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Biomedical subjects

M Haag-Weber

Publications and source records attributed to M Haag-Weber.

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

Impaired cellular host defence in peritoneal dialysis by two granulocyte inhibitory proteins.

Bacterial and fungal peritonitis is associated with a high risk of morbidity and mortality in patients undergoing continuous ambulatory peritoneal dialysis (CAPD). Impaired cellular host defence in the peritoneal cavity underlies this risk. Two granulocyte inhibitory proteins with a molecular weight of 28,000 dalton (GIP I) and about 9500 dalton (GIP II) with homology to light-chain proteins and beta 2-microglobulin, respectively, were isolated from peritoneal dialysis effluents. In vitro, both granulocyte inhibitory proteins inhibit PMNL glucose uptake, phagocytosis and intracellular killing of bacteria. The IC50 of GIP I or GIP II required for inhibition of half-maximal FMLP-induced or PMA-stimulated PMNL function was found to be in the nanomolar range, suggesting very specific inhibition. These data may explain, at least in part, defective local cellular host defence in CAPD patients.

Cytokines↗
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

Effect of calcium channel blockers on intracellular calcium accumulation.

Protection against acute renal failure by calcium channel blockers include radiocontrast agent, cyclosporin, aminoglycosides, amphotericin B, cisplatin nephrotoxicity, and ischaemia-induced toxicity. Calcium overload occurs in ischaemic cells. The type of calcium channel blocker influences the potential effect on protection against nephrotoxicity. A number of growth factors and hormones induce cellular activation by increasing calcium concentrations. Calcium channel blockers interfere with activation of different cell types, e.g. decrease platelet aggregation, macrophage activation, platelet-activating factor release and also proliferative response of vascular smooth muscle and mesangial cells. Uraemia is also a state of calcium accumulation. Increase of intracellular calcium [Ca2+]i in PMNLs is associated with deactivation. Treatment with calcium channel blockers normalizes elevated PMNL [Ca2+]i and improves functional parameters of PMNLs. Normalization of enhanced [Ca2+]i of PMNLs can also be achieved with effective 1,25(OH)2 vitamin D3 therapy by lowering PTH. Uraemia is also a state of insulin resistance. Elevated levels of [Ca2+]i in insulin target cells diminish sensitivity to insulin at the postbinding site. Therapeutic manoeuvres preventing the increase of cytosolic calcium may improve insulin resistance.

Acute Kidney Injury↗
PubMed1994

Isolation of a granulocyte inhibitory protein from uraemic patients with homology of beta 2-microglobulin.

Increased incidence of infection in uraemic patients is mainly caused by granulocyte dysfunction. Recently we discovered a granulocyte inhibitory protein (GIP I) in the ultrafiltrate of haemodialysis patients, that inhibits four fundamental functions of polymorphonuclear leukocytes (PMNLs). We now report on the isolation of a further polypeptide in end-stage renal disease patient ultrafiltrate using a polyamide filter with biological activity inhibiting healthy PMNL function in vitro. This protein (GIP II) has a molecular weight of about 9500 Da. In-vitro nanomolar concentrations inhibit PMNL O2- production and glucose uptake stimulated by phorbol-myristate-acetate (PMA), but not by formyl-methionyl-leucyl-phenylalanine (FMLP). In-vitro studies were performed to compare the effects of GIP I and GIP II on several PMNL functions. In contrast to GIP II, GIP I inhibits only FMLP-, but not PMA-stimulated PMNL glucose uptake. The NH2 terminal amino acid sequence (21 amino acids) of GIP II shows homology to beta 2-microglobulin. Commercially available intact beta 2-microglobulin had no effect on PMNL glucose uptake and O2- production. The beta 2-microglobulin homologue protein isolated from plasma ultrafiltrates of uraemic patients cross-reacts with three different commercially available assays for intact beta 2-microglobulin. Therefore, beta 2-microglobulin levels measured in the plasma ultrafiltrates of regular haemodialysis patients are overestimated with contribution of an uncertain amount of the beta 2-microglobulin homologue protein (GIP II).

Amino Acid Sequence↗
PubMed1993

Normalization of enhanced neutrophil cytosolic free calcium of hemodialysis patients by 1,25-dihydroxyvitamin D3 or calcium channel blocker.

