Distribution of indications and procedures within the framework of centers participating in the WAA apheresis registry.

The WAA apheresis registry was established in 2003 and an increasing number of centers have since then included their experience and data of their procedures. The registry now contains data of more than 74,000 apheresis procedures in more than 10,000 patients. This report shows that the indications for apheresis procedures are changing towards more oncological diagnoses and stem cell collections from patients and donors and less therapeutic apheresis procedures. In centers that continue to register, the total extent of apheresis procedures and patients treated have expanded during the latest years.

Adverse events in apheresis: An update of the WAA registry data.

Apheresis with different procedures and devices are used for a variety of indications that may have different adverse events (AEs). The aim of this study was to clarify the extent and possible reasons of various side effects based on data from a multinational registry. The WAA-apheresis registry data focus on adverse events in a total of 50846 procedures in 7142 patients (42% women). AEs were graded as mild, moderate (need for medication), severe (interruption due to the AE) or death (due to AE). More AEs occurred during the first procedures versus subsequent (8.4 and 5.5%, respectively). AEs were mild in 2.4% (due to access 54%, device 7%, hypotension 15%, tingling 8%), moderate in 3% (tingling 58%, urticaria 15%, hypotension 10%, nausea 3%), and severe in 0.4% of procedures (syncope/hypotension 32%, urticaria 17%, chills/fever 8%, arrhythmia/asystole 4.5%, nausea/vomiting 4%). Hypotension was most common if albumin was used as the replacement fluid, and urticaria when plasma was used. Arrhythmia occurred to similar extents when using plasma or albumin as replacement. In 64% of procedures with bronchospasm, plasma was part of the replacement fluid used. Severe AEs are rare. Although most reactions are mild and moderate, several side effects may be critical for the patient. We present side effects in relation to the procedures and suggest that safety is increased by regular vital sign measurements, cardiac monitoring and by having emergency equipment nearby.

An update on uremic toxins.

In the last decade, uremic toxicity as a potential cause for the excess of cardiovascular disease and mortality observed in chronic kidney disease gained more and more interest. This review focuses on uremic toxins with known cardiovascular effects and their removal. For protein-bound solutes, for example, indoxylsulfate and the conjugates of p-cresol, and for small water-soluble solutes, for example, guanidines, such as ADMA and SDMA, there is a growing evidence for a role in cardiovascular toxicity in vitro (e.g., affecting leukocyte, endothelial, vascular smooth muscle cell function) and/or in vivo. Several middle molecules (e.g., beta-2-microglobulin, interleukin-6, TNF-alpha and FGF-23) were shown to be predictors for cardiovascular disease and/or mortality. Most of these solutes, however, are difficult to remove during dialysis, which is traditionally assessed by studying the removal of urea, which can be considered as a relatively inert uremic retention solute. However, even the effective removal of other small water-soluble toxins than urea can be hampered by their larger distribution volumes. Middle molecules (beta-2-microglobulin as prototype, but not necessarily representative for others) are cleared more efficiently when the pore size of the dialyzer membrane increases, convection is applied and dialysis time is prolonged. Only adding convection to diffusion improves the removal of protein-bound toxins. Therefore, alternative removal strategies, such as intestinal adsorption, drugs interfering with toxic biochemical pathways or decreasing toxin concentration, and extracorporeal plasma adsorption, as well as kinetic behavior during dialysis need further investigation. Even more importantly, randomized clinical studies are required to demonstrate a survival advantage through these strategies.

A computational exploration of helical arterio-venous graft designs.

Although arterio-venous grafts (AVGs) are the second best option as long-term vascular access for hemodialysis, they suffer from complications caused by intimal hyperplasia, mainly located in vessel regions of low and oscillating wall shear stress. However, certain flow patterns in the bulk may reduce these unfavorable hemodynamic conditions. We therefore studied, with computational fluid dynamics (CFD), the impact of a helical AVG design on the occurrence of (un)favorable hemodynamic conditions at the venous anastomosis. Six CFD-models of an AVG in closed-loop configuration were constructed: one conventional straight graft, and five helical designed grafts with a pitch of 105 mm down to 35 mm. At the venous anastomosis, disturbed shear was assessed by quantifying the area with unfavorable conditions, and by analyzing averaged values in a case-specific patch. The bulk hemodynamics were assessed by analyzing the kinetic helicity in and the pressure drop over the graft. The most helical design scores best, being instrumental to suppress disturbed shear in the venous segment. There is, however, no trivial relationship between the number of helix turns of the graft and disturbed shear in the venous segment, when a realistic closed-loop AVG model is investigated. Bulk flow investigation showed a marked increase of helicity intensity in, and a moderate pressure drop over the AVG by introducing a lower pitch. At the venous anastomosis, unfavorable hemodynamic conditions can be reduced by introducing a helical design. However, due to the complex flow conditions, the optimal helical design for an AVG cannot be derived without studying case by case.

