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S Shaldon

Publications and source records attributed to S Shaldon.

At least 19 recordsLinked to original sources
PubMed1992

Permeability of dialyzer membranes to TNF alpha-inducing substances derived from water bacteria.

Pro-inflammatory cytokine-inducing substances derived from cultured E. coli have previously been shown to pass across low-flux regenerated cellulosic dialyzer membranes. In the present study, a sterile filtrate of Pseudomonas maltophilia grown from standard bicarbonate dialysis fluid was used to test the permeability of various dialyzer membranes (regenerated cellulose, cellulose triacetate, polyacrylonitrile, polysulfone and polyamide) to TNF alpha-inducing bacterial substances. Pyrogen-free tissue culture medium (MEM) was recirculated for 60 minutes in the dialysate compartment of a closed-loop dialysis system, then P. maltophilia filtrate was added and recirculation was continued for a further hour. Samples from the dialysate (MEM) and the blood side (containing 10% human plasma in MEM) were incubated with donor mononuclear cells (MNC) for 18 hours and TNF alpha release was measured in MNC supernatants by radioimmunoassay. Five minutes after the addition of P. maltophilia filtrate, mean TNF alpha-inducing activity in the dialysate increased from (mean +/- SEM) 0.10 +/- 0.02 to 18.2 +2- 1.5 (ng/2.5 x 10(6) MNC/18 hr). TNF alpha-inducing activity in the blood side increased with regenerated cellulose from 0.10 +/- 0.01 to 4.57 +/- 1.55 (N = 8; P less than 0.001); with cellulose triacetate from 0.20 +/- 0.05 to 0.44 +/- 0.10 (N = 5; P less than 0.05), and with polyacrylonitrile from 0.10 +/- 0.02 to 1.16 +/- 0.45 (N = 5; P less than 0.03). No increased TNF alpha-inducing activity was observed in the blood side of polysulfone (N = 5) or polyamide dialyzers (N = 5).(ABSTRACT TRUNCATED AT 250 WORDS)

Complement C5a↗
PubMed1992

Adequacy of long-term hemodialysis.

The gross mortality rates for end-stage renal disease patients treated with hemodialysis in the United States are twice those reported in Japan and Europe. This observation has prompted an inquiry into the methods used to administer dialysis therapy in these three areas of the world. It is apparent that shorter treatment time with multiple reuse of dialyzers was more frequently employed in the United States, and adequacy was more often judged by urea kinetic modeling, with the assumption that urea was a suitable surrogate for uremic toxicity. The possibility that inadequate therapy may result from too short dialysis time along with dialyzer reuse is suggested.

Humans↗
PubMed1992

Dialysis related amyloidosis: a disease of chronic retention and inflammation?

Dialysis related amyloidosis (DRA) has become a major complication of long-term therapy in chronic hemodialysis or peritoneal dialysis patients. DRA is characterized by the presence of beta 2-microglobulin (beta 2m) in the amyloid fibrils. The pathogenesis of DRA is incompletely understood, but most likely is based on the uremic retention of beta 2m. In contrast, current evidence does not favor a significant role of an enhanced beta 2m synthesis rate in uremic patients. Apart from the beta 2m retention, posttranslational modification of the molecule also seems to be an important step in the amyloidogenesis, since, in addition to intact beta 2m, fragmented beta 2m or beta 2, with altered isoelectric properties can be detected in the DRA fibrils. The occurrence of these beta 2m species could be linked to a chronic intermittent stimulation of monokine release or other subclinical inflammatory processes during renal replacement therapy. Thus, it is possible that, as a consequence of repeated cellular activation, protease release and/or intracellular processing of beta 2m occurs. Renal transplantation has been shown to arrest the further progression of DRA. However, since transplantation is not feasible for a significant number of patients, non-transplant strategies to prevent DRA also need to be evaluated. Some, but not all, retrospective studies on DRA associated symptomatology in patients on chronic hemodialysis with high flux membranes have suggested a lesser prevalence in these patients as compared to patients treated with standard cellulosic membranes. To further clarify this issue and to test whether non-transplant therapies indeed may play a role in the prevention of DRA, prospective studies will be needed.(ABSTRACT TRUNCATED AT 250 WORDS)

Amyloidosis↗
PubMed1991

Experience of pain after subcutaneous administration of different preparations of recombinant human erythropoietin: a randomized, double-blind crossover study.

