Numerous in vivo studies on the ketogenic diet, a diet that can induce metabolic conditions resembling those following extended starvation, demonstrate strong outcomes on cancer survival, particularly when combined with chemo-, radio- or immunological treatments. However, the therapeutic application of ketogenic diets requires strict dietary adherence from well-informed and motivated patients, and it has recently been proposed that hemodialysis might be utilized to boost ketosis and further destabilize the environment for cancer cells. Yet, plasma ketones may be lost in the dialysate—lowering blood ketone levels. Here we performed a single 180-min experimental hemodialysis (HD) session in six anesthetized Sprague–Dawley rats given ketogenic diet for five days. Median blood ketone levels pre-dialysis were 3.5 mmol/L (IQR 2.2 to 5.6) and 3.8 mmol/L (IQR 2.2 to 5.1) after 180 min HD, p = 0.54 (95% CI − 0.6 to 1.2). Plasma glucose levels were reduced by 36% (− 4.5 mmol/L), p < 0.05 (95% CI − 6.7 to − 2.5). Standard base excess was increased from − 3.5 mmol/L (IQR − 4 to − 2) to 0.5 mmol/L (IQR − 1 to 3), p < 0.01 (95% CI 2.0 to 5.0). A theoretical model was applied confirming that intra-dialytic glucose levels decrease, and ketone levels slightly increase since hepatic ketone production far exceeds dialytic removal. Our experimental data and in-silico modeling indicate that elevated blood ketone levels during ketosis are maintained during hemodialysis despite dialytic removal.

In recent years, dopamine has stood out as an all-round talent in the field of membrane modification. Membranes post-modified with polydopamine or made out of materials pre-modified with polydopamine show applicability in almost all membrane processes. These approaches have in common that they require additional fabrication steps to accomplish the final membrane product. In this study, the first part presents the post-modification of hollow fiber membrane modules with polydopamine. The resulting coated membranes suit further functionalization and exhibit excellent properties. The successful coating of commercial dialysis membranes with polydopamine and heparin while maintaining their selectivities for proteins present in human blood is highlighted in this work. Further and most importantly, membranes are successfully in-situ modified with polydopamine using the 'chemistry-in-a-spinneret' technology base. Flat sheet and hollow fiber membranes with polydopamine modification evolve in a single-step process. The polydopamine functionalized membranes exhibit increased anti-fouling properties and bind heparin on their surface. The 'chemistry-in-a-spinneret' approach fabricates directly polydopamine-functionalized membranes. These membranes have promising properties for application in the field of hemodialysis and pave the way for applications in other membrane processes.

Background A retrospective analysis of SUPERNOVA trial data showed that reductions in tidal volume to ultraprotective levels without significant increases in arterial partial pressure of carbon dioxide (PaCO2) for critically ill, mechanically ventilated patients with acute respiratory distress syndrome (ARDS) depends on the rate of extracorporeal carbon dioxide removal (ECCO2R). Methods We used a whole-body mathematical model of acid-base balance to quantify the effect of altering carbon dioxide (CO2) removal rates using different ECCO2R devices to achieve target PaCO2 levels in ARDS patients. Specifically, we predicted the effect of using a new, larger surface area PrismaLung+ device instead of the original PrismaLung device on the results from two multicenter clinical studies in critically ill, mechanically ventilated ARDS patients. Results After calibrating model parameters to the clinical study data using the PrismaLung device, model predictions determined optimal extracorporeal blood flow rates for the PrismaLung+ and mechanical ventilation frequencies to obtain target PaCO2 levels of 45 and 50 mm Hg in mild and moderate ARDS patients treated at a tidal volume of 3.98 ml/kg predicted body weight (PW). Comparable model predictions showed that reductions in tidal volumes below 6 ml/kg PBW may be difficult for hypercapnic mechanically ventilated ARDS patients with acute kidney injury and high CO2 production rates using a PrismaLung+ device in-series with a continuous venovenous hemofiltration device. Conclusions The described model provides guidance on achieving target PaCO2 levels in mechanically ventilated ARDS patients using protective and ultraprotective tidal volumes when increasing CO2 removal rates from ECCO2R devices.

