Dialysis membrane-dependent removal of middle molecules during hemodiafiltration: the beta2-microglobulin/albumin relationship.

AIM: Current hemodialysis therapy modalities such as online hemodiafiltration (HDF) attempt to enhance solute removal over a wide molecular weight range through a combination of diffusion and convection. While the effects of variations of treatment modalities and conditions have been studied reasonably well, few studies have examined the efficacy of HDF to remove middle molecules in relation to the dialyzer and membrane characteristics. In this investigation, diverse high-flux dialyzers, covering a wide range of membrane permeabilities, were compared under identical in vivo conditions to assess their ability to eliminate larger uremic retention solutes (using beta2-microglobulin as a surrogate of middle molecules) without simultaneously causing excessive leakage of useful proteins such as albumin. PATIENTS AND METHODS: In a prospective, crossover study, 3 ESRD patients were treated with 8 different brands of high-flux dialyzers at 4 different ultrafiltration (UF)/substitution flow rates (QS: 0, 30, 60, 90 ml/min) in post-dilution HDF mode. Thus, each patient underwent 32 treatment sessions, with a total of 96 treatment sessions conducted during the entire clinical study. Albumin and beta2-microglobulin levels were measured in both, dialysate and blood. Both, albumin and beta2-microglobulin elimination was dependent upon the permeability of the dialysis membrane as well as on the ultrafiltration/substitution flow rates applied. RESULTS: At the maximum UF rate of 90 ml/min, the total albumin loss (measured in the dialysate) ranged from 300 mg/4 h (for the FLX-15 GWS dialyzers) to 7,000 mg/4 h (for the BS-1.3U dialyzers). Up to 50% reduction of albumin occurred within the first 30 minutes of the dialysis treatment, and the leakage of albumin increased exponentially with increasing UF rates as well as increasing transmembrane pressure (TMP). The various dialyzers could be classified according to their UFR-dependent beta2-m reduction rates (RR), into low (< 50%; FLX-15 GWS, CT 150G), medium (50-70%; Polyflux 14 S, BLS 814SD, H4) and high (> 70%; BS-1.3U, APS 650, FX 60) removers of middle molecules. One dialyzer type (CT 150G) showed extremely low beta2-m RR and relatively high albumin losses. Most membranes, however, showed either low albumin leakage coupled with low beta2-m removal, or high beta2-m RR but at the expense of considerable albumin leakage. Only 2 membrane types approached the desired balance between high to medium beta2-m RR while simultaneously restricting the albumin leakage especially at higher filtration/substitution rates. CONCLUSION: Our investigations demonstrate that not all dialysis membranes classified as "high-flux" are comparable in their ability to specifically and efficiently remove middle molecules, or curtail the unwanted excessive leakage of essential proteins from the patient's blood. Thus, the selection of appropriate high-flux dialyzers for specific patient requirements should be based more upon clinical evaluations and analyses rather than on product specifications alone.

Release of microparticles in LDL apheresis.

Particle contamination of blood always takes place in extracorporeal systems and few studies have been conducted to evaluate potential risks. Particle concentration was measured in the efferent blood line on original equipment for two established LDL elimination procedures (DALI) (Fresenius) and Liposorber (Kaneka). Acquired data were compared with standards for infusion solutions from European (EP) and American (USP) Pharmacopoeia. All values were well below the given limits. Even in extreme situations (>20 pump stops) particle concentration did not exceed the standards. Considering an average treated blood volume of 7.31 for the DALI-System and 17.01 for Liposorber (long term clinical studies) the absolute amount of particles infused per treatment was 167,000 (DALI) and 465,000 (Liposorber) particles > or = 2 microm.

Particle release in extracorporeal low-density lipoprotein lowering therapies.

Release of microparticles into the blood during extracorporeal circulation must be kept low because of possibly serious acute and chronic adverse effects. Concentration and size distribution of microparticles were measured during simulated treatments (n = 7) on original equipment for 2 standard low-density lipoprotein (LDL) elimination procedures (DALI 750, Fresenius AG, St. Wendel, Germany and Liposorber, Kaneka Corporation, Osaka, Japan) and compared to hemofiltration solutions. For both systems as well as in hemofiltration solutions, the mean particle concentrations in 500 ml portions gathered from the efferent blood line stayed below 10% of pharmacopoeia standards for infusion solutions (United States Pharmacopoeia, European Pharmacopoeia) in all measured size classes. Although particle concentrations were comparable in all systems, the mean total number of particles > or =2 microm released per session was lowest in the DALI (167,000) compared to the Liposorber (465,000) and hemofiltration solutions (2,240,000). This was mainly due to different total processed blood volumes necessary to achieve the required LDL reduction.