Subcutaneous erythropoietin (SCEPO) is considered to be more effective than intravenously administered erythropoietin. Patient compliance with SC injections will be important in long-term therapy as there have been reports of pain associated with SCEPO. A double-blind randomized study was performed upon 18 ESRD hemodialysis patients receiving regular subcutaneous erythropoietin replacement therapy for treatment of their anemia. The study involved pain assessment by a visual analogue scale VAS and a verbal descriptive scale VDS following 2 subcutaneous injections of preparation A: rhEPO 2000 IU in 1 ml (Cilag), preparation B: rhEPO 2000 IU in 1 ml (Boehringer Mannheim) and 0.9% saline 1 ml (placebo) over a two-week period. The injections were all administered by the same person and replaced the normal EPO injections for the patient during the study period. Results by VAS and VDS based upon 107 responses showed that preparation A was significantly more painful than preparation B (p less than 0.001) or saline (p less than 0.01). An unexpected finding was that preparation B was less painful than the placebo for VAS (p less than 0.05). It seems unlikely that the erythropoietin itself was responsible for the difference. Further work will be necessary to determine the pain causing factor in preparation A, and the possible local anaesthetic factor in preparation B.

Anemia↗
PubMed1991

Clearance and synthesis rates of beta 2-microglobulin in patients undergoing hemodialysis and in normal subjects.

Retention of beta 2-microglobulin in patients undergoing hemodialysis is associated with a beta 2-microglobulin-derived amyloidosis. Removal of beta 2-microglobulin by renal replacement therapy has been proposed for the prevention of this amyloidosis. Currently, however, data on the beta 2-microglobulin synthesis rate in patients undergoing hemodialysis are scarce, and consequently it remains speculative how much removal would be necessary to counterbalance synthesis. The plasma kinetics of iodine 131-labeled beta 2-microglobulin were therefore examined in 11 patients with anuria who were undergoing long-term hemodialysis. Five healthy persons served as controls. Kinetic modeling of the plasma curves showed that the data fitted a two-pool model (r2 greater than 0.96) consisting of a rapid 2 to 4 hour distribution phase followed by a less steep curve, described by the plasma (metabolic) clearance (Clp). Synthetic rates were calculated from Clp and the beta 2-microglobulin steady state plasma concentration (plus beta 2-microglobulin removal during hemodialysis in the case of high flux hemodialysis). The results showed a significantly higher Clp in normal controls as compared with patients undergoing hemodialysis (65.5 +/- 12.8 ml/min (mean +/- SD) versus 3.4 +/- 0.7 ml/min). In contrast, the beta 2-microglobulin synthesis rate in the patient group (3.10 +/- 0.79 mg/kg/day) was not significantly different from that of normal controls (2.40 +/- 0.67 mg/kg/day), which was due to markedly elevated beta 2-microglobulin plasma concentrations in the patients (37.6 +/- 14.1 mg/L vs 1.92 +/- 0.27 mg/L). These findings suggest that the presence of end-stage renal disease does not have a significant impact on the beta 2-microglobulin generation rate. The degree of accumulation of beta 2-microglobulin in patients undergoing hemodialysis seems to depend on the loss of renal excretory function.

Hemofiltration↗
PubMed1990

Transcription, not synthesis, of interleukin-1 and tumor necrosis factor by complement.

Stimulation of interleukin-1 beta (IL-1 beta) and tumor necrosis factor (TNF alpha) production was studied during in vitro hemodialysis (HD) of whole blood using cuprammonium (Cup) or polysulfone (PS) dialyzers. In the absence of LPS, circulation of whole blood for two hours through Cup or PS dialyzers was not sufficient to induce production of IL-1 beta or TNF alpha in peripheral blood mononuclear cells (PBMC) during subsequent 24 hour culture. However, compared to freshly isolated cells, post-HD PBMC were primed to produce more IL-1 beta and TNF alpha when subsequently stimulated with LPS. Despite the lack of spontaneous monokine synthesis after HD, we observed transcription of mRNA coding for IL-1 beta and TNF alpha after two hours of LPS-free HD. When compared to levels of mRNA induced by 5 ng/ml LPS (100%), Cup induced 27 +/- 6% whereas PS did not induce detectable transcription of IL-1 beta. In the case of TNF alpha mRNA, Cup induced 26 +/- 8% and PS 13 +/- 3%. Recombinant C5a induced mRNA for IL-1 beta in PBMC without detectable IL-1 beta protein synthesis. We conclude that transcription of mRNA for IL-1 beta and TNF alpha during HD is primarily caused by complement activation by Cup, but that LPS or other factors are required for translation of IL-1 beta and TNF alpha mRNA transcribed during HD.

