Immunomodulation: clinical aspects.
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Biomedical subjects
Publications and source records attributed to W Samtleben.
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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.
Membrane and centrifugal apheresis operate on different physical principles but are both capable of efficiently fractionating plasma proteins from whole blood. For therapeutic purposes, both formats yield about the same protein clearance per liter of solute exchanged and neither is significantly more rapid than the other. Only continuous centrifugation can be used to pherese cellular elements and only membrane filter can be deployed in 'spontaneous' circuits. Hardware for continuous centrifugation is more expensive and disposables less expensive than for the membrane methods; the 'crossover' occurs at 200 treatments. To date, only the centrifugal method is employed for donor apheresis; this may change in the future as membranes can yield a truly platelet-free product and appear to offer a much more rapid collection cycle.
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Of 20 patients who presented to our hospital with the histologically confirmed diagnosis of SLE, nine met the criteria of presence of both a rapidly progressive disease state and contraindications for conventional therapy required for admission to our plasma exchange programme. Five patients improved; two patients progressed to end-stage renal failure; two patients died as a result of complications of advanced SLE. Severe lupus erythematosus (SLE) is usually treated with a combination of steroids and cytotoxic drugs. Even when treated with high dose therapy some patients develop life-threatening complications, such as renal failure, heart failure and respiratory insufficiency. Moreover, both treatment with high dose of corticosteroids and long lasting cytotoxic therapy may produce troublesome side-effects, including severe infections, gastroduodenal ulcers, bone marrow depressions and lymphomas (1, 2). One of the manifestation of SLE is the presence of antibodies against ds-DNA and ss-DNA. These antibodies can either react with DNA bound to te basement membrane and induce an inflammatory reaction (3), or can form circulating immune complexes which deposit in tissues and may impair the function of lymphocytes or macrophages in the RES (4, 5). The presence of anti-DNA-antibodies appears to be secondary to enhanced B-cell activity along with a depression of suppressor T-cells function proteins mediating the inflammatory process, such as fibrinogen, may deposit in membranes already compromised by the disease. Even though the pathogenic mechanisms operating in SLE are not completely understood, it can be expected, from a theoretical point of view, that the extracorporeal removal of any immunopathogens could improve the disease state.(ABSTRACT TRUNCATED AT 250 WORDS)