On-line hemodiafiltration with pre- and postdilution: impact on the acid-base status.

With on-line formation of the substitution fluid, high substitution rates in predilution (PRD) and postdilution (POD) can be obtained (Fresenius 4008 On-Line HDF; Gambro AK 100 Ultra). The substitution fluid is branched off from the dialysate produced by the dialysate delivery system of the HDF machine. Under these conditions it is desirable to consider the effect of the different treatment modes on the acid-base status. Using Fresenius 4008 On-Line HDF machines, ESRD-patients were treated alternately with high-flux hemodialysis (HD), postdilution HDF (POD-HDF) and predilution HDF (PRD-HDF), while all other treatment parameters were kept constant, in particular the bicarbonate dialysate concentration. Plasma-HCO3, -pH and -pCO2 were measured and compared with the results of a multicompartment bicarbonate model developed by Thews. Also plasma-pO2 and K+ were measured. The results showed no significant differences between HD, POD- and PRD-HDF. Acidosis was corrected effectively and no excessive compensation of the acid-base disturbance was observed.

On-line hemodiafiltration with pre- and postdilution: a comparison of efficacy.

Since the introduction of on-line substituate preparation, high substituate rates (Qs) in pre- and postdilution for hemodiafiltration (HDF) procedures can be realized. During postdilution HDF (POD-HDF) and additional convective removal is possible, but in vivo Qs is limited to approx. 1/3Qb (bloodflow). With predilution HDF (PRD-HDF) higher Qs and therefore high convective transport rates by ultrafiltration can be reached. On the other hand the blood concentration is diminished by predilution. Further decrease of the diffusive transport is caused by reduced dialysate flow Qd due to separation of the substituate from the dialysate (Fresenius 4008 On-Line HDF, Gambro AK100 Ultra). The theoretical description of the combined diffusive-convective transport is limited to 1-dimensional models and small UF-rates. Therefore for practical and theoretical purposes the assessment of the efficacy of on-line PRD-HDF and POD-HDF in different molecular weight ranges is desirable. By means of in vitro experiments the effective clearances Keff of hemodialysis (HD, dialyzer: Fresenius F60) for urea, creatinine, vitamin B12 and inulin were compared with measured and theoretical Keff of POD- and PRD-HDF. The theoretical expectation is confirmed that Keff for small molecular weight substances decreases slightly with PRD-HDF and increases for larger molecules. In the case of POD-HDF Keff for small molecular weight substances increases slightly and strongly for larger molecules. In vivo experiments were performed to measure the real substance removal from patient's blood and to figure out the impact of dialysate flow (collection of the used dialysate during the 1. treatment hour and concentration measurements for urea, creatinine, phosphate, beta 2-MG). The results show that the subtraction of Qs from Qd reduces Keff for urea, creatinine and phosphate but not for beta 2-MG. PRD-HDF with Qd = 500 ml/min is significantly less effective for small molecules than HD. There is no significant difference of Keff for urea, creatinine, phosphate during HD and PRD-HDF with Qd = 800 ml/min, but a significant increase of 10-15% for POD-HDF. Keff for beta 2-MG increases by 75% for PRD-HDF and 95% for POD-HDF compared with HD (Qd = 500 ml/min).

Theoretical basis and experimental verification of the impact of ultrafiltration on dialyzer clearance.

Dialyzer clearance K is usually presented as K = K0 + Tr Qu, were Qu is ultrafiltration rate, K0 is clearance for Qu = 0, and Tr is transmittance coefficient. Although a simple and accurate mathematical description of K0 is widely used, only a somewhat inaccurate formula for Tr that predicts a linear relationship between Tr and K0 has been proposed before. In this study the detailed investigation of Tr using a one-dimensional theory of a dialyzer is presented. In general, the application of a one-dimensional theory requires sophisticated numerical methods, but for small and middle molecular weight solutes an analytical formula for K can be derived. Tr predicted by the developed theory in comparison to Tr predicted by the previous linear formula is higher for small molecular weight solutes and lower for middle and large molecular weight solutes. These theoretical results were confirmed in experiments carried out in vitro for hollow-fiber dialyzers and small molecular weight solutes (urea, creatinine, sodium, TcO4) as well as middle molecular weight solutes (vitamin B12).

