Hemodialysis is a renal replacement therapy that removes waste solutes from the blood stream using concentration gradients across a membrane. In order to overcome several shortcomings and increase the waste removal rate, a new dialyzer (filter) design is proposed in this study. In the new dialyzer design, the blood concurrently flows with a sheath fluid in a micro-fluidic channel. Because the blood stream directly contacts the sheath stream, it is important to prevent blood cell migration from the blood stream to the sheath stream while providing enough time for the waste solutes to diffuse into the sheath stream. This research was intended to understand the migration behavior of red blood cells (RBC) and platelets in non-uniform suspension flow, where the blood and sheath flows in direct contact, and apply the results to identify the feasible design space of the proposed dialyzer. The effect of different flow conditions and channel geometry on the blood cell extraction ratios (ER), the ratio of cells lost into the sheath stream, in non-uniform suspension flows was parametrically studied using Lattice Boltzmann and Spectrin Link (LB-SL) method based direct numerical simulation (DNS). Analyzing ER over the flow distance showed that the channel size and the area ratio of sheath to channel are the main variables that affect the ER. Based on the relationship found, a meta-model of RBC ER was created, although platelet ERs showed only a general trend. Based on the study, feasible conditions that will retain blood cells in the blood stream were identified. Then, the DNS results of blood cell ER were used with a molecule diffusion model and a hemodialysis system model to study the feasibility of the proposed dialyzer design that maximizes middle molecule filtration with limited blood cell and protein loss. No feasible design was found in the studied range suggesting that relying purely on the diffusion based on the direct contact for the removal of middle molecules is not a feasible solution with the small channel size (~700 µm) due to the loss of protein. It suggested that in order to increase the middle molecule removal while maintain the protein level, clearance ratio of middle molecule to protein should be increased using large channel size, small sheath stream thickness, long tubule length, and slow blood flow velocity. The intellectual merit of this research lies in understanding the migration behavior of blood cells in a non-uniform suspension. This knowledge helped to establish the feasibility of the proposed dialyzer design and can be applied in a variety of applications for the manipulation of cells in a micro-fluidic channel.

Cardiovascular disease is a major cause of mortality and morbidity in patients on chronic haemodialysis (HD). One main contributing factor is renal dyslipidaemia, characterized by an impaired catabolism of triglyceride (TG)-rich lipoproteins with accumulation of atherogenic remnant particles. The enzyme lipoprotein lipase (LPL) is a key molecule in the lipolysis of TG-rich lipoproteins into free fatty acids. The activity of LPL is reduced in HD-patients. This study was performed to elucidate various conditions and factors that may have an impact on LPL-related lipid metabolism. I. The functional pool of LPL is located at the vascular surface. The enzyme is released by heparin and low molecular weight heparins (LMWH) into the circulating blood and extracted and degraded by the liver. Heparin and LMWH are used for anticoagulation during HD to avoid clotting in the extracorporeal devices. This raises a concern that the LPL system may become exhausted by repeated administration of LMWH in patients on HD. In a randomized cross over designed study twenty patients on chronic HD were switched from a primed infusion of heparin to a single bolus of LMWH (tinzaparin).  The LPL activity in blood was higher on HD with LMWH at 40 minutes but lower at 180 minutes compared to HD with heparin. These values did not change during the 6-month study period. With heparin a significant TG reduction was found at 40 minutes and a significantly higher TG value at 180 and 210 minutes than at start. TG was higher during the HD-session with tinzaparin than with heparin. Our data demonstrate that repeated HD with heparin or with LMWH does not exhaust the LPL-system in the long term but does disturb the LPL system and TG metabolism during every HD session. II. In this study HD patients were compared with patients on peritoneal dialysis (PD) in a case control fashion. PD patients showed the same reaction of the LPL system to LMWH as HD patients. This confirmed that both HD and PD patients had the same, reduced, heparin-releasable LPL pool. The main difference was that in PD patients the TG continued to be cleared effectively even at 180 minutes after the bolus of LMWH injection. This may be due to a slower removal of the released LPL by the liver in PD patients.  