Blotting, Northern↗
PubMed1990

Imaging of dialysis-related amyloid (AB-amyloid) deposits with 131I-beta 2-microglobulin.

The diagnosis of dialysis-related amyloid (AB-amyloid) has been based usually on clinical and radiological criteria. Following the discovery that beta 2-microglobulin was the major protein of this amyloid, we isolated and radiolabelled uremic plasma beta 2-microglobulin. After intravenous injection, gamma-camera images of selected joint areas were obtained from 42 patients who were on regular hemodialysis therapy. Positive scans involving the shoulder, hip, knee and carpal regions were found in 13 of 14 patients treated for more than 10 years and 10 of 16 patients treated for 5 to 10 years. Patients treated for less time had negative scans. Specificity was indicated by negative scans in non-amyloid inflammatory lesions in control hemodialysis patients. Up to 48-fold tracer enrichment was detected in excised AB-amyloid containing tissue as compared to amyloid-free tissue. These findings suggest that circulating radiolabelled beta 2-microglobulin is taken up by the amyloid deposits. This method may non-invasively detect tissue infiltrates of amyloid. It may also permit prospective evaluation of the efficacy of prophylactic dialysis strategies which are designed to prevent or delay the onset of this complication of long-term dialysis.

Amyloidosis↗
PubMed1990

Long-term effects of treatment with recombinant human erythropoietin on haemodynamics and tissue oxygenation in patients with renal anaemia.

Regional peripheral vascular resistance, transcutaneous oxygen pressure and blood pressure were studied in seven normotensive, chronically haemodialysed patients with renal anaemia before and after 3 and 12 months of rHuEpo therapy. Haematocrit increased from 21% to 33% within 3 months of commencing therapy, and remained stable throughout the following observation time. Though regional blood flow of the calf was markedly reduced after 3 and 12 months of rHuEpo compared to pretreatment values, transcutaneous oxygen pressure was significantly increased after 3 months and remained constantly elevated after 12 months. Mean arterial blood pressure increased significantly by 7.3 mmHg after 3 months of rHuEpo treatment but did not reach hypertensive values and was no longer different from pretreatment values 12 months after the start of rHuEpo. Results of peripheral haemodynamic studies were compared to those obtained by measurement of central haemodynamics in four further normotensive anaemic patients. In these patients cardiac output decreased, total peripheral vascular resistance increased and blood pressure increased slightly (by 5.5 mmHg) when a haematocrit of 37% was reached after 8 weeks of rHuEpo therapy. These effects were partly reversed when the maintenance haematocrit decreased to 32% (after 16 weeks of rHuEpo). In summary rHuEpo treatment induced a long-term increase of the total and regional peripheral resistance, an increase of blood pressure within the normal range, and a decrease in cardiac output. Despite these changes tissue oxygenation improved.

Adult↗
PubMed1990

Two years experience of daily self-administered subcutaneous erythropoietin.

Recombinant human erythropoietin (EPO) has been used for 4 years in end-stage renal disease patients, administered intravenously 3 times a week. A study was undertaken to determine the optimal way of administration comparing 3 times weekly intravenous EPO to self-administered daily subcutaneous EPO (SADSCEPO). In a first group of 4 patients, we demonstrated that the change from 3 times weekly intravenous EPO to SADSCEPO permitted a dose reduction of 70%. In a second group of 20 patients who started the EPO therapy with the daily subcutaneous route at a median dose of 12 U/kg/day, the hematocrit increased from 20 to 30% in 4 months and remained over 30% in spite of a median dose reduction to 9 U/kg/day. The patients' acceptance of SADSCEPO was good. The mechanism allowing such a dose reduction is unknown. However, the significant reduction in median dosage requirement with the subcutaneous route should allow a greater number of patients to be treated more cost-effectively.

Adult↗
PubMed1990

Chronic haemodialysis with bicarbonate dialysate. Technical and clinical aspects.

