Medicine (RMH) - Theses
Now showing items 1-12 of 198
Multiple sclerosis: modifiable risk factors and quantifiable outcomes
Multiple sclerosis (MS) is a chronic inflammatory, demyelinating and neurodegenerative disease of the central nervous system. It is one of the most common causes of disability in young adults and represents a significant personal and societal burden. The aetiology of MS is unknown but involves both environmental and genetic risk factors. Women are three times more likely to develop relapsing-remitting MS (RRMS) than men, and sex hormones are hypothesised to be protective in MS. Further understanding the role of these risk factors will advance our knowledge of the aetiology of MS and lead to improved counselling. MS is also a heterogeneous disease and there is currently no good measure of predicting which patients are at highest risk of disability accrual. Brain atrophy is one potential biomarker of neurodegeneration but there are a paucity of studies exploring its application in the real-world clinical setting. This thesis has two parts. In the first part, we selected one modifiable risk factor, pregnancy, to further explore its association with MS. In chapter 1, we reported on the epidemiology of pregnancy in women with MS over the last 15 years using the international MSBase registry. Of 9098 women with RRMS, we found a low but increasing incidence of pregnancy as well as a greater proportion of women who conceived on disease-modifying therapy (DMT) over time. We did not find any differences in pregnancy outcomes between those pregnancies conceived on or off therapy. A higher disability was associated with a reduced pregnancy incidence. In chapter 2, we investigated the association of pregnancy with time to onset of clinically isolated syndrome (CIS), the first clinical demyelinating episode of MS. We recruited 2557 women across 4 sites and found that women with previous pregnancies and childbirths had a later onset of CIS compared to women without pregnancies and childbirths. A higher number of pregnancies and childbirths was not associated with a delayed CIS onset. In the second part, we selected one quantifiable outcome, MRI brain volumetry, and modelled its association with MS disability in a real-world setting. We used an automated volumetry software, icobrain, for centralised analysis of clinical MRIs. In chapter 3, we assessed the variability of percentage brain volume change (PBVC) measurements in a multicentre clinical setting. 6829 brain MRIs acquired on different scanners across 4 sites were analysed by icobrain. We found that after applying strict selection criteria for MRI pairs, which included filtering by image quality and an alignment similarity above the threshold for same-scanner scan-rescan images, only 42% of the original number of consecutive MRI pairs remained. The final MRI pairs had a mean PBVC comparable to single-site centres (-0.26% +/- 0.34). In chapter 4, we determined the association between various MRI metrics and MS disability using the subgroup of MRI pairs with the lowest variance from chapter 3. Our cohort of 260 relapse-onset MS patients were almost all treated, had a mean PBVC in the range for healthy individuals (-0.26% +/- 0.52), and a low disability accrue. We found no association between PBVC and future disability, however, cross-sectional whole brain volume was associated with disability. Our study findings highlight that pregnancy plays an important immunomodulatory role in women predisposed to MS, and whole brain volume may be the best performing MRI outcome to predict future disability in patients with minimal brain atrophy.
Ultrasound in the assessment of respiratory function and disease
This thesis advances the use of clinician-performed ultrasound for two common respiratory presentations; acute respiratory failure, and chronic obstructive pulmonary disease. Ultrasound in acute respiratory failure (ARF) To begin, a narrative review of ultrasound in ARF was undertaken and identified a paucity of evidence for the efficacy of ultrasound in ARF beyond diagnostic accuracy, and consequently a need for studies to examine its impact on clinical management efficacy, and patient and societal outcome efficacy. A prospective study of ultrasound in ARF was undertaken to establish clinical management efficacy. Ultrasound yielded new or additional diagnoses in 34% and enabled multiple clinical diagnoses in individual patients to be rationalised to a single diagnosis in 69%. Clinician diagnostic confidence was increased in 44%. Following ultrasound, patient management was altered in 30%, most frequently in patients with multiple diagnoses on admission. Additionally, a protocol was developed for a randomised controlled trial of ultrasound in ARF. Set in a high-dependency respiratory unit, primary study outcomes will be (i) time to resolution of respiratory failure, representing patient outcome efficacy, and (ii) time to readiness for unit discharge, representing societal outcome efficacy. Ultrasound in chronic obstructive pulmonary disease (COPD) A systematic review of diaphragm and intercostal muscle imaging in COPD was undertaken and included 52 studies. In COPD alterations in diaphragm morphology and function were detected across different imaging modalities, with reduced diaphragm excursion correlated with greater physiological impairment, and diaphragm dysfunction in ICU settings associated with poor outcomes. CT-intercostal muscle