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Biomedical subjects

I C Macdougall

Publications and source records attributed to I C Macdougall.

At least 19 recordsLinked to original sources
PubMed2002

Erythropoietin response to hypoxia in patients with diabetic autonomic neuropathy and non-diabetic chronic renal failure.

AIMS: An erythropoietin (EPO)-deficient anaemia is recognized in Type 1 diabetic patients with early nephropathy and symptomatic autonomic neuropathy (DN). The aim of this study was to determine whether the EPO response to hypoxia was deficient in order to clarify the mechanisms involved in this process. METHODS: Five Type 1 diabetic patients DN (age 39 (28-48) years (mean (range))) with EPO-deficient anaemia (haemoglobin, Hb 10.6 (9.5-12.0) g/dl, EPO 5.0 (3.2-6.5) IU/l) and early diabetic nephropathy (persistent proteinuria 1161.6 (130-2835) mg/day, serum creatinine 97.6 (63-123) micromol/l)) were compared with nine normal subjects (age 31 (24-39) years, Hb 13.4 (11.8-15.7) g/dl, EPO 7.6 (5.6-10.3) IU/l) and four patients with non-diabetic advanced chronic renal failure RF (proteinuria 2157.5 (571-4578) mg/day, serum creatinine 490.2 (406-659) micromol/l, Hb 10.3 (9.0-11.3) g/dl, EPO 4.6 (2.9-8.5) IU/l). The subjects were exposed to 6 h of hypoxia (inspired oxygen 11.6-12.6%) by breathing a gas mixture via a hood. Hourly serum EPO levels were measured. RESULTS: All groups showed a rise in EPO production after 2 h. The diabetic DN group achieved a similar maximal response to the normal subjects at 6 h (EPO 17.3 +/-5.4 vs. 17.8 +/-7.9 IU/l). The renal failure patients mounted an EPO response to hypoxia but at lower EPO levels. CONCLUSIONS: Although the DN patients have inappropriately low EPO levels for the severity of their anaemia, they can mount an appropriate EPO response to moderate hypoxia. The mechanism underlying the EPO-deficient anaemia present in some diabetic patients remains unclear.

Adult↗
PubMed2001

Role of uremic toxins in exacerbating anemia in renal failure.

The anemia associated with renal failure is largely due to inappropriate erythropoietin production. There is also good evidence, however, that substances present in uremic serum can inhibit erythropoiesis, although the exact identity of these substances and the mechanism(s) by which they exert this effect remain obscure. Candidates that have been suggested to play a role in uremic inhibition of erythropoiesis include the polyamines (such as spermine, spermidine, putrescine, and cadaverine), parathyroid hormone, and some of the inflammatory cytokines. The potential role of each of these inhibitory substances is discussed in this article.

Anemia↗
PubMed2001

Intravenous iron sucrose: establishing a safe dose.

It is now recognized that the majority of patients on epoetin therapy require intravenous (IV) iron supplementation to maximize the response to treatment. Of the IV iron preparations available, iron sucrose has proved its efficacy and safety; however, there are no guidelines or systematic studies examining the optimum safe dosage regimen for this compound. The aim of the present study was to investigate prospectively a variety of dosing regimens for IV iron sucrose in patients with renal failure to develop treatment strategies for this preparation. A total of 335 iron infusions was administered to 249 patients in this study, which was conducted in four phases. In phase I, 89 patients were administered a dose of 200 mg as an IV infusion over 2 hours. No adverse events were seen. A 500-mg dose by 2-hour infusion was then assessed, but was abandoned after 8 of 22 patients developed reactions characterized by dizziness, hypotension, and nausea. The dose was then reduced to 300 mg by 2-hour infusion for the next 189 patients, and again, no adverse reactions were witnessed. Finally, a 400-mg dose by 2-hour infusion was examined in 35 patients, but 2 patients experienced such symptoms as hypotension, nausea, and lower back pain. Both the 200- and 300-mg doses of IV iron sucrose administered over 2 hours appear to be safe. The incidence of adverse events with the 400- and 500-mg doses administered as a 2-hour infusion seems too high to recommend their routine use, although it may be possible to administer these doses over a longer period.

