Detection of functional iron deficiency during erythropoietin treatment: a new approach.
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Deficiency Diseases↗
Biomedical subjects
G A Coles
Publications and source records attributed to G A Coles.
Estimation of erythropoietin secretion rate in normal and uremic subjects.
We have developed a method for directly estimating the secretion rate of endogenous erythropoietin (EPO) in human subjects. Carrier-free recombinant human EPO was labeled with 125I by the chloramine T method. Human serum albumin was then added prior to removal of free iodide. Seven normal subjects and nine patients with chronic uremia and anemia were studied. Each subject received a bolus of 125I-EPO according to body size and then a constant infusion for 5 h. Secretion rate was calculated as the rate of infusion divided by serum EPO specific activity given by the protein-bound counts divided by the EPO concentration. Serum EPO concentration was significantly higher in the patients than the controls (mean 30.9 pg/ml vs. 11.1 pg/ml, P < 0.05), although all values were within the normal range. Mean EPO secretion rate was 255 in the patients (range 68-1,101) and 190 pg.kg-1 x h-1 in the normal group (range 52-382). This difference was not significant. As the subjects were in a steady state, EPO disappearance/degradation was the same in patients compared with controls despite a relatively hypoplastic marrow.
Adult↗
Down-regulation of cyclooxygenase product generation by human peritoneal macrophages.
Isolated human peritoneal macrophages under resting conditions synthesize and release significant quantities of the cyclooxygenase products prostaglandin E2 (PGE2) and thromboxane B2 (TXB2). These increased linearly with time and were dependent on de novo protein synthesis. Following the addition of calcium ionophore A23187 there was a marked decrease in total generation of immunoreactive cyclooxygenase products. In contrast, there was a concomitant increase in the release of 5-lipoxygenase products. The down-regulation of both PGE2 and TXB2 was not due to diversion of substrate from the cyclooxygenase pathway to the 5-lipoxygenase pathway nor was it due to inhibitory effects of products of the 5-lipoxygenase pathway on the generation of cyclooxygenase products. Instead, the inhibitory effects of A23187 were thought to be due to a down-regulation of cyclooxygenase itself, a hypothesis supported by the finding that TXA2 synthase proved to be unaltered and Western analysis of crude peritoneal macrophage (PM phi) membranes demonstrated lesser quantities of cyclooxygenase in membranes from A23187-treated PM phi than in those prepared from control cells.
Adult↗
Effect of dialyser composition and reuse on neutrophil count and elastase alpha-1 proteinase inhibitor complex formation.
To assess the inter-relationship of leucopenia and PMN elastase release we undertook a prospective crossover study of 6 patients dialysed with new and reused cuprophane, cellulose acetate and polysulfone membranes. Serial blood samples were analysed for PMN count, and elastase-alpha 1-proteinase inhibitor complex (E alpha 1PI) concentrations. After 15 min dialysis with new membranes median PMN counts fell by 72.2%, 25.3% and 22.1% with cuprophane, cellulose and polysulfone, respectively. With reuse the decreases were reduced to 6.4%, 8% and 13.6%. All membranes produced a gradual increase of E alpha 1PI. Median E alpha 1PI accumulation rates (ng ml-1 min-1) with new membranes were 175, 169 and 187 for cuprophane, cellulose acetate and polysulfone, respectively. With reuse of cuphrophane and cellulose acetate these rates fell to 99 and 109 (p less than 0.05 and p less than 0.05, respectively), however, with polysulfone it remained unchanged at 180 ng ml-1 min-1. This study highlights differences between two aspects of the neutrophil response to haemodialysis, and demonstrates that extrapolation from individual parameters to conclusions concerning biocompatibility may be inappropriate.
Adult↗
Enalapril can treat the proteinuria of membranous glomerulonephritis without detriment to systemic or renal hemodynamics.