[Precision of data from models of sodium kinetics in hemodialysis]. / Präzision der Aussagen von Modellen der Natrium-Kinetik bei der Hämodialyse.

The 1-pool-model of sodium kinetics during hemodialysis is based upon the assumption of an immediate compensation of osmotic shifts. This assumption is not supported by measurements of plasma sodium, total protein concentration and colloid osmotic pressure kinetics. When a high dialysate sodium concentration is applied, an inflow of sodium into the plasma space occurs, which results in an osmotic suction and thus a plasma dilution. These conditions can be represented by a 2-pool-model taking into consideration capillary filtration. The results indicate that following the first treatment period the sodium kinetics are sufficiently explained by a 1-pool-model with the total body water as distribution volume. Both the plasma sodium concentration and the eliminated sodium at the end of a hemodialysis treatment can be described to an acceptable level by the 1-pool-model. The input of the measured in-vivo sodium dialysance value (or alternatively the urea clearance) is necessary.

Measurements of plasma colloid osmotic pressure, total protein and sodium concentration during haemodialysis: can single-pool sodium modelling explain the results?

Considering the plasma colloid osmotic pressure (COP) as a possible parameter for the monitoring of dialysis treatment compatibility, a characteristic time course was found. The COP and the total protein concentration very often do not increase significantly during the first treatment hour in spite of ultrafiltration. An increase in the plasma sodium concentration, which was higher than expected, was found to be the reason for a plasma dilution effect. This can be explained by a transcapillary sodium transfer coefficient which is not infinitely high as assumed in single-pool sodium modelling. From a 2-pool model considering the plasma volume as a separate pool and including capillary filtration time courses for plasma sodium, total protein concentration and COP could be calculated, which was very similar to the measured curves.

A simplified procedure to compute dialysis time and frequency by means of urea kinetics.

A simplified urea model is presented based on the concept of the time-averaged deviation (TAD) of the blood urea concentration and the introduction of an effective urea generation rate. The increase in the interdialytic blood urea concentration delta c is specific for the individual patient and includes the urea generation rate, distribution volume and residual kidney clearance. By measuring delta c of the largest interdialytic interval of the week the treatment frequency and duration can be calculated. Even for larger residual clearances Kr less than or equal to 5 ml/min this calculated treatment time does not differ by more than 5 min from the result of the exact urea kinetics. In vivo estimation of the urea clearances versus blood flow for the dialyzer types used is necessary for the application of urea modelling in clinical practice.

[Determination of clearance for urea-controlled hemodialysis]. / Clearancebestimmungen für die harnstoffgeführte Hämodialyse.

Through a simple variant of the urea model the qualitative influence of the dialyzer-clearance on the individual dialysis guidance is elucidated. Realization of the respective Kdtd/V-value require an exact knowledge of the in-vivo-urea-clearance of all available dialyzer types and their manipulation with the aid of blood flow. The theoretical connections are explained and possible parameters affecting the in-vivo-clearance are discussed. The results concerning the dependence of urea-clearance on the blood flow are presented in an urea-guided dialysis patient pool for all in the GDR customary in the trade or temporary available dialyzers. It is shown, that in MLW-dialyzers an influence on the urea-clearance about the blood flow is small because of their relatively thick-walled membrane. Therefore, the development of dialysis membranes with superior diffusible permeability is necessary.

[Current status and future perspectives of extracorporeal blood purification]. / Gegenwärtiger Stand und Entwicklungsperspektiven der extrakorporalen Blutreinigung.

After the description of the main indications for an extracorporeal blood purification the authors enter the at present existing and applied detoxication methods on the basis of membranes and absorbents, respectively. A short characterization of the most important membrane separation techniques peritoneal dialysis, haemodialysis, haemofiltration, haemodiafiltration and membrane plasma separation, respectively, is given. Moreover, an estimation of the cascade methods is given, i.e. the application of several separation filters. As adsorptive methods the haemoperfusion and the plasma perfusion, respectively, are assessed with their advantages and disadvantages and the authors enter the possibility of the combination of the procedures mentioned. As problems which are to be solved still in the first place the deficient blood compatibility, selectivity, individualization and continuity are discussed and ways of solution are shown which up to now are entered upon for the improvement and optimization, respectively, of the problems mentioned. In this case particularly the surface modification of materials and the search for new materials, respectively, as well as the use of special models is emphasized as important for future. In the field of selectivity adsorptive methods are to be developed in the first place which without danger of complications remove relevant metabolites from the organism. For the future is above all to be reckoned with the further development of so-called hybrid organs, since such organs may best repeat biological processes.

