A mechatronic haemodialysis system for the treatment of acute renal failure and metabolic disorders

The aim of this project was to produce a fully automated prototype system for the treatment of premature babies who are suffering from renal failure or metabolic disorders. These patients are difficult or impossible to treat conventionally, due to their very small total blood volume and their intolerance to donated blood. There was a strong case for developing a dialysis system specifically designed for the treatment of such patients. The system is based on a manually operated device developed at the Royal Victoria Infirmary, Newcastle Upon Tyne. It differs from conventional dialysis methods in several ways. Blood access to the patient is via a single venous catheter. Only a very small amount of blood is needed to prime the extracorporeal circuit - this can be as little as 6.8 ml in the smallest patients. This compares very favourably with the volumes needed in conventional circuits, which are in the range of 15 - 40 ml. This small priming volume means that donated blood is not needed to prime the circuit. The clearance and ultrafiltration rates that can be achieved are independent of the rate that blood can be accessed from the patient, since the same blood passes back and forth through the haemofilter several times. The clearances that have been obtained experimentally are consistently above 40% of the mean blood flow rate through the system. The largest mean blood flow rate available is 5 ml/min, so the maximum clearance is approximately 2 ml/min. The maximum ultrafiltration rate that can be obtained is 50 ml/h. The new system is more effective at treating premature babies than conventional dialysis circuits. The hand driven system was tested in vivo and found to work well, so the automated system was developed on a solid foundation. A prototype system has been successfully developed and tested. This thesis details both the development and the testing. The new system uses stepper motors and DC servo motors for actuation, and is controlled by Labwindows/CVI and NIDAQ software running on a standard PC platform. The interface between the PC and the machine is provided by a National Instruments data acquisition board. A comprehensive single fault analysis of the safety of the system was undertaken, including both software and hardware. In vitro testing covered several areas of operation. The accuracy of the ultrafiltration process was established. The clearance rates that could be achieved were determined. The amount of damage caused to the blood by the system was also tested. This was found to be well within acceptable clinical limits. In vivo testing established the feasibility of using a computer algorithm to control the withdrawal of blood from the patient. Finally, the system was successfully used to treat a patient with an in-born metabolic disorder. In summary, a new system has been developed that is superior to any other treatment method currently available for neonates with these types of disorders

Renal Association Clinical Practice Guideline on Haemodialysis

© The Author(s) 2019. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.This guideline is written primarily for doctors and nurses working in dialysis units and related areas of medicine in the UK, and is an update of a previous version written in 2009. It aims to provide guidance on how to look after patients and how to run dialysis units, and provides standards which units should in general aim to achieve. We would not advise patients to interpret the guideline as a rulebook, but perhaps to answer the question: "what does good quality haemodialysis look like?"The guideline is split into sections: each begins with a few statements which are graded by strength (1 is a firm recommendation, 2 is more like a sensible suggestion), and the type of research available to back up the statement, ranging from A (good quality trials so we are pretty sure this is right) to D (more like the opinion of experts than known for sure). After the statements there is a short summary explaining why we think this, often including a discussion of some of the most helpful research. There is then a list of the most important medical articles so that you can read further if you want to - most of this is freely available online, at least in summary form.A few notes on the individual sections: 1. This section is about how much dialysis a patient should have. The effectiveness of dialysis varies between patients because of differences in body size and age etc., so different people need different amounts, and this section gives guidance on what defines "enough" dialysis and how to make sure each person is getting that. Quite a bit of this section is very technical, for example, the term "eKt/V" is often used: this is a calculation based on blood tests before and after dialysis, which measures the effectiveness of a single dialysis session in a particular patient. 2. This section deals with "non-standard" dialysis, which basically means anything other than 3 times per week. For example, a few people need 4 or more sessions per week to keep healthy, and some people are fine with only 2 sessions per week - this is usually people who are older, or those who have only just started dialysis. Special considerations for children and pregnant patients are also covered here. 3. This section deals with membranes (the type of "filter" used in the dialysis machine) and "HDF" (haemodiafiltration) which is a more complex kind of dialysis which some doctors think is better. Studies are still being done, but at the moment we think it's as good as but not better than regular dialysis. 4. This section deals with fluid removal during dialysis sessions: how to remove enough fluid without causing cramps and low blood pressure. Amongst other recommendations we advise close collaboration with patients over this. 5. This section deals with dialysate, which is the fluid used to "pull" toxins out of the blood (it is sometimes called the "bath"). The level of things like potassium in the dialysate is important, otherwise too much or too little may be removed. There is a section on dialysate buffer (bicarbonate) and also a section on phosphate, which occasionally needs to be added into the dialysate. 6. This section is about anticoagulation (blood thinning) which is needed to stop the circuit from clotting, but sometimes causes side effects. 7. This section is about certain safety aspects of dialysis, not seeking to replace well-established local protocols, but focussing on just a few where we thought some national-level guidance would be useful. 8. This section draws together a few aspects of dialysis which don't easily fit elsewhere, and which impact on how dialysis feels to patients, rather than the medical outcome, though of course these are linked. This is where home haemodialysis and exercise are covered. There is an appendix at the end which covers a few aspects in more detail, especially the mathematical ideas. Several aspects of dialysis are not included in this guideline since they are covered elsewhere, often because they are aspects which affect non-dialysis patients too. This includes: anaemia, calcium and bone health, high blood pressure, nutrition, infection control, vascular access, transplant planning, and when dialysis should be started.Peer reviewe

