Analysis of haemoperfusion through fixed-bed adsorber

An attempt is made to analyse the haemoperfusion system. The patient's body is modelled as a 3-compartment system and the adsorber unit (perfusion system) is modelled as a 2-phase system with axial dispersion accounting for both the inter-particle and the intra-particle mass-transfer resistances. Results indicate that although the clearance of solute increases with an increasing blood-flow rate through the adsorber unit, the increase in clearance is not significant. The particle size (intra-particle mass-transfer resistance) and the volume of the adsorbent have a significant effect on the clearance of the solute.     

Blood ultrafiltration: A design analysis

Ultrafiltration of blood finds application in the conventional dialysis and adsorber-ultrafilter artificial-kidney systems. The ultrafilters used for these processes are either flat-membrane thin-channel flow systems or bundles of capillary-like hollow fibres. The design analysis of hollow-fibre and thin-channel ultrafilters is carried out by assuming 2-dimensional and axisymmetric flow of a Newtonian fluid accompanied by convective and diffusive mass transfer across the semipermeable membrane wall. The wall permeation velocity is assumed to be small and (a) decaying exponentially along the flow direction and (b) proportional to the transmembrane pressure difference. The ultrafilter is simulated for the operation of (a) a conventional dialyser and (b) and ultrafilter as used in the adsorber-ultrafilter artificial kidney. The parametric analysis of the ultrafilter is studied.     

Nitric oxide generation by peripheral blood cells in chronic renal failure

Nitric oxide (NO), a labile free radical synthesised from L-arginine by the action of nitric oxide synthase (NOS), is said to be implicated in uraemic complications, such as infection and a tendency to bleed. In this study of NO production by peripheral blood cells, an increased level is seen in platelets from uraemic patients (both non-dialysed and haemodialysed) and a decreased level in leucocytes (neutrophils and monocytes). A negative correlation was noted between blood urea level and inducible NO in neutrophils and monocytes in uraemic patients not on dialysis. In contrast, haemodialysis appears to lead to an increase in inducible NO production in neutrophils and monocytes. Plasma NO levels were significantly increased in uraemic patients, compared with normal controls, and hemodialysis led to further increases. Superoxide dismutase (SOD) activity was significantly reduced in platelets, neutrophils and monocytes in the uraemic group. It is concluded that increased NO production by platelets may contribute to the bleeding tendency observed in uraemia, and high urea concentrations may contribute to the regulation of inducible NO production in leucocytes.     

New method of extracorporeal concentration of ascitic fluid as a treatment of refractory ascites

A new piece of equipment for the treatment of ascites is described. Ascitic fluid is drained by gravity in a unit consisting of an Amicon D-30 ultrafilter and a bag used as transit reservoir placed below the patient. When the bag is full, it is raised to a height sufficient to let the fluid flow back through the filter to the peritoneal cavity. Mainly during this step ultrafiltration of ascitic fluid occurs through the membrane of the filter. Ultrafiltration is enhanced by the negative pressure created in the filtrate compartment due to the height difference between filter unit and filtrate drainage bag placed at the bottom of the machine. Proteins in the ascitic fluid are retained and returned to the abdominal cavity. The machine cycle is automatically repeated as many times as necessary to achieve the scheduled patient weight loss. 17 patients have been treated for a total of 1.94 sessions/patient with reinfusion of the fluid in the abdominal cavity. In all patients a significant reduction of the amount of ascitic fluid and of its rate of formation have been achieved. The treatment was well tolerated and no side effects were observed. After treatment the diuresis and the sodium excretion increased significantly in all patients. The system is safe and reliable for the treatment of refractory ascites without major complications.     

A consensus structure for membrane transport

Combined information from biochemical and molecular biological experiments reveals a consistent structural rhythm that underlies the construction of all membrane carriers and perhaps all transport systems. Biochemical work shows that while some carrier proteins function as monomers, others operate as dimers. But despite this variation, all examples can be modelled as having a pair of membrane-embedded domains, each of which contains an array of (about) six transmembrane helical elements. This pattern is best documented among membrane carriers, where the minimal functional unit is known in a reasonable number of cases. Nevertheless, the same conclusion is likely to characterize other solute transporters. These unexpected correlations suggest that all membrane carriers, including those that take part in "energy coupling", have a uniform structural design on which is superimposed a variety of kinetic and biochemical mechanisms.     

