Publications by authors named "Iain C Macdougall"

199 Publications

Randomized Trial-PrEscription of intraDialytic exercise to improve quAlity of Life in Patients Receiving Hemodialysis.

Kidney Int Rep 2021 Aug 30;6(8):2159-2170. Epub 2021 May 30.

School of Health Sciences, Queen Margaret University, Edinburgh, UK.

Introduction: Whether clinically implementable exercise interventions in people receiving hemodialysis (HD) therapy improve health-related quality of life (HRQoL) remains unknown. The PrEscription of intraDialytic exercise to improve quAlity of Life PEDAL) study evaluated the clinical benefit and cost-effectiveness of a 6-month intradialytic exercise program.

Methods: In a multicenter, single-blinded, randomized, controlled trial, people receiving HD were randomly assigned to (i) intradialytic exercise training (exercise intervention group [EX]) and (ii) usual care (control group [CON]). Primary outcome was change in Kidney Disease Quality of Life Short-Form Physical Component Summary (KDQOL-SF 1.3 PCS) from baseline to 6 months. Cost-effectiveness was determined using health economic analysis; physiological impairment was evaluated by peak oxygen uptake; and harms were recorded.

Results: We randomized 379 participants; 335 and 243 patients (EX  = 127; CON  = 116) completed baseline and 6-month assessments, respectively. Mean difference in change PCS from baseline to 6 months between EX and CON was 2.4 (95% confidence interval [CI]: -0.1 to 4.8) arbitrary units ( = 0.055); no improvements were observed in peak oxygen uptake or secondary outcome measures. Participants in the intervention group had poor compliance (47%) and poor adherence (18%) to the exercise prescription. Cost of delivering intervention ranged from US$598 to US$1092 per participant per year. The number of participants with harms was similar between EX ( = 69) and CON ( = 56). A primary limitation was the lack of an attention CON. Many patients also withdrew from the study or were too unwell to complete all physiological outcome assessments.

Conclusions: A 6-month intradialytic aerobic exercise program was not clinically beneficial in improving HRQoL as delivered to this cohort of deconditioned patients on HD.
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http://dx.doi.org/10.1016/j.ekir.2021.05.034DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8343798PMC
August 2021

Exercise programme to improve quality of life for patients with end-stage kidney disease receiving haemodialysis: the PEDAL RCT.

Health Technol Assess 2021 Jun;25(40):1-52

School of Health Sciences, Queen Margaret University, Edinburgh, UK.

Background: Whether or not clinically implementable exercise interventions in haemodialysis patients improve quality of life remains unknown.

Objectives: The PEDAL (PrEscription of intraDialytic exercise to improve quAlity of Life in patients with chronic kidney disease) trial evaluated the clinical effectiveness and cost-effectiveness of a 6-month intradialytic exercise programme on quality of life compared with usual care for haemodialysis patients.

Design: We conducted a prospective, multicentre randomised controlled trial of haemodialysis patients from five haemodialysis centres in the UK and randomly assigned them (1 : 1) using a web-based system to (1) intradialytic exercise training plus usual-care maintenance haemodialysis or (2) usual-care maintenance haemodialysis.

Setting: The setting was five dialysis units across the UK from 2015 to 2019.

Participants: The participants were adult patients with end-stage kidney disease who had been receiving haemodialysis therapy for > 1 year.

Interventions: Participants were randomised to receive usual-care maintenance haemodialysis or usual-care maintenance haemodialysis plus intradialytic exercise training.

Main Outcome Measures: The primary outcome of the study was change in Kidney Disease Quality of Life Short Form, version 1.3, physical component summary score (from baseline to 6 months). Cost-effectiveness was determined using health economic analysis and the EuroQol-5 Dimensions, five-level version. Additional secondary outcomes included quality of life (Kidney Disease Quality of Life Short Form, version 1.3, generic multi-item and burden of kidney disease scales), functional capacity (sit-to-stand 60 and 10-metre Timed Up and Go tests), physiological measures (peak oxygen uptake and arterial stiffness), habitual physical activity levels (measured by the International Physical Activity Questionnaire and Duke Activity Status Index), fear of falling (measured by the Tinetti Falls Efficacy Scale), anthropometric measures (body mass index and waist circumference), clinical measures (including medication use, resting blood pressure, routine biochemistry, hospitalisations) and harms associated with intervention. A nested qualitative study was conducted.

Results: We randomised 379 participants; 335 patients completed baseline assessments and 243 patients (intervention,  = 127; control,  = 116) completed 6-month assessments. The mean difference in change in physical component summary score from baseline to 6 months between the intervention group and control group was 2.4 arbitrary units (95% confidence interval -0.1 to 4.8 arbitrary units;  = 0.055). Participants in the intervention group had poor compliance (49%) and very poor adherence (18%) to the exercise prescription. The cost of delivering the intervention ranged from £463 to £848 per participant per year. The number of participants with harms was similar in the intervention ( = 69) and control ( = 56) groups.

Limitations: Participants could not be blinded to the intervention; however, outcome assessors were blinded to group allocation.

Conclusions: On trial completion the primary outcome (Kidney Disease Quality of Life Short Form, version 1.3, physical component summary score) was not statistically improved compared with usual care. The findings suggest that implementation of an intradialytic cycling programme is not an effective intervention to enhance health-related quality of life, as delivered to this cohort of deconditioned patients receiving haemodialysis.

Future Work: The benefits of longer interventions, including progressive resistance training, should be confirmed even if extradialytic delivery is required. Future studies also need to evaluate whether or not there are subgroups of patients who may benefit from this type of intervention, and whether or not there is scope to optimise the exercise intervention to improve compliance and clinical effectiveness.

Trial Registration: Current Controlled Trials ISRCTN83508514.

Funding: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in ; Vol. 25, No. 40. See the NIHR Journals Library website for further project information.
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http://dx.doi.org/10.3310/hta25400DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8256322PMC
June 2021

Heart Failure Hospitalization in Adults Receiving Hemodialysis and the Effect of Intravenous Iron Therapy.

JACC Heart Fail 2021 Jul 9;9(7):518-527. Epub 2021 Jun 9.

Department of Renal Medicine, King's College Hospital, London, United Kingdom.

Objectives: This study sought to examine the effect of intravenous iron on heart failure events in hemodialysis patients.

Background: Heart failure is a common and deadly complication in patients receiving hemodialysis and is difficult to diagnose and treat.

Methods: The study analyzed heart failure events in the PIVOTAL (Proactive IV Iron Therapy in Hemodialysis Patients) trial, which compared intravenous iron administered proactively in a high-dose regimen with a low-dose regimen administered reactively. Heart failure hospitalization was an adjudicated outcome, a component of the primary composite outcome, and a prespecified secondary endpoint in the trial.

