Simon J. Fleming

The Use of Vaccines in Renal Failure

SummaryRenal insufficiency is characterised by impaired host defences, which are compromised further by each of the 3 modes of renal replacement — haemodialysis, continuous ambulatory peritoneal dialysis (CAPD) and renal transplantation. Reduced renal clearance of unknown toxins, possible development of nutritional deficiencies and administration of immunosuppressive medications lead to aberrant immune regulation early in the course of renal failure. This results subsequently in increased frequency and severity of infection. Vaccination plays an important role in attenuating this infection risk, but impaired cell-mediated and humoral immunity contraindicates the use of live vaccines and engenders suboptimal and short-lived antibody responses to inactivated vaccines. Reinforced vaccination schedules, increased vaccine dosage and concomitantly administered adjuvant immunomodulators have variably improved the defective antibody responses to certain vaccines.Immunisation against hepatitis B virus has resulted in a significant decrease in prevalence and incidence of this infection in haemodialysis units. Similarly, the inoculation of influenza vaccine in patients with uraemia and of polyvalent pneumococcal vaccine in special risk circumstances has been recommended because of perceived reductions in morbidity and mortality from infection with these agents. Cytomegalovirus (CMV) vaccine may attenuate CMV disease severity in recipients of renal allografts. Staphylococcus aureus vaccine, on the other hand, is ineffective in preventing peritonitis or exit site infections in patients receiving CAPD. Other killed vaccines have not been comprehensively studied, but generally have the same indications for use as in normal individuals. However, the protection that these vaccines afford may be either inadequate or transient, so that other infection control strategies should be simultaneously implemented.

Effect of preoperative supplementation with α-tocopherol and ascorbic acid on myocardial injury in patients undergoing cardiac operations

Augmentation of antioxidant defenses may help protect tissues against ischemia-reperfusion injury associated with operations involving cardiopulmonary bypass. In this study we examined the effect of pretreating patients with alpha-tocopherol (vitamin E) and ascorbic acid (vitamin C) or placebo on injury to the myocardium. Seventy-six subjects undergoing elective coronary artery bypass grafting participated in a prospective, double-blind, placebo-controlled randomized trial, receiving either placebo or both 750 IU dl-alpha-tocopherol per day for 7 to 10 days and 1 gm ascorbic acid 12 hours before the operation. Plasma alpha-tocopherol concentrations, raised fourfold by supplementation, fell by 70% after the operation in the supplemented group and to negligible levels in the placebo group. There were no significant differences between the groups with respect to release of creatine kinase MB isoenzyme over 72 hours, nor in the reduction of the myocardial perfusion defect determined by thallium 201 uptake. Electrocardiography provided no evidence of a benefit from antioxidant supplementation. Thus the supplementation regimen prevented the depletion of the primary lipid soluble antioxidant in plasma, but provided no measurable reduction in myocardial injury after the operation.

Evidence for Oxidative Stress during in vitro Dialysis

The evidence for oxidative stress during haemodialysis is controversial. We therefore examined markers of oxidative stress and lipid peroxidation using an in vitro dialysis circuit. A unit of fresh blood (500 ml) therapeutically removed from each of 7 haemochromatosis patients was oxygenated and circulated for 4 h at 37 degrees C through a cuprophane dialyser (Clirans C08) against saline dialysate (1,000 ml recirculating; +FIL group). In a second series of experiments (n = 7), the dialyser was omitted from the circuit (-FIL group). Concentrations of anti-oxidants and malondialdehyde (MDA) were measured at 7 time points during the study. Blood thiol concentrations decreased by 25.6% in the +FIL group (p < 0.05) but were unchanged in the -FIL group (p > 0.05; group comparison, p = 0.006). There were no significant differences between the groups, for the lipid-soluble anti-oxidants alpha-tocopherol, retinol and beta-carotene. Plasma MDA concentrations increased in both circuits (p < 0.001, respectively, no difference between groups). However, the susceptibility of red blood cells to lipid peroxidation (as determined by MDA production following a challenge with hydrogen peroxide) was unchanged by 120 min of dialysis. These in vitro experiments provide supporting evidence that haemodialysis is accompanied by measurable oxidative stress and plasma lipid peroxidation.

Effect of Dialyzer Reprocessing with Renalin on Serum Beta-2-Microglobulin and Complement Activation in Hemodialysis Patients

The peracetic acid-based sterilant Renalin is increasingly being used for reprocessing hemodialyzers. In order to evaluate the effects of reprocessing on beta 2-microglobulin (beta 2M) kinetics and complement activation in chronic hemodialysis patients, we compared 4 dialyzer membranes on 1st, 2nd and 4th use of the membrane. Dialysis with new cuprammonium rayon dialyzers (0.8 m2) for 4 h resulted in a nonsignificant increase in serum beta 2M concentrations of 10.7% (corrected for changes in extracellular volume) and significant generation of the complement component C3a des Arg. On reuse, minimal changes in serum beta 2M levels were noted and complement activation was absent. Dialysis with new cellulose acetate (CA, 1.5 m2), polyacrylonitrile (AN69 HF, 1.6 m2) or polymethylmethacrylate (PMMA, 1.6 m2) membranes resulted in significant decreases in serum beta 2M levels (19.5, 31.7 and 50.8%, respectively). Reprocessing had negligible effects on the removal of beta 2M by CA and AN69, but by the 4th use halved the effectiveness of PMMA. Reprocessing reduced the significant generation of C3a des Arg observed with new CA and PMMA membranes. We conclude that, except for PMMA, Renalin reprocessing has minor effects on the ability of the membranes to remove beta 2M and improves the biocompatibility of all membranes studied.