Abdominal Pain↗
PubMed2001

An overview of the efficacy and safety of novel erythropoiesis stimulating protein (NESP).

Novel erythropoiesis stimulating protein (NESP, also known as darbepoetin alfa) is a molecule that stimulates erythropoiesis by the same mechanism as both native and recombinant human erythropoietin (rHuEPO). The extra sialic residues on NESP, however, allow it to be more stable in vivo with a 2- to 3-fold longer elimination half-life. Thus, following intravenous administration, the mean elimination half-life of NESP is 25.3 vs 8.5 h for rHuEPO. After subcutaneous administration, the mean terminal half-life for NESP is 48.8 h. The mean bioavailability of NESP after subcutaneous administration is approximately 37%, similar to that reported for rHuEPO. The pharmacokinetic data suggested that patients with renal anaemia would require less frequent dosing with NESP than with rHuEPO. NESP 0.45 microg/kg administered once weekly either intravenously or subcutaneously has been evaluated for the correction of chronic renal failure (CRF)-associated anaemia. The study population included CRF patients not receiving dialysis, along with those on haemodialysis or peritoneal dialysis. In patients who are rHuEPO-naïve, NESP has a similar effect in correcting the anaemia as is seen with rHuEPO, but with less frequent dosing. Similarly, in patients previously receiving rHuEPO, NESP (whether administered intravenously or subcutaneously) is as effective as rHuEPO treatment for maintaining haemoglobin concentration when administered at a reduced frequency (i.e. either once weekly or once every other week). NESP is well tolerated, adverse effects are similar to those seen with rHuEPO, and no antibodies have been detected in >1500 patients exposed to NESP thus far.

Anemia↗
PubMed2001

Present and future strategies in the treatment of renal anaemia.

Recombinant human erythropoietin therapy has transformed the management of renal anaemia over the last decade or so. We have learned much about the optimum regimens for using this drug, including the route of administration, dosage frequency, use of iron supplementation, and management of poor response. Thus, dosage requirements of epoetin are generally lower if the drug is administered subcutaneously, and the most commonly used dosage frequency is two or three times weekly. The vast majority of patients respond very well to treatment, but approximately 5-10% of patients show some resistance to epoetin, the most common cause of which is iron deficiency. The presence of infection or inflammation and underdialysis are other important causes of a poor response to epoetin. There is increasing interest in treating renal anaemia at an earlier stage in the course of the disease, and there is much circumstantial evidence to support this strategy. This usually involves giving epoetin to pre-dialysis patients, and a study has also recently commenced to investigate the effects of preventing renal anaemia ever developing. Other erythropoietic substances are being developed, and the first of these to be ready for clinical use is novel erythropoiesis stimulating protein (NESP), which is an analogue of erythropoietin containing two extra N-linked carbohydrate side-chains. Other potential erythropoietic substances are still at the laboratory stage of development, but may be available for therapeutic use in the next decade or so.

Anemia↗
PubMed2001

Individualizing target haemoglobin concentrations--tailoring treatment for renal anaemia.

Despite the publication of National Kidney Foundation and European Best Practice Guidelines, there is still uncertainty among nephrologists regarding the optimum target haemoglobin (Hb) concentration for patients treated with erythropoietin. For most patients, the target Hb concentration is 11-12 g/dl, resulting in only partial correction of anaemia. However, there is a link between subnormal Hb concentration and the development of cardiovascular disease. Thus, it may be more beneficial to normalize Hb, although this has to be balanced against the concern that full correction of anaemia may result in adverse effects, such as hypertension and progression of renal disease. There is increasing evidence that it may be appropriate to treat each patient individually, and to tailor treatment according to a number of physiological and lifestyle variables, avoiding higher Hb concentrations in certain patient groups (such as those with cardiac problems). This was supported by the results of a survey of nephrologists and specialists in the field of renal anaemia. It was generally agreed that a higher target Hb concentration (12-14 g/dl) might be appropriate for a fit, young patient with no significant co-morbidity, whereas a lower target Hb (10-12 g/dl) might be appropriate for an elderly patient with multiple medical problems. In conclusion, guidelines for target Hb in the US and Europe are probably not applicable to all patients. It is important that renal anaemia patients are considered as individuals, and their treatment tailored accordingly. It is time to establish evidence-based criteria for individualizing renal anaemia treatment.

