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Biomedical subjects

R Deppisch

Publications and source records attributed to R Deppisch.

At least 37 records · Page 2Linked to original sources
PubMed1994

Role of proteinase/antiproteinase inhibitor disequilibrium in the bioincompatibility induced by artificial surfaces.

As one aspect of bioincompatibility, the importance of activation of proteolytic systems as a result of an imbalance between protease and antiprotease activity has been increasingly recognized. This principle is illustrated by selected studies in our laboratory. These concern (i) generation of kinins on membranes with negative surface charge, (ii) activation of the complement system as a function of binding to the membrane of the regulatory protein H, (iii) generation of thrombin-antithrombin complexes (TAT), and (iv) generation of plasmin/antiplasmin complexes with an interesting discrepancy between in vivo and in vitro.

Animals↗
PubMed1994

Studies of biocompatibility of different dialyzer membranes: role of complement system, intracellular calcium and inositol-triphosphate.

PMNLs are activated during extracorporeal circulation. The aim of this cross-over biocompatibility study was to investigate the role of complement system, intracellular calcium [Ca2+]i and inositol-triphosphate (IP3) on PMNL degranulation during hemodialysis (HD) with following membranes: polyamide, hemophane and cuprophane. In a second study the effect of complement system, intracellular calcium and IP3 on lactoferrin release during HD with polysulfone and polymethylmethacrylate (PMMA) was also investigated. HD with cuprophane leads to the highest formation of terminal complement component (TCC) followed by PMMA and hemophane. There was a strong correlation between maximal arterial TCC formation and procentual increase of plasma lactoferrin during hemodialysis treatment with all membranes. Both HD with PMMA and hemophane leads to a significant increase of resting [Ca2+]i after 30 minutes of HD. Lowest TCC formation and lowest rise in [Ca2+]i were observed with polysulfone and polyamide. Procentual and absolute increase of [Ca2+]i did also correlate with maximal TCC formation during HD using PMMA, hemophane, polyamide and polysulfone. Since cuprophane induces an initial drop of PMNLs, these cells could not be isolated during HD with cuprophane membranes. Resting PMNL IP3 values were similar before and 30 minutes after begin of hemodialysis and comparable with all membranes used. These data indicate that TCC and intracellular calcium are important signals for PMNL degranulation during HD with cuprophane, PMMA and hemophane. However, mild degranulation of specific PMNL granules can also occur in the absence of significant change in TCC, [Ca2+]i or IP3 levels during HD with polyamide or polysulfone.

Biocompatible Materials↗
PubMed1994

Atherogenesis and cardiac death: are they related to dialysis procedure and biocompatibility?

Cardiac events are a major cause of death in dialysed patients. This is due, at least in part, to the high prevalence of atherosclerotic coronary heart disease. To a large extent, however, coronary lesions are acquired in the predialytic phase of chronic renal failure. The susceptibility of the heart to ischaemia is modulated by a number of factors, e.g. microvascular abnormalities, increased cardiac pulsatile workload, disturbed cardiac glucose metabolism, imbalanced autonomic innervation. The paradoxical result of there being no relationship of cardiac death in dialysis patients to blood pressure may be explained by confounding factors. Intradialytic hypotension appears to be an independent risk factor. The dialysis patient is exposed to hypertension and dyslipidaemia, two potent risk factors of atherosclerosis. Although no definite information is available, it is conceivable that factors related to dialysis procedures may also influence early or late events in atherogenesis. Such potential factors include oxidative modification of lipids, modulation of insulin resistance or glucose metabolism by non-insulin-dependent pathways, expression of adhesion molecules and activation of potential effector cells in atherogenesis, particularly monocytes and platelets, changes of synthesis and/or response to endothelin and nitroxide (EDRF), and possibly also accelerated formation of advanced plaques by hyperphosphataemia and/or hyperparathyroidism. Such proatherogenic mechanisms must be balanced against factors potentially protecting against atherogenesis; these comprise altered arachidonic acid metabolism (increased prostacyclin and decreased thromboxane synthesis), impaired platelet aggregation, antiatherosclerotic effects of heparin, and diminished concentrations of 1,25(OH)2D3, i.e. of a proatherogenic compound.

