Biomedical subjects
Publications and source records attributed to W Samtleben.
In a 61-year-old woman recurrent bacterial infections were caused by immune neutropenia which was resistant to high-dose cortisone and plasmapheresis. However, high-dose intravenous 7S-immunoglobulin therapy (30 g for 6 days) induced a long-term remission for 35 months. This treatment modality is safe and should be used as a first-line agent.
To evaluate membrane biocompatibility, an open loop ex vivo model was designed simulating the hemodialysis procedure. Blood was withdrawn continuously from healthy nonuremic donors, heparinized, and pumped through a module containing the membrane to be studied. C3a generation in the module was determined at various time points comparing the cuprammonium cellulose (CC) membrane and four types of modified cellulose (MC) membrane, each with a different degree of hydroxyl (OH-) group substitution. In other studies, C3a generation in the ex vivo mode was compared with that during in vivo dialysis. In the ex vivo model, C3a generation with MC membranes was reduced by 70% compared with CC. However, within the MC group, the degree of C3a generation did not correlate with the degree of OH-group substitution. In vivo studies confirmed the reduced degree of C3a generation with the MC membrane compared with CC. Additionally, validation studies using the CC membrane showed excellent agreement between C3a generation during ex vivo perfusion and in vivo dialysis. The results suggest that a group of new MC membranes causes substantially less complement activation than the CC membrane but that the degree of complement activation with various subtypes of MC membranes is not related to the degree of OH-group substitution.
During the past several years clinical protein A perfusion has attracted much attention because it allows to selectively remove IgG subclasses 1, 2, 4 and probably IgG-containing immune complexes, and has a tumoricidal effect in experimental animals and in some cancer patients. Due to several drawbacks, this therapy is not yet generally accepted. Our first experience with laboratory and clinical protein A perfusions confirms several limitations of this new apheresis therapy. Plasma IgG extraction in the ex vivo system under investigation and during clinical application of protein A perfusion reached a 10:1 ratio of grams IgG removed per gram solid-phase protein A only in 2 of 5 runs. Nevertheless, the absolute amount of IgG removed was very low in all runs due to the restricted protein A load (maximum 200 mg) per column. Removal capacity can be increased by a two-column switch-over system with subsequent perfusion and elution. Furthermore, the side effects observed in both in vivo treatments exceeded by far those of other extracorporeal therapies and had not been observed in more than 1,200 unselective plasma exchanges or in 50 cascade filtrations in our center. C3a generation in protein A perfusion is, however, comparable to cascade filtration, but exceeds that of unselective plasma exchange and is lower than in hemodialysis. Consequently, side effects in protein A perfusion cannot be correlated with the total amount of anaphylatoxin generated but may be due to a leakage of protein A or contaminants. Clinical application of protein A perfusion needs a more detailed elaboration in respect to biocompatibility, removal capacity, and the significance of the induced biological effects.
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Routine C1q-fluid phase radioimmunoassay identified high levels of C1q-binding immune complexes in 3 patients with infected ventriculoatrial shunts (VAS). Accordingly, C1q-binding activity was prospectively studied in additional 36. VAS patients to learn whether the observed immune complex activity was secondary to bacterially contaminated shunts or was a normal sequela of continuous intravenous infusion of cerebrospinal fluid into the vascular space. Pathological levels of C1q-binding activity were detected in only 3 out of 32 patients without evidence of shunt infection. However, extremely high C1q-binding activities were measured in 4 more patients with proven shunt infections. Thus, elevated levels of C1q-binding immune complexes correlate with infected VAS. As shunt infection is otherwise difficult to detect, serum C1q-binding activity may prove to be a valuable diagnostic tool for this condition.
A new modified cellulose dialysis membrane (MC, 1.2 m2) in which less than 5% of cellulosic OH-groups are substituted by tertiary amino groups was tested in a 6-week clinical trial for biocompatibility and clinical performance and compared to both regenerated cellulose (RC, 1.2 m2) and cellulose acetate (CA, 1.0 m2). Ten patients on maintenance hemodialysis took part in the study; all hollow fiber modules were equally well tolerated and no adverse reactions were observed. Using MC/RC/CA, mean clearances after 15 min of hemodialysis (HD) amounted to 162/169/150 ml/min for urea, to 143/143/124 ml/min for creatinine, and to 104/107/84 ml/min for phosphate (QB = 200 ml/min, QD = 500 ml/min, UFR = 0). Mean drop of systolic blood pressure was 6/10/8 mmHg and mean decrease of heart rate averaged 3/3/3 beats per minute, respectively, during the first hour of HD as compared to starting conditions. Residual blood volume in the modules after HD was low and heparin consumption identical for all 3 membranes (34 IU/kg X h). Mean peak C3a generation for MC/RC/CA amounted to 1312/3486/3099 ng/ml, respectively; leucocyte and platelet counts dropped to a minimum of 67/24/47% and 81/86/91%, respectively during the first hour of HD as compared to initial values. Elastase release from PMNL and platelet factor 4 from platelets showed no significant differences between the membranes. In conclusion, the new MC membrane showed a significantly better biocompatibility and equally good clinical performance as compared to RC and CA.