area correlated to worse airflow obstruction. Lung volume reduction and physiotherapy were associated with improvements in diaphragm parameters. A prospective study was undertaken in COPD to examine parasternal intercostal muscle thickness and echogenicity in the 2nd and 3rd intercostal spaces by ultrasound. Inter- and intra-rater reliability for thickness was moderate-to-high. Inter-rater measurement of echogenicity was moderate, with moderate-to-high intra-rater reliability. Reduced parasternal intercostal thickness and increased echogenicity (indicative of higher fat content) were both correlated to worse airflow obstruction as measured by FEV1. Finally, parasternal intercostal muscle thickness and echogenicity was studied in COPD patients before and after endobronchial valve (EBV) insertion. There was no change in echogenicity, but there was a strong correlation between reductions in residual volume and increases in parasternal intercostal muscle thickness in the treated hemi-thorax, suggesting length-tension relationships are a key determinant of muscle thickness. Ultrasound is a useful technique in patients presenting with acute respiratory failure and assists clinician decision-making and confidence. Ultrasound measured changes in parasternal intercostal muscles correlate with severity of airflow obstruction in COPD, with strong correlations between change in residual volume and thickness following relief of hyperinflation.
An eHealth model of care in the management of chronic disease: Chronic hepatitis C infection
The rising burden of chronic disease in the developed world has resulted in an increasing accumulation of patients requiring long-term specialist input in care, despite a relatively stagnant specialist capacity in tertiary hospital services. Newer models of care, incorporating specialist input whilst empowering and enabling community-based treatment in a more cost-effective primary care setting are desirable. This thesis details the adaptation, implementation and evaluation of a new model of care that is underpinned by digital technology, using the HealthElink system, in facilitating community and prison-based treatment of chronic hepatitis C virus (HCV). This approach involved establishing outcomes for current treatment models, preliminary system functionality testing and prospective implementation of the eHealth model of care in both community and prison settings throughout Australia. Chronic hepatitis C virus represents a model disease in which rapid treatment advances have allowed care to primarily shift from hospital to community-based treatment. The advent and availability of direct-acting antiviral (DAA) therapy for chronic hepatitis C virus (HCV) in Australia in March 2016 represented a treatment revolution. In effect, HCV became the first chronic viral infection for which a safe, efficacious and permanent cure exists, affording the opportunity to facilitate global eradication programs. The World Health Organisation therefore issued a position paper, calling for the elimination of HCV as a major public health threat by 2030 and ending onward transmission through ‘treatment as prevention’ programs. Owing to the efficacy, ease and safety of DAA therapy, Australia became one of the first jurisdictions to allow any prescriber to use these lifesaving medications. Despite an estimated 80% of patients deemed suitable for treatment by a primary care practitioner, only 18% of prescriptions were from a GP in the first twelve-months. This formed the ideal opportunity to deploy and examine the eHealth model of care. This thesis is built upon the largest prospective clinical study of a novel shared eHealth model of care in Australia. Baseline studies in this thesis established the real-world outcomes of DAA treatment in Australia in the new era of treatment. Failure to test for HCV cure and loss to follow-up were higher than previously reported in controlled trials, particularly in community and prison settings compared to tertiary-based treatment. The eHealth model of care was usable, acceptable and more accurate in treatment selection than the current standard of care in preliminary functionality testing. A quasi-experimental, hybrid implementation-effectiveness study of the eHealth model in both community settings and prisons was undertaken showing similar clinical outcomes to the standard of care, with an improvement in guideline-based quality of care and efficiency. Uptake of the eHealth model was low by general practitioners, likely influenced in part by low HCV screening particularly in regional areas. Integrated hepatitis nurses exhibited high uptake of the system, contrasting with lower usability scores. The electronic patient portal exhibited low utilisation and may hold limited value in the current iteration due to both clinician and patient factors. The clinical decision support system was the most useful component of the eHealth model of care. Integration into existing electronic systems is seen as crucial to future electronic shared care models amongst clinicians. When applied to chronic hepatitis C, the eHealth model is usable and acceptable and demonstrates similar clinical outcomes to the current standard of care. Additional benefits in adherence to guideline-based care and efficiency of care were found. An integrated eHealth model of care for chronic disease, although currently nascent, holds potential to profoundly improve the delivery and quality of care.