Arteriosclerosis↗
PubMed1994

Bioincompatibility--perspectives in 1993.

Bioincompatibility reactions related to the non-physiology of the procedure have plagued dialysis from its early days. Although the problem is certainly multifactorial, the present overview selectively focuses on some aspects of activation of late complement (C) components, the importance of which may have been underappreciated in the past. Dialysis patients are poised for intense C activation because of cumulation of the low molecular weight factor D, an intrinsically active serine esterase which is not inhibited by any known endogenous inhibitor and catalyzes an early step in the alternative pathway. C activation reflects the net balance between activation and inhibition, the latter particularly via factor H binding. Dialyzer membrane characteristics that are related to factor H binding and regulation of initial activation steps include not only membrane surface chemistry but also its microdomain structure. Kinetic studies of the generation of the terminal complement complex (TCC) suggest ongoing generation throughout the duration of a dialysis session (in contrast to the transient release of C-derived anaphylatoxins). Potential consequences of TCC generation include amplification of the non-C-dependent cell activation signals through L-fucose-dependent steps. Efforts to reduce TCC generation by membrane engineering, for example, end group derivatization and optimization of microdomain structure, open perspectives for the development of more biocompatible membranes.

Biocompatible Materials↗
PubMed1993

Stimulation of mononuclear cells by contact with cuprophan membranes: further increase of beta 2-microglobulin synthesis by activated late complement components.

Contact of mononuclear cells (MNC) with cuprophan membranes in vitro causes an increase in beta 2-microglobulin (beta 2m) synthesis. Since in vivo the dialyzer membrane is rapidly coated with plasma proteins, contact activation of MNC was tested in the presence of normal human serum (NHS). After contact with cuprophan, deposition of C5b-9 on the cells was seen, followed by an increase in beta 2m synthesis and cytokine release, exceeding that seen after contact activation in the absence of serum. Inactivated serum or serum deficient in C8 did not increase beta 2m production, indicating that the additional activation was due to complement C5b-9. The results suggest that there are two cuprophan-related mechanisms of cell activation: one by contact of cells with the membrane, the other by the complement activation products. Both might synergistically contribute to an increased beta 2m synthesis in hemodialysis patients.

Blotting, Northern↗
PubMed1993

Complement activation and C3 allotype distribution in patients with bronchial asthma.

61 patients suffering from intrinsic (idiotypic) or extrinsic (allergic) asthma were investigated for signs of complement activation and for C3 phenotype distribution. Activation of both the classical and alternative pathway of the complement system and generation of the membrane attack complex could be assessed by ELISAs for the activation-specific protein-protein complexes C1rsC1 inhibitor, C3b(Bb)P and SC5b-9, respectively. A possible deficiency of the complement regulatory proteins C1 inhibitor, factor H and factor I was excluded. In contrast to earlier studies, C3 allele frequencies did not differ from those found in the healthy population. Our results support the role of complement activation during bronchial asthma and, thereby, provide further evidence for the inflammatory nature of the disease.

Alleles↗
PubMed1992

25-Hydroxyvitamin D3 metabolism in vitro by mononuclear cells from hemodialysis patients.