Continuous arterio-venous haemodiafiltration: hydraulic and diffusive permeability index of an AN-69 capillary haemofilter

The dependence of uraemic solute clearance on the hydraulic and diffusive permeability index of an AN-69 capillary haemofilter is investigated during the treatment of patients with continuous arterio-venous haemodiafiltration (CAVHD). A mathematical model is presented to calculate solute clearance and the hydraulic and diffusive permeability index parameters from clinical data and to predict the blood flow rate entering the extra-corporeal circuit from the manufacturer's specifications and blood viscosity. By measuring the flow rates, the patient's mean arterio-venous pressure difference and uraemic solute clearance under different clinical and operational conditions, mathematical model equations are evaluated. During the average survival time of an AN-69 capillary haemofilter of about five days, it is found that both the hydraulic permeability index and the diffusive permeability index decline over treatment time, independent of the haemofilter resistance to blood flow. The measured haemofilter resistance to blood flow is three times higher than the haemofilter resistance predicted from the manufacturer's specifications and blood viscosity. Predicting the blood flow rate entering the extra-corporeal circuit from the arterial haematocrit, plasma protein concentration and temperature and the manufacturer's specifications is not reliable.     

A new method to evaluate the local clearance at different annular rings inside hemodialyzers

Recent research indicated that the dialysate flow distribution inside a hemodialyzer was not uniform ("channeling" of the dialysate flows). However, effect of the channeling on the solute clearance has not been directly and quantitatively examined. In this report, a novel experiment approach is presented to test the hypothesis that hollow fibers in different regions within a given hemodialyzer may contribute differently to the solute clearance. Water solution with urea (molecular weight 60) and creatinine (molecular weight 113) were made as "blood," and pure water was used as dialysate. Two high flux dialyzers, dialyzer A (cellulose triacetate) and dialyzer B (polyethersulfone), were used in this study. The hollow fiber potting area at the blood inlet of a dialyzer was divided into equal area concentric rings. In each experiment, only one of the rings was open for blood flow, and the other rings were blocked by epoxy. The "blood" was pumped at 120 ml/min while the dialysate flow rate (Qd) varied at 500, 800, and 1,000 ml/min, respectively. The solute clearance with a specific ring open (local clearance) was determined by measuring solute (urea/creatinine) concentration at the "blood" inlet and outlet. For dialyzer A, local clearance of urea and creatinine were significantly higher in the outer ring than in the inner ring. With increasing Qd, local solute clearance increased significantly for all rings. For dialyzer B, at any given Qd, solutes local clearance also increased from the inner to outer rings. In comparison, the effect of increasing Qd on solute clearance was greater for dialyzer B than for dialyzer A. In conclusion, using the new experimental method, the authors quantitatively evaluated the solute clearance contributed by the hollow fibers at different locations (concentric rings) in dialyzers. Hollow fibers at different locations did contribute differently to the solute clearance, which may be caused by the channeling of dialysate flow. A careful design of the dialyzer to minimize the channeling is needed.     

Plasma ammonia is the principal source of ammonia in sweat

Summary Sweat contains ammonia. However, neither its source nor factors affecting its concentration in the sweat are known. The aim of this study was to examine the effect of plasma concentrations of ammonia and urea on the concentration of ammonia in the sweat. Four groups of male volunteers were examined: one control, two after ingestion of ammonium chloride, three cirrhotic, hyperammonaemic, four uraemic. Sweat was collected from each subject from the palmar side of the forearm using gauze pads, after previous iontophoresis of pilocarpine. Ammonia and urea concentrations were determined in the sweat and in the plasma. It was found that elevated plasma ammonia concentration in healthy subjects after ingestion of ammonium chloride as well in the cirrhotic patients resulted in an increase of ammonia concentration in the sweat. High plasma and sweat urea concentration in the uraemic subjects did not affect the concentration of ammonia in the sweat. It was concluded that plasma ammonia was the principal source of ammonia in the sweat.     