Transforming pre-hospital care of stroke
Stroke is the second leading cause of death, as well as the second leading cause of disability worldwide. In Australia, the estimated financial burden of stroke on direct healthcare costs and healthy life lost is upwards of $50 billion Australian dollars annually. Highly effective reperfusion therapies exist to improve outcomes for ischaemic stroke but must generally be administered within the first few hours of stroke onset to ensure salvageable tissue is still present. Similarly, most haematoma expansion in intracerebral haemorrhage occurs early and promising interventions are being investigated to potentially reduce growth in this hyperacute period. The journey of a patient from stroke onset through to paramedic management, transport to hospital and eventual treatment is complex, with many workflow steps both in the pre-hospital and in-hospital phases that are susceptible to delays. This means that effective acute interventions in stroke may be delayed or may not be available to a proportion of patients. Historically, much of the effort for improving time to treatment has focussed largely on optimisation of in-hospital workflows. However, the pre-hospital phase may account for up to 50% of the time from stroke recognition to treatment. This is even greater if patients require a secondary inter-hospital transfer, should the initial centre not have capability to provide specialised treatments like endovascular thrombectomy or neurosurgery. This thesis explores two complementary methods of improving pre-hospital care of patients suffering from stroke. The first method is optimising ambulance triage of patients to allow direct transport to specialised stroke centres with advanced treatments. This is achieved through paramedic-led assessment of a clinical severity tool to determine patients likely to benefit from endovascular thrombectomy or neurosurgical services. This thesis studies the feasibility of such a system in metropolitan Melbourne, the design of a new triage tool adapted to local needs and validation of the tool in a real-world pre-hospital cohort of stroke patients. The second method is the use of an Australian-first mobile stroke unit, a custom-built ambulance with on-board computed tomography scanner and multidisciplinary stroke team, that allows pre-hospital assessment, imaging, treatment and triage of stroke patients. This thesis explores the operationalisation of the Melbourne Mobile Stroke Unit, the clinical benefits achieved by the service for treatment of both ischaemic and haemorrhagic stroke and the provision of novel therapies in the pre-hospital setting. Future adoption of the two synergistic pre-hospital strategies on a larger scale is expected to deliver substantial benefits to patients with stroke. Those eligible for time-critical treatment will be able to receive such therapies significantly faster, with expected improvements in longer term health outcomes. Improved pre-hospital management minimises the disadvantage experienced by patients located further away from appropriate stroke services, allowing some mitigation of healthcare inequality. Successful implementation in Melbourne will provide a template for roll-out of the strategies nationally and internationally.
Treatment and prognosis in posterior circulation ischaemic stroke
Acute ischemic stroke is caused by a blocked blood vessel in the cerebral circulation. It is the most common form of stroke worldwide and a major cause of disability and death. One in five ischaemic strokes affects the posterior circulation. This type of stroke is associated with high risk of recurrence, disability and mortality. Diagnosing posterior circulation stroke can be challenging, as it often presents with non-specific or fluctuating symptoms. Several aspects of posterior circulation stroke are poorly understood compared to anterior circulation stroke. Treatments to reopen the blocked blood vessel and reperfuse the brain are available but patients with posterior circulation stroke were excluded from most of the randomized controlled trials which showed the benefit of reperfusion therapies in ischaemic stroke. This thesis examines the natural history, clinical and neuroimaging prognostic factors of outcome and treatment response in patients with posterior circulation stroke. We created the Basilar Artery Treatment and MANagement (BATMAN) collaboration, an international multicentre prospective registry aiming to answer clinical questions regarding this devastating and under-researched form of stroke. The overarching aim of this registry is to identify clinical and neuroimaging prognostic factors of outcome and treatment response in patients with posterior circulation stroke. This thesis examines clinical and imaging predictors of outcome in patients with posterior circulation stroke and how they may be applied in clinical practice. The ultimate aim is to push boundaries of treatment in patients with posterior circulation stroke allowing treatment in extended time windows when favourable imaging profiles are present and identify the optimal treatment management for these patients.