Dialysability of sugammadex and its complex with rocuronium in intensive care patients with severe renal impairment.

BACKGROUND: Renal excretion is the primary route for the elimination of sugammadex. We evaluated the dialysability of sugammadex and the sugammadex-rocuronium complex in patients with severe renal impairment in the intensive care unit (ICU). METHODS: Six patients in the ICU with acute severe renal impairment received general anaesthesia for transoesophageal echocardiography, to replace their tracheal tubes, or for bronchoscopy. Five of the six patients were in the ICU after cardiac/vascular surgery and one for pneumonia-induced respiratory failure. They all received rocuronium 0.6 mg kg(-1), followed 15 min later by sugammadex 4.0 mg kg(-1). Two patients were studied for two dialysis episodes and four patients for four episodes. Rocuronium and sugammadex concentrations were measured in plasma and dialysate at several time points before, during, and after high-flux dialysis. Dialysis clearance in plasma and dialysate, and reduction ratio (RR) (the extent of the plasma concentration reduction at the end of a dialysis episode when compared with before dialysis) were calculated for each dialysis episode. RESULTS: Dialysis episodes lasted on average 6 h. Observed RRs indicated mean reductions of 69% and 75% in the plasma concentrations of sugammadex and rocuronium, respectively, during the first dialysis episode. Reductions were around 50% during sequential dialysis episodes. On average, dialysis clearance of sugammadex and rocuronium in blood was 78 and 89 ml min(-1), respectively. CONCLUSIONS: Haemodialysis using a high-flux dialysis method is effective in removing sugammadex and the sugammadex-rocuronium complex in patients with severe renal impairment.

Experimental validation of a pulse wave propagation model for predicting hemodynamics after vascular access surgery.

Hemodialysis patients require a vascular access that is, preferably, surgically created by connecting an artery and vein in the arm, i.e. an arteriovenous fistula (AVF). The site for AVF creation is chosen by the surgeon based on preoperative diagnostics, but AVFs are still compromised by flow-associated complications. Previously, it was shown that a computational 1D-model is able to describe pressure and flow after AVF surgery. However, predicted flows differed from measurements in 4/10 patients. Differences can be attributed to inaccuracies in Doppler measurements and input data, to neglecting physiological mechanisms or to an incomplete physical description of the pulse wave propagation after AVF surgery. The physical description can be checked by validating against an experimental setup consisting of silicone tubes mimicking the aorta and arm vasculature both before and after AVF surgery, which is the aim of the current study. In such an analysis, the output uncertainty resulting from measurement uncertainty in model input should be quantified. The computational model was fed by geometrical and mechanical properties collected from the setup. Pressure and flow waveforms were simulated and compared with experimental waveforms. The precision of the simulations was determined by performing a Monte Carlo study. It was concluded that the computational model was able to simulate mean pressures and flows accurately, whereas simulated waveforms were less attenuated than experimental ones, likely resulting from neglecting viscoelasticity. Furthermore, it was found that in the analysis output uncertainties, resulting from input uncertainties, cannot be neglected and should thus be considered.

Thrombotic microangiopathy.

Thrombotic microangiopathy (TMA) is a histopathological feature of various diseases including thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS). There are many secondary causes of TMA, many of them could mimic TTP or HUS. This article presents a short overview on TMA. In conclusion TMA is the result of various etiology reasons and pathologic reactions with various clinical entities. It is important to focus on a thorough history including family history when deciding on a diagnosis. Analysis of ADAMTS 13 and ADAMTS 13-antibodies may help to decide continued therapy.

