Iain C. Macdougall
University of Cambridge
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Archive | 2012
Jjv McMurray; Patrick S. Parfrey; John W. Adamson; Pedro Aljama; Jeffrey S. Berns; Julia Bohlius; Tilman B. Drüeke; Fredric O. Finkelstein; Steven Fishbane; Tomas Ganz; Iain C. Macdougall; Ruth A. McDonald; Lawrence P. McMahon; Gregorio T. Obrador; Gfm Strippoli; Günter Weiss; Andrzej Więcek
To the Editor: We have read the letter to the editor by Jerzy Przedlacki1 and the response from the authors2 of the Kidney Disease-Improving Global Outcomes (KDIGO) clinical practice guidelines for bisphosphonate (BP) treatment in chronic kidney disease (CKD), and would like to share our concerns regarding the use of BP treatment of CKD. The kidney is the organ that excretes many drugs, and any change in renal function will affect the pharmacology of these drugs. Existing or residual renal function of the patient will have to be taken into account while prescribing drugs. This is just as important for the patient with CKD 4 or 5, including those with CKD 5 already on peritoneal dialysis or hemodialysis, who may still have residual renal function. Nephrotoxic drugs including nonsteroidal anti-inflammatory drugs can very readily destroy whatever residual renal function patients may still have. Residual renal function is important to preserve as it contributes to less patient morbidity and mortality3 in the dialysis patient. Recently, there have been adverse reports of a certain BP that works by inhibiting osteoclast-mediated bone resorption, thereby slowing the breakdown of bone to reduce the risk of fractures. As of 14 August 2009, there have been 139 post-marketing reports of renal impairment following its use as an infusion worldwide. Many of these occur in patients with pre-existing medical conditions or risk factors (elderly, renal impairment, and/or concurrent dehydration), or in those on nonsteroidal anti-inflammatory drugs or other concurrent exposure to other nephrotoxic agents. There have also been cases requiring dialysis, and occasional fatal outcomes have been reported in patients with pre-existing renal impairment and concomitant risk factors.4, 5, 6, 7
The Lancet | 2016
Anthony Lopez; Patrice Cacoub; Iain C. Macdougall; Laurent Peyrin-Biroulet
Anaemia affects roughly a third of the worlds population; half the cases are due to iron deficiency. It is a major and global public health problem that affects maternal and child mortality, physical performance, and referral to health-care professionals. Children aged 0-5 years, women of childbearing age, and pregnant women are particularly at risk. Several chronic diseases are frequently associated with iron deficiency anaemia--notably chronic kidney disease, chronic heart failure, cancer, and inflammatory bowel disease. Measurement of serum ferritin, transferrin saturation, serum soluble transferrin receptors, and the serum soluble transferrin receptors-ferritin index are more accurate than classic red cell indices in the diagnosis of iron deficiency anaemia. In addition to the search for and treatment of the cause of iron deficiency, treatment strategies encompass prevention, including food fortification and iron supplementation. Oral iron is usually recommended as first-line therapy, but the most recent intravenous iron formulations, which have been available for nearly a decade, seem to replenish iron stores safely and effectively. Hepcidin has a key role in iron homoeostasis and could be a future diagnostic and therapeutic target. In this Seminar, we discuss the clinical presentation, epidemiology, pathophysiology, diagnosis, and acute management of iron deficiency anaemia, and outstanding research questions for treatment.
Clinical Journal of The American Society of Nephrology | 2006
Iain C. Macdougall; Richard Robson; Sylvie Opatrna; Xavier Liogier; Anne Pannier; Paul Jordan; Frank C. Dougherty; Bruno Reigner
Continuous Erythropoietin Receptor Activator (C.E.R.A.) is a new agent that is in development for the treatment of anemia with extended administration intervals in patients who have chronic kidney disease (CKD), both those on and those not on dialysis. This was an open-label, randomized, multicenter, two-period, crossover study in erythropoiesis-stimulating agentnaïve patients who had CKD and anemia and were receiving peritoneal dialysis. After a 1-wk run-in period, 16 patients were randomly assigned to receive a single administration of intravenous C.E.R.A. 0.4 microg/kg (n = 8) or subcutaneous C.E.R.A. 0.8 microg/kg (n = 8). Six weeks after the first administration of C.E.R.A. (4-wk assessment, 2-wk washout), the route of administration was switched so that all patients received single administrations of both intravenous C.E.R.A. 0.4 microg/kg and subcutaneous C.E.R.A. 0.8 microg/kg. C.E.R.A. had a prolonged and comparable half-life after intravenous (mean 134 h) and subcutaneous (mean 139 h) administration. Reticulocyte counts peaked at a median of 8 d after intravenous and subcutaneous administration with no difference in the time course between administration routes. This resulted in similar mean values for the area under the reticulocyte count-time curve (1191 x 10(9) and 1193 x 10(9).d per L, respectively) and the maximum absolute increase in reticulocyte counts (36 x 10(9) and 41 x 10(9)/L, respectively). C.E.R.A. has a prolonged and comparable half-life after intravenous or subcutaneous injection, suggesting that extended administration intervals may be feasible in patients with CKD.