Patients with acute respiratory distress syndrome and acute kidney injury (AKI) treated by kidney replacement therapy may also require treatment with extracorporeal carbon dioxide removal (ECCO2 R) devices to permit protective or ultraprotective mechanical ventilation. We developed a mathematical model of acid-base balance during extracorporeal therapy using ECCO2 R and continuous venovenous hemofiltration (CVVH) devices applied in series for the treatment of mechanically ventilated AKI patients. Published data from clinical studies of mechanically ventilated AKI patients treated by CVVH at known infusion rates of substitution fluid without ECCO2 R were used to adjust the model parameters to fit plasma levels of arterial partial pressure of carbon dioxide (PaCO2 ), arterial plasma bicarbonate concentration ([HCO3 ]), and plasma pH (as well as certain other unmeasured physiological variables). The effects of applying ECCO2 R at an unchanged and a reduced tidal volume on PaCO2 , [HCO3 ] and plasma pH were then simulated assuming carbon dioxide removal rates from the ECCO2 R device measured in the clinical studies. Agreement of such model predictions with clinical data was good whether the ECCO2 R device was positioned proximal or distal to the CVVH device in the extracorporeal circuit. Although carbon dioxide removal rates from the ECCO2 R device measured in one previous clinical study were higher when it was placed proximal to the CVVH device, suggesting that such in-series positioning was optimal, the current mathematical model demonstrates that proximal positioning of the ECCO2 R device also results in lower bicarbonate (and, therefore, total carbon dioxide) removal from the distal CVVH device. Thus, the removal of total carbon dioxide by such extracorporeal circuits is relatively independent of the position of the in-series devices. It is concluded that the described mathematical model has quantitative accuracy; these results suggest that the overall acid-base balance when using ECCO2 R and CVVH devices in a single extracorporeal circuit will be similar, independent of their in-series position.

Abstract Background and Aims Critically ill acute kidney injury (AKI) patients may require treatment by extracorporeal carbon dioxide removal (ECCO2R) devices to allow protective or ultraprotective mechanical ventilation and avoid hypercapnic acidosis. Continuous venovenous hemofiltration (CVVH) and ECCO2R devices can be arranged in series to form a single extracorporeal circuit; such a circuit has been proposed to be optimal, based carbon dioxide removal efficacy, if the ECCO2R device is placed proximal to the CVVH device (Allardet-Servent et al, Crit Care Med 43:2570-2581, 2015). Method We developed a mathematical model of whole-body, acid-base balance during extracorporeal therapy using in-series ECCO2R and CVVH devices for treatment of mechanically ventilated AKI patients. Equilibrium acid-base chemistry in blood was assumed as reported previously (Rees and Andreassen, Crit Rev Biomed Eng 33:209-264, 2005). Published clinical data from Allardet-Servent et al of mechanically ventilated (6 mL/kg predicted body weight or PBW) AKI patients treated by CVVH without ECCO2R were used to adjust model parameters to fit plasma levels of arterial partial pressure of carbon dioxide (PaCO2) and arterial plasma bicarbonate concentration ([HCO3]). The effects of applying ECCO2R at an unchanged tidal volume and a reduced tidal volume (4 mL/kg PBW) on PaCO2 and [HCO3] were then simulated assuming carbon dioxide removal rates from the ECCO2R device measured in the clinical study (91 mL of CO2/min when ECCO2R was proximal and 72 mL of CO2/min when CVVH was proximal). Results Agreement of model predictions with the clinical data was good, and model predictions were relatively independent of the in-series position of the devices (see Table). Total carbon dioxide removal from the CVVH device via ultrafiltration predicted by the model was lower after applying ECCO2R at both the unchanged tidal volume (25 mL of CO2/min when ECCO2R was proximal and 39 mL of CO2/min when CVVH was proximal) and the reduced tidal volume (30 mL of CO2/min when ECCO2R was proximal and 44 mL of CO2/min when CVVH was proximal). The reduced removal of total carbon dioxide via ultrafiltration when ECCO2R was proximal resulted from the lower total carbon dioxide concentration in blood entering the CVVH device. Thus, independent of the in-series position of the devices, the magnitude of this difference in total carbon dioxide removal by the CVVH device (14 mL of CO2/min) approximately cancels out the relative greater efficacy of the ECCO2R device (19 mL of CO2/min). Conclusion The described mathematical model has quantitative accuracy. It suggests that overall acid-base balance when using ECCO2R and CVVH devices in a single, combined extracorporeal circuit will be similar, independent of their in-series position.