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Blood and plasma processing by membranes was introduced into clinical medicine in 1979. In the meantime, membrane plasma separation (plasmapheresis) has become very satisfactory and is now a routine therapeutic procedure in many apheresis centers. Plasma fractionation by membranes (plasma filtration or cascade filtration) for unselective removal of high molecular weight pathogens from the separated plasma is technically possible but its routine clinical application is still limited to a few diseases with at least IgM-sized target proteins. The separation of IgG from albumin needed to treat many autoimmune diseases requires further development of both the membranes and the filtration technology.
Membrane plasmapheresis was introduced in 1978 as a new method for performing therapeutic plasma exchange. Its principal advantages over traditional techniques include speed, ease of performance, and ready adaptability to clinical centers already performing routine extracorporeal therapy. The appearance of a membrane plasmapheresis circuit (vascular access, anticoagulation, connectology) is similar to that of hemodialysis and especially hemofiltration; the operating protocols (treatment time, filtration rates, pressures, pharmacokinetics) are quite different. Particular attention must be paid to avoiding operating conditions that lead to hemolysis. In clinical use membrane plasma separation is as effective as centrifugal plasma exchange in removing plasma proteins. The sieving coefficients for proteins with a molecular weight (MW) ranging from 67,000 (albumin) to 2,400,000 (beta-lipoprotein) daltons are unity. An exchange of one patient plasma volume has been shown to cause a 55% reduction of the serum levels of intravascular proteins. There are no significant differences between membrane and centrifugal plasmapheresis in substitution fluid requirements (human albumin or fresh frozen plasma), indications for treatment and complications. The next major advance in plasmapheresis technology will almost certainly be development of a "closed loop" circuit in which filtered plasma is treated to remove the offending moiety and returned to the patient. This would eliminate both the cost and the possible side effects of replacement fluid. Membrane-based systems are already available for removing cryoglobulins or proteins with MW of at least 900,000 daltons.
Derived mathematical models are employed to compare cascade filtration plasmapheresis in the dead-end and single-pass formats. The high filtration fraction and low sieving coefficients associated with single-pass cascade filtration are shown to require treatment of the retentate concentration profile in an integrated rather than a length-averaged fashion. The models are best applied to specific simulations, but in general predict that (a) for a given membrane, the dead-end format will yield a higher albumin recovery but a lower macroglobulin rejection than single pass; (b) the single-pass format is more suited to loose membranes and the dead-end to tight membranes; and (c) in the single-pass but not the dead-end format, solute recovery is conveniently independent of the quantity filtered. Agreement between predicted and measured performance is good, although a larger data base would be required for complete validation of the models.
Protocols were developed for in vivo and in vitro characterization of the mass transfer performance of filters intended for use in membrane plasmapheresis. The protocols were applied to all presently available filters and also to secondary filters used in cascade filtration. Virtually no distinction was found in filtration rate or sieving coefficient of the ten plasma filters tested and all, except for one early model now considered obsolete, are clinically equivalent. In contrast, filters for cascade filtration varied widely in performance and still require further development for optimal use.
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Since plasma exchange was introduced in the management of thrombotic thrombocytopenic purpura (TTP) in 1977, patient survival rate has increased from 10 to 80%. However, approximately 50 subsequent case reports in the literature provide no consensus as to the optimal therapy. We review here 4 episodes of TTP in 3 patients. In all cases, treatment was started with intensive FFP plasma exchange combined with administration of antiplatelet agents and corticosteroids. Remission was achieved in 3 out of 4 episodes although all required individualization of the medication regimen. In the remaining patient, cytotoxic therapy (vincristine) and ultimately splenectomy were required to achieve stable remission. The variable clinical response to these therapeutic protocols indicates that TTP may not represent a single homogeneous disease entity but rather may involve various underlying pathologies. We conclude that the most effective present therapy for the management of TTP is daily plasma exchange with fresh frozen plasma infusions combined with antiplatelet agents and steroids. Vincristine and splenectomy should only be employed if this protocol proves ineffective.