Hemodialysis patients have a capacity for extrarenal production of 1 alpha,25-dihydroxyvitamin D3 [1,25(OH)2D3]; however, the source of the hormone is unknown in these patients. Since 1,25(OH)2D3 synthesis by cultured hematopoietic cells has been demonstrated previously, we assessed hormone production by mononuclear cells from peripheral blood obtained from normal subjects (n = 6), uremic patients not yet requiring dialysis (n = 4) and hemodialysis patients (n = 14). 1,25(OH)2D3 production was analyzed by sequential straight phase and reverse phase HPLC. In the hemodialysis group, the mean specific production of a metabolite co-eluting with 1,25(OH)2D3 (in fmol/100,000 cells/h) both by monocyte-enriched adherent cells (Mo) and lymphocyte-enriched non-adherent cells (Ly) was increased as compared to non-dialyzed subjects (119 vs. 22 for Mo, not significant, 65 vs. 14 for Ly, p < 0.05). Taken together, Mo and Ly from hemodialysis patients synthesized significantly more 1,25(OH)2D3 (p < 0.02) than non-dialyzed subjects (184 vs. 36, means). No differences were found between cells from normal subjects and patients with preterminal renal failure. Exposure of cultured normal Mo (n = 6) to cuprophane (CU), polyacrylonitrile (AN69) or polycarbonate-polyether (PC) membrane devices resulted in increased 1,25(OH)2D3 production as compared to control incubations without membrane. The rank order of increase was PC > AN69 > CU, whereby only PC (p < 0.05) was significantly different from control. Our results suggest that blood mononuclear cells contribute to extrarenal 1,25(OH)2D3 synthesis in hemodialysis patients, and that this synthetic activity may be related to the hemodialysis procedures.

Calcifediol↗
PubMed1991

Stimulation of beta 2-microglobulin synthesis in lymphocytes after exposure to Cuprophan dialyzer membranes.

We tested beta 2-microglobulin (beta 2m) synthesis by peripheral blood lymphocytes of non-uremic donors after contact with dialyzer membranes. Under serum-free conditions, lymphocytes were incubated with different dialyzer membranes for four hours. After subsequent culture in the absence of membranes to yield an overall culture time of 24 hours, RNA was extracted. Messenger RNA for beta 2m was quantitated by Northern blotting with specific probes. Increased beta 2m mRNA was seen after a minimum of one hour contact time with Cuprophan both in the presence and absence of cycloheximide. While no consistent stimulation was seen with polyacrylonitrile or polycarbonate-polyether membranes, respectively, the stimulation of beta 2m mRNA with Cuprophan was of the same order of magnitude as that obtained with interferon gamma. Stimulation of beta 2m mRNA by Cuprophan was stereospecifically diminished by 5 mM L-fucose. Apart from stimulated transcription of beta 2m we could also show increased surface expression of MHC class I molecules, using FACS technique. The results further prove complement-independent blood cell activation by Cuprophan membranes. It is uncertain whether the results are relevant for beta 2m amyloidosis.

Blood Proteins↗
PubMed1991

Induction of mediator release from human glomerular mesangial cells by the terminal complement components C5b-9.

Exposure of cultured human glomerular mesangial cells (GMC) to normal human serum and an activator of the complement system results in rapid uptake of the terminal complement proteins C5b-9 by the cells. This 'innocent bystander' complement attack, however, does not result in cell killing, but in the stimulation of the GMC to release prostaglandin E (PGE), interleukin 1 (Il-1) and tumor necrosis factor (TNF). Endogenously synthesized Il-1 in turn activates PGE release, indicating that the C5b-9 attack initiates an autocrine feedback stimulation. Together with the fact that C5b-9 is found in many forms of glomerulonephritis, the data point to a role of the terminal complement proteins in the initiation and perpetuation of an inflammatory response.

Complement Membrane Attack Complex↗
PubMed1990

Several epitopes on native human complement C9 are involved in interaction with the C5b-8 complex and other C9 molecules.

Ten monoclonal antibodies (mAb) against native human C9 exhibiting various inhibitory effects on the hemolytic activity of C9 (Bausback, J., Kontermann, R. and Rauterberg, E. W., Immunobiology 1988. 178: 58) were further analyzed regarding their reactivities with monomeric C9 (mC9), polymerized C9 (pC9), and the non-lytic SC5b-9 complex in enzyme-linked immunosorbent assay and with the membrane attack complex (MAC) generated on rabbit erythrocytes analyzed by flow cytometry. In addition, the inhibitory effects of mAb on zinc-induced C9 polymerization were investigated. One epitope of the C-terminal half of C9b exposed on the surface of pC9 and the MAC seems not to participate directly in lytic function or polymerization since no inhibitory effect of the respective mAb was observed. The nine other mAb directed against epitopes of the C9a part exhibit various inhibitory potentials. The mAb inhibit either hemolysis or polymerization, or both processes. Due to the reactivity with the tested antigens the mAb can be divided into two groups. mAb of the first group bind with nearly the same affinity to all four antigens, whereas mAb of the second group react preferentially with mC9 while their affinity to pC9, SC5b-9 and the MAC is reduced. Comparison of reaction patterns and inhibitory effects strongly suggest that different epitopes on the surface of native C9 are involved in interaction of C9 with C5b-8 and/or in C9-C9 interaction. The finding that mAb inhibiting polymerization of C9 in vitro have no inhibitory effect on hemolysis confirms that C9 polymers are no prerequisite for lysis.