III. In recent years, citrate (Citrasate) in the dialysate has been used in Sweden as a local anticoagulant for chronic HD. We performed a randomized cross over study that included 23 patients (16 men and 7 women) to investigate if citrate in the dialysate is safe and efficient enough as anticoagulant. The study showed that citrate anticoagulation eliminated the need of heparin or LMWH as anticoagulation for HD in half of the patients. However, individual optimization of doses of anticoagulants used together with citrate have to be made. IV. Recently angiopoietin-like proteins, ANGPTL3 and 4 have emerged as important modulators of lipid metabolism as potent inhibitors of LPL. Twenty-three patients on chronic HD and 23 healthy persons were included as case and controls to investigate the levels of these proteins in plasma of HD-patients and to evaluate if HD may alter these levels. The data showed that plasma levels of ANGPTL3 and 4 were increased in patients with kidney disease compared to controls. This may lead to inactivation of LPL. High flux-HD, but not low flux-HD, reduced the levels of ANGPTL4, while the levels of ANGPTL3 were not significantly influenced.  On HD with local citrate as anticoagulant, no LPL activity was released into plasma during dialysis in contrast to the massive release of LPL with heparin (LMWH). Citrate HD was not associated with a significant drop in plasma TG at 40 minutes, while both HD with citrate and heparin resulted in significantly increased TG levels at 180 minutes compared to the start values. Conclusions:  Citrate as a local anticoagulant during haemodialysis eliminates the need of heparin or LMWH in about half of the HD patients. Citrate does not induce release of LPL from its endothelial binding sites. We have shown that although HD with heparin causes release of the endothelial pool of LPL during each dialysis session, the basal pool is similarly low in PD patients that do not receive heparin. This indicates that the LPL pool is lowered as a consequence of the uraemia, per se. One explanation could be the increased levels of ANGPTL3 and 4. HD with high flux filters can temporarily lower the levels of ANGPTL4. Further studies are, however, needed to understand why LPL activity is low in patients with kidney disease.

Despite chronic dialysis treatment, patients with end stage renal disease undergoing maintenance haemodialysis (HD) remain at a substantially increased risk of morbidity. Previous reports using Doppler ultrasound (DU) during HD have revealed microembolic signals (ME) in the venous circulation. In vitro studies confirm the emergence of microbubbles of air that may pass the security system of the HD circuit without triggering the alarm. The aim of this thesis was to elucidate the presence of ME during HD and examine methods that might reduce exposure to ME in vivo. The first study utilized DU to verify the presence of ME in 40 patients during standard HD. Investigation within 30 minutes after the start of HD and just before the end of session revealed the presence of ME in the venous blood line during both phases. The air trap did not alert for the presence of ME. This indicated that ME may pass into the patient during the entire HD run. Study 2 analyzed the presence of ME prior to start and during HD when measured at the AV-access and also carotid artery. A total of 54 patients were examined using DU as the investigative technique. ME increased significantly after start of HD in the AV-access, but also at the carotid artery site. These data indicated that ME can enter the body and even pass the lung barrier. The question arose if microbubbles of air are resorbed or may cause ischemic lesions in organs such as the brain. Study 3 examined whether the amount of ME detected in the AV-access would change by using either a high or a low blood level in the venous air trap/chamber. This was a prospective, randomized and double-blind study of 20 HD patients who were their own controls. After 30 min of standard HD, measurement of ME with DU was performed for two minutes. The chamber setting was changed and after another 30 minutes a new recording was carried out for two minutes. Data showed that setting a high blood level significantly reduced the extent of ME that entered the patient. The results also indicated that ME consisted mainly of microbubbles. In study 4, twenty patients were randomized in a cross-over setting of HD. Three options were used: a wet-stored dialyzer with high blood level (WH) and a dry-stored dialyzer using either a high (DH) or a low (DL) blood level in the venous chamber. The exposure of ME, detected by DU, was least when using mode WF, more with mode DH, and most with mode DL. There was a correlation between higher blood flow and more extensive exposure to ME. Study 5 was an autopsy study of a chronic HD patient with the aim of searching for microbubbles deposited in organs. Microbubbles of gas were verified in the vessels of the lungs, brain and heart. By using a fluorescent stain of anti-fibrinogen it was verified that the microbubbles were covered by clots that had to be preformed before death occurred. This indicated that air microbubbles are not completely absorbed and could result in embolic deposition in the organs of HD patients. In conclusion, these in vivo studies showed that ME pass the air trap without inducing an alarm and enter the venous blood line of the patient. The data confirmed the presence of ME in the AV-access and also in the carotid artery. Autopsy data of a deceased HD patient demonstrated the presence of microbubbles in the capillaries of the lungs, but also in the systemic circulation such as in the brain and the heart. A high blood level in the venous chamber and wet-stored dialyzer can reduce, but not eliminate the exposure to microbubbles for patients undergoing HD.