Analyses of data of patients with Thrombotic Microangiopathy in the WAA registry.

UNLABELLED: Thrombotic Microangiopathy (TMA) is a histopathological feature of various diseases including thrombotic thrombocytopenic purpura and hemolytic uremic syndrome. The aim of this study was to investigate the outcome and prognostic variables of TMA-patients. MATERIALS AND METHODS: Data were consecutively retrieved from the WAA-apheresis registry (www.waa-registry.org) during 2003-2009. Included were all 120 patients (1237 procedures) who suffered from various forms of TMA, as registered by the ICD-10 code M31.1. Besides registry data, more extensive information was retrieved from the latest 64 patients. Adverse events of the TMA patients were compared to those of the other patients in the registry. RESULTS: The mean age was 46 years (range 11-85 years, 57% women). In 72% therapeutic apheresis was due to an acute indication while a long-term indication was present in 28%. Plasma exchange was performed by centrifugation and filtration technique (95% and 4%, respectively), and immunoadsorption in 1% of the patients. Only fresh frozen plasma was used as replacement fluid in 69% of procedures. Adverse events were more frequent than in the general apheresis population (10% versus 5%, RR 1.9, CI 1.6-2.3). No death occurred due to apheresis treatment. Three percent of the procedures were interrupted. Bronchospasm and/or anaphylactic shock were present in two patients and one patient suffered from TRALI. At admission 26% were bedridden and needed to be fed. The risk of dying during the treatment period was significantly higher if the patient also suffered from a compromising disease, such as cancer. There was an inverse correlation between the ADAMTS13 level and the antibody titer (r=-0.47, p=0.034). CONCLUSIONS: Patients with TMA have an increased risk for moderate and severe AE compared to the general apheresis population. Many patients were severely ill at admission. The prognosis is worse if the patient also has a severe chronic disease. Even slightly increased ADAMTS13-antibody titers seem to have a negative impact on the ADAMTS13 levels.

Impact of hemodialysis duration on the removal of uremic retention solutes.

Several studies have stressed the importance of dialysis time in the removal of uremic retention solutes. To further investigate this, nine stable chronic hemodialysis patients were dialyzed for 4, 6, or 8 h processing the same total blood and dialysate volume by the Genius system and high-flux FX80 dialyzers. Inlet blood and outlet dialysate were analyzed for urea, creatinine, phosphorus, and beta2-microglobulin at various times. Total solute removal, dialyzer extraction ratios, and total cleared volumes were significantly larger during prolonged dialysis for urea, creatinine, phosphorus, and beta2-microglobulin. Reduction ratios increased progressively, except for phosphate and beta2-microglobulin, where the ratios remained constant after 2 h. In contrast, no significant difference was found for the reduction ratios of all solutes and Kt/V(urea) between the three different sessions. With longer dialyses, solutes are efficiently removed from the deeper compartments of the patient's body. Our study shows that care must be taken when using Kt/Vurea or reduction ratios as the only parameters to quantify dialysis adequacy.

Optimisation of solute transport in dialysers using a three-dimensional finite volume model.

Dialyser manufacturers only provide limited information about mass removal under well-defined flow and solute conditions in commercially available dialysers for hemodialysis. This computational study aimed at assessing the solute transport efficiency in a dialyser for different geometries (fiber lengths and diameters). A three-dimensional finite volume model of a single fiber in a high flux polysulphone dialyser (Fresenius F60) was developed. Different equations describe blood and dialysate flow (Navier-Stokes), radial filtration flow (Darcy) and solute transport (convection-diffusion). Fluid and membrane properties were derived from in vitro and in vivo tests as well as from literature data. Urea (MW60) was used as marker to simulate small molecule removal, while middle molecule transport was modelled using vitamin B12 (MW1355) and inulin (MW5200). Keeping the fluid velocity in a single fiber constant, fiber diameter and length were changed in a wide range for evaluation of solute removal efficiency. Clearances were found enhanced by 13% (urea), 50% (vitamin B12) and 89% (inulin) for a fiber twice as long as a standard one and by 5.5% (vitamin B12) and 21% (inulin) for a fiber diameter of 150 mum instead of 200 mum. The impact of fiber dimensions was more pronounced for the middle molecules compared to urea.