Role of sodium and urea in the renal concentrating mechanism inPsammomys obesus

Summary Micropunctures were performed at the tip of Henle's loops and vasa recta accessible at the extrarenal surface of the papilla in a desert rodent (Psammomys obesus) studied under mild NaCl (NaCl 4%, 0.0375 ml/min) and mild urea (urea 4%, 0.0375 ml/min) loading conditions.In NaCl loaded animals, it was confirmed that solute addition (mainly sodium) contributes in a large proportion to the concentrating process along the thin descending limb. Comparison of sodium and urea concentrations in the loops with those in vasa recta at the same level of the papilla demonstrated that 1. the transepithelial sodium gradient was compatible with a diffusion transport of this ion from the interstitium to the thin descending limb; 2. the sodium concentration higher in interstitium than in the loop fluid was not compatible with the existence of a purely passive concentrating process in inner medulla as was recently proposed [8], 3. the transepithelial urea gradient was very limited which indicates that this solute does not play an important part in the concentrating process.In urea loaded psammomys, solute addition (mainly urea) to the thin descending limb fluid was still present but water abstraction was enhanced as compared to salt loaded animals, probably on account to the higher interstitial urea concentration. It is, thus, brought to evidence that the relative contribution of water abstraction and solute addition to the concentrating process along the thin descending limb can vary in a given species as a function of the physiological state.     

The effect of urea loading on volume and concentration of urine in rabbits

1. To find how urea contributes to the water-conserving ability of a herbivore's kidney, groups of ten young rabbits on a low-protein diet and at three different levels of dietary electrolyte were given 1.8 g urea by mouth daily for 3 days. Vasopressin was administered daily to half the animals in each group.2. The urinary osmolarity and urea output of each animal was recorded daily during the urea loading and for a 3-day control period before and after loading. The renal water requirement for non-urea solute output (defined as daily volume/daily non-urea solute output) was calculated. The sodium content of renal cortex and medulla was measured in some animals from each group.3. Urea caused additional water excretion only in those rabbits which were receiving the low-salt diet. There was invariably increased water excretion when the ratio of urea to non-urea solute output exceeded 2.4. In most of the rabbits on normal-salt and high-salt intake, urea produced little change in the volume in which non-urea solute was excreted. Three out of the ten high-salt animals showed significant reduction of this volume during urea-loading.5. Vasopressin significantly reduced the volume required for non-urea solute output, but the effect of vasopressin was independent of urea-loading and of dietary electrolyte level.6. The low-electrolyte diet significantly reduced the sodium concentration in the rabbits' renal medullary tissue.7. It is concluded that in rabbits urea contributes to water retention mainly by its high permeability, enhanced by vasopressin, which permits maximal water reabsorption in the renal medulla. Water retention by means of uphill transport of urea, if it occurs at all, is slight.     

Computer-aided design of hollow-fiber dialyzers

Blood and dialysate flow patterns in hollow-fiber dialyzers are complicated, and hence the flow patterns and mass transfer are difficult to analyze theoretically. Consequently, dialyzers are usually developed by a trial-and-error method. We attempt to design dialyzers by computer simulation analysis in this work. Blood-side and dialysate-side flows were modeled using the Hagen-Poiseuille equation and the Blake-Kozeny equation, respectively. These flow patterns were evaluated as pressure drop and velocity distribution. The mass transfer rate was evaluated as solute clearance. Computed values of the pressure drops and clearance for urea and vitamin B₁₂ were found to agree closely with those obtained experimentally. We evaluated the influences of the inner diameter of hollow fibers, module geometry, and void fraction on the pressure drop and clearance, and computer-aided design was performed.     

