Selenium in uremia: culprit or bystander?
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Biomedical subjects
Publications and source records attributed to P Ivanovich.
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To check whether in vivo EDTA prevents complement activation resulting from blood contact with the dialyzer membrane, sham hemodialysis (HD) was performed in seven healthy volunteers using Cuprophan hollow-fiber dialyzers. Blood samples were drawn from the arterial and venous blood lines of the dialyzer before and after EDTA was infused into the arterial line. Venous line plasma C3a concentrations before EDTA infusion were significantly higher than after EDTA. Also, venous line plasma C3a concentrations before and after EDTA infusion were significantly higher than in the arterial line. These results indicate that complement activation can be attenuated by EDTA during sham HD. Technical improvements in the procedure may permit complete inhibition of complement activation.
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Elimination characteristics of beta 2-microglobulin (BMG) during hemofiltration (HF) with acrylonitrile (AN69) and polysulfone (PS) hemofilters were investigated in a prospective clinical investigation. Seven chronic uremics on regular HF were treated for 4 weeks, three times a week, with AN69 hemofilters. The study was then repeated with PS hemofilters. There were no significant differences in the patients' body weight, the ultrafiltrate volume per session, and the duration of each HF session between both treatments. At the start of HF, arterial plasma concentration of BMG was (for AN69) 33.5 +/- 4.0 mg/L (mean +/- SD) and (for PS) 35.8 +/- 6.5 mg/L (NS); at the end of HF it was (for AN69) 11.0 +/- 1.8 mg/L and (for PS) 17.5 +/- 4.2 mg/L (p less than 0.001). The amount of BMG in total ultrafiltrate was (for AN69) 179.3 +/- 22.6 mg and (for PS) 140.6 +/- 26.8 mg (p less than 0.02). With AN69 hemofilter, maximum BMG plasma clearance and sieving coefficient were 51.0 +/- 9.5 mL/min and 0.42 +/- 0.04 at 60 minutes. With PS hemofilter, maximum BMG plasma clearance and sieving coefficient were 37.4 +/- 5.7 mL/min and 0.27 +/- 0.03 at 15 minutes. Twenty-two percents of BMG entering the AN69 hemofilter at 15 minutes were adsorbed on the membrane (p less than 0.001). BMG elimination with the AN69 hemofilter was more efficient than with the PS hemofilter. Long-term studies will be necessary to demonstrate whether this difference is of any clinical significance.
We studied the adsorption of anaphylatoxins C3a and C5a on acrylonitrile (AN69) hollow-fiber (AN69HF) and plate (AN69P) dialyzers in 8 patients during 4-hour hemodialyses (HD). Blood passed first through a cuprophan dialyzer and then through AN69 dialyzers that were not in contact with dialysis fluid. Plasma C3a and C5a were measured in samples taken from the afferent and efferent blood lines of the acrylonitrile dialyzers at 15, 60 and 240 min. Plasma C3a concentrations decreased significantly in blood that had passed through AN69 dialyzers. This decrease, indicating membrane adsorption, was maximal (by 65% in AN69HF and by 59% in AN69P) at 15 min and minimal (by 53% in AN69HF and by 18% in AN69P) at 240 min. The decrease in plasma C5a concentrations was smaller and significant throughout HD only with AN69HF. The amount of C3a adsorbed was at least 45,000 micrograms in AN69HF and 18,000 micrograms in AN69P. These findings demonstrate that acrylonitrile dialyzers adsorb more C3a and C5a than they produce. This membrane adsorption may explain why the increase of plasma C3a and C5a is inhibited during HD.
rEPO therapy provides a unique opportunity to correct anemia in end-stage renal failure patients. Complete correction of the anemia, although possible, has some obvious disadvantages over a partial correction with a target hemoglobin of 10-13 g/dl or a hematocrit of 30-35%, respectively. Unresponsiveness to rEPO seems to be rare; in most cases the predicted hemoglobin increase could be seen as soon as an underlying iron deficiency was treated adequately. Blood loss and aluminum toxicity are the next most frequent reasons for an inadequate response to rEPO. Hypertension (and its complications) as well as fistula clotting are the most important side-effects which require close attention when patients at risk for these complications are treated with rEPO.
The concept of developing an implantable artificial kidney demands, in addition to the regeneration of endogenous filtrate, a small hemofilter with a high filtration rate. Conventional capillary filters are limited in their capacity to yield adequate filtrate, even if the number of capillaries is increased. To improve filter design so as to modify flow conditions for filtration rate augmentation, it is necessary to consider such factors as blood flow through a single capillary, wall shear rate, and transmembrane pressure (ptm) in in vivo applications, where such biological considerations as blood pressure, blood flow, and flow characteristics of blood are important. These requirements lead to a completely new filter type, the "curl filter," characterized by a large effective filtration surface in a relatively small number of hollow fibers in which optimal flow conditions prevail.