The effect of enalapril on renal hemodynamics and glomerular permselectivity was studied in eight patients with nephrotic syndrome secondary to biopsy-proven membranous glomerulonephritis. The patients received the drug in incremental doses (median, 5 mg) until 24-hour urinary protein excretion had decreased persistently by 30%. Median treatment duration was 6 weeks. Patients were studied three times: (I) after a 4-week run-in period, (II) on the final day of treatment, and (III) after a 4-week wash-out. Median 24-hour urinary protein excretion decreased on treatment from 10.45 g/d to 5.25 g/d and increased to pretreatment levels after the drug was stopped (P less than 0.05 for both changes). Fractional clearance of dextrans greater than 4.1 nm decreased on treatment, indicating both a reduction of macromolecules passing through the shunt pathway of the glomerular basement membrane (GBM) and a possible decrease in ultrafiltration coefficient. There were no significant changes in glomerular filtration rate (GFR), effective renal plasma flow (ERPF), or mean arterial blood pressure (MAP) throughout the study. The effect of enalapril in treating proteinuria appears therefore to be due to a specific intraglomerular action.
Adult↗
The response of human peritoneal macrophages to stimulation with bacteria isolated from episodes of continuous ambulatory peritoneal dialysis-related peritonitis.
The metabolism of arachidonic acid, by isolated peritoneal macrophages in response to stimulation with microorganisms isolated from continuous ambulatory peritoneal dialysis (CAPD) patients, is not specific to the individual strain but is determined by species. Isolates of Staphylococcus aureus (n = 7) and Staphylococcus epidermidis (n = 13) produced a significant increase in leukotriene B4 generation by peritoneal macrophages compared with unstimulated cells (P less than .001). The coincubation of peritoneal macrophages with gram-negative organisms (n = 3), however, did not result in an increase in leukotriene B4 synthesis. In contrast, all the organisms tested significantly inhibited the formation of prostaglandin E2 and thromboxane B2 but the degree of inhibition was species dependent. The above results were reproduced using bacteria-free supernatants, indicating that the interaction was dependent on a secreted bacterial product. Thus in response to certain bacterial species, the recruitment of neutrophils may be facilitated by the generation of leukotriene B4 from peritoneal macrophages. In addition, the reduction in synthesis of prostaglandin E2 may remove a regulatory effect that this metabolite has on the immune response.
Adult↗
Gram-positive infections related to CAPD.
The majority of infections associated with continuous ambulatory peritoneal dialysis (CAPD) are caused by Gram-positive bacteria. The coagulase-negative staphylococci are the most common cause of peritonitis and Staphylococcus aureus is the organism most frequently associated with tunnel and exit site infections. The advent of newer techniques for bag change in CAPD has significantly reduced the incidence of peritonitis but relapse is still common among a few isolated individuals. Carriage of staphylococci in the nose is important in predisposing individuals for exit site infections. The possibility that eradication of nasal carriage may prevent CAPD infection has yet to be evaluated.
Bacterial Adhesion↗
Coagulation studies and fistula blood flow during erythropoietin therapy in haemodialysis patients.
An increased incidence of fistula thrombosis has been reported in haemodialysis patients treated with recombinant human erythropoietin (rHuEpo). The present study sought to investigate this problem by measuring fistula blood flow, blood viscosity, and a variety of tests of coagulation and haemostasis in a group of ten haemodialysis patients treated with rHuEpo. Fistula blood flow did not alter during the first 12 months of rHuEpo despite a significant increase in whole-blood viscosity. Bleeding time improved in all ten patients after 4 months of therapy, and this improvement was maintained at 12 months. There were no significant changes in one-stage prothrombin time, kaolin cephalin clotting time, whole-blood clotting time, prothrombin consumption index, plasma fibrinogen factor VII, factor VIII, antithrombin III, or platelet aggregability to ADP over the first 4 months of rHuEpo. In contrast, protein C decreased from 84.3 to 66.4% (P less than 0.01) and protein S from 124.1 to 68.3% (P less than 0.001) over the first 4 months. By 8 and 12 months, the concentrations of these substances had returned to pretreatment values. The levels of protein C and S attained at 4 months are known to predispose to thrombosis, and it is possible that this effect may contribute to the increased incidence of fistula thrombosis observed in haemodialysis patients treated with rHuEpo.
Adult↗
In vitro testing of a potentially biocompatible continuous ambulatory peritoneal dialysis fluid.