A 25-year retrospective study of equine abortion in Australia
Horses (Equus caballus, a subspecies of Equus ferus) have many roles in Australian society and several equine industries contribute greatly to the Australian economy. A recognised major welfare and economic issue to the equine industry is abortion in mares which may be due to infectious or non-infectious causes. Although equine herpesvirus 1 (EHV-1) is considered as a principal cause of infectious abortion in horses, other infectious agents including Chlamydia psittaci, Coxiella burnetii, Toxoplasma gondii, and Leptospira spp. have also been identified as a cause of abortion. Additionally, some of the abortigenic infectious agents are zoonotic, with implications for both human and animal health. The present study investigated abortigenic pathogens in equine abortion cases in Australia using qPCR and metagenomic deep sequencing methods. Using qPCR the prevalence of EHV- 1, C. psittaci, C. burnetii, Leptospira spp. and T. gondii was determined in 600 aborted equine foetal tissues that were submitted from 1994 to 2019 to the diagnostic laboratories at the University of Melbourne.The overall prevalence of C. psittaci and C. burnetii was 6.5% (39/600, 95% CI: 4.7 – 8.8%) and 4% (21/600, 95% CI: 2.2 – 5.3%) respectively. None of the samples were positive for Leptospira spp. and T. gondii. C. psittaci and C. burnetii positive cases were detected in most years that were represented in this study. The prevalence of C. psittaci in Victoria, New South Wales, and South Australia was 7.6% (30/395, 95% CI: 5.4 – 10.6%) and 3.9% (7/182, 95% CI: 1.9 – 7.7%) and 15.4% (2/13, 95% CI: 4.3 – 42.2%) respectively. The prevalence of C. burnetii in Victoria and New South Wales was 3% (10/395, 95% CI: 1 – 5%) and 6% (11/182, 95% CI: 3 – 11%) respectively. These findings highlight the abortigenic potential of these agents in horses across wide geographical regions in Australia and underscore the importance of strict adherence to personal protection and biosecurity measures when dealing with cases of equine abortion. Genotyping and phylogenetic analysis performed on the archived C. psittaci positive samples, as well as samples from recent cases of equine reproductive loss in Victoria, revealed that the C. psittaci detected in the equine abortion cases clustered with the parrot-associated 6BC clade (Genotype A/ST24). The findings suggest that infection of horses may be due to spill-over from native Australian parrots. DNA from a total of 49 equine aborted foetal tissues and 8 placentas from normal deliveries were sequenced using next-generation sequencing (NGS) technology. Several potential abortigenic pathogens including Escherichia coli, Klebsiella pneumoniae, Klebsiella oxytoca, Streptococcus equi subspecies zooepidemicus, Pantoea agglomerans, Acinetobacter lwoffii, Acinetobacter calcoaceticus, and Chlamydia psittaci were identified at a high level of relative abundance in a number of the abortion cases. No novel potential abortigenic pathogens were identified. Although NGS offers enhanced diagnostic capability, the findings suggest that existing diagnostic methods to detect known pathogens may be appropriate for identifying infectious causes of equine abortion in Australia given some of the current NGS limitations. Improvements in NGS technologies are likely to facilitate the use of NGS for diagnostics in the future. Greater awareness of the different pathogens causing equine abortions in Australia may assist diagnostic accuracy, reduce human infections and limit disease spread and further losses.