Renal failure or kidney failure is a medical condition when the kidneys fail to filter toxins and waste products from the blood. Most of the time, problems encountered in kidney malfunction include abnormal fluid levels in the body, increased acid levels and abnormal levels of Urea, Glucose, Endothelin, β2-Microglobulin, Complement Factor D. In medicine, dialysis is a method that is used to remove waste products from blood when the kidneys are in a state of renal failure. Parameters characterizing the structure of dialyzers are very important because they decide overall clearance of toxin molecules and at the same time should allow retaining useful molecules in the blood. It is however not clear how the changes of dialyzer parameters will affect the clearance. This can be found out by doing simulation of a dialysis process. In this thesis, a numerical model was developed to simulate the process that goes on inside a dialyzer to determine which parameters are important for getting better clearance of toxin molecules and how the changes of those parameters can improve the performance of dialysis. In order to do that, a model of dialyzer membrane with details of the porosity is necessary. The dialyzer membrane that was considered in this research was Polyflux 210H. Here the cross sectional images of Polyflux 210H dialyzer membrane were taken by FESEM (Field Emission Scanning Electron Microscope) to obtain the porosity values of different layers. Using these porosity values, a multilayered membrane model was developed in Finite Element Software- COMSOL Multiphysics 4.3. Then a blood flow containing - Urea, Glucose, Endothelin, β2-Microglobulin, Complement Factor D and Albumin was introduced. For a certain blood flow rate the toxins diffuse through the membrane and on the other side of the membrane a dialysate flow was introduced to remove the toxins. Two different definitions of effective diffusivity were considered for the phenomenon of the diffusion of the molecules in the membrane. Between the two, the better definition was found out by comparing the results with experimental data of the manufacturer of Polyflux 210H. Then for the chosen definition, further analysis was done and the results were compared with another set of experimental data to validate the model. Then different parameters - magnitude and direction of both blood and dialysate flow, length and diameter of the fiber, pore sizes were changed to simulate how these changes affect toxin clearance and the removal of useful molecules. The results suggest some very interesting points to achieve better dialysis performance. First of all, the clearance rate of both Urea and Glucose increase rapidly with the increasing blood flow rate. When a maximum allowable blood flow rate is attained, increasing the dialysate flow rate can ensure better clearance rate for Urea and Glucose. In both the cases of increasing radius or length of the dialyzer fiber, the clearance rate of Glucose increases more rapidly than the clearance rate of Urea. For Endothelin and β2-Microglobulin the clearance rate increases twice compared to the initial condition. Meanwhile, the clearance rate of Albumin does not change that much. Also increasing the pore diameter up to 20 nm (but not more than that) can ensure higher clearance rate of Urea and Glucose, moderate clearance rate of middle molecules and minimum loss of Albumin.