Results: Overall, 2,141 participants were followed for a median of 2.1 years. A first fatal or nonfatal heart failure event occurred in 51 (4.7%) of 1,093 patients in the high-dose iron group and in 70 (6.7%) of 1,048 patients in the low-dose group (HR: 0.66; 95% CI: 0.46-0.94; P = 0.023). There was a total of 63 heart failure events (including first and recurrent events) in the high-dose iron group and 98 in the low-dose group, giving a rate ratio of 0.59 (95% CI: 0.40-0.87; P = 0.0084). Most patients presented with pulmonary edema and were mainly treated by mechanical removal of fluid. History of heart failure and diabetes were independent predictors of a heart failure event.

Conclusions: Compared with a lower-dose regimen, high-dose intravenous iron decreased the occurrence of first and recurrent heart failure events in patients undergoing hemodialysis, with large relative and absolute risk reductions. (UK Multicentre Open-label Randomised Controlled Trial Of IV Iron Therapy In Incident Haemodialysis Patients; 2013-002267-25).
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http://dx.doi.org/10.1016/j.jchf.2021.04.005DOI Listing
July 2021

The PrEscription of intraDialytic exercise to improve quAlity of Life in patients with chronic kidney disease trial: study design and baseline data for a multicentre randomized controlled trial.

Clin Kidney J 2021 May 10;14(5):1345-1355. Epub 2020 Sep 10.

School of Health Sciences, Centre for Health, Activity and Rehabilitation Research, Queen Margaret University, Edinburgh, UK.

Background: Exercise interventions designed to improve physical function and reduce sedentary behaviour in haemodialysis (HD) patients might improve exercise capacity, reduce fatigue and lead to improved quality of life (QOL). The PrEscription of intraDialytic exercise to improve quAlity of Life study aimed to evaluate the effectiveness of a 6-month intradialytic exercise programme on QOL and physical function, compared with usual care for patients on HD in the UK.

Methods: We conducted a prospective, pragmatic multicentre randomized controlled trial in 335 HD patients and randomly (1:1) assigned them to either (i) intradialytic exercise training plus usual care maintenance HD or (ii) usual care maintenance HD. The primary outcome of the study was the change in Kidney Disease Quality of Life Short Form (KDQOL-SF 1.3) Physical Component Score between baseline and 6 months. Additional secondary outcomes included changes in peak aerobic capacity, physical fitness, habitual physical activity levels and falls (International Physical Activity Questionnaire, Duke's Activity Status Index and Tinetti Falls Efficacy Scale), QOL and symptom burden assessments (EQ5D), arterial stiffness (pulse wave velocity), anthropometric measures, resting blood pressure, clinical chemistry, safety and harms associated with the intervention, hospitalizations and cost-effectiveness. A nested qualitative study investigated the experience and acceptability of the intervention for both participants and members of the renal health care team.

Results: At baseline assessment, 62.4% of the randomized cohort were male, the median age was 59.3 years and 50.4% were white. Prior cerebrovascular events and myocardial infarction were present in 8 and 12% of the cohort, respectively, 77.9% of patients had hypertension and 39.4% had diabetes. Baseline clinical characteristics and laboratory data for the randomized cohort were generally concordant with data from the UK Renal Registry.

Conclusion: The results from this study will address a significant knowledge gap in the prescription of exercise interventions for patients receiving maintenance HD therapy and inform the development of intradialytic exercise programmes both nationally and internationally.

Trial Registration: ISRCTN N83508514; registered on 17 December 2014.
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http://dx.doi.org/10.1093/ckj/sfaa107DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8087141PMC
May 2021

Study design and baseline characteristics of patients on dialysis in the ASCEND-D trial.

Nephrol Dial Transplant 2021 Mar 21. Epub 2021 Mar 21.

Medical University of Silesia, Katowice, Poland.

Background: The Anemia Studies in chronic kidney disease (CKD): Erythropoiesis via a Novel prolyl hydroxylase inhibitor (PHI) Daprodustat-Dialysis (ASCEND-D) trial will test the hypothesis that daprodustat is non-inferior to comparator epoetin alfa or darbepoetin alfa for two co-primary endpoints: haemoglobin efficacy and cardiovascular safety.

Methods: We report the trial design, key demographic, clinical, and laboratory findings, and baseline therapies of 2964 patients randomised in the open-label (sponsor-blinded) active-controlled, parallel-group, randomised ASCEND-D clinical trial. We also compare baseline characteristics of ASCEND-D patients with patients who are on dialysis (CKD G5D) enrolled in other large cardiovascular outcome trials (CVOTs) and in the most relevant registries.

Results: The median age of patients was 58 years, 43% were female; 67% were white and 16% were black. The median haemoglobin at baseline was 10.4 g/dL. Among randomised patients, 89% were receiving haemodialysis and 11% peritoneal dialysis. Among key co-morbidities, 42% reported a history of diabetes mellitus, and 45% a history of cardiovascular disease. Median blood pressure was 134/74 mmHg. The median weekly dose of epoetin was 5751 units. Intravenous and oral iron use was noted in 64% and 11% of patients, respectively. Baseline demographics were similar to patients with CKD G5D enrolled in other CVOTs and renal patient registries.

Conclusion: ASCEND-D will evaluate the efficacy and safety of daprodustat compared with epoetin alfa or darbepoetin alfa in the treatment of patients with anaemia with CKD G5D.
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http://dx.doi.org/10.1093/ndt/gfab065DOI Listing
March 2021

Nomenclature in nephrology: preserving 'renal' and 'nephro' in the glossary of kidney health and disease.

J Nephrol 2021 06 13;34(3):639-648. Epub 2021 Mar 13.

Guy's & Saint Thomas' Hospital, London, UK.

A recently published nomenclature by a "Kidney Disease Improving Global Outcomes" (KDIGO) Consensus Conference suggested that the word "kidney" should be used in medical writings instead of "renal" or "nephro" when referring to kidney disease and kidney health. Whereas the decade-old move to use "kidney" more frequently should be supported when communicating with the public-at-large, such as the World Kidney Day, or in English speaking countries in communications with patients, care-partners, and non-medical persons, our point of view is that "renal" or "nephro" should not be removed from scientific and technical writings. Instead, the terms can coexist and be used in their relevant contexts. Cardiologists use "heart" and "cardio" as appropriate such as "heart failure" and "cardiac care units" and have not replaced "cardiovascular" with "heartvessel", for instance. Likewise, in nephrology, we consider that "chronic kidney disease" and "continuous renal replacement therapy" should coexist. We suggest that in scientific writings and technical communications, the words "renal" and "nephro" and their derivatives are more appropriate and should be freely used without any pressure by medical journals to compel patients, care-partners, healthcare providers, researchers and other stakeholders to change their selected words and terminologies. We call to embrace the terms "kidney", "renal" and "nephro" as they are used in different contexts and ask that scientific and medical journals not impose terminology restrictions for kidney disease and kidney health. The choice should be at the discretion of the authors, in the different contexts including in scientific journals.
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http://dx.doi.org/10.1007/s40620-021-01011-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8192439PMC
June 2021

Questions and answers on iron deficiency treatment selection and the use of intravenous iron in routine clinical practice.