Abstract Background Invasive mechanical ventilation is lifesaving in the setting of severe acute respiratory failure but can cause ventilation-induced lung injury. Advances in extracorporeal CO2 removal (ECCO2R) technologies may facilitate more protective lung ventilation in acute respiratory distress syndrome, and enable earlier weaning and/or avoid invasive mechanical ventilation entirely in chronic obstructive pulmonary disease exacerbations. We evaluated the in vitro CO2 removal capacity of the novel PrismaLung+ ECCO2R device compared with two existing gas exchangers. Methods The in vitro CO2 removal capacity of the PrismaLung+ (surface area 0.8 m2, Baxter) was compared with the PrismaLung (surface area 0.35 m2, Baxter) and A.L.ONE (surface area 1.35 m2, Eurosets) devices, using a closed-loop bovine blood–perfused extracorporeal circuit. The efficacy of each device was measured at varying pCO2 inlet (pinCO2) levels (45, 60, and 80 mmHg) and blood flow rates (Q B) of 200–450 mL/min; the PrismaLung+ and A.L.ONE devices were also tested at a Q B of 600 mL/min. The amount of CO2 removed by each device was assessed by measurement of the CO2 infused to maintain circuit equilibrium (CO2 infusion method) and compared with measured CO2 concentrations in the inlet and outlet of the CO2 removal device (blood gas analysis method). Results The PrismaLung+ device performed similarly to the A.L.ONE device, with both devices demonstrating CO2 removal rates ~ 50% greater than the PrismaLung device. CO2 removal rates were 73 ± 4.0, 44 ± 2.5, and 72 ± 1.9 mL/min, for PrismaLung+, PrismaLung, and A.L.ONE, respectively, at Q B 300 mL/min and pinCO2 45 mmHg. A Bland–Altman plot demonstrated that the CO2 infusion method was comparable to the blood gas analysis method for calculating CO2 removal. The resistance to blood flow across the test device, as measured by pressure drop, varied as a function of blood flow rate, and was greatest for PrismaLung and lowest for the A.L.ONE device. Conclusions The newly developed PrismaLung+ performed more effectively than PrismaLung, with performance of CO2 removal comparable to A.L.ONE at the flow rates tested, despite the smaller membrane surface area of PrismaLung+ versus A.L.ONE. Clinical testing of PrismaLung+ is warranted to further characterize its performance.

Background. Ultrafiltration failure (UFF) in peritoneal dialysis (PD) patients is due to altered peritoneal transport properties leading to reduced capacity to remove excess water. Here, with the aim to establish the role of local alterations of the two major transport barriers, peritoneal tissue and capillary wall, we investigate changes in overall peritoneal transport characteristics in UFF patients in relation to corresponding local alterations of peritoneal tissue and capillary wall transport properties. Methods. Six-hour dwell studies using 3.86% glucose solutions and radioisotopically labelled serum albumin added to dialysate as a volume marker were analysed in 31 continuous ambulatory PD patients, 20 with normal ultrafiltration (NUF) and 11 with UFF. For each patient, the physiologically based parameters were evaluated for both transport barriers using the spatially distributed approach based on the individual intraperitoneal profiles of volume and concentrations of glucose, sodium, urea and creatinine. Results. UFF patients as compared with NUF patients had increased solute diffusivity in both barriers, peritoneal tissue and capillary wall, decreased tissue hydraulic conductivity and increased local lymphatic absorption and functional decrease in the fraction of the ultra-small pores. This resulted in altered distribution of fluid and solutes in the peritoneal tissue, and decreased penetration depths of fluid and solutes into the tissue in UFF patients. Conclusions. Mathematical modelling using a spatially distributed approach for the description of clinical data suggests that alterations both in the capillary wall and in the tissue barrier contribute to UFF through their effect on transport and distribution of solutes and fluid within the tissue.