The Role of Rehabilitation in Disaster Settings
Disaster may lead to significant economic losses, huge loss of lives, severe traumatic injuries, and psychological consequences which may result in long-term disability, requiring comprehensive multi- or interdisciplinary rehabilitation input for optimisation of physical and functional outcomes. The purpose of this thesis is to address the issues and gaps in knowledge for disaster rehabilitation. This thesis presents a body of work that incorporates five linked studies integrating different methodological models, such as The International Classification of Functioning, Disability and Health (ICF), Priority Sequence Model, The Integrated Care Models and Four-Phase Process by the World Health Organization (WHO), Model of Care for Traumatic Brain Injury (TBI), and Disaster Rehabilitation Continuum Cycle. Studies 1 and 2 are the first reviews to comprehensively evaluate the quality of TBI Clinical Practice Guidelines (CPGs) from a rehabilitative perspective using the Appraisal of Guidelines for Research and Evaluation II (AGREE-II) tool, and summarise recommendations from these relevant CPGs for applicability in disaster settings. The key rehabilitation recommendations for TBI survivors in disaster settings, include: patient/carer education, general physical therapy, practice in daily living activities and safe equipment use, direct cognitive/behavioural feedback, basic compensatory memory/visual and swallowing/communication strategies, and psychological input. Study 3 evaluated functional outcome, quality of life and community re-integration of community-based disaster survivors in Pakistan. The findings suggest that study participants (members of the Pakistani Armed Forces) seemed to have settled well in the community. The severity of impairments (such as walking, self-caring, fatigue, pain etc.) negatively impacted on participants’ community re-integration and in relation to their social roles and productivity. The longer the time since the injury was sustained, the fewer the impairments, and better community re-integration and perceived health status. Study 4 was a pilot study using a structured survey to gain insight from rehabilitation professionals, mainly rehabilitation physicians, regarding their preparedness and willingness for future deployment to disaster settings. Most participants (63%) expressed interest in future deployment to disaster settings, and only 24% had previously received some form of disaster management training. However, the survey provided valuable information on those who responded, including their experience in their respective profession, level of education, and types of preferred disaster management training etc. Study 5 is the first Disaster Rehabilitation Response Plan (DRRP) using a three-tier approach: Tier 1 - Immediate disaster response at a national or international level, Tier 2 - Deployment of rehabilitation medical personnel to the disaster settings, and Tier 3 - Rehabilitation management and community reintegration of disaster survivors. The DRRP can serve as a model for the International Society of Physical and Rehabilitation Medicine (ISPRM) to coordinate and deliver rehabilitation assistance with WHO in future disasters. Findings in this body of work confirm the complexity of disaster rehabilitation and the many challenges for integration of rehabilitation medicine in disaster management. It also supports the view that rehabilitation should be an ongoing process to maintain, restore and maximise function and health status in the long-term.
Medications and oral restrictions
Many patients presenting for a procedure/surgery take long-term oral medications. Many of these medications are omitted inappropriately during the fasting period, which can put patients at risk of undesirable complications. The PhD took a qualitative-quantitative approach to explore potential causes, solutions, implementation considerations and impact of strategies to improve medication management in patients with oral intake restrictions, such as when fasting before a procedure/surgery. Four studies were conducted: The first identified barriers to managing medications appropriately, while the second investigated barriers and enablers to implementation of improvement initiatives. The third was a focus group exploring the perceptions and experiences of surgical nurses operating the initiatives. This was followed by a retrospective interrupted time series analyses of medications omitted inappropriately and overall omissions in patients fasting before a procedure/surgery, pre- and post-implementation of improvement strategies in Medical and Surgical areas of one hospital. The barriers analysis indicated confusion about how to manage medications when patients have oral intake restrictions. This was exacerbated by lack of a standardised approach, leadership and using fasting and nil by mouth interchangeably. These findings supported development of improvement strategies that provide clarity and guidance for staff; specifically, clear definitions for fasting and nil by mouth in relation to medication administration and decision aids to highlight these instructions at the frontline. This was the basis of the Medications and Oral Restrictions Policy (the Policy). Resource and infrastructure, staff interpretation of their roles and the perceived applicability and credibility of the Policy were common themes for both barriers and enablers to policy implementation. Challenging barriers included variability in the communication structure, differing interpretation of responsibility and staff movement and turnover. Despite a considered implementation approach, the enablers and strategies employed were insufficient to manage the barriers. The focus group findings corroborated those from the medication management barriers analysis and barriers and enablers to policy implementation. Surgical nurses concurred about the confusion and lack of guidance pre-policy introduction; however, although the Policy offered clarity, guidance and context for managing medications for some, limitations in the Policy’s reach and individual staff interpretation of its messages and inherent decision-making process meant it was unhelpful for others. The interrupted time series study suggested a moderate but statistically significant reduction in inappropriate and overall medication omissions in patients fasting before a procedure/surgery following policy implementation, especially in Medical areas. Surgical baseline omissions were lower than Medical’s, which contrasted evidence from the literature and requires exploration. In summary, a pragmatic approach to medication management was associated with a moderate reduction in inappropriate and overall dose omissions in patients fasting before a procedure/surgery. The Policy provided clarity and guidance for some: Those who understood the context found the Policy helpful to their practice. Nonetheless, insufficient resources to provide context, ensure adequate uptake and sustainability affected wider policy impact. Existing systems that do not require ongoing staff effort to sustain, that are relatively impervious to staff movement, such as the electronic prescribing platform, should be capitalised on to improve the reach and uptake of the Policy.
