the index biopsy to predict the outcome of patients with PVN after therapeutic reduction in immunosuppression. The ultimate goal is to develop a tool for more precise diagnosis and risk stratification in PVN patients. This will provide the opportunity for immunosuppression to be more specifically tailored to the individual patient, thus reducing the risk of allograft failure due to either persistent PVN (i.e. insufficient reduction in immunosuppression) or rejection (i.e. excessive reduction in immunosuppression). This will ultimately facilitate improved survival and quality of life in renal transplant recipients.

Dr Steven Greenway

University of Calgary, Calgary, AB

Study Title: Mechanism of microbiome-mediated gastrointestinal toxicity of mycophenolate mofetil

New CNTRP study within Project 7

Abstract:

Microbes that live on and within humans have an important role in our health but the microbiome remains understudied post-transplantation. The immunosuppressive drug mycophenolate mofetil (MMF) is commonly used after both solid organ and hematopoietic stem cell transplantation but its use is frequently limited by unpleasant or dangerous gastrointestinal (GI) side effects (diarrhea, abdominal pain, weight loss and colitis). This proposal outlines a study to understand the mechanism underlying the GI toxicity of MMF which our data suggests is driven by the microbiome. We have developed a mouse model of MMF exposure whose phenotype of weight loss and colonic inflammation recapitulates some of the side effects seen in humans. These changes are preventable or reversible when mice consuming MMF are treated with antibiotics (particularly vancomycin) suggesting that bacteria mediate the GI side effects of MMF. We hypothesize that the bacterial metabolism of MMF in the gut generates toxic compounds that cause GI inflammation and that vancomycin depletes the responsible bacteria to relieve this toxicity. To address our hypothesis we will use mass spectrometry to measure the concentrations of MMF-derived metabolites in the fecal pellets of mice treated with MMF. We will also characterize the bacterial response to vancomycin in MMF-treated mice to identify the bacteria responsible and finally we will characterize bacterial composition and function in stool samples from heart transplant patients with MMF-related GI toxicity. Understanding the mechanism behind the GI toxicity of MMF is a step towards realizing personalized transplant medicine and improving patient health and quality of life.

Dr Aldo Montano-Loza

University of Alberta, Edmonton, AB

Study Title: A prospective, longitudinal evaluation of skeletal muscle for prognosis of patients with cirrhosis evaluated for liver transplantation

New CNTRP study within Project 7

Abstract:

Background: Our research to unveil abnormalities in skeletal muscle including low muscle mass and strength (sarcopenia) and fatty infiltration (myosteatosis) to be prognostic of survival permits a new dimension of personalized evaluation for each liver transplant candidate. The evolution of these features as well as the clinical impact before and after liver transplantation (LT) requires further study. Further, little is known about the biology of the muscle that confers poor prognosis.

Objectives of the Research: The objective of this study is to determine clinical and biological importance of these new poor prognostic variables, by using CT imaging to precisely quantify muscle mass (for sarcopenia), radiodensity (for myosteatosis), combined with muscle strength assessment by a hand-grip dynamometer at 6 month time intervals in cirrhotic patients being assessed for LT. Sarcopenia and myosteatosis will be evaluated in relation to adverse outcomes over the trajectory of pre- and post- liver transplantation (LT). The second objective is to understand the underlying pathology of muscle loss by analyzing a muscle biopsy, obtained at the time of LT, in relation to changes in muscle mass and strength.

Hypotheses: Our hypotheses are 1) Patients presenting with sarcopenia and reduced radiodensity at assessment of LT will have a higher incidence of adverse clinical outcomes (i.e. admission to hospital, infections, mortality) before and after LT; 2) Loss of muscle mass and strength and development of myosteatosis that occurs during the wait period for LT are associated with worse outcomes than those whose muscle condition does not change; 3) Muscle that is characterized by sarcopenia and myosteatosis will exhibit greater fat content, and higher numbers of inflammatory cells than those whose muscles do not exhibit these features.

Methods: All patients with cirrhosis being evaluated for LT in our center will be prospectively followed for a minimum of two years. Muscle cross sectional area and radiodensity will be evaluated using CT images taken routinely at the time of LT assessment and every 6-month thereafter (both before and after LT; Figure 1). Muscle strength will be assessed by a hand-grip dynamometer at the same time intervals. Morbidity and mortality in patients awaiting LT and complications after LT, survival, and length of stay will be compared between patients according to whether they have sarcopenia, myosteatosis, neither or both. Patients who undergo LT will provide a muscle biopsy from the rectus abdominis at the time of surgical procedure which will be evaluated for histology, lipid deposition and inflammatory cells.

Significance of the Research: This study will reveal the rate of muscle mass and strength loss and development of myosteatosis and provide insight into their underlying biology to enable refinement of the prognostic value of these measurements, to help prioritize patients for transplant, and which might be adopted at other LT centres. This research presents a personalized approach to develop a predictive model that would serve as a clinical tool to identify patient risk at time of assessment for LT, to enable patient selection, planning of clinical trials and identification of potential targets of treatment to improve outcomes in LT transplant.

Dr Tereza Martinu

University Health Network, Toronto, ON

Study Title: Targeting the renin-angiotensin system to monitor and treat fibrosis in chronic lung allograft dysfunction

New CNTRP study within Project 3 and Core 2

Abstract :

Chronic lung allograft dysfunction (CLAD) is a leading cause of mortality in long-term lung transplant recipients and manifests as two main subtypes: Bronchiolitis obliterans syndrome (BOS) that is characterized by fibrous tissue development mainly in the small airways and Restrictive allograft syndrome (RAS), that results in more severe peripheral lung fibrosis. The local renin-angiotensin system of the lungs has been shown to play an important role in preliminary studies of lung fibrosis via crosstalk with TGF-β1. Our work in kidney transplant patients has revealed six Angiotensin II-regulated proteins, BST1, GLNA, LAMB2, LYPLA1, RHOB and TSP-1 that segregate patients based on severity of interstitial fibrosis/tubular atrophy.

The proposed study entitled “Developing renin-angiotensin system markers and therapeutic targets to treat fibrosis in chronic lung allograft dysfunction” has two main objectives: 1) To develop early markers of fibrosis that can better diagnose and classify CLAD patients and 2) To evaluate novel therapeutic agents for treatment of fibrosis in CLAD patients. We will test whether Angiotensin II-regulated proteins also show an increase in bronchoalveolar lavage (BAL) from CLAD patients as they did in the urine from kidney transplant patients. We will further assess whether the levels of Angiotensin II-regulated proteins in the BAL can distinguish CLAD from no-CLAD and further RAS from BOS disease states. By identifying the type and severity of CLAD, these proteins can help identify disease early, allowing more timely therapy, and personalize treatment in CLAD patients to prolong graft survival. Our second aim is to test the anti-fibrotic effects of renin-angiotensin system inhibition on lung fibroblasts from CLAD vs. no-CLAD patients. This aim will help identify whether reninangiotensin system inhibitors may be useful in lung transplant recipients with progressive fibrosis and evaluate potential mechanisms and downstream markers of effectiveness.

With support of the CNTRP, we hope to leverage our expertise across organs and apply valuable information learned from kidney transplantation to identify novel mechanisms of fibrosis, biomarkers, and therapeutic targets to improve survival in lung transplant recipients.

#researchcompetition #astellas #UHN #alberta #ATI #CRCHUM

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