Treatment of renal diseases with plasma exchange: a single center experience

Over the last decades, plasma exchange (PE) has been applied in the treatment of over 150 different diseases including nephrological, hematological, neurological, and rheumatological. Clinical benefit has been demonstrated in only about 40 of them and the best results were achieved in diseases with pathogenic autoimmune mechanisms. We used PE most frequently in patients with immune and autoimmune nephropathies aiming to decrease pathologically elevated antibody levels, autoantibodies and immune complexes. PE was applied in 40 patients with chronic glomerulonephritis, 29 patients with lupus nephritis, and 9 patients with Schoenlein‐Henoch nephritis. After 3 to 4 PE sessions, continuous immunosuppressive drug therapy was initiated. Significant reduction of antibody titers and immune complexes was achieved. PE was also applied in 45 plasmacytoma patients with nephropathy to reduce plasma viscosity and slow down the progression of myeloma nephropathy. The result was a significant reduction of pathologically elevated plasma viscosity and a detoxification effect. In our clinic plasma exchange procedures were performed by either centrifugal method with Haemonetics M‐30 device or by plasma filtration. An average of 1316 mL plasma was removed during a PE session. For substitution purposes donor plasma and saline solutions were used. Clinical remission was achieved in 61.3% of all patients without slowing the progression of renal failure, however.     

Ambivalent roles of carboxypeptidase B in the lytic susceptibility of fibrin

Background

Removal of C-terminal lysine residues that are continuously exposed in lysing fibrin is an established anti-fibrinolytic mechanism dependent on the plasma carboxypeptidase TAFIa, which also removes arginines that are exposed at the time of fibrinogen clotting by thrombin.

Objective

To evaluate the impact of alterations in fibrin structure mediated by constitutive carboxypeptidase activity on the function of fibrin as a template for tissue plasminogen activator-(tPA) induced plasminogen activation and its susceptibility to digestion by plasmin.

Methods and results

We used the stable carboxypeptidase B (CPB), which shows the same substrate specificity as TAFIa. If 1.5 – 6 μM fibrinogen was clotted in the presence of 8 U/mL CPB, a denser fibrin network was formed with thinner fibers (the median fiber diameter decreased from 138 – 144 nm to 89 – 109 nm as established with scanning electron microscopy). If clotting was initiated in the presence of 5 – 10 μM arginine, a similar decrease in fiber diameter (82 -95 nm) was measured. The fine structure of arginine-treated fibrin enhanced plasminogen activation by tPA, but slowed down lysis monitored using fluorescent tPA and confocal laser microscopy. However, if lysis was initiated with plasmin in CPB-treated fibrin, the rate of dissolution increased to a degree corresponding to doubling of the plasmin concentration.

Conclusion

The present data evidence that CPB activity generates fine-mesh fibrin which is more difficult to lyse by tPA, but conversely, CPB and plasmin together can stimulate fibrinolysis, possibly by enhancing plasmin diffusion.     

Myosin: a noncovalent stabilizer of fibrin in the process of clot dissolution

Myosin modulates the fibrinolytic process as a cofactor of the tissue plasminogen activator and as a substrate of plasmin. We report now that myosin is present in arterial thrombi and it forms reversible noncovalent complexes with fibrinogen and fibrin with equilibrium dissociation constants in the micromolar range (1.70 and 0.94 microM, respectively). Competition studies using a peptide inhibitor of fibrin polymerization (glycl-prolyl-arginyl-proline [GPRP]) indicate that myosin interacts with domains common in fibrinogen and fibrin and this interaction is independent of the GPRP-binding polymerization site in the fibrinogen molecule. An association rate constant of 1.81 x 10(2) M(-1) x s(-1) and a dissociation rate constant of 3.07 x 10(-4) s(-1) are determined for the fibrinogen-myosin interaction. Surface plasmon resonance studies indicate that fibrin serves as a matrix core for myosin aggregation. The fibrin clots equilibrated with myosin are stabilized against dissolution initiated by plasminogen and tissue-type plasminogen activator (tPA) or urokinase (at fibrin monomer-myosin molar ratio as high as 30) and by plasmin under static and flow conditions (at fibrin monomer-myosin molar ratio lower than 15). Myosin exerts similar effects on the tPA-induced dissolution of blood plasma clots. Covalent modification involving factor XIIIa does not contribute to this stabilizing effect; myosin is not covalently attached to the clot by the time of complete cross-linking of fibrin. Thus, our in vitro data suggest that myosin detected in arterial thrombi binds to the polymerized fibrin, in the bound form its tPA-cofactor properties are masked, and the myosin fibrin clot is relatively resistant to plasmin.     

Effects of long term feeding of raw soya bean flour on virus-induced pancreatic carcinogenesis in guinea fowl

The effects of a diet enriched with 25% raw soya bean flour (RSF) on the pancreas and on the avian retrovirus Pts 56-induced pancreatic carcinogenesis in guinea fowl were studied. It has been shown that prolonged RSF feeding of new-hatched virus-infected and uninfected guinea fowl-poults induced enlargement of the pancreas, which was less pronounced when administration of the RSF supplemented diet started at the age of 75 days. Time-dependent multifocal inter- and intralobular hyperplasia of pleomorphic ducts lined by mucin-producing epithelium in the exocrine pancreas of virus-infected guinea fowls fed a RSF supplemented diet was regularly observed. Enlargement of virus-induced ductular neoplasms has been shown only after simultaneous RSF and virus administration.