Anemia↗
PubMed2001

Anemia with erythropoietin deficiency occurs early in diabetic nephropathy.

OBJECTIVE: The normochromic normocytic anemia of erythropoietin (EPO) deficiency is recognized in advanced renal failure but not in early renal disease. The aim of this study was to determine whether anemia with EPO deficiency is found in type 1 diabetic patients with diabetic nephropathy in the absence of advanced renal failure and to compare them with patients with nondiabetic renal disease of similar severity. RESEARCH DESIGN AND METHODS: A total of 27 type 1 diabetic patients with diabetic nephropathy (DN), defined as having persistent proteinuria (mean 1,086 mg/day [CI 120-5,1901), a serum creatinine < or = 180 micromol/l, and retinopathy, were compared with 26 nondiabetic patients with glomerulonephritis (GN) and persistent proteinuria (1,874 mg/day [349-5,005]). The Hb concentration, red cell indexes, and serum EPO levels were measured, and other causes for the anemia were excluded. The EPO values were compared with a normal reference range obtained from nondiabetic patients with a microcytic anemia. The DN patients were tested for signs of diabetic peripheral and autonomic neuropathy. RESULTS: We found that 13 of the 27 DN patients were anemic (Hb 10.6 +/- 0.9 g/dl) in marked contrast to none of the GN patients (Hb 13.7 +/- 1.4 g/dl, P < 0.005). In the DN group, serum EPO concentrations failed to increase in response to anemia compared with the response seen in patients with microcytic anemia. Thus, the anemia of the DN group was associated with EPO deficiency. The anemic DN patients showed evidence of more severe proteinuria and diabetic neuropathy than the nonanemic DN patients. CONCLUSIONS: Anemia associated with EPO deficiency can occur early in DN before the onset of advanced renal failure, but does not normally occur in nondiabetic renal disease of similar severity. The pathogenesis requires elucidation.

Adult↗
PubMed2000

How to improve survival in pre-dialysis patients.

AIMS: This survey was performed to determine how anaemia in pre-dialysis patients is currently managed. METHODS: A random sample of 200 nephrologists attending the 1999 ERA/EDTA Congress participated in an interactive survey session. Participants were questioned on their current prescribing attitudes and preferences, and asked to select a preferred answer from a number of alternatives by means of an electronic key-pad. RESULTS: Three quarters of the audience treated their pre-dialysis patients with erythropoietin. However, approximately 50% treated </=10% of patients and only 8% of respondents treated >/=75%. In addition, more than half of the respondents said that very few of their patients currently self-administer erythropoietin. Increased healthcare expenditure was the main reason given for limiting treatment. CONCLUSIONS: The survey highlighted important gaps in long-term treatment strategies for pre-dialysis patients. It indicated that new approaches to the treatment of renal anaemia are needed to minimise disease progression and to prevent cardiac dysfunction and associated mortality. Erythropoietin has already been shown to significantly improve the survival of dialysis patients with renal anaemia, and new strategies might, therefore, include the prevention of anaemia in pre-dialysis patients by earlier initiation of erythropoietin therapy.

Adult↗
PubMed2000

Novel erythropoiesis stimulating protein.

Novel erythropoiesis stimulating protein (NESP) is a hyperglycosylated analogue of recombinant human erythropoietin (rHuEPO) that stimulates erythropoiesis by the same mechanism as the native hormone. The addition of two extra carbohydrate chains, however, gives NESP greater metabolic stability in vivo, and its terminal half-life after IV administration is three-fold longer than for IV rHuEPO. This allows injections of both IV and SC NESP to be given less frequently, and indeed studies have shown that once-weekly, and even once every other week, dosing can maintain the hemoglobin concentration in patients treated for renal anemia. The optimum starting dose is 0.45 microg/kg once weekly via the IV and SC routes of administration. Adverse effects are very similar to those seen with rHuEPO, and no antibodies have been detected in over 1,500 patients exposed to NESP thus far. NESP therefore represents a triumph for drug synthesis by recombinant DNA technology, and we can look to the future of this new therapeutic agent with much hope and expectation.

Anemia, Iron-Deficiency↗