Ann Med 2021 12;53(1):274-285

Department of Internal Medicine II, Medical University Innsbruck, Innsbruck, Austria.

Iron deficiency is a common cause of morbidity and can arise as a consequence or complication from many diseases. The use of intravenous iron has increased significantly in the last decade, but concerns remain about indications and administration. Modern intravenous iron preparations can facilitate rapid iron repletion in one or two doses, both for absolute iron deficiency and, in the presence of inflammation, functional iron deficiency, where oral iron therapy is ineffective or has not worked. A multidisciplinary team of experts experienced in iron deficiency undertook a consensus review to support healthcare professionals with practical advice on managing iron deficiency in gastrointestinal, renal and cardiac disease, as well as; pregnancy, heavy menstrual bleeding, and surgery. We explain how intravenous iron may work where oral iron has not. We provide context on how and when intravenous iron should be administered, and informed opinion on potential benefits balanced with potential side-effects. We propose how intravenous iron side-effects can be anticipated in terms of what they may be and when they may occur. The aim of this consensus is to provide a practical basis for educating and preparing staff and patients on when and how iron infusions can be administered safely and efficiently. Key messages Iron deficiency treatment selection is driven by several factors, including the presence of inflammation, the time available for iron replenishment, and the anticipated risk of side-effects or intolerance. Intravenous iron preparations are indicated for the treatment of iron deficiency when oral preparations are ineffective or cannot be used, and therefore have applicability in a wide range of clinical contexts, including chronic inflammatory conditions, perioperative settings, and disorders associated with chronic blood loss. Adverse events occurring with intravenous iron can be anticipated according to when they typically occur, which provides a basis for educating and preparing staff and patients on how iron infusions can be administered safely and efficiently.
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http://dx.doi.org/10.1080/07853890.2020.1867323DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7877947PMC
December 2021

Feasibility Trial of Cognitive Behavioral Therapy for Fatigue in Hemodialysis (BReF Intervention).

J Pain Symptom Manage 2021 06 14;61(6):1234-1246.e5. Epub 2020 Oct 14.

Health Psychology Section, Psychology Department, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.

Context: Fatigue affects at least half of patients who are on hemodialysis (HD) with considerable repercussions on their functioning, quality of life, and clinical outcomes.

Objectives: This study assessed the feasibility, acceptability, and potential benefits of a cognitive behavioral therapy intervention for renal fatigue (BReF intervention).

Methods: This was a feasibility randomized controlled trial of the BReF intervention vs. waiting-list control. Outcomes included recruitment, retention, and adherence rates. Exploratory estimates of treatment effect were computed. The statistician was blinded to allocation.

Results: Twenty-four prevalent HD patients experiencing clinical levels of fatigue were individually randomized (1:1) to BReF (N = 12) or waiting-list control arms (N = 12). Fifty-three (16.6%; 95% CI = 12.7-21.1) of 320 patients approached consented and completed the screening questionnaire. It was necessary to approach 13 patients for screening for every one patient randomized. The rate of retention at follow-up was 75% (95% CI = 53.29-90.23). Moderate to large treatment effects were observed in favor of BReF on fatigue severity, fatigue-related functional impairment, depression, and anxiety (standardized mean difference [SMD] = 0.81; SMD = 0.93; SMD = 0.38; SMD = 0.42, respectively) but not sleep quality (SMD = -0.31). No trial adverse events occurred.

Conclusion: There was promising evidence in support of the need and benefits of a cognitive behavioral therapy-based intervention for fatigue in HD. However, uptake was low, possibly as a result of an already high treatment burden in this setting. Considerations on the context of delivery are necessary before pursuing a definitive trial.
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http://dx.doi.org/10.1016/j.jpainsymman.2020.10.005DOI Listing
June 2021

Preoperative intravenous iron to treat anaemia before major abdominal surgery (PREVENTT): a randomised, double-blind, controlled trial.

Lancet 2020 Oct 5;396(10259):1353-1361. Epub 2020 Sep 5.

Department of Anaesthesia and Intensive Care, Royal Papworth Hospital, Cambridge, UK.

Background: Preoperative anaemia affects a high proportion of patients undergoing major elective surgery and is associated with poor outcomes. We aimed to test the hypothesis that intravenous iron given to anaemic patients before major open elective abdominal surgery would correct anaemia, reduce the need for blood transfusions, and improve patient outcomes.

Methods: In a double-blind, parallel-group randomised trial, we recruited adult participants identified with anaemia at preoperative hospital visits before elective major open abdominal surgery at 46 UK tertiary care centres. Anaemia was defined as haemoglobin less than 130 g/L for men and 120 g/L for women. We randomly allocated participants (1:1) via a secure web-based service to receive intravenous iron or placebo 10-42 days before surgery. Intravenous iron was administered as a single 1000 mg dose of ferric carboxymaltose in 100 mL normal saline, and placebo was 100 mL normal saline, both given as an infusion over 15 min. Unblinded study personnel prepared and administered the study drug; participants and other clinical and research staff were blinded to treatment allocation. Coprimary endpoints were risk of the composite outcome of blood transfusion or death, and number of blood transfusions from randomisation to 30 days postoperatively. The primary analysis included all randomly assigned patients with data available for the primary endpoints; safety analysis included all randomly assigned patients according to the treatment received. This study is registered, ISRCTN67322816, and is closed to new participants.

Findings: Of 487 participants randomly assigned to placebo (n=243) or intravenous iron (n=244) between Jan 6, 2014, and Sept 28, 2018, complete data for the primary endpoints were available for 474 (97%) individuals. Death or blood transfusion occurred in 67 (28%) of the 237 patients in the placebo group and 69 (29%) of the 237 patients in the intravenous iron group (risk ratio 1·03, 95% CI 0·78-1·37; p=0·84). There were 111 blood transfusions in the placebo group and 105 in the intravenous iron group (rate ratio 0·98, 95% CI 0·68-1·43; p=0·93). There were no significant differences between the two groups for any of the prespecified safety endpoints.

Interpretation: Preoperative intravenous iron was not superior to placebo to reduce need for blood transfusion when administered to patients with anaemia 10-42 days before elective major abdominal surgery.