Patients undergoing regular hemodialysis treatment display elevated intracellular free calcium and impaired glucose uptake in polymorphonuclear leukocytes (PMNLs) in the presence of enhanced serum parathyroid hormone (PTH) levels. Normalization of intracellular calcium can be achieved by different therapeutic interventions acting by different mechanisms. Effective oral 1,25-dihydroxyvitamin D3 therapy (0.5-1.0 microgram/day) normalizes PMNL cytosolic calcium via suppression of PTH levels. Hemodialysis patients treated orally with the calcium channel blocker nitrendipine (20-40 mg/day) normalizes calcium without affecting serum PTH levels. Both therapeutic interventions improved glucose uptake and displayed no synergistic effect.

Blood Glucose↗
PubMed1992

Effect of hemodialysis on intracellular calcium in human polymorphonuclear neutrophils.

Hemodialysis (HD) leads to neutrophil activation depending on the membrane material used. Calcium plays a major role in PMN function and metabolism. A rise of cytosolic free calcium [Ca2+]i is an important intracellular messenger for neutrophils. In this study we measured intracellular resting Ca2+ and the chemotactic peptide FMLP-stimulated intracellular Ca2+ during HD using membranes made of polysulfone and polymethylmethacrylate (PMMA). Also, we investigated the effect of continuous infusion of nifedipine in a dose of 18 micrograms/kg/h during HD with PMMA. Only HD with PMMA causes an increase of both resting and FMLP-stimulated [Ca2+]i after 30 min of starting HD. Polysulfone did not affect [Ca2+]i. Continuous infusion of nifedipine during HD with PMMA completely inhibited these changes of [Ca2+]i. Although the existence of voltage-sensitive calcium channels has not been proved, the present data provide further indirect evidence either for the existence of calcium channels or for a mechanism of action that is independent of antagonism.

Calcium↗
PubMed1992

Effect of malnutrition and uremia on impaired cellular host defence.

There is a high incidence of infection in hospitalized patients with chronic renal failure. Nutritional and metabolic factors, as well as vitamins and trace elements are involved in impaired host defence and altered PMN function in dialysis patients. A circulating peptide (GIP) could be isolated from uremic serum that inhibits PMN glucose uptake, chemotaxis, oxidative metabolism and intracellular killing of Staphylococcus aureus. In addition to enhanced susceptibility to infection by impaired PMN function, uremic patients show profound defects of specific immune system represented by monocytes, B cells and T cells. T cells show decreased proliferation and Il-2 production on the one hand and enhanced Il-2 receptor expression on the other. Monocytes fail to elicit adequate help for T cell proliferation despite normal production of Il-1 and Il-6, but they produce elevated amounts of TNF alpha. B cells secrete decreased amounts of IgG and respond insufficiently to various vaccines. Malnutrition and uremia induce severe alterations of host defence and specific immune system if a combination of both these diseases occur.

Humans↗
PubMed1991

Effect of immunosuppressive drugs on the release of metalloproteinases from human polymorphonuclear leukocytes.

The concentration of the metalloproteinases type I collagenase and gelatinase was measured in isolated polymorphonuclear leukocytes (PMNLs) of renal transplant recipients treated either with cyclosporin A (CyA) and prednisolone (Pr) (n = 8) or azathioprine (Aza) and Pr (n = 8), and of healthy subjects (n = 12). PMNLs of CyA- and Aza-treated transplant patients displayed markedly higher gelatinase content (2427 +/- 489 and 3284 +/- 357 ng/10(7) cells) than PMNLs of controls (528 +/- 83 ng/10(7) cells). There was also a higher content of type I collagenase in PMNLs (3374 +/- 292 ng/10(7) cells) of Aza-treated patients and significantly elevated levels in PMNLs of patients receiving CyA (3625 +/- 229 ng/10(7) cells) compared with healthy subjects (2878 +/- 151 ng/10(7) cells). In contrast, neutrophil lactoferrin content was lower in transplant patients. Thus, immunosuppressive drugs may reduce the release of leukocyte proteinases, which are known for their deleterious role in proteolytic tissue and matrix breakdown. In vitro, the effects of different immunosuppressive drugs on the release of lactoferrin, collagenase and gelatinase were investigated on FMLPNTL-stimulated PMNLs isolated from healthy subjects. CyA but not Aza or Pr caused inhibition of gelatinase, collagenase and lactoferrin release.

Adult↗
PubMed1991

Alterations of polymorphonuclear leukocyte glycogen metabolism and glucose uptake in dialysis patients.