Middle molecules (MMs) are associated with the pathology of uraemia, and are not effectively removed by standard extracorporeal treatments. Increased convection used in haemodiafiltration (HDF) can enhance the removal of MMs; however, high-volume HDF is not available to all patients. The new medium cut-off (MCO) membrane has been developed to allow increased removal of MMs using standard haemodialysis (HD). Improved removal of MMs has been shown with the MCO membrane compared with standard high-flux dialysers, but it is not known whether the increased pore size affects the retention of commonly used medications or that of coagulation factors in dialysis patients. Using an in vitro model, the retention of erythropoietin, heparin, insulin, vancomycin and several coagulation factors (Factors II, VII and X, protein C and antithrombin III) was investigated with the MCO membrane dialyser, compared with high-flux dialysers with polysulfone (in HDF) or polyethersulfone membranes (in HD and HDF). The retention of all molecules investigated was comparable between the MCO membrane and the high-flux dialysers. Results from the in vitro studies suggest that switching from a high-flux dialyser to the MCO membrane should not require changes to the medication dosing or anticoagulation protocols of dialysis patients.

The recent development of dialyzers equipped with medium cut-off membranes has made it possible to perform a new technique, termed expanded hemodialysis, in which the removal of middle molecular weight solutes from patients suffering from end-stage kidney disease is increased by enhanced internal filtration, without requiring complex setup and fluid reinfusion, as in hemodiafiltration. A systematic analysis of the effect of all dialyzer design parameters on the rate of internal filtration has not been reported yet. This makes it difficult to develop optimized dialyzers in which internal filtration rate is maximized to enhance convective transport of solutes from the patient's blood. In this paper, a mathematical model of transport recently developed is used to investigate the effect of the geometrical and transport-related dimensionless groups determining momentum transport in dialyzers, identified with dimensional analysis, on the rate of internal filtration. Model predictions show that filtration fraction can be maximized by increasing the value of the membrane pressure modulus and the packing density. Dialyzers design can be optimized for maximal filtration fraction by combining design parameters so that the values of the membrane pressure modulus and the packing density range between 0.39 and 0.42, and between 55% and 60%, respectively.