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NAPA pharmacokinetics were studied in 6 functionally anephric patients. Distribution and nonrenal elimination of this drug were found to be the same as in individuals with normal renal function but renal clearance was reduced, resulting in a mean elimination t 1/2 of 41.9 hr (6.2 hr in normal subjects). Renal clearance of NAPA correlated well with ClCr. Dialysis removed NAPA from both red blood cells and plasma and increased ClT approximately fourfold. Dialysis itself resulted in a 77% reduction in ClS that limited the total amount of NAPA removed by this procedure. This reduction in ClS was sustained for at least 3 hr after dialysis and attenuated rebound in plasma NAPA concentrations.
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Removal of methotrexate by Amberlite XAD-4 hemoperfusion was determined in a patient with metastatic breast carcinoma. During 4 hr of hemoperfusion the plasma concentration of methotrexate fell from 5.5 x 10(-7) M TO 3.1 x 10(-7) M. After hemoperfusion methotrexate concentration increased as a consequence of multicompartmental pharmacokinetics to 5.5 x 10(-7) M and then slowly declined. Plasma methotrexate clearance decreased from 79 ml/min 30 min into hemoperfusion to 28 ml/min at the conclusion. In vitro clearance of methotrexate by 17 artificial kidneys, Amberlite XAD-4, and uncoated charcoal was determined. Uncoated charcoal had the greatest clearance of methotrexate of all the devices tested. We conclude that: (1) Amberlite XAD-4 transiently reduces plasma methotrexate concentration; (2) in vitro, charcoal hemoperfusion is more effective than XAD-4 in removing methotrexate; (3) as a consequence of the multicompartmental pharmacokinetics of methotrexate a postperfusion rebound in plasma methotrexate concentration is to be expected.
Removal of digoxin by hemoperfusion over Amberlite XAD-4 was determined in a functionally anephric patient. During four hours of hemoperfusion, 50.45 microgram of digoxin were removed by the column and serum digoxin concentrations decreased by 0.2 ng/ml after the post-hemoperfusion reequilibration was complete.
Removal of digoxin by XAD-4 hemoperfusion columns was tested after four dogs were given 0.06 mg/kg of digoxin i.v. Dogs were perfused for 4 to 5 hr at a flow of 105 ml/min through a 100 gm XAD-4 column 16 hr after the dose. Pharmacokinetic analysis of digoxin levels was performed with a three-compartment model. The apparent postdistribution t1/2 was 16.0 +/- 2.9 (S.D.) hr and decreased to 7.1 +/- 2.1 hr during perfusion. Digoxin perfusion clearance was 46 ml/min. An average of 51 microgram of digoxin was recovered from used columns. CP of digoxin calculated from the total R was 127.5 +/- 13 ml/min or 2.3 times greater than plasma flow. With the use of 3H-digoxin, canine blood was found to contain 2.5 times as much digoxin as did plasma. After perfusion there was an increase in serum digoxin levels in all dogs. Computer analysis showed that the increase in plasma digoxin levels immediately after hemoperfusion occurred because the central compartment, which was depleted of digoxin during hemoperfusion, was refilled from peripheral compartments. This study demonstrated that (1) XAD-4 hemoperfusion doubles the rate of removal of digoxin from dogs, (2) dog whole blood contains more than twice as much digoxin than does plasma, so that hemoperfusion clearance exceeds plasma flow, and (3) a multicompartmental pharmacokinetic model explains the increase in serum digoxin concentrations observed at the completion of hemoperfusion.
Platelet function was studied in 34 patients during 74 hemodialyses by means of a Cordis-Dow hollow fiber hemodialyzer (CDAK-4) with anticoagulation by porcine mucosal heparin. The mean arterial platelet levels fell 11% from predialysis values and remained stable throughout a 5 hr hemodialysis session. After 30 min of dialysis, the platelet concentration in afferent and efferent limbs of the dialyzer were similar, although retention of leukocytes was apparent. As measured by platelet aggregometry, heparin was clearly shown to potentiate the extent of aggregation induced by low concentrations of ADP. Platelets of the dialyzer afferent limb were less aggregable than normal and resistant to aggregation induced by submaximal concentrations of ADP or epinephrine. Platelets of the dialyzer efferent limb were aggregable only after excessive stimuli of 50 micrometer ADP or 10 micrometer epinephrine. These findings suggest that direct contact between dialyzer fibers and platelets or rheological effects led to impaired platelet function but that most platelets are not irreversibly injured.