Duloxetine for pain in Parkinsons disease
Pain in Parkinsons disease is common and poorly managed. The body of literature showing that pain adversely impacts on the quality of life of Parkinsons disease patients is overwhelming. Different strategies have been adopted to address pain in Parkinsons disease but results have been mixed. The pathophysiology of pain in Parkinsons disease is thought to involve dopaminergic and extra-dopaminergic factors. Duloxetine, a serotonin and noradrenaline reuptake inhibitor has been used for pain in multiple sclerosis and painful diabetic peripheral neuropathy. We embarked on a project to explore the role of duloxetine in Parkinsons disease patients with pain in a randomized double blind placebo controlled trial using validated pain questionnaires, pain sensitivity measurements and functional imaging techniques. We showed a statistically significant improvement in the pain scores of the affective component of the Short-Form McGill Questionnaire and a trend towards improvement in pain tolerance following evoked pressure stimulus in the duloxetine group as compared to the placebo group. Additionally, the changes were not associated with changes in the affective states of the participants, as measured by the Geriatric Depression Scale and Positive Affect and Negative Affect Schedule. We did not find any statistically significant difference in the task-based fMRI and the resting state fMRI between the groups. In conclusion, our study showed that duloxetine may be most effective in addressing symptoms arising from the affective dimension of pain in Parkinsons disease patients.
Integrated approaches to immunisation and other health services for maternal, newborn and child health in resource-constrained settings
Background Integrating immunization and other health services during infancy could dramatically expand access to health care. During the first year after childbirth, immunisation services reach over 115 million families globally, at a point in the life-course where disease prevention, nutrition, and other preventive services can have high impact. Immunisation coverage could also benefit from integration, when catch-up vaccination is incorporated into illness or other care. There is encouraging evidence for malaria, HIV, or family planning programs and many global strategies advocate integrated services, especially for resource-constrained settings. However there are significant unresolved implementation questions, such as how best to link services, avoid staff overload, and maintain quality. Some attempts at integration fail to achieve expected benefits due to difficulties in re-organisation of services, or unexplained gaps in demand for and uptake of new arrangements. Methods This researched focused on low- and middle-income countries, using methods from health policy and systems research. Firstly, a new systematic review of global evidence examined outcomes and processes in controlled studies attempting integration of other services with infant immunisation. Secondly, in rural Papua New Guinea (PNG), integration questions were nested in a prospective observational cohort study following 699 mother-infant pairs from first antenatal visit until 12 months after childbirth. Repeated assessments examined co-morbidity and preventive care needs, experiences of integrated services, and a unique open exploration of women’s preferences for future integration. Thirdly, a cross-sectional health services assessment, in the same setting, examined integration practices and preferences of health managers and front-line staff. Integration of Immunisation and Other Services Findings Review of global evidence documented new work integrating family planning, HIV, malaria and nutrition. Most linked services benefited, with mixed outcomes for immunisation. A new typology of integrated services emerged, with richer detail on what determines success. In PNG, need for integrated care is high but provision is low. PNG women’s preferences surpassed current evidence, policy and practice; seeking addition of maternal illness care, comprehensive child illness care, better education on important disease threats, and sexual and reproductive health care. They had many insights for improved implementation of integrated services. Women privilege holistic quality care over savings in time and money, although the latter are valued. Acceptability is not universal, with sensitive topics needing careful management. The existing immunisation program in PNG offers some integration opportunities, but meeting women’s preferences will require additional investments in planning and staffing. Synergies when strengthening immunisation for integration may also expand routine coverage and capacity to support emergency responses. Priorities include addressing maternal health during immunisation clinics, integration of nutrition, family planning and immunisation in the first and second years of life, and reducing missed opportunities for vaccination during illness care. Conclusion Integration of other services with immunisation in infancy should be pursued; first because it can offer holistic care for the multiple health needs in families, and then for potential efficiencies. Implementation details, especially addressing users’ preferences, are critical to success. Better understanding of families’ needs and preferences is essential to health planning, as more responsive services offer pathways to system resilience and universal coverage.