Background In multiple myeloma, severe acute kidney injury due to myeloma cast nephropathy is caused by pathogenic free light chain immunoglobulin in serum. High cutoff haemodialysis (HCO-HD) can remove large quantities of free light chain immunoglobulin from serum, but its effect on clinical outcomes is uncertain. We therefore aimed to assess whether HCO-HD could increase the frequency of renal recovery in patients with de novo multiple myeloma, severe acute kidney injury, and myeloma cast nephropathy relative to treatment with standard high-flux haemodialysis (HF-HD). Methods In this open-label, phase 2, multicentre, randomised controlled trial (EuLITE), we recruited patients with newly diagnosed multiple myeloma, biopsy-confirmed cast nephropathy, and acute kidney injury that required dialysis from renal services in 16 hospitals in the UK and Germany. Patients were randomly assigned (1:1) by random number generation to receive intensive HCO-HD (in sessions lasting 6-8 h) or standard HF-HD and they were stratified by age and centre. Patients and the medical staff treating them were not masked to treatment allocation. Patients received bortezomib, doxorubicin, and dexamethasone chemotherapy, and were then followed up for 2 years. The primary outcome was independence from dialysis at 90 days after random allocation to groups, which was assessed in an intention-to-treat population. The trial has completed follow-up, and is registered at the ISRCTN registry, number ISRCTN45967602. Findings Between June 7, 2008, and Sept 18, 2013, we recruited 90 patients, of whom 43 (48%) were randomly assigned to receive HCO-HD and 47 (52%) were randomly assigned to receive HF-HD. All 90 patients were included in the analysis of the primary outcome. One (2%) patient from the HF-HD group withdrew consent before receiving treatment. During treatment, nine (21%) patients from the HCO-HD group and two (4%) patients in the HF-HD group discontinued trial treatment. After 90 days, 24 (56%) patients in the HCO-HD group and 24 (51%) patients in the HF-HD group were independent from dialysis (relative risk 1 . 09, 95% CI 0 . 74-1 . 61; p= 0 . 81). During the 2-year follow-up, 98 serious adverse events were reported in the HCO-HD group and 82 serious adverse events were reported in the HF-HD group. The most common serious adverse events were infections and adverse events related to the cardiovascular and thrombotic and musculoskeletal systems. During the first 90 days, 26 infections were reported in the HCO-HD group and 13 infections were reported in the HF-HD group, including 14 lung infections in the HCO-HD group and three lung infections in the HF-HD group. Interpretation In this phase 2 study, HCO-HD did not improve clinical outcomes for patients with de novo multiple myeloma and myeloma cast nephropathy who required haemodialysis for acute kidney injury and who received a bortezomib-based chemotherapy regimen relative to those receiving HF-HD. These results do not support proceeding to a phase 3 study for HCO-HD in these patients.

Modern methods in analytical biochemistry have established that uraemia is associated with the retention of proteins, both in their native state and post-translationally modified, over a wide range of molecular weights up to 60 kDa. Evidence is accumulating that these higher molecular weight retention solutes are important uraemic toxins, and therapies such as online haemo-diafiltration (HDF), which enhance their removal, are associated with improved outcomes. However, HDF has limitations regarding cost, clinical implementation and the need for an external source of sterile substitution solution to maintain fluid balance. New membranes that have a solute removal profile more closely approaching that of the glomerular filtration barrier when used for conventional haemodialysis, while at the same time not allowing the passage of clinically significant amounts of beneficial proteins, are needed to address these limitations. Tighter control of the molecular characteristics of the polymers used for membrane fabrication, along with the introduction of additives and improvements in the manufacturing process, has led to membranes with a tighter pore size distribution that allows the use of an increased absolute pore size without leaking substantial amounts of albumin. At the same time, the wall thickness and internal diameter of membrane fibres have been decreased, enhancing convective transport within the dialyser without the need for an external source of substitution solution. These new expanded range membranes provide a solute removal profile more like that of the native kidney than currently available membranes when used in conventional haemodialysis.

Background:Vascular calcification is enhanced in uraemic chronic haemodialysis patients, likely due to the accumulation of midsize uraemic toxins, such as interleukin 6 (IL-6) and tumor necrosis factor-alpha (TNF-α). Here we have assessed the impact of uraemia on vascular smooth muscle cell (VSMC) calcification and examined the role of IL-6 and TNF-α as possible mediators and, most importantly, its underlying signalling pathway in VSMCs.Methods:VSMCs were incubated with samples of uraemic serum obtained from patients treated with haemodialysis for renal failure in the Permeability Enhancement to Reduce Chronic Inflammation-I clinical trial. The VSMCs were assessed for IL-6 gene regulation and promoter activation in response to uraemic serum and TNF-α with reporter assays and electrophoretic mobility shift assay and for osteoblastic transition, cellular calcification and cell viability upon osteogenic differentiation.Results:Uraemic serum contained higher levels of TNF-α and IL-6 compared with serum from healthy individuals. Exposure of VSMCs to uraemic serum or recombinant TNF-α lead to a strong upregulation of IL-6 mRNA expression and protein secretion, which was mediated by activator protein 1 (AP-1)/c-FOS-pathway signalling. Uraemic serum induced osteoblastic transition and calcification of VSMCs could be strongly attenuated by blocking TNF-α, IL-6 or AP-1/c-FOS signalling, which was accompanied by improved cell viability.Conclusion:These results demonstrate that uraemic serum contains higher levels of uraemic toxins TNF-α and IL-6 and that uraemia promotes vascular calcification through a signalling pathway involving TNF-α, IL-6 and the AP-1/c-FOS cytokine-signalling axis. Thus treatment modalities aiming to reduce systemic TNF-α and IL-6 levels in chronic haemodialysis patients should be evaluated in future clinical trials.

