Characterising haemodialysis-associated cardiomyopathy using deformation imaging by cardiovascular magnetic resonance tagging and speckle-tracking echocardiography

Haemodialysis patients represent an extreme phenotype of cardiovascular risk with a pattern of disease distinct from that in the general population. Non-traditional risk factors, specific to chronic kidney disease such as hypervolaemia, arterial stiffness and advanced glycation end-product deposition are increasingly recognised. A previously demonstrated non-traditional risk factor associated with worse outcomes is the presence of uraemic cardiomyopathy. This pattern of cardiac morphology and function has previously been defined as the presence of left ventricular abnormalities, including left ventricular hypertrophy, dilatation and left ventricular systolic dysfunction. For the first time the work in this thesis studies an incident haemodialysis population using multi-parametric strain-based imaging. This uses the accuracy of cardiovascular magnetic resonance imaging of resting cardiac and aortic morphology and function augmented with strain by tagging to longitudinal strain changes during haemodialysis by speckle-tracking echocardiography. The general aim of this thesis was to characterise the relationship of left ventricular function to haemodialysis using strain-based imaging. This might allow characterisation of haemodialysis-associated cardiomyopathy which may be distinct from the traditional definition of uraemic cardiomyopathy and may better define those patients who would benefit from modifications to the process of haemodialysis

Characterising haemodialysis-associated cardiomyopathy using deformation imaging by cardiovascular magnetic resonance tagging and speckle-tracking echocardiography

Haemodialysis patients represent an extreme phenotype of cardiovascular risk with a pattern of disease distinct from that in the general population. Non-traditional risk factors, specific to chronic kidney disease such as hypervolaemia, arterial stiffness and advanced glycation end-product deposition are increasingly recognised. A previously demonstrated non-traditional risk factor associated with worse outcomes is the presence of uraemic cardiomyopathy. This pattern of cardiac morphology and function has previously been defined as the presence of left ventricular abnormalities, including left ventricular hypertrophy, dilatation and left ventricular systolic dysfunction. For the first time the work in this thesis studies an incident haemodialysis population using multi-parametric strain-based imaging. This uses the accuracy of cardiovascular magnetic resonance imaging of resting cardiac and aortic morphology and function augmented with strain by tagging to longitudinal strain changes during haemodialysis by speckle-tracking echocardiography. The general aim of this thesis was to characterise the relationship of left ventricular function to haemodialysis using strain-based imaging. This might allow characterisation of haemodialysis-associated cardiomyopathy which may be distinct from the traditional definition of uraemic cardiomyopathy and may better define those patients who would benefit from modifications to the process of haemodialysis

Evaluation of the effect of Cooled HaEmodialysis on Cognitive function in patients suffering with end-stage KidnEy Disease (E-CHECKED): feasibility randomised control trial protocol

BACKGROUND: Cognitive impairment is common in haemodialysis (HD) patients and is associated independently with depression and mortality. This association is poorly understood, and no intervention is proven to slow cognitive decline. There is evidence that cooler dialysis fluid (dialysate) may slow white matter changes in the brain, but no study has investigated the effect of cooler dialysate on cognition. This study addresses whether cooler dialysate can prevent the decline in cognition and improve quality of life (QOL) in HD patients. METHODS: This is a multi-site prospective randomised, double-blinded feasibility trial. SETTING: Four HD units in the UK. PARTICIPANTS AND INTERVENTIONS: Ninety HD patients randomised (1:1) to standard care (dialysate temperature 36.5 °C) or intervention (dialysate temperature 35 °C) for 12 months. PRIMARY OUTCOME MEASURE: Change in cognition using the Montreal Cognitive Assessment (MoCA). SECONDARY OUTCOME MEASURES: Recruitment and attrition rates, reasons for non-recruitment, frequency of intradialytic hypotension, depressive symptom scores, patient and carers burden, a detailed computerised cognitive test and QOL assessments. ANALYSIS: mixed method approach, utilising measurement of cognition, questionnaires, physiological measurements and semi-structured interviews. DISCUSSION: The results of this feasibility trial will inform the design of a future adequately powered substantive trial investigating the effect of dialysate cooling on prevention and/or slowing in cognitive decline in patients undergoing haemodialysis using a computerised battery of neuro-cognitive tests. The main hypothesis that would be tested in this future trial is that patients treated with regular conventional haemodialysis will have a lesser decline in cognitive function and a better quality of life over 1 year by using cooler dialysis fluid at 35 °C, versus a standard dialysis fluid temperature of 36.5 °C. This also should reflect in improvements in their abilities for activities of daily living and therefore reduce carers' burden. If successful, the treatment could be universally applied at no extra cost. TRIAL REGISTRATION: ClinicalTrials.gov NCT03645733 . Registered retrospectively on 24 August 2018