Bicarbonate as a physiological buffer should be preferred in haemodialysis treatments. The use of bicarbonate dialysis, however, varies from 30 to 100% in the different industrialised countries. Except for the many advantages using bicarbonate dialysate, there are also clinical pitfalls in the use of the bicarbonate buffer substrate. Furthermore, technical problems can be expected in the use of varying dialysate bicarbonate concentrations, as in the concomitant use of acetate and bicarbonate dialysate in the same dialysis unit. This paper deals with the clinical and technical aspects of bicarbonate dialysis.

Acetates↗
PubMed1990

Renal elimination of beta-2-microglobulin and myoglobin in patients with normal and impaired renal function.

Since the demonstration that beta 2-microglobulin (beta 2M) is an amyloidogenic protein in man, the excretion of this low-molecular-weight protein under conditions with normal and reduced renal function has received increased interest. The renal arteriovenous extraction of beta 2M, polyfructosan (an inulin analogue), and a second low-molecular-weight protein, myoglobin, was measured in vivo in 16 human kidneys with normal renal function/gross morphology and in 22 kidneys with reduced function. In kidneys with normal function, the extraction of beta 2M significantly exceeded that of polyfructosan (0.198 +/- 0.037 vs. 0.182 +/- 0.05; p = 0.04), while that of myoglobin (0.177 +/- 0.068) was not different from that of polyfructosan. In kidneys with reduced function, the extraction of polyfructosan or myoglobin was not significantly altered. In contrast, the beta 2M extraction decreased to 0.110 +/- 0.060 (p less than 0.01 vs. extraction of polyfructosan or myoglobin). This decrease was significantly correlated with the decrease of the endogenous creatinine clearance or the total or unilateral 131I-hippuran clearance. These results indicate that in normal renal function the glomerular filtration of beta 2M may be supplemented by a peritubular mode of removal. The mechanism(s) underlying the selective decrease of beta 2M extraction in kidneys with reduced function remain speculative. However, this decrease will lead to a further augmentation of the retention of beta 2M in renal failure.

Female↗
PubMed1990

Hemodialysis-related induction of beta 2-microglobulin synthesis and release by mononuclear phagocytes.

We have investigated beta 2-microglobulin (beta 2M) synthesis and release by blood leukocytes and isolated mononuclear phagocytes. Since beta 2M was discovered to form amyloid fibrils in patients undergoing long term, chronic hemodialysis and monomeric beta 2M levels in plasma of these patients are highly elevated, and since hemodialysis-related factors that increase beta 2M production are unknown, we evaluated beta 2M production by mononuclear phagocytes under a variety of conditions. We utilized a novel enzyme-lined immunoabsorbant assay to quantitate beta 2M release. Adherence of macrophages onto polystyrene or Cuprophan membranes does not induce beta 2M synthesis or release. In contrast, interaction of macrophages with lipopolysaccharide, gamma-interferon, tumor necrosis factor, or interleukin 1 induces synthesis or release. In contrast, interaction of macrophages with lipopolysaccharide, gamma-interferon, tumor necrosis factor, or interleukin 1 induces synthesis and release of beta 2M, indicating that beta 2M synthesis is increased during macrophage activation. Exposing leukocytes or macrophages to changes in osmotic or oncotic pressure induces a rapid release of beta 2M and interleukin 1 into the cellular medium. These results suggest that during hemodialysis, beta 2M production is more likely to result from endotoxin contamination, or osmotic and oncotic changes, rather than direct interaction of mononuclear phagocytes with cellulosic membranes.

Cell Adhesion↗
PubMed1990

Detection of endotoxin antibody in long-term dialysis patients.

Endotoxins are often seen in dialysate. They are derived from Gram-negative bacteria especially Pseudomonas, E. coli and Serratia. Endotoxins are large-molecular-weight substances with an average molecular weight of 10(8). These large units can be divided into subunits down to a molecular weight of 10,000 which are thought to pass through dialyzer membranes. To investigate this, endotoxin antibody levels were measured in two groups of patients on chronic regular hemodialysis, a low-flux group using cellulosic membrane dialyzers (cuprophan and cuproammonium rayon (CAR) and a high-flux group using synthetic polymer membrane dialyzers (PMMA, EVAL). Using an ELISA based on standard endotoxin antibodies the percentages of patients in the low flux group with endotoxin antibodies were 26.9% with Cuprophan and 25% with CAR, not significantly different from a normal control group. In the PMMA and EVAL groups, it was 53.6% and 68.4% respectively. Back filtration of dialysate into blood is understood as the main reason for the entry of endotoxin in patients treated with high-flux dialyzers.

Antibodies↗