Funding: UK National Institute of Health Research Health Technology Assessment Program.
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http://dx.doi.org/10.1016/S0140-6736(20)31539-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7581899PMC
October 2020

Iron Administration, Infection, and Anemia Management in CKD: Untangling the Effects of Intravenous Iron Therapy on Immunity and Infection Risk.

Kidney Med 2020 May-Jun;2(3):341-353. Epub 2020 Mar 27.

Division of Nephrology, Indiana University Health, Indianapolis, IN.

Patients with chronic kidney disease (CKD) are at increased risk for infection, attributable to immune dysfunction, increased exposure to infectious agents, loss of cutaneous barriers, comorbid conditions, and treatment-related factors (eg, hemodialysis and immunosuppressant therapy). Because iron plays a vital role in pathogen reproduction and host immunity, it is biologically plausible that intravenous iron therapy and/or iron deficiency influence infection risk in CKD. Available data from preclinical experiments, observational studies, and randomized controlled trials are summarized to explore the interplay between intravenous iron and infection risk among patients with CKD, particularly those receiving maintenance hemodialysis. The current evidence base, including data from a recent randomized controlled trial, suggests that proactive judicious use of intravenous iron (in a manner that minimizes the accumulation of non-transferrin-bound iron) beneficially replaces iron stores while avoiding a clinically relevant effect on infection risk. In the absence of an urgent clinical need, intravenous iron therapy should be avoided in patients with active infection. Although serum ferritin concentration and transferrin saturation can help guide clinical decision making about intravenous iron therapy, definition of an optimal iron status and its precise determination in individual patients remain clinically challenging in CKD and warrant additional study.
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http://dx.doi.org/10.1016/j.xkme.2020.01.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7380433PMC
March 2020

Authors' Reply.

J Am Soc Nephrol 2020 07 1;31(7):1654. Epub 2020 Jun 1.

Robertson Centre for Biostatistics, University of Glasgow, Glasgow, United Kingdom.

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http://dx.doi.org/10.1681/ASN.2020050624DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7350994PMC
July 2020

Protocol and Baseline Data of a Multicentre Prospective Double-Blinded Randomized Study of Intravenous Iron on Functional Status in Patients with Chronic Kidney Disease.

Am J Nephrol 2020 29;51(6):493-500. Epub 2020 Apr 29.

Salford Royal NHS Foundation Trust, Salford, United Kingdom.

Background: Iron deficiency (ID) is common in patients with chronic kidney disease (CKD) due to an inadequate dietary intake of iron, poor absorption from the gut and increased iron losses. In addition to preventing anaemia, iron is important for normal heart function, being involved in processes that generate a necessary continuous energy supply. Treatment with intravenous (IV) iron has been suggested to lead to improvement in heart function and well-being in people with ID and CKD. In the Iron and the Heart Study, we hypothesized that IV iron treatment will primarily improve exercise capacity and may secondarily impact the feeling of well-being in comparison to placebo over 3 months in non-anaemic CKD patients who have ID.

Methods: This was a prospective double-blinded explorative randomized, multi-centre study designed to compare the effects of IV iron supplementation and placebo in iron-deficient but not anaemic patients with established CKD stages 3b-5 on functional status, and in addition cardiac structure and function. The study included 54 adults with serum ferritin (SF) <100 µg/L and/or transferrin saturation <20%, randomized in a 1:1 ratio to 1,000 mg IV ferric derisomaltose or placebo. Following randomization, participants underwent baseline assessments and then received IV iron or placebo infusion. Each participant was followed up at months 1 and 3. At each visit, patients underwent clinical review, measurements of hematinics and haemoglobin (Hb), and assessments of physical function and well-being. The primary outcome was exercise capacity using the 6-minute walk test. Secondary objectives included effects on hematinic profiles and Hb concentration, changes in myocardial parameters assessed with speckle tracking echocardiography and change in patients' quality of life.

Results: Between October 2016 and April 2018, 55 from 326 individuals from 3 UK centres attended screening and were randomized. The mean (SD) age was 59.6 (11.7) years, 26 (48%) patients were male, the majority were Caucasians (42; 78%), and 32 (59%) were non-smokers. The mean (SD) body mass index was 30.3 (6.5); SF was 66.3 (44.1) µg/L, TS was 20.1 (7.4) % and Hb was 128.7 (10.1) g/L at randomization for the whole group. Mean (SD) serum creatinine was 186.7 (58.6) µmol/L, estimated glomerular filtration rate was 31.1 (9.6) mL/min/1.73 m2 and urinary albumin and protein/creatinine ratios 60.9 (133.3) and 83.8 (128.4) mg/mmol respectively. The mean (SD) C-reactive protein was 5.0 (4.4) mg/L and the mean (SD) 6-minute walk distance at baseline was 401.2 (120.2) m.

Conclusion: The Iron and the Heart Trial will provide important information on the short-term effects of IV iron treatment in CKD patients with ID without anaemia on measures of exercise capacity, quality of life and mechanistic data on myocardial structure and function.

Trial Registration: European Clinical Trials Database (No. 2014-004133-6; REC no. 14/YH/1209; Sponsor ref. R1766).
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http://dx.doi.org/10.1159/000507872DOI Listing
July 2021

Iron Sucrose: A Wealth of Experience in Treating Iron Deficiency.

Adv Ther 2020 05 15;37(5):1960-2002. Epub 2020 Apr 15.

Department of Gastroenterology, University Hospital Heraklion, Crete, Greece.

Iron deficiency and iron-deficiency anemia are associated with increased morbidity and mortality in a wide range of conditions. In many patient populations, this can be treated effectively with oral iron supplementation; but in patients who are unable to take or who do not respond to oral iron therapy, intravenous iron administration is recommended. Furthermore, in certain conditions, such as end-stage kidney disease, chronic heart failure, and inflammatory bowel disease, intravenous iron administration has become first-line treatment. One of the first available intravenous iron preparations is iron sucrose (Venofer), a nanomedicine that has been used clinically since 1949. Treatment with iron sucrose is particularly beneficial owing to its ability to rapidly increase hemoglobin, ferritin, and transferrin saturation levels, with an acceptable safety profile. Recently, important new data relating to the use of iron sucrose, including the findings from the landmark PIVOTAL trial in patients with end-stage kidney disease, have been reported. Several years ago, a number of iron sucrose similars became available, although there have been concerns about the clinical appropriateness of substituting the original iron sucrose with an iron sucrose similar because of differences in efficacy and safety. This is a result of the complex and unique physicochemical properties of nanomedicines such as iron sucrose, which make copying the molecule difficult and problematic. In this review, we summarize the evidence accumulated during 70 years of clinical experience with iron sucrose in terms of efficacy, safety, and cost-effectiveness.
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http://dx.doi.org/10.1007/s12325-020-01323-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7467495PMC
May 2020

Intravenous Iron Dosing and Infection Risk in Patients on Hemodialysis: A Prespecified Secondary Analysis of the PIVOTAL Trial.