In the present study a newly formulated dialysis solution (HDF) was tested for its effects on phagocyte viability and function as well as its ability to support bacterial growth. This solution differs from standard CAPD solution (NPD) by the inclusion of histidine to buffer the fluid to pH 6.7. Low-dextrose HDF (1.36% w/v dextrose) did not significantly decrease the viability or inhibit any of the PMN functional parameters measured (phagocytosis, LTB4 release or respiratory burst activation) when compared to control buffer. NPD (1.36% w/v dextrose) at low pH as well as all high-dextrose dialysis solutions (NPD and HDF) significantly inhibited most PMN functions independently of reduced viability. Peritoneal mesothelial cell viability was unaffected by either low- or high-dextrose HDF but was significantly reduced by NPD (1.36 and 3.86% dextrose) at pH 5.2. The inhibitory effects of low dextrose dialysis solutions were confirmed as being partly related to their low initial pH. High-dextrose dialysis fluids, however, inhibit PMN function by a mechanism which, in addition to initial pH, appears to be directly related to their dextrose content but not their osmolality.
Bacteria↗
Rheological studies during treatment of renal anaemia with recombinant human erythropoietin.
Whole blood, plasma, and serum viscosity together with red cell deformability were measured before and during treatment of renal anaemia with recombinant human erythropoietin (EPO). Whole blood viscosity (WBV) progressively increased during the first 4 months of treatment in association with the rise in haemoglobin concentration. When the WBV was corrected to a standard haemoglobin concentration no change in blood viscosity was observed, neither was there any alteration in a derived index of red cell deformability, or in the plasma and serum viscosities. In addition, a direct measurement of red cell deformability using a filtration technique before EPO therapy was similar to that obtained in 30 healthy volunteers. There was no significant change in this parameter over the first 9 months of treatment. The rheological changes which occur with correction of anaemia with EPO can be explained solely by the increase in circulating haemoglobin mass rather than to any change in the properties of the plasma or red cells themselves.
Adult↗
The use of erythropoietin in renal failure.
The treatment of renal anaemia by recombinant human erythropoietin (EPO) is now well established. Several studies have examined the pharmacokinetics and efficacy of the drug given intravenously, intraperitoneally and subcutaneously and there is increasing evidence that the subcutaneous route has several advantages including the requirement for a lower dose. It is also important to stress the need for careful determination of baseline iron status of all patients before commencing EPO therapy. In the long term the extremely high iron stores of transfusion dependent patients will disappear. In the short term, however, the majority of the patients whose serum ferritin is less than 100 micrograms/l will require iron supplementation to allow an appropriate haemoglobin response. Alternatively, a fall in transferrin saturation to less than 20% is certainly an indication for iron supplementation and if oral iron therapy is not adequate then intravenous preparations may have to be considered. Although the anaemia of renal failure can be fully corrected by EPO, partial correction may be sufficient to reverse the problems of reduced exercise capacity, myocardial ischaemia and cardiomegaly which are frequently associated with end-stage renal disease. Partial correction will also result in a lesser rise in whole blood viscosity and, in turn, possibly reduce hypertension, thrombosis and increased peripheral resistance and thus lessen the side effects of EPO therapy.
Anemia, Hypochromic↗
Genetic counselling in adult polycystic kidney disease.
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Adult↗
Subcutaneous erythropoietin therapy: comparison of three different sites of injection.
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Adult↗
Clinical pharmacokinetics of epoetin (recombinant human erythropoietin).
Epoetin (recombinant human erythropoietin, EPO) is of proven benefit in the treatment of renal anaemia, and preliminary reports suggest that it may have a role in the management of other anaemic conditions. Pharmacokinetic and therapeutic studies have examined the use of epoetin administered intravenously, intraperitoneally and subcutaneously, and there is accumulating evidence that the last route has several advantages. After intravenous administration, epoetin is distributed in a volume comparable to the plasma volume, and plasma concentrations decay monoexponentially with a half-life of between 4 and 12 hours. Administration of epoetin in peritoneal dialysis fluid results in detectable concentrations in the bloodstream after 1 to 2 hours, and peak concentrations of the order of 2 to 4% of those obtained with the same intravenous dose are found after approximately 12 hours. The bioavailability of epoetin administered intraperitoneally in dialysis fluid is about 3 to 8%, but this may be increased by injecting the drug into a dry peritoneal cavity. Subcutaneous administration results in peak concentrations at about 18 hours which are 5 to 10% of those found after the same intravenous dose. The bioavailability of subcutaneous epoetin is about 20 to 30% and detectable serum concentrations are still present 4 days after administration, in contrast to intravenous administration after which concentrations have returned to baseline within 2 to 3 days. Remarkably little is known about the metabolic fate of either erythropoietin or epoetin. In addition, there is much controversy surrounding the relative roles of the kidney and liver in the catabolism of epoetin. About 3 to 10% of epoetin is excreted unchanged in the urine. In common with other glycoproteins, the carbohydrate residues which constitute 40% of its molecular size are essential for maintaining the stability of epoetin in circulation. Desialated epoetin, although biologically active in vitro, is cleared very rapidly from plasma with resultant loss of activity. Further work is required, however, in identifying the pathways of metabolism and elimination of this glycoprotein hormone.