Volumetrically controlled ultrafiltration. Current experiences and future prospects.

Exact control of ultrafiltration (UF) is a prerequisite for high flux dialysis and hemodiafiltration. Volumetric dialysate balancing is the best current method for the use of dialyzers with high water permeabilities. The precision of UF control by volumetric dialysate balancing is in agreement with all medical requirements. A positive influence of volumetric UF control on patients undergoing chronic hemodialysis can be shown by the frequencies of dialysis side effects. Volumetric UF control is only a first step towards an intelligent UF module to correlate water removal, solute removal and sodium balance.

Tc-99m-DTPA--a new test substance for detoxification devices.

Tc99m labeled diethylenetriaminepentaacetic acid (Tc-99m-DTPA) is an appropriate in vivo test solute for all extracorporeal detoxification procedures. The molecular weight of the Tc-99m-DTPA complex is within the biologically relevant middle molecular range of 400 to 700 daltons. Tc-99m-DTPA is distributed in the extracellular space in the same way as inulin. Regarding its localization in the gel filtration spectra and plasma clearance, Tc-99m-DTPA corresponds to middle molecule peak 2. The evaluation of elimination rate and plasma clearance CP of Tc-99m-DTPA is possible by measuring the pulse rates before and after the detoxification device. Taking into account the corrections for Ht and UFR, the Tc-99m-DTPA plasma clearances were calculated for different dialyzers, high flux dialyzers, hemofilters and a hemoperfusion device. The continuous measurement of pulse rates and the use of a UFR-controller (A2008) allow an exact tracking of CP vs. time, the estimation of CP (QB), CP(UFR) and of the sieving coefficient. Examples are given for these cases. It was shown that an increase in plasma clearance to more than about 100 ml/min does not greatly increase the Tc-99m-DTPA elimination rate.

Continuous measurement of DTPA-clearance in extracorporeal detoxification circuits.

A new method for investigating clearances is described. DTPA labelled with technetium 99m (MW: 496 daltons) is used as an agent to be measured. Continuous determination of the DTPA-clearance is possible in extracorporeal detoxification circuits including dialyzers, hemofilters and hemoperfusion columns. As an example, DTPA-clearances are given for two different dialyzers. In comparison to clearance measurements of peak 7, DTPA-clearance was very similar to that obtained for peak 7.

[Developmental tendencies of hemadsorption in uremia treatment]. / Entwicklungstendenzen der Hämoadsorbentien für die Urämiebehandlung.

After at first having dealt with the present stage of haemoperfusion in the therapy of chronic renal insufficiency, the developmental tendencies for the haemoadsorbers to be expected are mentioned which in future allow to think of a diminution of the artificial kidney. Own results concerning the behaviour of blood compatibility and the effectivity of different active charcoals show that it is to be reckoned with the further development of unstratified adsorbents or such ones with ultra-thin layer. Comparative examinations of 4 patients from the chronic haemodialytic programme, who were treated for 4 months with the CDAK 1.8 and then for 4 months with the sorbent dialyser 1.3, could not show any essential differences in the behaviour of the low-molecular substances urea, creatinine and uric acid and of the clinical condition of the patients.

[Technics and indications for hemofiltration treatment]. / Technik und Indikationen der Hämofiltrationsbehandlung.

Technique, possibilities of application, advantages and disadvantages of haemofiltration are described. A convective mass transport underlies the method. By this means the elimination of molecules of different size takes place with the same speed and the removal of so-called middle molecules is performed more effectively than in the usual method of dialysis.

[Use of the bicoagulation technic in irreversible contraception]. / Die Anwendung der Bikoagulationstechnik bei der irreversiblen Kontrazeption.

PIP: An apparatus is described for the performance of bipolar electrocoagulation of the Fallopian tubes to effect sterilization. A model with two tongs was chosen over a model with 4 tongs. Coagulation is achieved in about 30 seconds; resistance increases in the tissue to a maximum after about 10 seconds. After the water is evaporated from the tissue and coagulation is complete, the resistance drops again. No carbonization of the tissue has been observed while using this method.^ieng