Redesigning deceased donor kidney transplant allocation in Australia
Kidney transplantation is a life changing event for a person living with end stage kidney disease and the allocation of deceased donor kidneys can have profound impacts on who has access to this treatment, the benefit that is derived from the gift of donation and the long term outcomes for the individual receiving the organ. The system that determines the allocation of deceased donor kidneys comprises a number of interconnected processes and must address a range of competing priorities. This thesis presents a series of related studies that provide evidence on the current state of deceased donor kidney allocation and demonstrate the feasibility and effectiveness of a novel framework for redesigning organ allocation protocols in Australia. In order to better understand the context in which allocation occurs, Chapters 3 and 4 address key knowledge gaps in the Australian deceased donor kidney transplant system, reporting on the predictors of access to kidney transplant waitlisting in Australia, highlighting the disadvantage experienced by key populations, and exploring the causes of a recent increase in kidney non-utilisation. Chapter 5, 6 and 7 analyse the impacts of previous changes to the allocation system, assessing their effectiveness, unintended consequences and highlighting key areas in which further policy intervention is required. The study reported in chapter 5 demonstrates that the reporting of the Kidney Donor Performance Index (KDPI) with organ offers in Australia was associated with changes in acceptance behaviour but not an increase in non-utilisation and provide insights into how donor risk indices might be incorporated into future allocating algorithms. Analysis of the impact of the introduction of calculated panel reactive antibody (cPRA) to define sensitization for kidney transplant candidates, described in chapter 6, reveals the scale of disadvantage experienced by very highly sensitized patients and the ineffectiveness of the current allocation system in addressing this, adding urgency to the call for policy change to address this. Further evidence to support change is reported in chapter 7, in an analysis of the effectiveness of paediatric bonuses in the Australian deceased donor kidney allocation system. This shows that whilst paediatric candidates are achieving rapid access to high quality organs, under current rules children are not receiving kidneys with optimal immunological matching. Chapter 8 explores the association between HLA epitope based matching and clinical outcomes in the paediatric population to investigate whether this may have potential as a novel approach to reducing immunological risk through optimised allocation. Addressing the broader question of what the allocation system should be trying to achieve, results of a best worse scaling choice experiment presented in Chapter 9 show key differences in the principles prioritized by healthcare professionals when compared to the general community. The final chapter of the thesis reports the development, validation and implementation of a platform to simulate deceased donor kidney allocation in Australia. In working closely with the national Renal Transplant Allocation Committee (RTAC), this study not only provided proof of concept for the value of simulation in organ allocation policy development in Australia but produced direct and tangible improvements in the policy that will be implemented. In taking a holistic approach to the process of redesigning deceased donor kidney allocation this work reports several novel findings that have had a direct impact on policy development and lays the foundations for an ongoing framework of evidence-based design for deceased donor kidney allocation in Australia.
Novel Aspects in the pathogenesis of Chronic Kidney Disease-Mineral Bone Disorder (CKD-MBD)
Chronic Kidney Disease – Mineral and Bone Disorder (CKD-MBD) is a clinical entity, broadly defined by (a) disturbances in mineral metabolism, (b) abnormal bone remodeling and (c) accelerated vascular calcification. CKD-MBD is ubiquitous as kidney function deteriorates and contributes significantly to increased fracture risk and excess cardiovascular morbidity and mortality. Due to the complex and multifactorial nature of this condition, there remains many unanswered questions on how to best investigate and manage all aspects of CKD-MBD. The general aim of this thesis was to investigate the pathophysiology, clinical outcomes and novel assessment strategies of the three domains of CKD-MBD. More specifically, this thesis aimed to 1) evaluate the outcomes of calciphylaxis in Australian patients, 2) develop a greater understanding of changes in skin and subcutaneous tissue in patients with kidney disease, 3) demonstrate the consequences of severe secondary hyperparathyroidism (SHPT) in the absence of calcimimetic treatment, 4) understand the temporal relationship between calciprotein particles and biochemical markers of CKD-MBD and 5) evaluate bone microarchitecture in patients with severe SHPT using a novel imaging modality. Although calciphylaxis is a rare disease, it can be considered a form of accelerated vascular calcification. It predominantly affects patients with chronic kidney disease (CKD) and is associated with significant morbidity and mortality due to progressive cutaneous calcification, necrotic ulceration and infection. Clinical registries have been established to better understand risk factors, optimal treatments