Background. High mortality of haemodialysis patients is associated with systemic chronic inflammation and overactivation of the renin-angiotensin system (RAS). Insufficient elimination of pro-inflammatory immune mediators, especially in the molecular weight range of 15-45 kDa, may be one of the reasons for this. Employment of haemodialysis membranes with increased permeability was shown to ameliorate the inflammatory response and might modulate the effects of local RAS. In this study, we tested the impact of high cut-off (HCO), medium cut-off (MCO) and high-flux (HF) dialysis on leucocytic transcripts of angiotensin-converting enzymes (ACE and ACE2). Additionally, the impact of HCO, MCO and HF sera and dialysates on local ACEs and inflammation markers was tested in THP-1 monocytes. Methods. Patients' leucocytes were obtained from our recent clinical studies comparing HCO and MCO dialysers with HF. The cells were subjected to quantitaive polymerase chain reaction (qPCR) analyses with TaqMan probes specific for ACE, ACE2 and angiotensin II (AngII) and Ang1-7 receptors. Sera and dialysates from the clinical trials as well as samples from in vitro dialysis were tested on THP-1 monocytic cells. The cells were subjected to qPCR analyses with TaqMan probes specific for ACE, ACE2, interleukin-6 and tumour necrosis factor a and immunocytochemistry with ACE and ACE2 antibodies. Results. Leucocytes obtained from patients treated with HCO or MCO demonstrated decreased transcript expression of ACE, while ACE2 was significantly upregulated as compared with HF. Receptors for AngII and Ang1-7 remained unchanged. THP-1 monocytes preconditioned with HCO and MCO patients' or in vitro dialysis sera reflected the same expressional regulation of ACE and ACE2 as those observed in HCO and MCO leucocytes. As a complementary finding, treatment with HCO and MCO in vitro dialysates induced a pro-inflammatory response of the cells as demonstrated by elevated messenger RNA expression of tumour necrosis factor a and interleukin-6, as well as upregulation of ACE and decreased levels of ACE2. Conclusions. Taken together, these data demonstrate that employment of membranes with high permeability eliminates a spectrum of mediators from circulation that affect the RAS components in leucocytes, especially ACE/ACE2.

Background. The kinetics of beta(2)-microglobulin during hemodialysis and hemodiafiltration is well described by a two-compartment model where clearance by the dialyzer is from a central compartment volume that approximates plasma volume and a total distribution volume that approximates extracellular fluid volume. The kinetics of middle molecules with molecular weights larger than beta(2)-microglobulin have not been extensively studied. Methods. Intradialytic plasma concentrations and overall dialyzer clearances of beta(2)-microglobulin (11.8 kD), myoglobin (16.7 kD) and complement factor D (24.4 kD) were used to estimate three kinetic parameters from a two-compartment model, namely intercompartmental clearance, central compartment volume and total distribution volume, in hemodialysis patients; these data were collected during two clinical trials of medium cut-off dialyzers (with extended middle molecule removal) during hemodialysis and high-flux dialyzers during hemodialysis and hemodiafiltration. In the current exploratory analyses, the kinetic parameters from all dialyzers were combined. Overall dialyzer clearance was evaluated by total mass removed in the dialysate. Results. In total, 345 sets of kinetic parameters from 35 patients were determined. Intercompartmental clearance and central compartment volume for myoglobin and complement factor D were smaller (P < 0.001) than those for beta(2)-microglobulin. Independent of middle molecule, intercompartmental clearance and central compartment volume were associated with overall dialyzer clearance (P < 0.001), but total distribution volume was not (P = 0.083). Conclusions. A two-compartment kinetic model can only describe intradialytic kinetics of middle molecules with molecular weights larger than beta(2)-microglobulin if the central compartment is small and dependent on overall dialyzer clearance.