Animals↗
Design and testing of the Baxter Integrated Disconnect Systems (IDS).
This paper describes the result of a miltidisciplinary approach to the design and evaluation of a new CAPD disconnect system: the Baxter Integrated Disconnect System (IDS). This system consists of a bag full of fresh Dianeal, an empty bag for the drainage of spent dialysate and tubings connecting the 2 in a Y fashion. With this system, the patient makes only one connection. The system is disposable. The major property that makes this unique is that all components are preassembled, and the whole system is steam-sterilized as 1 unit. In general, similar systems use different sterilization methods for the various components of the system. Those components are then assembled, under clean conditions by the manufacturer, without final sterilization of the unit. Assembly of the components is sometimes left to the patient. The concept of IDS, therefore, is unique and warrants lower rates of contamination. This system has been tested on patients for a total observation period of 765 patient months, and has proven to be simple, safe and effective. It yields a 63% probability of peritonitis-free patients at 24 months.
Dialysis Solutions↗
Polycystic kidney disease re-evaluated: a population-based study.
A genetic register of all known cases of autosomal dominant polycystic kidney disease occurring in South and Mid-Wales has been established. In a population of 2.1 million, 209 families with affected members were identified, 303 of whom are currently alive, 70 on renal replacement therapy. An additional 551 cases would be predicted amongst family members at 50 per cent and 25 per cent risk, giving an apparent prevalence of 1:2459 in the general population. Five possible new mutations were seen where adults with phenotypic autosomal dominant polycystic kidney disease had both parents alive, age greater than 55 years with no cysts visible on ultrasound. The take-on rate for renal replacement therapy increased during 1970-79 but has apparently reached a plateau of 4.8 cases per million population per year over the last 8 years, despite a rapidly increasing acceptance of uraemic patients as a whole (72/10(6)/year in 1988-89). Considerably more patients with autosomal dominant polycystic kidney disease aged over 50 years were started on treatment in 1980-89 than in 1970-79, but the survival overall improved with time. All cases of autosomal dominant polycystic kidney disease reaching end-stage renal disease are now being treated, but the apparent clinical prevalence of this condition in our region is less than half the supposed gene frequency, suggesting that undiagnosed cases have a benign prognosis.
Adolescent↗
Proteinases and the glomerulus: their role in glomerular diseases.
Degradation of matrix in normal glomeruli occurs through the action of neutral metalloproteinases which are in turn regulated by specific inhibitors. Both of these proteins are secreted by mesangial cells. Macrophages and IL-1 enhance the secretion of the proteinase. Decreased production of the metalloproteinase and for increased secretion of its inhibitor may lead to matrix accumulation. Neutrophil serine paternases degrade glomerular basement membrane (GBM) in vitro. In both animal and human disease urine excretion of these enzymes is accompanied by proteinuria and the presence of GBM-fragments. Further knowledge of the processes involved in matrix degradation may lead to improved therapy of glomerular disease.
Basement Membrane↗
Treating renal anaemia with recombinant human erythropoietin: practical guidelines and a clinical algorithm.
Treatment with erythropoietin is highly effective and beneficial if given with care. In view of its cost, however, it is essential to exclude and treat other causes of anaemia before considering using this hormone. After treatment is started the important points for success are regular review of iron availability state combined with a slow correction of the anaemia. Failure of response requires a thorough search for a possible cause, which should be corrected before considering an increased dose of the hormone. Regular monitoring for potential complications, particularly a rise in blood pressure, is required.
Algorithms↗