Complexed plasma elastase as an in vivo marker for leukocyte activation in antineutrophil cytoplasmic antibody-associated vasculitis.

OBJECTIVE: It has been postulated that antineutrophil cytoplasmic antibody (ANCA)-induced degranulation of primed granulocytes and monocytes is involved in the pathogenesis of ANCA-associated vasculitis. Since elastase is the major lysosomal protein released during leukocyte degranulation, we investigated cell activation in vivo in patients with ANCA-associated vasculitis by determining complexed plasma elastase levels. METHODS: Plasma elastase complexed with alpha1-antitrypsin was measured in 20 patients with ANCA-associated vasculitis, using an immunoactivation assay. In parallel, C-reactive protein (CRP) and ANCA levels were determined and clinical disease activity was assessed. RESULTS: Complexed elastase levels were significantly elevated in patients with ANCA-associated vasculitis who had not received immunosuppressive therapy (mean +/- SD 71.5 +/- 22.6 microg/liter), compared with healthy volunteers (12.2 +/- 11.4 microg/liter; P < 0.001). Elastase decreased significantly after 2 weeks (46.5 +/- 26.8 microg/liter; P < 0.01) and further after 8-10 weeks of immunosuppressive treatment (28.1 +/- 13.4 microg/liter; P < 0.02), in correlation with decreasing vasculitis activity. Concomitantly, ANCA titers and CRP levels decreased. CONCLUSION: These data support the theory that, by the release of lysosomal proteinases, leukocyte activation may be involved in the pathogenesis of ANCA-associated vasculitis. In addition, plasma elastase may be used as a marker for disease activity.

Plasma levels of bactericidal/permeability-increasing protein (BPI) and lipopolysaccharide-binding protein (LBP) during hemodialysis.

Several proteins modify the biological response to lipopolysaccharide (LPS). Both bactericidal/permeability-increasing factor (BPI), a protein stored in neutrophils, and the acute phase protein LPS-binding protein (LBP) bind to LPS; however, BPI inhibits while LBP enhances binding of LPS to leukocytes and subsequent induction of cytokines. We investigated plasma levels of BPI, LBP, elastase and C5a before, during and after hemodialysis (HD). Six patients were dialysed with Cuprophane (Cup) and polysulfone (PS) low-flux dialyzers on two consecutive HD sessions. There was a significant, 10.9 +/- 2.8-fold increase in BPI after 4-hour HD compared to predialysis and a 4.4 +/- 1.6-fold increase in elastase after 4-hour HD using Cup. Plasma levels of BPI and elastase decreased rapidly after the dialysis session. HD with PS resulted in a smaller, but still significant rise in BPI (3.7 +/- 1.6-fold at 4 hours) and elastase (1.69 +/- 0.2-fold at 4 hours). Levels for BPI and elastase were similar in the arterial and venous blood lines of the dialyzer. Plasma levels of LBP did not change during or after the HD session. These data indicate that BPI, but not LBP is released during HD with Cup and to a lesser extent with PS. Activation of neutrophils and release of BPI during HD may influence the biological response to bacterial products possibly introduced during HD.

Long-term experience with extracorporeal low-density lipoprotein cholesterol removal by dextran sulfate cellulose adsorption.

Patients with familial hypercholesterolemia have a high incidence of coronary heart disease due to diet- and drug-resistant, elevated low-density lipoprotein cholesterol (LDL-C). Five patients with familial hypercholesterolemia and diet- and drug-resistant LDL-C greater than 230 mg/dl were treated by LDL apheresis using dextran sulfate cellulose adsorption (Liposorber System LA-15, Kaneka). Plasma separation was by 0.5-m2 polysulfone hollow fiber filter. Two columns containing 150 ml of dextran sulfate cellulose alternately adsorbed LDL and were regenerated by 4.1% saline. The five patients received a total of 360 treatments at 7-day intervals. The treated plasma volume per session was 4.1 +/- 0.4 l. Postapheresis values compared with preapheresis were: total cholesterol, 40%; LDL-C, 28%; VLDL-C, 65%; HDL-C, 95%; triglycerides, 70%; white blood cells, 116%; platelets, 87%; C3 complement, 79%; fibrinogen, 64%; albumin, 94%. The decrease in HDL-C per treatment was not significant. The safety parameters showed only slight changes. The initial LDL of 436 +/- 172 mg/dl decreased to mean pre-apheresis levels of between 150 and 100 mg/dl. The anti-atherogenic HDL increased in three and remained unchanged in two patients. Adverse events like hypotension, angina pectoris, and technical problems occurred in 11 of the 360 treatments. Long-term treatment of patients with diet- and drug-resistant familial hypercholesterolemia by extracorporeal dextran sulfate cellulose adsorption is effective and safe.

LDL cholesterol apheresis by dextran sulfate cellulose adsorption. Long-term experience in patients with familial hypercholesterolemia.

Five patients with diet and drug resistant familial hypercholesterolemia (FH) (low density lipoprotein [LDL] cholesterol, LDL greater than 230 mg/dl) were treated by LDL apheresis, using dextran sulfate cellulose adsorption (DSC), to prevent coronary heart disease (CHD). After membrane plasma separation, two 150 ml columns of DSC alternately adsorbed LDL, and were regenerated by 4.1% saline. Five patients received 230 treatments with 7 to 14 days intervals over 6 to 30 months. The treated plasma volume per session was 3.8 +/- 0.6 L. Post-apheresis values in percent of pre-apheresis were: total cholesterol, 42%; LDL, 27%; VLDL, 62%; HDL, 96%; triglycerides, 70%; WBC, 115%; platelets, 88%; C3 complement, 78%; fibrinogen, 67%; albumin, 94% (p less than or equal to 0.005 for all values). Safety parameters showed only slight changes. The initial LDL of 436 +/- 172 mg/dl decreased to nonatherogenic levels of between 150 and 100 mg/dl, whereas high density lipoprotein remained unchanged. Adverse events (hypotension, angina pectoris, technical problems) occurred in six treatments. Long-term treatment of patients with therapy resistant FH by extracorporeal DSC adsorption is effective and safe.

Comparison between simvastatin and bezafibrate in effect on plasma lipoproteins and apolipoproteins in primary hypercholesterolaemia.

The ability of simvastatin, a competitive inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase, to lower lipid levels in 16 patients with primary hypercholesterolaemia was compared with that of bezafibrate in a 16-week, double-blind, parallel, placebo-controlled trial that was continued in an open crossover fashion. Simvastatin was better than bezafibrate at lowering total and low-density lipoprotein (LDL)-cholesterol and apolipoprotein B concentrations (30.4% [p less than 0.001], 37.3% [p less than 0.001], and 37.8% [p less than 0.001] vs 17.0%, 19.6%, and 24.0%, respectively). Both drugs increased the high-density lipoprotein (HDL)-cholesterol and apolipoprotein A-I, but this change was significant only with bezafibrate (p less than 0.05). Bezafibrate and simvastatin reduced triglycerides by 25.6% (p less than 0.001) and 13.7% (p less than 0.05), respectively. Very low-density lipoprotein (VLDL)-cholesterol was significantly reduced only by bezafibrate (44.3%, p less than 0.001). Both drugs were tolerated well and no serious side-effects were noted. The results show that simvastatin was more effective than bezafibrate in lowering total-cholesterol, LDL-cholesterol, and apolipoprotein B, while bezafibrate was better at lowering triglycerides and VLDL-cholesterol and at raising HDL-cholesterol and apolipoprotein A-I.