Murine models of renal ischemia reperfusion injury: An opportunity for refinement using noninvasive monitoring methods

BACKGROUND: Renal ischemia reperfusion injury (R‐IRI) can cause acute kidney injury (AKI) and chronic kidney disease (CKD), resulting in significant morbidity and mortality. To understand the underlying mechanisms, reproducible small‐animal models of AKI and CKD are needed. We describe how innovative technologies for measuring kidney function noninvasively in small rodents allow successful refinement of the R‐IRI models, and offer the unique opportunity to monitor longitudinally in individual animals the transition from AKI to CKD. METHODS: Male BALB/c mice underwent bilateral renal pedicle clamping (AKI) or unilateral renal pedicle clamping with delayed contralateral nephrectomy (CKD) under isoflurane anesthetic. Transdermal GFR monitoring and multispectral optoacoustic tomography (MSOT) in combination with statistical analysis were used to identify and standardize variables within these models. RESULTS: Pre‐clamping anesthetic time was one of the most important predictors of AKI severity after R‐IRI. Standardizing pre‐clamping time resulted in a more predictably severe AKI model. In the CKD model, MSOT demonstrated initial improvement in renal function, followed by significant progressive reduction in function between weeks 2 and 4. Performing contralateral nephrectomy on day 14 enabled the development of CKD with minimal mortality. CONCLUSIONS: Noninvasive monitoring of global and individual renal function after R‐IRI is feasible and reproducible. These techniques can facilitate refinement of kidney injury models and enable the degree of injury seen in preclinical models to be translated to those seen in the clinical setting. Thus, future therapies can be tested in a clinically relevant, noninvasive manner

Arterial spin labelling MRI to measure renal perfusion: a systematic review and statement paper

Renal perfusion provides the driving pressure for glomerular filtration and delivers the oxygen and nutrients to fuel solute reabsorption. Renal ischaemia is a major mechanism in acute kidney injury and may promote the progression of chronic kidney disease. Thus, quantifying renal tissue perfusion is critically important for both clinicians and physiologists. Current reference techniques for assessing renal tissue perfusion have significant limitations. Arterial spin labelling (ASL) is a magnetic resonance imaging (MRI) technique that uses magnetic labelling of water in arterial blood as an endogenous tracer to generate maps of absolute regional perfusion without requiring exogenous contrast. The technique holds enormous potential for clinical use but remains restricted to research settings. This statement paper from the PARENCHIMA network briefly outlines the ASL technique and reviews renal perfusion data in 53 studies published in English through January 2018. Renal perfusion by ASL has been validated against reference methods and has good reproducibility. Renal perfusion by ASL reduces with age and excretory function. Technical advancements mean that a renal ASL study can acquire a whole kidney perfusion measurement in less than 5–10min. The short acquisition time permits combination with other MRI techniques that might inform drug mechanisms and renal physiology. The flexibility of renal ASL has yielded several variants of the technique, but there are limited data comparing these approaches. We make recommendations for acquiring and reporting renal ASL data and outline the knowledge gaps that future research should address

Technical recommendations for clinical translation of renal MRI: a consensus project of the Cooperation in Science and Technology Action PARENCHIMA.

PURPOSE: The potential of renal MRI biomarkers has been increasingly recognised, but clinical translation requires more standardisation. The PARENCHIMA consensus project aims to develop and apply a process for generating technical recommendations on renal MRI. METHODS: A task force was formed in July 2018 focused on five methods. A draft process for attaining consensus was distributed publicly for consultation and finalised at an open meeting (Prague, October 2018). Four expert panels completed surveys between October 2018 and March 2019, discussed results and refined the surveys at a face-to-face meeting (Aarhus, March 2019) and completed a second round (May 2019). RESULTS: A seven-stage process was defined: (1) formation of expert panels; (2) definition of the context of use; (3) literature review; (4) collection and comparison of MRI protocols; (5) consensus generation by an approximate Delphi method; (6) reporting of results in vendor-neutral and vendor-specific terms; (7) ongoing review and updating. Application of the process resulted in 166 consensus statements. CONCLUSION: The process generated meaningful technical recommendations across very different MRI methods, while allowing for improvement and refinement as open issues are resolved. The results are likely to be widely supported by the renal MRI community and thereby promote more harmonisation