Recombinant Human Erythropoietin in the Treatment of Renal Anaemia

This thesis is concerned with a study of the clinical and biological effects of recombinant human erythropoietin (EPO) which recently became available as a novel treatment for the anaemia of end-stage renal disease. The dissertation begins with an introductory chapter which contains a historical note and survey of the relevant published literature. In this section is included a review of the pathogenesis of renal anaemia, the traditional treatment options for this condition, the development of recombinant human EPO, the biochemistry and physiology of erythropoietin, the metabolic fate of EPO, and the early clinical trials with EPO. This is followed by seven chapters of original work undertaken in Cardiff between April 1988 and July 1990

A pharmaceutical human apotransferrin product for iron binding therapy

Transferrin is the major iron binding protein in human plasma. It binds iron with high affinity in a redox inactive form and delivers it to growing cells. Each molecule is capable of binding two molecules of ferric iron. Normally, transferrin is only about 30 % saturated with iron. In certain clinical conditions, the iron concentration in serum is increased so that the iron binding capacity is exceeded and non-transferrin-bound iron (NTBI) is formed in serum. NTBI is potentially toxic because it generates free radical formation and can be taken up by tissues, leading to excess deposits that can potentiate tissue damage. It is also known that iron enhances the growth of bacteria and fungi, and can predispose patients to septic infections. This thesis describes the development of an efficient process for producing pharmaceutical grade iron-free apotransferrin. The biochemical efficacy of apotransferrin for iron binding therapy was studied in early phase clinical trials in haematological stem cell transplant (SCT) patients. The scope of this work did not include studying the clinical efficacy of apotransferrin. The manufacturing method used fraction IV of the Cohn cold ethanol human plasma fractionation process as starting material. Apotransferrin was purified in two ion exchange chromatography steps and ultrafiltration with over 90 % recovery. In order to obtain a virus-safe product, the process comprised solvent detergent treatment as the main virus inactivation step and virus filtration and polyethylene glycol precipitation to remove physico-chemically resistant infectious agents. The purity of the product was at least 98 %, main impurities being IgG, IgA and hemopexin. Methods for studying the iron binding capacity, the transferrin conformation and its iron forms, and the glycosylation variants were developed and used to study the quality of the finished product batches. The product had intact iron binding capacity and a native conformation. The results of several production batches indicated that the manufacturing could be carried out reproducibly. Product characterisation by electrospray and MALDI-TOF mass spectrometry indicated no other chemical modifications than N-linked glycan chains and disulphide bonds, except minor oxidation. A stable liquid formulation suitable for intravenous infusion was developed. The biochemical binding of NTBI to apotransferrin in vivo was studied by several methods. The bleomycin method for NTBI determination was modified for microwell measurement and evaluated. The bleomycin assay was reproducible and NTBI was found in serum samples only when transferrin saturation was > 80 % and haemolysed samples were excluded. The bleomycin assay that measures redox-active iron underestimated the true concentration of NTBI. The concentration of NTBI could be calculated from the shift of transferrin iron forms found in vivo after intravenous infusion of apotransferrin to patients. It could also be determined with a chelation based method, which, however, had a lower specificity than the bleomycin method. In haematological SCT patients, the concentration of NTBI could be as high as 20 µmol / l. Apotransferrin given in single intravenous doses to six patients bound NTBI effectively, although in most cases temporarily. With repeated high dose regimens, the appearance of NTBI was prevented in 5 of 8 patients. The influence of NTBI on the growth of the opportunistic pathogen Staphylococcus epidermidis was studied both with purified transferrin and in serum milieu. In both cases, growth was critically dependent on NTBI and on a high transferrin saturation. Only at high initial bacterial concentrations could growth be detected with partially saturated transferrin. Apotransferrin administered to SCT patients bound NTBI and restored the growth inhibitory effect of serum. Exogenous apotransferrin might protect the patients against infections by S. epidermidis and other opportunistic pathogens whose growth is dependent on NTBI. In conclusion, the apotransferrin was pure and safe and showed in vivo the biochemical effects that could be expected of a functional human apotransferrin product. In SCT patients it was possible to prevent the appearance of NTBI and maintain the bacterial growth inhibitory effect in serum.reviewe