Objectives: In critically ill patients with acute kidney injury receiving vasopressors, high cytokine levels may sustain the shock state. High cutoff hemofiltration achieves greater cytokine removal in ex vivo and in animal models and may reduce the duration of shock but may also increase albumin losses. Design: This was a single-center double-blind randomized controlled trial comparing continuous venovenous hemofiltration-high cutoff to continuous venovenous hemofiltration-standard. Setting: Tertiary care hospital in Australia. Patients: Vasopressor-dependent patients in acute kidney injury who were admitted to the ICU. Interventions: Norepinephrine-free time were calculated in critically ill vasopressor-dependent patients in acute kidney injury, randomized to either continuous venovenous hemofiltration-high cutoff or continuous venovenous hemofiltration-standard. Measurement and Main Results: A total of 76 patients were randomized with the following characteristics (continuous venovenous hemofiltration-high cutoff vs continuous venovenous hemofiltration-standard); median age of 65 versus 70 year, percentage of males 47% versus 68%, and median Acute Physiology and Chronic Health Evaluation scores of 25 versus 23.5. The median hours of norepinephrine-free time at day 7 were 32 (0–110.8) for continuous venovenous hemofiltration-high cutoff and 56 hours (0–109.3 hr) (p = 0.520) for continuous venovenous hemofiltration-standard. Inhospital mortality was 55.6% with continuous venovenous hemofiltration-high cutoff versus 34.2% with continuous venovenous hemofiltration-standard (adjusted odds ratio, 2.49; 95% CI, 0.81–7.66; p = 0.191). There was no significant difference in time to cessation of norepinephrine (p = 0.358), time to cessation of hemofiltration (p = 0.563), and filter life (p = 0.21). Serum albumin levels (p = 0.192) were similar and the median dose of IV albumin given was 90 grams (20–212 g) for continuous venovenous hemofiltration-high cutoff and 80 grams (15–132 g) for continuous venovenous hemofiltration-standard (p = 0.252). Conclusions: In critically ill patients with acute kidney injury, continuous venovenous hemofiltration-high cutoff did not reduce the duration of vasopressor support or mortality or change albumin levels compared with continuous venovenous hemofiltration-standard.

Despite advances in renal replacement therapy, the adequate removal of uremic toxins over a broad molecular weight range remains one of the unmet needs in hemodialysis. Therefore, membrane innovation is currently directed towards enhanced removal of uremic toxins and increased membrane permeability. This chapter presents a variety of opportunities where innovation is brought into dialysis membranes. It covers the membrane formation from solution, describing different approaches to control the phase inversion process through additives that either swell in the polymer solution or influence the pore shrinkage during the membrane drying process. Additionally, large-scale manufacturing is described, and the influence of raw materials, spinning, and drying processes on membrane selectivity are presented. Finally, new characterization methods developed for the latest innovations around the application of membranes in dialysis are discussed, which allow the membrane performance for removal of a broad range of uremic toxins and the expected albumin loss in clinical use.