Impact of blood and dialysate flow and surface on performance of new polysulfone hemodialysis dialyzers

Optimization of hemodialysis treatment parameters and the characteristics of the dialyzer are crucial for short- and long-term outcome of end stage renal disease patients. The new high-flux membrane Helixone in the dialyzer of the FX series (Fresenius Medical Care, Germany) has interesting features, such as the relationship of membrane thickness and capillary diameter which increases middle molecule elimination by convection, as well as higher capillary packing and microondulation to improve the dialysate flow and distribution. Blood flow, dialysate flow and surface area are the main determinants of the performance of a dialyzer, however the impact of each parameter on small and middle molecule clearance in high flux dialysis has not been well explored. In order to find the best treatment condition for the new dialyzer series, we evaluated urea, creatinine, phosphate clearances and reduction rate of beta2-microglobulin in ten stable patients treated with different blood flows (effective Qb 280 and 360 ml/min), dialysate flow (Qd 300 or 500 ml/min) and dialyzer surfaces (1.4 and 2.2 m2, FX60 or FX100). KoA and Kt/V were also calculated. Blood flow, dialysate flow and surface area demonstrated a significant and independent effect on clearance of urea, creatinine and phosphate, as well as on Kt/V. Small solute clearance was stable over the treatment. In contrast to small solutes, reduction rate of beta2-microglobulin was related to increasing dialyzer surface only. The new dialyzer design of the FX series proves highly effective due to improved dialysate distribution and reduced diffusive resistance as shown by the small solute clearance. A high reduction rate of beta2-microglobulin is favored by improved fiber geometry and pore size distribution. These findings have potential long-term benefits for the patient.     

Perturbation of homogeneous magnetic fields by isolated single and confocal spheroids. Implications for NMR spectroscopy of cells

Analytical expressions for the magnetic potential and the magnetic field strength vector in cells modelled as isolated confocal prolate and oblate spheroids have been derived. The important results which emerged from the analysis are that the magnetic field in the central spheroid, in a series of confocal spheroids, is always uniform; but its magnitude depends upon the orientation of the spheroids relative to the external field. Therefore, the NMR line-shape derived from an internal solute in a population of sparsely distributed spheroids, with random orientation of the members, is a superposition of Lorentzians; the resulting 'complicated' line shape may often appear to be Gaussian. This spectral phenomenon is at least part of the explanation for the non-Lorentzian character of NMR line-shapes in the spectra of many biological samples. Quantitative analysis of the NMR line-shape of an appropriate intracellular solute can in principal yield the orientational distribution of a dilute suspension of cells of uniform size and shape.     

Host immune status in uraemia. I. Cell-mediated immune mechanisms.

An experimental model of stable uraemia has been used to determine the effect of uraemia on cell-mediated immune mechanisms in the rat. Controlled resection of renal tissue allowed the establishment of a 'moderate' (blood urea 100-200 mg/100 ml) and 'severe' grade of uraemia (BU > 200 mg/100 ml). The immune responsiveness of isolated lymphocyte suspensions from uraemic animals was similar to that of sham-operated animals but lymphocyte function in both groups was suppressed compared with control non-manipulated animals. This was particularly evident in the graft vs host reaction. The host vs graft which assumes the cell-mediated immune status in the live animals, was also depressed in the uraemic animals but in contrast to the previous results sham-operated animals exhibited normal responses. The results underscore the importance of surgically induced anergy as a factor complicating the assessment of immune function in uraemia and may explain some of the inconsistencies observed in the evaluation of cell-mediated immunity by in vitro analysis of lymphocyte suspensions and tests of immune function in the intact host.     

Uraemic serum induces dysfunction of vascular endothelial cells: role of ubiquitin-proteasome pathway