Characterisation of Circulating Cell-free DNA in Women and Implications for the Development of an Ovarian Cancer Screening Test

Ovarian cancer (OC) has a poor 5-year survival rate due to common late-stage diagnosis impeding surgical resection. Shifting the diagnosis to early stage is therefore imperative for reducing mortality. Circulating cell-free DNA (cirDNA) is a promising biomarker for non-invasive population-wide OC screening, however, a clinically useful test requires highly optimised sensitivity and specificity. This thesis investigated potential artefacts of cirDNA with regard to stability during prolonged biospecimen storage, fluctuations during menstruation, and changes due to endometriosis. Herein we report our findings that may improve the specificity and technical validity of a cirDNA-based screening test with particular implications for OC. Firstly, the rarity of OC means that study cohorts can take years to accumulate. cirDNA stability was tracked in healthy women over up to two years of storage. cirDNA in both plasma and purified DNA deteriorated by 24.5% annually. Hence, the blood of control subjects in future studies should be collected and biobanked concurrently with test samples, to avoid artefacts due to different storage intervals. Secondly, high specificity is a prerequisite for OC population screening. OC originates from fallopian tube cells. In development, endometrium and fallopian tubes arise from a common precursor tissue and are thus likely to share methylation patterns, which may be a source of false positives in tests based on cirDNA methylation. This thesis investigated cirDNA changes during menstruation, a recurring physiological process in women, and endometriosis, a highly prevalent gynaecological disease, as potential sources of false-positive signals. Menstruation did not drive increases in total, endothelial or endometrial derived cirDNA, indicating that it is not a likely source of screening artefacts. Endometriosis is a disease characterised by the growth of endometrium-like tissue outside of the uterine cavity. Nonetheless, women with endometriosis did not have an elevated amount of either total or endometrial derived cirDNA, so we conclude that a false-positive test result from this disease is not likely. Therefore, neither menstruation nor endometriosis require additional screening exclusion criteria. In conclusion, careful attention to technical parameters and physiological fluctuations is important in maximising the sensitivity and specificity of a screening test, including one for OC. This will enable successful translation from basic research to clinical utility in the early OC diagnosis

Fibroblast growth factor 23: translating analytical improvement into clinical effectiveness for tertiary prevention in chronic kidney disease

Fibroblast growth factor 23 (FGF23) plays a key role in the pathophysiology of chronic kidney disease (CKD) and of the associated cardiovascular diseases, ranking on the crossroads of several evolving areas with a relevant impact on the health-care system (ageing, treatment of CKD and prevention from cardiovascular and renal events). In this review, we will critically appraise the overall issues concerning the clinical usefulness of FGF23 determination in CKD, focusing on the analytical performances of the methods, aiming to assess whether and how the clinical introduction of FGF23 may promote cost-effective health care policies in these patients