The topic of this diploma thesis is the design of a device for dialysis, which is intended for medical institutions. During this thesis existing products were analyzed from the design and technical side. Also was achieved an understanding of the problem of existing dialysis devices. The result is a new conceptual solution with an emphasis on creating clean forms of equipment and taking into ergonomic, technical and aesthetic requirements.

The effects of the dialysis membranes, hemodialysis (HD) session, and dialyzer reuse on markers of oxidative stress were studied. Patients with end stage renal disease who have undergone regular HD treatment three times a week were randomized in two study groups according to the type of HD membrane (cellulose acetate membrane (CA) vs. polysulfone membrane (PS)). All the patients participated of the two study groups and used the two different membranes. To analyze the parameters, the blood samples were colleted before and after HD sessions, in the irst use, 6th, 12th reuse of the membranes. The indicator parameters of oxidative stress analyzed were thiobarbituric acid reactive species (TBARS) and dichlorofluorescein reactive species (DRS) levels, carbonyl groups, antioxidant enzyme (catalase (CAT), superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px)), and non-enzymatic antioxidant (protein (PSH) and non-protein thiol groups (NPSH) and vitamin C). The results demonstrated that there was no significant difference in the markers of oxidative stress between the two membranes used. However, HD session contributed to the increase in TBARS (1st use and the 6th reuse), DRS (6th and 12th reuse), protein (all uses) and NPSH (1st use and 6th reuse) levels, GSH-Px activity (12th reuse) and to the decrease in vitamin C levels (all uses). The dialyzer reuse practice contributed to the increase in the PSH levels, to the decrease in the NPSH levels and to the reduction of the effects of the HD session on the TBARS levels. Therefore, the results obtained from this study revealed that regular HD with CA or PS membranes did not interfere with the oxidative status in the patients. However, HD session may contribute to the increase of oxidative stress and the dialyzer reuse practice appears to be efficient in the reduction of the peroxidation lipidic in these patients / Neste trabalho, foram investigados os efeitos do tipo de membrana de hemodiálise (HD) e da sua reutilização, bem como os efeitos da sessão de HD nos marcadores de estresse oxidativo. Pacientes com insuficiência renal crônica que realizavam HD três vezes por semana foram divididos em dois grupos, de acordo com o tipo de membrana usada (membrana de acetato de celulose (AC) X membrana de polisulfona (PS)). Todos os pacientes participaram dos dois grupos e usaram os dois tipos de membrana. Para análise dos parâmetros, amostras de sangue foram coletadas antes e após a sessão de HD, no 1º uso, 6º e 12º reuso das membranas. Os parâmetros indicadores de estresse oxidativo analisados foram: espécies reativas ao ácido tiobarbitúrico (TBARS), espécies reativas a diclorofluoresceína (DRS), carbonilação de proteínas, antioxidantes enzimáticos (catalase, superóxido dismutase e glutationa peroxidase (GSH-Px)) e antioxidantes não-enzimáticos (grupos tióis protéicos (PSH), grupos tióis não-protéicos (NPSH) e vitamina C). Os resultados demonstraram que não houve diferença significativa nos marcadores do estresse oxidativo entre as duas membranas usadas. Entretanto, houve um aumento dos níveis de TBARS após a sessão de HD (no 1º uso e no 6º reuso), de DRS (6º e 12º reuso), de PSH (em todos os usos), de NPSH (1º uso e 6º reuso), da atividade da GSH-Px (no 12º reuso) e uma diminuição dos níveis de vitamina C após a sessão de HD (em todos os usos). A reutilização das membranas contribuiu para o aumento dos níveis de PSH, para a diminuição dos níveis de NPSH e diminuiu os efeitos da sessão de HD sobre os níveis de TBARS. Portanto, os resultados obtidos neste estudo sugerem que HD com membrana de AC ou de PS não interfere de forma diferente nos marcadores de estresse oxidativo. Entretanto, a sessão de HD pode contribuir para o aumento da geração de estresse oxidativo e a reutilização dos dialisadores parece ser eficiente como forma de redução da peroxidação lipídica nos pacientes em HD