J Am Soc Nephrol 2020 05 6;31(5):1118-1127. Epub 2020 Apr 6.

Robertson Centre for Biostatistics, University of Glasgow, Glasgow, United Kingdom.

Background: Experimental and observational studies have raised concerns that giving intravenous (IV) iron to patients, such as individuals receiving maintenance hemodialysis, might increase the risk of infections. The Proactive IV Iron Therapy in Haemodialysis Patients (PIVOTAL) trial randomized 2141 patients undergoing maintenance hemodialysis for ESKD to a high-dose or a low-dose IV iron regimen, with a primary composite outcome of all-cause death, heart attack, stroke, or hospitalization for heart failure. Comparison of infection rates between the two groups was a prespecified secondary analysis.

Methods: Secondary end points included any infection, hospitalization for infection, and death from infection; we calculated cumulative event rates for these end points. We also interrogated the interaction between iron dose and vascular access (fistula versus catheter).

Results: We found no significant difference between the high-dose IV iron group compared with the lose-dose group in event rates for all infections (46.5% versus 45.5%, respectively, which represented incidences of 63.3 versus 69.4 per 100 patient years, respectively); rates of hospitalization for infection (29.6% versus 29.3%, respectively) also did not differ. We did find a significant association between risk of a first cardiovascular event and any infection in the previous 30 days. Compared with patients undergoing dialysis with an arteriovenous fistula, those doing so a catheter had a higher incidence of having any infection, hospitalization for infection, or fatal infection, but IV iron dosing had no effect on these outcomes.

Conclusions: The high-dose and low-dose IV iron groups exhibited identical infection rates. Risk of a first cardiovascular event strongly associated with a recent infection.
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http://dx.doi.org/10.1681/ASN.2019090972DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7217408PMC
May 2020

Intravenous iron: a framework for changing the management of iron deficiency.

Lancet Haematol 2020 Apr;7(4):e342-e350

Department of Renal Medicine, King's College Hospital, London, UK.

For decades intravenous iron was considered dangerous. Newer formulations with carbohydrate cores binding elemental iron more tightly allow complete iron replacement within 15-60 min in one visit. Meta-analyses and prospective comparisons of different formulations support equivalent safety to placebo with less toxicity than oral iron. Of the available formulations, the preponderance of published evidence supports equal safety and efficacy. In this Viewpoint, we report evidence supporting repositioning of intravenous iron to the frontline in multiple disorders with iron deficiency, which include heart failure, chronic kidney disease, inflammatory bowel disease, patient blood management in the perioperative period, and obstetrics and gynaecology. We have also highlighted neonatal evidence supporting the inadequacy of oral iron in late pregnancy, a critical period of iron need for normal foetal brain development. Physicians should consider prioritising the use of intravenous iron rather than oral iron as a treatment for iron deficiency in some of these clinical scenarios.
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http://dx.doi.org/10.1016/S2352-3026(19)30264-9DOI Listing
April 2020

A prospective study of fatigue trajectories among in-centre haemodialysis patients.

Br J Health Psychol 2020 02 19;25(1):61-88. Epub 2019 Nov 19.

Health Psychology Section, Psychology Department, Institute of Psychiatry, Psychology and Neuroscience, King's College London, UK.

Objectives: Fatigue is common and debilitating among dialysis patients. The aim of this study was to understand the longitudinal trajectory of fatigue and consider sociodemographic, clinical, and psychological factors that are related to variation in fatigue levels over time.

Design: A prospective study of fatigue with yearly assessments over 3 years among prevalent in-centre haemodialysis (HD) patients.

Methods: Fatigue severity was measured using the Chalder Fatigue Questionnaire and fatigue-related functional impairment using the Work and Social Adjustment Scale. The trajectories of fatigue outcomes were examined using piecewise growth models, using length of time on dialysis as time. Sociodemographic, clinical, and psychological predictors of fatigue were assessed using linear growth models, using follow-up time.

Results: One hundred and seventy-four prevalent HD patients completed baseline measures, 118 at 12 months, 84 at 24 months, and 66 at 36 months. Fatigue severity scores decreased by 0.15 each year. Fatigue-related functional impairment increased by 1.17 each year. In adjusted linear growth models, non-white ethnicity was a significant predictor of lower initial fatigue severity (B = -2.95, 95% CI -5.51 to -0.40) and a greater reduction in fatigue severity of 1.60 each year (95% CI 0.35-2.36). A one-point increase in damage beliefs was associated with a 0.36 increase in fatigue-related functional impairment each year (95% CI -0.61 to -0.01).

Conclusion: Damage beliefs predicted an increase in fatigue-related functional impairment over time. However, the data strongly suggested that fatigue outcomes vary by length of time on dialysis. Statement of contribution What is already known on this subject? At least 1 in 2 haemodialysis (HD) patients are clinically fatigued. Growing evidence is available on the important role of psychological factors in fatigue across chronic conditions. The contribution of psychological factors, beyond distress, to fatigue in HD has not been examined to date. What does this study add? Ethnicity played a role in the initial level of fatigue severity and over time. Damage beliefs predicted an increase in fatigue-related impairment over time. Data strongly suggested that fatigue outcomes vary by length of time on dialysis.
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http://dx.doi.org/10.1111/bjhp.12395DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7004141PMC
February 2020

Iron Regulation by Molidustat, a Daily Oral Hypoxia-Inducible Factor Prolyl Hydroxylase Inhibitor, in Patients with Chronic Kidney Disease.

Nephron 2019 6;143(4):243-254. Epub 2019 Aug 6.

Bayer Pharma AG, Berlin, Germany.

Background/aims: The current treatment for anemia associated with chronic kidney disease (CKD) includes the administration of erythropoiesis stimulating agents (ESAs) combined with iron supplementation. Molidustat, a hypoxia-inducible factor prolyl hydroxylase inhibitor, has potential to treat anemia associated with CKD through increased erythropoietin production and improved iron availability. Here, we report the effect of molidustat on iron metabolism.

Method: Parameters of iron metabolism were monitored in three 16-week, randomized, controlled, phase 2 studies assessing the safety and efficacy of molidustat in the treatment of anemia associated with CKD in different populations: treatment-naïve and previously ESA-treated patients not on dialysis, and previously ESA-treated patients on hemodialysis. Iron supplementation was left at the discretion of the investigator.