Antibodies, Monoclonal↗
PubMed1990

Fluid phase generation of terminal complement complex as a novel index of bioincompatibility.

Blood membrane interactions in hemodialysis have been shown to trigger complement (C) activation. As indicators of C-activation the anaphylatoxins (C3a and C5a) are problematical because of methodological difficulties and their kinetic properties. We developed a sensitive and specific micro-ELISA using a monoclonal antibody against neoantigens on the terminal complement complex (TCC); highly purified human TCC served as standard. Concentrations of TCC were measured in single-path perfusion systems (in vitro) and in the blood lines (arterial inlet; venous outlet) of patients on hemodialysis using steam-sterilized or ETO-sterilized dialyzers with the following membranes: cuprophan (CU), hemophan (HE) and polysulfone F6 (PS), respectively. All dialyzers with identical geometry were run under identical conditions. All membranes tested caused continuously ongoing net generation of TCC. In vitro, contact of serum with CU minidialyzers resulted in fivefold higher net release of TCC compared with HE and PS. In vivo TCC concentration-time profiles differed significantly between membranes in the rank order CU much much greater than HE greater than PS (mean basal concentration 58 x 10(-11) M; peak increase over baseline with CU 40-fold, HE fourfold, PS threefold). In addition, more TCC was generated from the same dialyzers with ETO than steam sterilization. TCC differed from C3a and C5a in the following respects: (i) lower detection limit (4 x 10(-11) vs. less than 5 x 10(-9) M for both C-anaphylatoxins); (ii) higher relative increment (inlet) during CU dialysis (25-fold vs. eightfold and twofold, respectively); (iii) C-anaphylatoxins yielded the same ranking (CU much greater than HE greater than PS), but TCC concentrations were not a linear function of C3a or C5a concentrations, respectively. Kinetic analysis (Bateman function) showed significant differences of invasion constants between membranes, that is, CU 0.088 min-1, HE 0.09, PS 0.168. The net amount of TCC released from the dialyzer was calculated under certain assumptions. It was 75.5 mg/4 hr for CU, 7.3 for HE and 5.0 for PS. The elimination constant was also dependent on the type of membrane. Using flow cytofluorometry and immunohistochemical methods (APAAP), TCC was demonstrated on membranes of granulocytes obtained during dialysis; this is compatible with potential in vivo cell activation. Generation of PGE2 and TNF alpha by adherent monocytes induced by cuprophan was C8 dependent: levels were significantly increased by addition of C8 to C8 deficient human serum concomitantly with generation of TCC.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1990

Assembly of terminal SC5b-9 complement complexes: a new index of blood-membrane interaction.

Activation of the complement system during the course of hemodialysis was recognized more than 20 years ago and since then the generation of C3a and C5a desarg has been used as parameters of blood-membrane interaction. More recently, determination of terminal C5b-9 complement complexes has become feasible. In the present study we determined plasma concentrations of C5b-9 complexes during hemodialysis using Cuprophan or Hemophan membranes. As early as 10 min into dialysis, Cuprophan membranes led to higher arterial plasma concentrations of C5b-9 complexes in comparison to Hemophan-containing devices. With Cuprophan, systemic arterial peak values of 237 +/- 27 U/ml were reached 45 min after the onset of dialysis, while corresponding peak values using Hemophan were only 58 +/- 16 U/ml. Venous concentrations of C5b-9 complexes, measured at the outlet of the dialyzer, were 489 +/- 102 U/ml with Cuprophan and 77 +/- 19 U/ml with Hemophan dialyzers. As an index of red cell lysis, plasma levels of free hemoglobin were evaluated. There was hemolysis with both membranes. Free hemoglobin levels increased threefold with Cuprophan and only twofold with Hemophan membranes. Taken together, plasma concentrations of C5b-9 complexes clearly discern between dialysis membranes of high or low compatibility. The fact that there is simultaneous lysis of red cells might indicate that deposition of C5b-9 complexes on innocent cells occurs which would lead subsequently to an array of diverse pathophysiological reactions.