European Heart Journal | 2013
Ewa A. Jankowska; Stephan von Haehling; Stefan D. Anker; Iain C. Macdougall; Piotr Ponikowski
Iron is a micronutrient essential for cellular energy and metabolism, necessary for maintaining body homoeostasis. Iron deficiency is an important co-morbidity in patients with heart failure (HF). A major factor in the pathogenesis of anaemia, it is also a separate condition with serious clinical consequences (e.g. impaired exercise capacity) and poor prognosis in HF patients. Experimental evidence suggests that iron therapy in iron-deficient animals may activate molecular pathways that can be cardio-protective. Clinical studies have demonstrated favourable effects of i.v. iron on the functional status, quality of life, and exercise capacity in HF patients. It is hypothesized that i.v. iron supplementation may become a novel therapy in HF patients with iron deficiency.
British Journal of Haematology | 2013
D. Wayne Thomas; Rod Hinchliffe; Carol Briggs; Iain C. Macdougall; Tim Littlewood; Ivor Cavill
Functional iron deficiency (FID) is a state in which there is insufficient iron incorporation into erythroid precursors in the face of apparently adequate body iron stores, as defined by the presence of stainable iron in the bone marrow together with a serum ferritin value within normal limits (Macdougall et al, 1989). In its broadest sense this definition encompasses the partial block in iron transport to the erythroid marrow seen in subjects with infectious, inflammatory and malignant diseases, and is a major component of the anaemia of chronic disease (ACD). One form of FID, found in some subjects treated with erythropoiesis-stimulating agents (ESAs), has been the subject of numerous studies following the widespread use of these agents, especially in subjects with chronic kidney disease (CKD).
The New England Journal of Medicine | 2009
Iain C. Macdougall; Jerome Rossert; Nicole Casadevall; Richard Stead; Anne-Marie Duliege; Marc Froissart; Kai-Uwe Eckardt
BACKGROUND We investigated whether a novel, synthetic, peptide-based erythropoietin-receptor agonist (Hematide, Affymax) can stimulate erythropoiesis in patients with anemia that is caused by antierythropoietin antibodies. METHODS In this open-label, single-group trial, we enrolled patients with chronic kidney disease who had pure red-cell aplasia or hypoplasia due to antierythropoietin antibodies and treated them with a synthetic peptide-based erythropoietin-receptor agonist. The agonist was administered by subcutaneous injection at an initial dose of 0.05 mg per kilogram of body weight every 4 weeks. The primary end point was a hemoglobin concentration above 11 g per deciliter without the need for transfusions. RESULTS We treated 14 patients with the peptide agonist for a median of 28 months. The median hemoglobin concentration increased from 9.0 g per deciliter (with transfusion support in the case of 12 patients) before treatment to 11.4 g per deciliter at the time of the last administration of the agonist; transfusion requirements diminished within 12 weeks after the first dose, after which 13 of the 14 patients no longer required regular transfusions. Peak reticulocyte counts increased from a median of 10x10(9) per liter before treatment to peak counts of greater than 100x10(9) per liter. The level of antierythropoietin antibodies declined over the course of the study and became undetectable in six patients. One patient who initially responded to treatment had a diminished hematologic response a few months later despite increased doses of the agonist and required transfusions again; this patient was found to have antibodies against the agonist. One patient died 4 months after the last dose of the agonist, and a grade 3 or 4 adverse event occurred in seven other patients during the study period. CONCLUSIONS This novel agonist of the erythropoietin receptor can correct anemia in patients with pure red-cell aplasia caused by antierythropoietin antibodies. (ClinicalTrials.gov number, NCT00314795.).
