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Biomedical subjects

S Shaldon

Publications and source records attributed to S Shaldon.

At least 55 records · Page 3Linked to original sources
PubMed1995

Biocompatibility in hemodialysis: clinical relevance in 1995.

Hemodialysis therapy for end-stage renal disease is still empirical even after more than 30 years of experience. Although long-term survival can now be assured in selected patients, clinical results tend to be disappointing. Hemodialysis therapy needs to be improved. Zealots of the biocompatibility school believe that this improvement will come from reducing undesirable consequences of blood membrane interaction, particularly complement activation. However, there is controversy over the clinical meaningfulness of biocompatibility when exclusively related to blood membrane interactions. Another dimension needs to be added, namely ultrapure dialysate to avoid subclinical chronic effects of activation of the cytokine cascade by bacterial fragments present in dialysate. While the pathogenesis of acute anaphylactoid reactions are understood and largely preventable, the relation of the chronic syndromes such as amyloidosis to the use of a particular membrane remain unproven. Prospective studies that will occupy at least a decade will be necessary to decide these issues.

Bacterial Toxins↗
PubMed1995

The role of plasma coating on the permeation of cytokine-inducing substances through dialyser membranes.

We studied the effects of coating of dialyser membranes with plasma proteins on the permeation of bacteria-derived cytokine-inducing substances (CIS). An in vitro dialysis circuit using polysulphone (PS) or modified cellulose triacetate (mCT) dialysers was used. Precoating of the dialysers was performed by recirculation of 10% normal human plasma for 30 min in the blood compartment and subsequent rinse with pyrogen-free saline. Samples from the blood compartment were tested for induction of interleukin-1 alpha (IL-1 alpha), interleukin-1 beta (IL-1 beta) and tumour necrosis factor (TNF alpha) at various time points after challenging the dialysate with sterile culture supernatants from Pseudomonas aeruginosa. Contamination of the dialysate resulted in the appearance of CIS in the blood compartment of both polysuphone modified cellulose triacetate (IL-1 alpha: PS, time 0: 81 +/- 11 pg/ml, time 60 min: 4747 +/- 1822 pg/ml, P < 0.05; mCT, time 0: 235 +/- 141 pg/ml, time 60 min: 1632 +/- 531 pg/ml, P < 0.05). The plasma protein layer reduced the penetration of CIS significantly only for polysulphone (IL-1 alpha: PS, time 60: 4747 +/- 1822 versus 880 +/- 525 pg/ml, P < 0.05; modified cellulose triacetate, time 60 min: 1632 +/- 531 pg/ml versus 930 +/- 326 pg/ml). Samples from the blood compartment contained < 6 pg/ml LAL-reactive material at all time points. We conclude that plasma coating of polysulphone dialysers reduces the permeability for CIS derived from Pseudomonas, either by reducing the effective pore size or by adsorption of proteins that bind CIS.(ABSTRACT TRUNCATED AT 250 WORDS)

ADP Ribose Transferases↗
PubMed1995

Beta 2-microglobulin amyloidosis: why and how to look for it.

Thirty years after the introduction of chronic dialysis into clinical practice, amyloidosis based on the precursor molecule beta 2-microglobulin (beta 2m-A) has emerged as an important complication of end-stage renal disease in patients on renal replacement therapies other than transplantation. For the individual patient, diagnosis of beta 2m-A is important to exclude other treatable causes of the symptoms, initiate symptomatic treatment, prevent possible life-threatening complications, and assign a high priority for transplantation. For the ESRD population as a whole, early specific diagnosis should help to assess the influence of various therapeutic modes on the development and course of beta 2m-A and to guide further the optimization of renal replacement therapy. Besides, sophisticated diagnostic techniques may yield valuable information on underlying pathogenetic mechanisms of beta 2m-A. Morphology, including immunohistochemistry, as the most definitive and specific diagnostic proof must rely on invasive procedures to obtain the appropriate material from clinically affected sites. Clinical assessment and imaging techniques such as x-ray and joint sonography suffer from non-specificity. Scintigraphic imaging of beta 2m-A after injection of radiolabelled beta 2-microglobulin is a non-invasive, specific, and highly sensitive way of diagnosis. Further refinement and more widespread use of this method can be expected to enhance the understanding of beta 2m-A pathogenesis and promote therapeutic and preventive efforts against this complication.