Human polymorphonuclear leukocytes (PMNs) are activated during extracorporeal circulation. An indicator of PMN activation may be the glycogen-degrading enzyme phosphorylase. It is unknown whether dialysis therapy may influence PMN carbohydrate metabolism. Therefore, PMNs were isolated from healthy control subjects, patients undergoing continuous ambulatory peritoneal dialysis (CAPD), and patients undergoing regular hemodialysis therapy (RDT) before, during, and at the end of hemodialysis (HD) treatment using dialyzers made of polysulfone or polymethylmethacrylate (PMMA). Nifedipine (NIF) was continuously infused during HD with PMMA in 5 patients at a dose of 18 micrograms/kg body weight per hour. Glycogen, activity of glycogen synthetase and phosphorylase (active and inactive forms of both enzymes), and glucose uptake with and without stimulation with the chemotactic peptide FMLP were determined in these PMNs. During HD with PMMA, there was a significant increase of PMN phosphorylase "a" activity 15 and 30 minutes after the start of HD. HD with polysulfone did not stimulate the active "a" form of the glycogen-degrading enzyme in PMNs. HD with PMMA significantly inhibited the active I-form of glycogen synthetase, whereas polysulfone activated glycogen synthetase I. NIF inhibited phosphorylase "a" activation during HD with PMMA. PMN glycogen content and glucose uptake were improved during HD with polysulfone, but not with PMMA. PMN glycogen content, activity of glycogen synthetase, and glucose uptake were significantly lower also in CAPD patients compared with healthy controls. These data show that HD with PMMA activates PMN glycogenolysis. This effect can be inhibited by calcium channel blockers. PMN glycogen content of RDT and CAPD patients is significantly lower compared with healthy controls due to inhibition of glycogen synthesis. Elimination of dialyzable factor(s) improves, but does not restore, PMN glycogen synthesis and glucose uptake.

Adult↗
PubMed1990

Physicochemical characterization of a polypeptide present in uremic serum that inhibits the biological activity of polymorphonuclear cells.

A granulocyte inhibitory protein was isolated and characterized from uremic serum by using ion-exchange column chromatography, high-performance size-exclusion chromatography, and immunochemical procedures. The purification process concentrated the protein 240-fold and to a purity of greater than 95%. An overall recovery of 45% was achieved; the purified protein had a specific activity of 104 units per mg of protein. The polypeptide had a molecular weight of approximately 28,000 and an isoelectric point of 4.0-4.5. Amino acid sequencing of the NH2 terminus revealed a single sequence (Asp-Ile-Val-Met-Thr-Gln-Ser-Pro-Gly-Thr-Leu-Ser-Val-Ser-Pro-Gly-Glu-Arg-Ala- Thr) that proved to be nonhomologous with other serum proteins that appear during an inflammatory state. The polypeptide inhibited the uptake of deoxyglucose, chemotaxis, oxidative metabolism, and intracellular bacterial killing by polymorphonuclear leukocytes. A specific rabbit polyclonal antibody raised against the protein nullified these inhibitory changes. We contend that the protein is responsible for the leukocyte dysfunction that is commonly seen in patients with uremia.

Amino Acid Sequence↗
PubMed1990

Failure to detect remarkable hypomagnesemia in renal transplant recipients receiving ciclosporin.

Serum magnesium as well as total and fractional urinary magnesium excretion were investigated in 87 renal transplant recipients under immunosuppression with azathioprine/prednisone (n = 18), ciclosporin/prednisone (n = 33) or ciclosporin/azathioprine/prednisone (n = 36). Only patients treated with ciclosporin and prednisone displayed significantly lower serum magnesium (1.8 +/- 0.03 mg/dl), compared to azathioprine-treated ones (2.0 +/- 0.07 mg/dl; p less than 0.05). Mean serum magnesium values of all three groups remained in the lower normal range (1.7-2.7 mg/dl). Fractional but not total magnesium excretion was significantly (p less than 0.05) higher in both ciclosporin-treated groups (5.8 +/- 0.38 and 5.6 +/- 0.40%) compared to patients on azathioprine (4.5 +/- 0.48%). None of the patients developed clinical signs of hypomagnesemia and only 7 patients were on oral supplementation with magnesium containing antacida. Our study did not confirm earlier observations of severe magnesium wasting and hypomagnesemia in renal transplant recipients under immunosuppression with ciclosporin.

Adult↗