Tubular nephrotoxicity after cardiac surgery utilising cardiopulmonary bypass

Markers of renal tubular injury were examined in 21 patients (16 male, 5 female, mean age 57.4 years) undergoing cardiac surgery utilising cardiopulmonary bypass. Postoperative urine outputs were very high (200-250 ml/h at 1-2 h), decreasing to 100 ml/h by 6 h. Although creatinine clearances did not vary significantly in the postoperative period (P = 0.16), significant changes were noted in the urinary concentrations of three tubular markers relative to creatinine concentration (P < 0.001). Urinary beta 2-microglobulin increased from negligible levels (median 0.01 mg/mmol creatinine) to peak at 4 h (median 4.55 mg/mmol), in part due to interference with its reabsorption by the plasma volume expander Haemaccel. Concentrations of the brush border antigen adenosine deaminase binding protein increased 6-fold, from a median of 5.03 arbitrary units (AU)/mumol to 31.2 AU/mumol at 48 h. The lysosomal enzyme N-acetyl-beta-D-glucosaminidase increased nearly 4-fold, from 0.68 units/mmol to 2.64 units/mmol at 48 h. Our results suggest that cardiac surgery utilising cardiopulmonary bypass is associated with acute tubular injury which can occur in the absence of overt changes in creatinine clearance.

Monitoring of extracellular and total body water during haemodialysis using multifrequency bio-electrical impedance analysis.

Multifrequency bio-electrical impedance analysis (MFBIA) was evaluated as a technique for monitoring changes in extracellular and total body water (ECW and TBW, respectively) of 15 subjects during dialysis. Dilution analysis, using deuterium oxide and sodium bromide, was also performed on each subject before dialysis so that prediction equations for ECW and TBW based on the MFBIA measures could be developed. These prediction equations were then used to estimate water compartment volume changes during dialysis and compared with volumetric measures of the dialysate removed. The results show that MFBIA does not accurately measure ECW and TBW changes during dialysis. The MFBIA measures tend to overestimate the changes and are not sufficiently precise to be clinically useful.

A non-invasive continuous method of measuring blood volume during haemodialysis using optical techniques.

Hypotension during haemodialysis and fluid overload between treatments are major problems for haemodialysis patients. Clinical means of assessing hydration state can be relatively imprecise. We describe a non-invasive method of measuring absolute blood volume (BV) during a mock in vitro haemodialysis session which adds objective information to that assessment. As fluid is removed by ultrafiltration, haemoglobin concentration [Hb] rises proportionately with the fall in BV. An optical monitor clamped across the transparent dialysis tubing gives a continuous readout of near infra-red light transmitted through the blood, and this can be converted to [Hb] values. The net change in BV is the difference between the volume of fluid ultrafiltered and the volume which refills the vascular compartment from the extravascular space. By analysing the change in [Hb] and therefore the change in BV at two different rates of fluid removal, the absolute BV can be determined. The accuracy of this method was tested in vitro. This optical method accurately measures the change in BV over a range of [Hb] from 4 to 15 g/dl and blood circulation pump speeds of 150-300 ml/min. A series of 10 in vitro experiments was performed. The mean relative difference between the measured BV and the calculated BV, was 5.7 +/- 2.5%. This readily repeatable technique can accurately measure BV during a mock in vitro haemodialysis session, thus providing information for the clinical assessment of the hydration state. Information from these experiments will assist in future in vivo studies.

Effect of supplementation with antioxidants (α-tocopherol and ascorbic acid) on markers of renal tubular injury in cardiac surgery patients

Summary: Cardiac surgery is accompanied by the risk of ischaemia‐reperfusion injury to both myocardial and peripheral tissues like the kidney due to the generation of oxygen‐derived free radicals. Supplementation with chain‐breaking antioxidants may trap free radicals and help protect tissues from injury. We therefore examined the effect of pre‐treating cardiac surgery patients with α‐tocopherol (vitamin E) and ascorbic acid (vitamin C) or placebo on a hypoxia‐sensitive tissue, the renal proximal tubule. Sixty‐nine subjects undergoing elective coronary artery bypass grafting participated in a prospective, double‐blind, placebo controlled randomized trail, receiving either placebo or both 750 IU/dL‐α‐tocopherol per day for 7‐10 days, and 1 g ascorbic acid 12 h prior to surgery. Plasma α‐tocopherol concentrations fell from elevated to normal levels in the supplemented group and from normal to negligible levels in the placebo group. Renal tubular markers (N‐acetyl‐β‐D‐glucosaminidase, adenosine deaminase binding protein, and γ‐glutamyl transpeptidase) increased significantly relative to creatinine in both groups following surgery (P > 0.001). However, there were no differences between the two patient groups. Thus, although antioxidant supplementation prior to cardiac surgery prevented the depletion of the primary lipid‐soluble antioxidant in plasma (α‐tocopherol), renal tubular injury was not measurably reduced.