Exploring haemodynamics of haemodialysis using extrema points analysis model

Background: Haemodialysis is a form of renal replacement therapy used to treat patients with end stage renal failure. It is becoming more appreciated that haemodialysis patients exhibit higher rates of multiple end organ damage compared to the general population. There is also a strong emerging evidence that haemodialysis itself causes circulatory stress. We aimed at examining haemodynamic patterns during haemodialysis using a new model and test that model against a normal control. Methods: We hypothesised that blood pressures generated by each heart beat constantly vary between local peaks and troughs (local extrema), the frequency and amplitude of which is regulated to maintain optimal organ perfusion. We also hypothesised that such model could reveal multiple haemodynamic aberrations during HD. Using a non-invasive cardiac output monitoring device (Finometer®) we compared various haemodynamic parameters using the above model between a haemodialysis patient during a dialysis session and an exercised normal control after comparison at rest. Results: Measurements yielded 29,751 data points for each haemodynamic parameter. Extrema points frequency of mean arterial blood pressure was higher in the HD subject compared to the normal control (0.761Hz IQR 0.5-0.818 vs 0.468Hz IQR 0.223-0.872, P < 0.0001). Similarly, extrema points frequency of systolic blood pressure was significantly higher in haemodialysis compared to normal. In contrary, the frequency of extrema points for TPR was higher in the normal control compared to HD (0.947 IQR 0.520-1.512 vs 0.845 IQR 0.730-1.569, P < 0.0001) with significantly higher amplitudes. Conclusion: Haemodialysis patients potentially exhibit an aberrant haemodynamic behaviour characterised by higher extrema frequencies of mean arterial blood pressure and lower extrema frequencies of total peripheral resistance. This, in theory, could lead to higher variation in organ perfusion and may be detrimental to vulnerable vascular beds

Consensus-based technical recommendations for clinical translation of renal ASL MRI

Objectives: To develop technical recommendations for the acquisition, processing and analysis of renal ASL data in the human kidney at 1.5T and 3T field strengths that can promote standardization of renal perfusion measurements and facilitate the comparability of results across scanners and in multi-center clinical studies.Methods: An international panel of 23 renal ASL experts followed a modified Delphi process, including on-line surveys and two in-person meetings, to formulate a series of consensus statements regarding patient preparation, hardware, acquisition protocol, analysis steps and data reporting.Results: Fifty-nine statements achieved consensus, while agreement could not be reached on two statements related to patient preparation. As a default protocol, the panel recommends pseudo-continuous (PCASL) or flow-sensitive alternating inversion recovery (FAIR) labeling with a single-slice spin-echo EPI readout with background suppression, and a simple but robust quantification model.Discussion: This approach is considered robust and reproducible and can provide renal perfusion images of adequate quality and SNR for most applications. If extended kidney coverage is desirable, a 2D multislice readout is recommended. These recommendations are based on current available evidence and expert opinion. Nonetheless they are expected to be updated as more data becomes available, since the renal ASL literature is rapidly expanding

Technical recommendations for clinical translation of renal MRI: a consensus project of the Cooperation in Science and Technology Action PARENCHIMA

Purpose The potential of renal MRI biomarkers has been increasingly recognised, but clinical translation requires more standardisation. The PARENCHIMA consensus project aims to develop and apply a process for generating technical recommendations on renal MRI. Methods A task force was formed in July 2018 focused on fve methods. A draft process for attaining consensus was distributed publicly for consultation and fnalised at an open meeting (Prague, October 2018). Four expert panels completed surveys between October 2018 and March 2019, discussed results and refned the surveys at a face-to-face meeting (Aarhus, March 2019) and completed a second round (May 2019). Results A seven-stage process was defned: (1) formation of expert panels; (2) defnition of the context of use; (3) literature review; (4) collection and comparison of MRI protocols; (5) consensus generation by an approximate Delphi method; (6) reporting of results in vendor-neutral and vendor-specifc terms; (7) ongoing review and updating. Application of the process resulted in 166 consensus statements. Conclusion The process generated meaningful technical recommendations across very diferent MRI methods, while allowing for improvement and refnement as open issues are resolved. The results are likely to be widely supported by the renal MRI community and thereby promote more harmonisation

Magnetic resonance imaging biomarkers for chronic kidney disease: a position paper from the European Cooperation in Science and Technology Action PARENCHIMA

Functional renal magnetic resonance imaging (MRI) has seen a number of recent advances, and techniques are now available that can generate quantitative imaging biomarkers with the potential to improve the management of kidney disease. Such biomarkers are sensitive to changes in renal blood flow, tissue perfusion, oxygenation and microstructure (including inflammation and fibrosis), processes that are important in a range of renal diseases including chronic kidney disease. However, several challenges remain to move these techniques towards clinical adoption, from technical validation through biological and clinical validation, to demonstration of cost-effectiveness and regulatory qualification. To address these challenges, the European Cooperation in Science and Technology Action PARENCHIMA was initiated in early 2017. PARENCHIMA is a multidisciplinary pan-European network with an overarching aim of eliminating the main barriers to the broader evaluation, commercial exploitation and clinical use of renal MRI biomarkers. This position paper lays out PARENCHIMA’s vision on key clinical questions that MRI must address to become more widely used in patients with kidney disease, first within research settings and ultimately in clinical practice. We then present a series of practical recommendations to accelerate the study and translation of these techniques