Adult↗
PubMed1986

PC-PE hollow-fiber membrane. Structure, performance characteristics and manufacturing.

Polyether-polycarbonate hollow fibers, spun by the phase inversion method, yield a dialysis membrane with a limited ultrafiltration coefficient but high diffusive permeability. Dialysers are made out of this membrane and are sterilized by gamma radiation. The dialysers show controlled ultrafiltration and clearance values for smaller molecular weight substances in the range of cellulosic membranes, but for larger molecular weight substances the clearances are higher. Correlation for ultrafiltration and clearance values, measured in saline and whole blood, indicate low interactions between blood and membrane.

Creatinine↗
PubMedDate not supplied

Significant reduction of factor D and immunosuppressive complement fragment Ba by hemofiltration.

Because of their effect on the immune response, especially in patients with chronic or acute renal failure, factor D (FD) and the immunosuppressive complement fragment Ba are substances which may be important for the immunological status. Since they cannot be eliminated by conventional Cuprophan hemodialysis because of their high molecular weight (24,000 and 33,000 D, respectively), the effect of hemofiltration (HF) on the plasma concentration of both components was tested. It was shown that plasma levels of FD can be lowered by 43.5% during an HF treatment and the plasma concentration of Ba by 30.6%. Moreover, the two substances could be detected in the hemofiltrate. Up to 75 mg FD and up to 37 mg Ba could be eliminated per treatment, depending on the plasma concentrations and the filtration volume. A convective method such as chronic HF is therefore clearly superior to diffusive methods of blood purification when substances with such a high molecular weight have to be eliminated. It has still to be established whether the elimination of FD and Ba by chronic intermittent HF results in a sustained improvement in the immunological status of patients treated in this way.

Adult↗
PubMedDate not supplied

Glucose degradation products in peritoneal dialysis fluids may have both local and systemic effects: a study of residual fluid and mesothelial cells.

OBJECTIVE: When peritoneal dialysis (PD) fluids are heat sterilized, glucose is degraded to carbonyl compounds. These compounds are known to interfere with many cellular functions and to promote the formation of advanced glycation end-products. However, little is known about what actually happens with glucose degradation products (GDPs) after infusion into the peritoneal cavity. The aim of the present study was to investigate possible targets for GDPs in the peritoneal cavity. DESIGN: In vitro reactions between residual fluid and GDPs were studied by incubating unused PD fluid with overnight dialysate. Confluent monolayer cultures of human mesothelial cells were used as a model to study the reactions of GDPs with the cells lining the peritoneal cavity. METHODS: Samples were analyzed, using high pressure liquid chromatography, for the presence of formaldehyde, acetaldehyde, 5-hydroxymethyl-2-furaldehyde (5-HMF), methylglyoxal, and 3-deoxyglucosone (3-DG). Cytotoxicity was determined as inhibition of proliferation of cultured fibroblasts. RESULTS: None of the analyzed GDPs reacted with overnight dialysate. Formaldehyde and methylglyoxal, in contrast to 3-DG and 5-HMF, reacted with the cultured mesothelial cells. CONCLUSIONS: Low molecular weight carbonyls such as formaldehyde and methylglyoxal most probably react with the mesothelial cells lining the peritoneal cavity, and could be responsible for the disappearance of these cells during long-term treatment. 3-Deoxyglucosone showed remarkably low reactivity and was most probably transported within the patient.

Animals↗