Results: In treatment-naïve patients not on dialysis, transferrin saturation (TSAT), hepcidin, ferritin, and iron concentrations decreased with molidustat, whereas total iron binding capacity (TIBC) increased. Similar results were observed in previously ESA-treated patients not on dialysis, although changes in those parameters were larger in treatment-naïve than in previously ESA-treated patients. In previously ESA-treated patients receiving hemodialysis, hepcidin concentration and TIBC remained stable with molidustat, whereas TSAT and ferritin and iron concentrations increased. Generally, similar trends were observed in secondary analyses of subgroups of patients not receiving iron supplementation.

Conclusions: Molidustat is a potential alternative to standard treatment of anemia associated with CKD, with a different mechanism of action. In patients not receiving dialysis, molidustat increases iron availability. In patients receiving hemodialysis, further investigation is required to understand fully the mechanisms underlying iron mobilization associated with molidustat.
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http://dx.doi.org/10.1159/000502012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6979436PMC
July 2020

Restricting Red-Cell Transfusions in Cardiac Surgery: No Increase in AKI.

J Am Soc Nephrol 2019 Jul 20;30(7):1143-1144. Epub 2019 Jun 20.

Fiona Stanley Hospital, University of Western Australia, Perth, Australia.

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http://dx.doi.org/10.1681/ASN.2019050509DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6622416PMC
July 2019

Intravenous Iron and Maintenance Hemodialysis. Reply.

N Engl J Med 2019 06;380(24):e46

University of Glasgow, Glasgow, United Kingdom

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http://dx.doi.org/10.1056/NEJMc1902945DOI Listing
June 2019

Intravenous Iron Use in the Care of Patients with Kidney Disease.

Clin J Am Soc Nephrol 2019 10 7;14(10):1528-1530. Epub 2019 Jun 7.

Department of Renal Medicine, King's College Hospital, London, UK

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http://dx.doi.org/10.2215/CJN.00510119DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6777593PMC
October 2019

Obesity and recovery from acute kidney injury (Ob AKI): a prospective cohort feasibility study.

BMJ Open 2019 03 20;9(3):e024033. Epub 2019 Mar 20.

Centre for Kidney Research and Innovation, University of Nottingham Faculty of Medicine and Health Sciences, Derby, UK.

Objectives: To test the methodology of recruitment, retention and data completeness in a prospective cohort recruited after a hospitalised episode of acute kidney injury (AKI), to inform a future prospective cohort study examining the effect of obesity on AKI outcomes.

Design: Feasibility study.

Setting: Single centre, multi-site UK tertiary hospital.

Participants: 101 participants (67M; 34F) with a median age of 64 (IQR 53-73) years, with and without obesity, recruited within 3 months of a hospitalised episode of AKI.

Outcome Measures: Feasibility outcomes were recruitment (>15% meeting inclusion criteria recruited), participant retention at 6 and 12 months (≥80%) and completeness of data collection. Exploratory measures included recovery from AKI (regaining >75% of pre-AKI estimated glomerular filtration rate [eGFR]) at 6 months, development or progression of chronic kidney disease (CKD) (kidney function decrease of ≥25% +  rise in CKD category) at 12 months, and associations with poorer kidney outcomes.

Results: 41% of eligible patients consented to take part, exceeding the target recruitment uptake rate of 15%. Retention was 86% at 6 months and 78% at 12 months; 10 patients died and three commenced dialysis during the study. Data were 90%-100% complete. Median BMI was 27.9 kg/m (range 18.1 kg/m-54.3 kg/m). 50% of the cohort had stage 3 AKI and 49% had pre-existing CKD. 46% of the cohort met the AKI recovery definition at 6 months. At 12 months, 20/51 patients developed CKD (39%) and CKD progression occurred in 11/49 patients (22%). Post-AKI interleukin-6 and cystatin-C were associated with 12 months decline in eGFR.

Conclusions: Feasibility to conduct a long-term observational study addressing AKI outcomes associated with obesity was demonstrated. A fully powered prospective cohort study to examine the relationships between obesity and outcomes of AKI is warranted.
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http://dx.doi.org/10.1136/bmjopen-2018-024033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6528015PMC
March 2019

Long-Term Efficacy and Safety of Molidustat for Anemia in Chronic Kidney Disease: DIALOGUE Extension Studies.

Am J Nephrol 2019 8;49(4):271-280. Epub 2019 Mar 8.

Research & Development, Pharmaceuticals, Bayer AG, Wuppertal, Germany.

Background: Molidustat, a novel hypoxia-inducible factor-prolyl hydroxylase inhibitor, is being investigated for the treatment of anemia associated with chronic kidney disease (CKD). The efficacy and safety of molidustat were recently evaluated in three 16-week phase 2b studies. Here, we report the results of two long-term extension studies of molidustat.

Methods: Both studies were parallel-group, open-label, multicenter studies of ≤36 months' duration, in patients with anemia due to CKD, and included an erythropoiesis-stimulating agent as active control. One study enrolled patients not receiving dialysis (n = 164), and the other enrolled patients receiving hemodialysis (n = 88). The primary efficacy variable for both studies was change in blood hemoglobin (Hb) level from baseline to each post-baseline visit, and safety outcomes included adverse events (AEs).

Results: In patients not on dialysis, the mean ± SD Hb concentrations at baseline were 11.28 ± 0.55 g/dL for molidustat and 11.08 ± 0.51 g/dL for darbepoetin. The mean ± SD blood Hb concentrations throughout the study (defined as mean of each patient's overall study Hb levels) were 11.10 ± 0.508 and 10.98 ± 0.571 g/dL in patients treated with molidustat and darbepoetin, respectively. Similar proportions of patients reported at least one AE in the molidustat (85.6%) and darbepoetin (85.7%) groups. In patients on dialysis, mean ± SD Hb levels at baseline were 10.40 ± 0.70 and 10.52 ± 0.53 g/dL in the molidustat and epoetin groups, respectively. The mean ± SD blood Hb concentrations during the study were 10.37 ± 0.56 g/dL in the molidustat group and 10.52 ± 0.47 g/dL in the epoetin group. Proportions of patients who reported at least one AE were 91.2% in the molidustat group and 93.3% in the epoetin group.

Conclusions: Molidustat was well tolerated for up to 36 months and appears to be an effective alternative to darbepoetin and epoetin in the long-term management of anemia associated with CKD.
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http://dx.doi.org/10.1159/000499111DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6518868PMC
May 2020

Ferumoxytol for iron deficiency anemia in patients undergoing hemodialysis. The FACT randomized controlled trial
.

Clin Nephrol 2019 Apr;91(4):237-245

Background: Patients with chronic kidney disease (CKD) undergoing dialysis often require intravenous iron for iron deficiency anemia (IDA).