and disease outcomes of calciphylaxis. To better understand outcomes of Australian patients with calciphylaxis, Chapter 2 investigated the five-year outcomes from the internet-based Australian Calciphylaxis Registry. Data was recorded on patient characteristics, biochemical parameters, treatments and disease outcomes. The Australian Calciphylaxis Registry highlights risk factors for calciphylaxis including diabetes, obesity and vitamin K antagonist use, whilst significantly elevated parathyroid hormone (PTH) levels were not a consistent finding at the time of diagnosis or in the preceding 12 months in this cohort. Unfortunately, resolution of calciphylaxis remains uncommon despite multimodal therapy and mortality from calciphylaxis in the first year following diagnosis is high. Vascular calcification is well described in large- and medium-sized vessels in patients with CKD, especially in those with end-stage kidney disease (ESKD) on dialysis. Medial calcification is particularly prevalent in this population and contributes to arterial stiffness and increased cardiovascular mortality and morbidity. Apart from in the setting of calciphylaxis, few studies have assessed skin and subcutaneous calcification and associations with abnormalities of bone and mineral metabolism in patients with CKD. In Chapter 3, patients with varying stages of CKD undergoing elective surgery underwent intraoperative incisional skin biopsy to evaluate for the histological presence of vascular calcification and upregulation of pro-calcific gene transcripts. This study reports the novel finding of dermal and subcutaneous small vessel calcification in multiple anatomical locations in 38% of patients with advanced CKD or ESKD undergoing elective surgery but free from calciphylaxis. Expression of pro-calcific gene transcripts, specifically TNAP or RUNX2, was not increased in samples from patients with CKD or those with histological evidence of vascular calcification. SHPT in patients with CKD is associated with cardiovascular and bone pathology. Measures to achieve target PTH values and control biochemical abnormalities associated with SHPT require complex therapies, and severe SHPT often requires parathyroidectomy or the calcimimetic cinacalcet. In Australia, cinacalcet prescription, in dialysis patients was reimbursed by the government from 2009 to 2015. However, after this time funding was withdrawn following publication of the EVOLVE study, which resulted in most patients on cinacalcet ceasing therapy. Changes to reimbursement of cinacalcet in Australia provided an opportunity to assess effects of medication cessation on biochemical and clinical outcomes in dialysis patients, including changes to novel biomarkers such as calciprotein particles (CPP). CPP are nanoparticles of mineral and protein in the circulation associated with increased vascular calcification in patients with CKD. Chapter 4 focused on changes to novel biochemical markers following cinacalcet withdrawal in dialysis patients with SHPT from a single centre with CPP levels assessed at four different time points over a 12-month period. Outcomes were compared with an age- and gender-matched cohort of cinacalcet-naive dialysis patients. Cinacalcet withdrawal in the real-world setting demonstrated increases in PTH, serum calcium and the novel prognostic marker CPP over a 12-month period. Following on from work in Chapter 4, Chapter 5 involved a multi-centre retrospective study of dialysis patients who ceased cinacalcet after August 2015 at 11 Australian institutions. Clinical outcomes and changes in biochemical parameters were assessed over a 12- and 24-month period from drug cessation. Significant increases in serum PTH, calcium and alkaline phosphatase occurred over a 12-month period following withdrawal of cinacalcet, without an associated increase in cardiovascular mortality and morbidity, fractures or calciphylaxis. SHPT in patients with CKD leads to complex bone disease, affecting both trabecular and cortical bone with resulting increased fracture risk. Optimal assessment of bone in patients with CKD is yet to be determined. High-resolution magnetic resonance imaging (MRI) can provide three-dimensional assessment of bone microarchitecture, as well as determination of mechanical strength with finite element analysis (FEA). Chapter 6 evaluated bone microarchitecture in patients with severe SHPT undergoing parathyroidectomy. Correlation of MRI findings of bone microarchitecture were made with biochemical markers. MRI in this patient population demonstrated evidence of significant changes in bone microarchitecture with trabecular deterioration, low trabecular and cortical bone volume, and reduced mechanical competence of bone with overall poor bone mechanical strength. In summary, this thesis presents insights into the vascular, biochemical and bone domains of CKD-MBD with both clinical and basic science research focusing on pathophysiology, novel biochemical markers and imaging techniques. The novel findings obtained in this thesis have broadened the understanding of all three domains of CKD-MBD, particularly with regards to CPP as a potential novel biomarker to evaluate biochemical derangement and vascular risk, and MRI as a novel imaging modality to gain a better understanding of bone microarchitecture. Further clinical and basic science studies are required to validate findings and to explore concepts established in this thesis, however, data presented here establishes important concepts for future research in this field.