Amyloidosis↗
PubMed1994

The effect of ultrafiltered dialysate on the cellular content of interleukin-1 receptor antagonist in patients on chronic hemodialysis.

We investigated the effect of dialysate ultrafiltration on the content of IL-1 receptor antagonist (IL-1Ra) in mononuclear cells (PBMC) as a marker of the inflammatory response. 11 patients on Cuprophan dialyzers were randomly assigned to treatment with standard bicarbonate dialysate first and then to ultrafiltered dialysate or the reverse order in a crossover design. In each treatment period (at least 4 weeks) weekly separations of PBMC were performed before the start of dialysis. Cellular content of IL-1Ra was determined in PBMC that were frozen immediately after separation; all values of IL-1Ra in each treatment period were averaged. The dialysate contained a median of 148 (range, 61-400) colony-forming units without dialysate filter; no bacterial growth was detected in ultrafiltered dialysate. The median endotoxin content was 80 pg/ml in nonfiltered dialysate; endotoxin was below 5 pg/ml in all ultrafiltered dialysate samples. Cellular content of IL-1Ra decreased in all but 1 patient with the use of ultrafiltered dialysate (mean +/- SEM: 1,467 +/- 113 pg/ml without dialysate filter vs. 1,166 +/- 104 pg/ml with filter, p = 0.016). The present study demonstrates that the bacterial contamination of the dialysate induces a systemic inflammatory response in hemodialysis patients.

Bacteria↗
PubMed1993

Gene expression of interleukin-1 beta during hemodialysis.

It is still controversial whether the hemodialysis (HD) procedure is an inflammatory process in vivo. Therefore, we studied the gene expression of interleukin-1 beta (IL-1 beta) as a marker of inflammation in peripheral blood mononuclear cells (PBMC) of patients during HD by Northern blotting and polymerase chain reaction. Compared to PBMC separated pre-HD (1.0 densitometric units), the amount of IL-1 beta mRNA was increased in PBMC leaving the dialyzer (12.2 +/- 2 densitometric units, P < 0.01), but was not increased in PBMC re-entering the dialyzer from the systemic circulation (0.6 +/- 0.1 densitometric units) in all 12 patients studied. The maximal amount of IL-1 beta mRNA in PBMC was seen at five minutes after start of HD. There was a significant correlation between the increase in IL-1 beta mRNA and the increase in activated complement C5a (r = 0.71, P < 0.01). HD using less complement-activating membranes (hemophan, polysulfone, polyamide or polyacrylonitrile) resulted in no detectable IL-1 beta mRNA. Furthermore, a monoclonal antibody against human C5a reduced the increase in IL-1 beta mRNA by 83% (P < 0.05), indicating that C5a plays a major role for induction of IL-1 beta mRNA during HD. This study demonstrates that during HD with regenerated cellulose, gene expression for IL-1 beta takes place in PBMC.

Base Sequence↗
PubMed1993

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.

Acute-Phase Proteins↗
PubMed1993

Unanswered questions pertaining to dialysis adequacy in 1992.

Adequacy and survival in long-term hemodialysis are discussed by attempting to answer three questions. Firstly, are hemodialysis times too short today? The answer is that the shortening, while still permitting adequate urea removal, does not permit adequate fluid removal unless high dialysate sodium is used. The consequence is hypertension which may affect mortality insidiously and take over five years to manifest. The extensive use of hypotensive drugs may conceal the danger of hypertension due to short dialysis times. Secondly, is adequacy of dialysis judged by Kt/V valid today? The answer is no. The basis for the prescription of adequate dialysis by the use of Kt/V assumes that urea is an adequate surrogate for uremic toxicity. There is no proof for this assumption. Furthermore, protein catabolism determined by urea kinetics is not valid. At best it is an approximation and has never been adequately validated by correctly performed nitrogen balance studies. The need for close clinical supervision to ensure adequate dialysis therapy is stressed. Thirdly, does reuse contribute to inadequate dialysis? The answer is yes. The unpredictable variability in dialyzer function with reuse is stressed in a certain percentage of patients and the lack of adequate quality control tests of the reused dialyzer are emphasized. The total failure to guarantee sterility has resulted in deaths directly attributable to reuse. Thus, today quality control assurances for function and sterility are inadequate. Prospective studies are necessary to ascertain whether mortality is affected by reuse of dialyzers. Meanwhile, a moratorium on reuse is suggested.

Humans↗
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↗