Materials And Methods: The Ferumoxytol for Anemia of CKD Trial (FACT), a randomized, multicenter, open-label, phase 4 study, compared the long-term safety and efficacy of ferumoxytol with iron sucrose for the treatment of IDA in patients with CKD undergoing hemodialysis. Patients with IDA and CKD undergoing hemodialysis were randomized 2:1 to ferumoxytol 1.02 g (2 × 510 mg) or iron sucrose 1.0 g (10 × 100 mg) for a 5-week treatment period (TP). Over 11 months, patients underwent additional 5-week TPs whenever IDA (hemoglobin < 11.5 g/dL and transferrin saturation < 30%) was detected. The primary efficacy endpoint was mean change in hemoglobin from baseline to week 5 for each TP. Adverse events were recorded during the study.

Results: Overall, 293 patients received ferumoxytol (n = 196) or iron sucrose (n = 97). Ferumoxytol was noninferior to iron sucrose regarding hemoglobin change from baseline to week 5. The mean change in hemoglobin in the ferumoxytol and iron sucrose groups was 0.5 and 0.4 g/dL, respectively, in TP 1 (least-squares mean difference, 0.13; 95% confidence interval, -0.11 to 0.36) and 0.6 and 0.3 g/dL, respectively, in TP 2 (0.30; 0.06 - 0.55). Treatment-related and serious adverse events were similar in both groups; no new safety signals emerged.

Conclusion: Long-term administration of ferumoxytol has noninferior efficacy and a similar safety profile to iron sucrose when used to treat IDA in patients with CKD undergoing hemodialysis.
.
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http://dx.doi.org/10.5414/CN109512DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6434426PMC
April 2019

New options for the anemia of chronic kidney disease.

Kidney Int Suppl (2011) 2017 Dec 17;7(3):157-163. Epub 2017 Nov 17.

Renal Unit, King's College Hospital, London, UK.

Anemia is a common complication of chronic kidney disease. Use of erythropoiesis-stimulating agents (ESA) has been a mainstay of treatment since 1990. A series of large trials demonstrated that ESAs have serious safety problems, including increasing cardiovascular and thrombotic events, and death. Analyses suggest high pharmacologic doses of ESAs, rather than the highly achieved hemoglobin, may mediate harm. Hypoxia-inducible factor (HIF) activators stimulate endogenous erythropoietin production and enhance iron availability. In early clinical trials, these oral agents appear to be capable of replacing ESA therapy and minimizing the need for i.v. iron therapy for chronic kidney disease-related anemia, while having other potentially advantageous actions. Large phase 3 trials are underway with several HIF activators. This commentary reviews trends in anemia management, the safety issues related to our present therapies, the role of HIF in regulating erythropoiesis, and the diverse actions of HIF activators.
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http://dx.doi.org/10.1016/j.kisu.2017.09.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6341017PMC
December 2017

Treatment of anaemia in end-stage renal disease: A double-edged iron sword?

EBioMedicine 2019 Feb 17;40:31-32. Epub 2019 Jan 17.

Department of Renal Medicine, Salford Royal NHS Foundation Trust, Salford, United Kingdom. Electronic address:

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http://dx.doi.org/10.1016/j.ebiom.2019.01.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6413296PMC
February 2019

Effects of Molidustat in the Treatment of Anemia in CKD.

Clin J Am Soc Nephrol 2019 01 17;14(1):28-39. Epub 2018 Dec 17.

Departments of Research and Development, and Pharmaceuticals, Bayer AG, Wuppertal, Germany.

Background And Objectives: The efficacy and safety of molidustat, a hypoxia-inducible factor-prolyl hydroxylase inhibitor, have been evaluated in three 16-week, phase 2b studies in patients with CKD and anemia who are not on dialysis (DaIly orAL treatment increasing endOGenoUs Erythropoietin [DIALOGUE] 1 and 2) and in those who are on dialysis (DIALOGUE 4).

Design, Setting, Participants, & Measurements: DIALOGUE 1 was a placebo-controlled, fixed-dose trial (25, 50, and 75 mg once daily; 25 and 50 mg twice daily). DIALOGUE 2 and 4 were open-label, variable-dose trials, in which treatment was switched from darbepoetin (DIAGLOGUE 2) or epoetin (DIALOGUE 4) to molidustat or continued with the original agents. Starting molidustat ranged between 25-75 and 25-150 mg daily in DIAGLOGUE 2 and 4, respectively, and could be titrated to maintain hemoglobin levels within predefined target ranges. The primary end point was the change in hemoglobin level between baseline and the mean value from the last 4 weeks of the treatment period.

Results: In DIAGLOGUE 1 (=121), molidustat treatment was associated with estimated increases in mean hemoglobin levels of 1.4-2.0 g/dl. In DIAGLOGUE 2 (=124), hemoglobin levels were maintained within the target range after switching to molidustat, with an estimated difference in mean change in hemoglobin levels between molidustat and darbepoetin treatments of up to 0.6 g/dl. In DIAGLOGUE 4 (=199), hemoglobin levels were maintained within the target range after switching to molidustat 75 and 150 mg, with estimated differences in mean change between molidustat and epoetin treatment of -0.1 and 0.4 g/dl. Molidustat was generally well tolerated, and most adverse events were mild or moderate in severity.

Conclusions: The overall phase 2 efficacy and safety profile of molidustat in patients with CKD and anemia enables the progression of its development into phase 3.
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http://dx.doi.org/10.2215/CJN.02510218DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6364546PMC
January 2019

Randomized trial of intravenous iron-induced hypophosphatemia.

JCI Insight 2018 12 6;3(23). Epub 2018 Dec 6.

AMAG Pharmaceuticals, Inc., Waltham, Massachusetts, USA.

Background: Hypophosphatemia can complicate intravenous iron therapy, but no head-to-head trials compared the effects of newer intravenous iron formulations on risks and mediators of hypophosphatemia.

Methods: In a randomized, double-blinded, controlled trial of adults with iron deficiency anemia from February 2016 to January 2017, we compared rates of hypophosphatemia in response to a single FDA-approved course of ferric carboxymaltose (n = 1,000) or ferumoxytol (n = 997). To investigate pathophysiological mediators of intravenous iron-induced hypophosphatemia, we nested within the parent trial a physiological substudy (ferric carboxymaltose, n = 98; ferumoxytol, n = 87) in which we measured fibroblast growth factor 23 (FGF23), calcitriol, and parathyroid hormone (PTH) at baseline and 1, 2, and 5 weeks later.