Combining SPECT medical imaging and computational fluid dynamics for analyzing blood and dialysate flow in hemodialyzers.

For a better insight in dialyzer efficiency with respect to local mass transport in a low flux dialyzer (Fresenius F6HPS), blood and dialysate flow distributions were visualized with computational fluid dynamic (CFD) simulations, which were validated with single photon emission computed tomography (SPECT) imaging. To visualize blood-side flow while avoiding transport through the fiber membrane, a bolus of 99m-Technetium labeled MAA (Macro Aggregated Albumin) was injected in the flow using an electronic valve. Water was used to simulate blood, but flow rate was adjusted according to laws of dynamic similarity to account for the viscosity difference (factor 2.75). For the visualization of dialysate flow, a bolus of 99m-Technetium labeled DMSA (Dimercaptosuccinic Acid) was injected, while pressurized air in the blood compartment avoided transmembrane flow. For each test series, 3D acquisitions were made on a two respectively three-headed SPECT camera. By evaluating the images at different time steps, dynamic 3D intensity plots were obtained, which were further used to derive local flow velocities. Additionally, three-dimensional CFD models were developed for simulating the overall blood and dialysate flow, respectively. In both models,the whole fiber compartment was defined as a porous medium with overall axial and radial permeability derived theoretically and from in vitro tests. With the imaging as well as with the computational technique, a homogeneous blood flow distribution was found, while vortices and fluid stagnation were observed in the dialyzer inlet manifold. The non-homogeneous dialysate distribution, as found with SPECT imaging, implies the occurrence of non-efficient sites with respect to mass transfer. The discrepancy between the dialysate results of both techniques indicated that the assumption of a constant fiber bundle permeability in the CFD model was too optimistic. In conclusion, medical imaging techniques like SPECT are very helpful to validate CFD models, which can be further applied for dialyzer design and optimization.

Diffusive clearance of small and middle-sized molecules in combined dialyzer flow configurations.

Clearance of low (LMW) and middle molecular weight (MMW) solutes was investigated in vitro for different dialyzer configurations and mutual flow directions. Single pass tests were performed with two low flux Fresenius F6HPS hemodialyzers placed in series (12 tests) and in parallel (6 tests), and results were compared with those for one single dialyzer (2 tests). Either high concentrated (45mS/cm) bicarbonate dialysis fluid (surrogate LMW) or trisodiumphosphate (surrogate MMW) concentration (31mS/cm) was used as blood substitution fluid. Standard blood and dialysate flows of 250 and 500ml/min, respectively, were prescribed. Clearance was derived from conductivity measurements in blood and dialysate compartment, correcting for the overall ultrafiltration rate of 0.1-0.5l/h. In a single dialyzer, changing the counter current flow to co-current deteriorates diffusive clearance by 14% (LMW) and 18% (MMW). Compared to one single dialyzer using counter current flow, clearance increases by 3 to 8% (LMW) and by 15 to 18% (MMW) using two dialyzers in parallel and in series, respectively. As a consequence, the benefit by using a second dialyzer is more prominent for larger molecules. Moreover, pressure profiles drawn for the different configurations show the impact of limited convection on diffusive clearance.

In vitro evaluation of the hydraulic permeability of polysulfone dialysers.

An in vitro set-up has been designed to study the hydraulic permeability of hollow fiber dialysers. Forward and reverse dialysate ultrafiltration were determined using both sterile dialysers and samples with a protein layer settled on the membrane (Fresenius F6, F8, F60 and F80). The ultrafiltration coefficient KUF (ml/h.mmHg) was calculated as the ratio of volumetrical flow (QUF) and transmembrane pressure (TMP) measurements. The protein layer on the membrane was induced either by recirculating human plasma through the dialysers (in vitro) or by a standard hemodialysis session (in vivo). KUF is largely independent of TMP up to 600mmHg (low flux) and 60mmHg (high flux) for forward and reverse flow In sterile dialysers, backfiltration yields a significantly different KUF except for the F80. An in vitro induced protein layer on the membrane decreases KUF15-30% (forward) and 4-12% (backward) in low flux and 45-70% (forward) and 65-73% (backward) in high flux dialysers.