Nature Reviews Cardiology | 2011
Dirk J. van Veldhuisen; Stefan D. Anker; Piotr Ponikowski; Iain C. Macdougall
Anemia and iron deficiency are common in patients with heart failure (HF), and are associated with worse symptoms and adverse outcomes in this population. Although the two can occur together, anemia in HF is often not caused by iron deficiency, and iron deficiency can be present without causing anemia. Erythropoiesis-stimulating agents have been investigated extensively in the past few years and might be of benefit in patients with HF and anemia. However, concerns have arisen regarding the safety of erythropoiesis-stimulating agents in patients with chronic kidney disease and so the results of a large mortality trial are eagerly awaited to provide information on safety in patients with HF. Iron supplementation or replacement is a much older treatment option for patients with HF and anemia, but questions about the safety of intravenous iron, and absorption problems with oral formulations have prevented its widespread use to date. In the past few years, however, new data on the importance of iron deficiency in HF have become available, and a number of studies with intravenous iron have shown promising results. Therefore, this treatment approach is likely to become an attractive option for patients with HF and iron deficiency, both with and without anemia.
Journal of The American Society of Nephrology | 2003
Angela C. Cooper; Ashraf Mikhail; M W Lethbridge; D. Michael Kemeny; Iain C. Macdougall
ABSTRACT. Resistance to recombinant human erythropoietin occurs in a small but important proportion of hemodialysis patients. This may be due to increased immune activation because pro-inflammatory cytokines inhibit erythropoiesis in vitro . Using FACScan flow cytometry, the proportion of PMA/ionomycin-stimulated T cells expressing cytokines ex vivo was compared in 18 poor responders to erythropoietin, 14 good responders to erythropoietin, and 14 normal controls. CD4 + T cells from poor responders expressed more interferon-γ (IFN-γ; 19 ± 6%) compared with good responders (11 ± 6%, P P + T cells from poor responders expressed more tumor necrosis factor-α (TNF-α; poor responders: 51 ± 19% versus good responders: 27 ± 15% [ P P + expression of IL-10 was also enhanced (poor responders: 1.6 ± 1.1% versus good responders: 0.7 ± 0.6% [ P P + expression of interleukin-13 (IL-13) was increased (poor responders: 4.4 ± 4.2% versus good responders: 1.6 ± 1.7% [ P P + T cells from poor responders also showed enhanced expression of cytokines. For IFN-γ, poor responder expression was 48 ± 20% compared with 31 ± 17% ( P P versus 25 ± 14% for good responders ( P P P P
The Lancet | 2006
Iain C. Macdougall; Kai-Uwe Eckardt
As with many other therapeutic areas in modern-day medicine, scientific advances in drug development (using such techniques as recombinant DNA technology, site-directed mutagenesis, pegylation of molecules, peptide library screening, and gene transfer) have resulted in the development of potential new agents and strategies for stimulating erythropoiesis. These advances are of possible benefit in treating anaemia due to various causes, including chronic renal failure. Several new treatments will soon become clinically available, while others are at present at an early stage of development but are nevertheless of scientific interest. We review these new therapeutic strategies, and discuss at what stage some of the newer products are in relation to their clinical development programme.
The Lancet | 1989
Iain C. Macdougall; Peter Neubert; GeraldA. Coles; DavidE. Roberts; A.Douglas Dharmasena; J. D. Williams
To determine the optimum regimen for giving recombinant human erythropoietin (EPO) to patients on continuous ambulatory peritoneal dialysis (CAPD), the pharmacokinetics of single-dose EPO administered intravenously (120 U/kg), intraperitoneally (50,000 U), and subcutaneously (120 U/kg) was investigated. After intravenous administration serum EPO levels decayed exponentially from a peak of 3959 mU/ml, with a half-life of 8.2 h. 2.3% of the total intravenous dose was lost in the dialysate during the first 24 h. Peak serum EPO levels of 375 mU/ml at 12 h and 176 mU/ml at 18 h were attained following intraperitoneal and subcutaneous administration, respectively. The bioavailability of subcutaneous EPO (21.5%) was seven times greater than that of intraperitoneal EPO (2.9%). These results suggest that subcutaneous EPO represents the most satisfactory route of administration for CAPD patients.