The ubiquitin-proteasome pathway (UPP) has been indicated to contribute to dysfunction of endothelial cells (ECs). Nevertheless, the relationship between UPP and vascular complications of uraemia remains unknown. We aimed to determine whether the UPP is activated in vascular ECs when cultured with uraemic serum, and to examine the role of the UPP on dysfunction of ECs in uraemia. Rabbit aortic endothelial cells (RAECs) were cultured with normal serum or different concentrations of uraemic serum. The expression of the ubiquitin-activating enzyme (E1), an indicator of the UPP, was detected by real-time RT-PCR and Western blot; proteasome activity was determined by fluorescence spectrophotometry; and nuclear factor-κB (NF-κB) activity and expression, as well as tumour necrosis factor-α (TNF-α) expression, were also detected. We found that the expression of E1 and the activities of three kinds of proteasomes were increased significantly in RAECs after incubation with uraemic serum. Proliferation of RAECs was increased significantly by incubation with 3-15% uraemic serum but decreased markedly when incubated with uraemic serum above 15% (increased apoptosis). Incubation of RAECs with uraemic serum induced increased NF-B DNA-binding activity and nuclear translocation of NF-κB, decreased nitric oxide production and increased expression of TNF-α, which is the final effector of inflammatory activation of cells. All of these responses in RAECs were suppressed by the specific proteasome inhibitor, MG132. The inhibition of inflammatory responses by MG132 was further supported by a parallel experiment with pyrrolidine dithiocarbamate, a specific inhibitor of κNF-B. These findings suggest that the UPP was activated in RAECs by administration of uraemic serum, and played a pivotal role in the dysfunction of vascular ECs, such as inflammatory activation.     

A clinical and experimental study of platelet function in chronic renal failure

Coagulation and platelet function studies were performed on 24 normal subjects and 29 patients with chronic renal failure due to various causes. Thrombocytopenia was uncommon in the uraemic patients but there was reduced platelet retention in glass bead columns and platelet aggregation with adenosine diphosphate (ADP) and thrombin was slower and less complete than normal. The rate of platelet disaggregation in uraemic patients was significantly reduced. The abnormalities tended to be more severe in more uraemic subjects. In normal subjects no inter-relationships were observed between the various measurements of platelet activity. In patients there were significant interrelationships between the measurements of platelet aggregation with ADP and thrombin and between the measurements of aggregation and retention in glass bead columns. It is suggested that if a common pathway is involved in these reactions it is adversely affected in uraemia.Plasma coagulation defects were uncommon and present in only five of the uraemic subjects. Impaired prothrombin consumption apparently due to defective platelet function was present in half the patients but was not detected by a kaolin activation method. Although platelet coagulation function was activated during ADP aggregation and disaggregation in normal and uraemic subjects, it did not correlate in the latter with impairment of aggregation. It is suggested that aggregation and activation of platelet coagulant activity are not necessarily related aspects of platelet function. An effect of uraemic plasma on normal platelets was demonstrated by mixing experiments consistent with a humoral cause for the uraemic platelet defects.     

Monte Carlo simulations of a scintillation camera using GATE: validation and application modelling

Geant4 application for tomographic emission (GATE) is a recently developed simulation platform based on Geant4, specifically designed for PET and SPECT studies. In this paper we present validation results of GATE based on the comparison of simulations against experimental data, acquired with a standard SPECT camera. The most important components of the scintillation camera were modelled. The photoelectric effect. Compton and Rayleigh scatter are included in the gamma transport process. Special attention was paid to the processes involved in the collimator: scatter, penetration and lead fluorescence. A LEHR and a MEGP collimator were modelled as closely as possible to their shape and dimensions. In the validation study, we compared the simulated and measured energy spectra of different isotopes: 99mTc, 22Na, 57Co and 67Ga. The sensitivity was evaluated by using sources at varying distances from the detector surface. Scatter component analysis was performed in different energy windows at different distances from the detector and for different attenuation geometries. Spatial resolution was evaluated using a 99mTc source at various distances. Overall results showed very good agreement between the acquisitions and the simulations. The clinical usefulness of GATE depends on its ability to use voxelized datasets. Therefore, a clinical extension was written so that digital patient data can be read in by the simulator as a source distribution or as an attenuating geometry. Following this validation we modelled two additional camera designs: the Beacon transmission device for attenuation correction and the Solstice scanner prototype with a rotating collimator. For the first setup a scatter analysis was performed and for the latter design. the simulated sensitivity results were compared against theoretical predictions. Both case studies demonstrated the flexibility and accuracy of GATE and exemplified its potential benefits in protocol optimization and in system design.