Background: Vascular calcification is a common phenomenon in patients with chronic kidney disease and strongly associated with increased cardiovascular mortality. Vascular calcification is an active process mediated in part by inflammatory processes in vascular smooth muscle cells (VSMC). These could be modified by the insufficient removal of proinflammatory cytokines through conventional high-flux (HF) membranes. Recent trials demonstrated a reduction of inflammation in VSMC by use of dialysis membranes with a higher and steeper cut-off. These membranes caused significant albumin loss. Therefore, the effect of high retention Onset (HRO) dialysis membranes on vascular calcification and its implications in vitro was evaluated. Methods: In the PERCI II trial, 48 chronic dialysis patients were dialyzed using HF and HRO dialyzers and serum samples were collected. Calcifying VSMC were incubated with the serum samples. Calcification was determined using alizarin red staining (AZR) and determination of alkaline phosphatase (ALP) activity. Furthermore, apoptosis was evaluated, and release of matrix Gla protein (MGP), osteopontin (OPN) and growth differentiation factor 15 (GDF-15) were measured in cell supernatants. Results: Vascular calcification in vitro was significantly reduced by 24% (ALP) and 36% (AZR) after 4 weeks of HRO dialysis and by 33% (ALP) and 48% (AZR) after 12 weeks of dialysis using HRO membranes compared to HF dialysis. Apoptosis was significantly lower in the HRO group. The concentrations of MGP and OPN were significantly elevated after incubation with HF serum compared to HRO serum and healthy controls. Similarly, GDF-15 release in the supernatant was elevated after incubation with HF serum, an effect significantly ameliorated after treatment with HRO medium. Conclusions: Expanded haemodialysis therapy reduces the pro-calcific potential of serum from dialysis patients in vitro. With a markedly reduced albumin filtration compared to high cut-off dialysis, use of the HRO dialyzers may possibly provide a treatment option for chronic dialysis patients to reduce the progression of vascular calcification.

Renal failure (RF) is characterized by the loss of the ability of the kidneys to excrete wastes, concentrate urine, conserve electrolytes, and maintain fluid balance. Acute kidney injury can be a life-threatening illness, with a mortality of between 50% and 80% (3). ESRD occurs in the late stages of chronic kidney disease and is associated with an irreversible loss of kidney function. Renal replacement therapy (RRT) replaces kidney function in patients with both types of renal failure. There are 2 possible alternatives to treat chronic RF: organ transplantation or, more commonly, dialysis. However, the natural secretion of kidney hormones, which influences blood pressure, cannot be achieved with dialysis treatment modalities. Over 2 million people worldwide currently receive treatment with dialysis or a kidney transplant to stay alive, yet this number may represent only 10% of people who actually need treatment to live (4). Of the 2 million people who receive treatment for kidney failure, the majority are treated in only 5 countries: the United States, Japan, Germany, Brazil, and Italy. These 5 countries represent only 12% of the world population. Only 20% are treated in approximately 100 developing countries that make up over 50% of the world population (4). In medicine, hemodialysis (HD) is the process of removing blood from a patient, purifying the blood through an artificial kidney (dialyzer), and then returning it to the patient’s bloodstream. On the basis of the developments of Willem Kolff and Nils Alwall in the 1940s, the dialyzer membrane systems have undergone multiple development cycles and are now the basis of an effective, reliable, and cost-effective treatment approach. In the early days of dialysis, large and unwieldy plate dialyzers made of cellulose membranes were used. Until the 1970s, cellulosic membranes were used exclusively and represented the majority of membranes used in hemodialysis worldwide (5). DOI: 10.5301/ijao.5000603

A systematic analysis of the effect of all the dialyzer-related factors on solute clearance has not been reported in the literature, making it difficult to optimize dialyzer design to maximize solute removal from patient's blood. In this paper, a two-dimensional axisymmetric mathematical model of momentum and mass transport in dialyzers is proposed to investigate the effect of the most relevant geometrical and operational dimensionless groups on solute clearance. Navier-Stokes and Darcy-Brinkman equations are used to describe steady-state momentum transport in blood and dialysate compartments, and across the membrane, respectively. Transport of low and middle molecular weight solutes from the blood through the membrane into the dialysate compartment is described with convection-diffusion equations. The effect of non-Newtonian blood behavior and concentration polarization is also taken into account. The complete set of dimensionless groups determining dialyzer efficiency is obtained from dimensional analysis of model equations. Their effect on solute clearances is investigated by solving model equations for values of geometrical and operational dimensionless groups typical in clinical practice. The most relevant dimensionless groups determining dialyzer efficiency were identified and a novel design approach to optimize dialyzers in order to maximize solute clearances in a cost-effective way is proposed based on their values.