Results: The incidence of hypophosphatemia was significantly higher in the ferric carboxymaltose versus the ferumoxytol group (<2.0 mg/dl, 50.8% vs. 0.9%; <1.3 mg/dl, 10.0% vs. 0.0%; P < 0.001), and hypophosphatemia persisted through the end of the 5-week study period in 29.1% of ferric carboxymaltose-treated patients versus none of the ferumoxytol-treated patients (P < 0.001). Ferric carboxymaltose, but not ferumoxytol, increased circulating concentrations of biologically active FGF23 (mean within-patient percentage change from baseline to week 2 peak: +302.8 ± 326.2% vs. +10.1 ± 61.0%; P < 0.001), which was significantly associated with contemporaneous hypophosphatemia, renal phosphate wasting, and decreased serum calcitriol and calcium, and increased PTH concentrations.

Conclusions: Ferric carboxymaltose rapidly increases biologically active FGF23 in patients with iron deficiency anemia. Paralleling hereditary and other acquired syndromes of hypophosphatemic rickets/osteomalacia, ferric carboxymaltose-induced FGF23 elevation triggers a pathophysiological cascade of renal phosphate wasting, calcitriol deficiency, and secondary hyperparathyroidism that frequently culminates in hypophosphatemia.

Trial Registration: ClinicalTrials.gov, NCT02694978FUNDING. AMAG Pharmaceuticals, Inc.Role of the funding source: This study was supported by AMAG Pharmaceuticals, Inc. The academic investigators designed the clinical trial, performed the analyses, and authored the manuscript with input from the coauthors from AMAG Pharmaceuticals, Inc.
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http://dx.doi.org/10.1172/jci.insight.124486DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6328019PMC
December 2018

Mortality and morbidity following exercise-based renal rehabilitation in patients with chronic kidney disease: the effect of programme completion and change in exercise capacity.

Nephrol Dial Transplant 2019 04;34(4):618-625

Renal Sciences, Department of Transplantation, Immunology and Mucosal Biology, King's College London University, London, UK.

Background: Twelve weeks of renal rehabilitation (RR) have been shown to improve exercise capacity in patients with chronic kidney disease (CKD); however, survival following RR has not been examined.

Methods: This study included a retrospective longitudinal analysis of clinical service outcomes. Programme completion and improvement in exercise capacity, characterised as change in incremental shuttle walk test (ISWT), were analysed with Kaplan-Meier survival analyses to predict risk of a combined event including death, cerebrovascular accident, myocardial infarction and hospitalisation for heart failure in a cohort of patients with CKD. Time to combined event was examined with Kaplan-Meier plots and log rank test between 'completers' (attended >50% planned sessions) and 'non-completers'. In completers, time to combined event was examined between 'improvers' (≥50 m increase ISWT) and 'non-improvers' (<50 m increase). Differences in time to combined event were investigated with Cox proportional hazards models (adjusted for baseline kidney function, body mass index, diabetes, age, gender, ethnicity, baseline ISWT and smoking status).

Results: In all, 757 patients (male 54%) (242 haemodialysis patients, 221 kidney transplant recipients, 43 peritoneal dialysis patients, 251 non-dialysis CKD patients) were referred for RR between 2005 and 2017. There were 193 events (136 deaths) during the follow-up period (median 34 months). A total of 43% of referrals were classified as 'completers', and time to event was significantly greater when compared with 'non-completers' (P = 0.009). Responding to RR was associated with improved event-free survival time (P = 0.02) with Kaplan-Meier analyses and log rank test. On multivariate analysis, completing RR contributed significantly to the minimal explanatory model relating clinical variables to the combined event (overall χ2 = 38.0, P < 0.001). 'Non-completers' of RR had a 1.6-fold [hazard ratio = 1.6; 95% confidence interval (CI) 1.00-2.58] greater risk of a combined event (P = 0.048). Change in ISWT of >50 m contributed significantly to the minimal explanatory model relating clinical variables to mortality and morbidity (overall χ2 = 54.0, P < 0.001). 'Improvers' had a 40% (hazard ratio = 0.6; 95% CI 0.36-0.98) independent lower risk of a combined event (P = 0.041).

Conclusions: There is an association between completion of an RR programme, and also RR success, and a lower risk of a combined event in this observational study. RR interventions to improve exercise capacity in patients with CKD may reduce risk of morbidity and mortality, and a pragmatic randomised controlled intervention trial is warranted.
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http://dx.doi.org/10.1093/ndt/gfy351DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6452180PMC
April 2019

Intravenous Iron in Patients Undergoing Maintenance Hemodialysis.

N Engl J Med 2019 01 26;380(5):447-458. Epub 2018 Oct 26.

From the Department of Renal Medicine, King's College Hospital (I.C.M., C.W.), and University College London (D.C.W.), London, Hull and East Yorkshire Hospitals NHS Trust and Hull York Medical School, Hull (S.B.), Lister Hospital, Stevenage (K.F.), and University of Hertfordshire, Hertfordshire (K.F.), the Department of Renal Medicine, Salford Royal NHS Foundation Trust, Salford (P.A.K.), the British Heart Foundation Cardiovascular Research Centre (J.J.V.M.) and the Robertson Centre for Biostatistics (H.M., I.F.), University of Glasgow, Glasgow, Freeman Hospital, Newcastle upon Tyne (C.R.V.T.), and the Oxford Kidney Unit, Churchill Hospital, Oxford University Hospitals NHS Foundation Trust, Oxford (C.G.W.) - all in the United Kingdom; and the Division of Cardiology and Metabolism, Department of Cardiology, Berlin-Brandenburg Center for Regenerative Therapies, German Center for Cardiovascular Research partner site Berlin, Charité Universitätsmedizin Berlin, Berlin (S.D.A.).

Background: Intravenous iron is a standard treatment for patients undergoing hemodialysis, but comparative data regarding clinically effective regimens are limited.

Methods: In a multicenter, open-label trial with blinded end-point evaluation, we randomly assigned adults undergoing maintenance hemodialysis to receive either high-dose iron sucrose, administered intravenously in a proactive fashion (400 mg monthly, unless the ferritin concentration was >700 μg per liter or the transferrin saturation was ≥40%), or low-dose iron sucrose, administered intravenously in a reactive fashion (0 to 400 mg monthly, with a ferritin concentration of <200 μg per liter or a transferrin saturation of <20% being a trigger for iron administration). The primary end point was the composite of nonfatal myocardial infarction, nonfatal stroke, hospitalization for heart failure, or death, assessed in a time-to-first-event analysis. These end points were also analyzed as recurrent events. Other secondary end points included death, infection rate, and dose of an erythropoiesis-stimulating agent. Noninferiority of the high-dose group to the low-dose group would be established if the upper boundary of the 95% confidence interval for the hazard ratio for the primary end point did not cross 1.25.

Results: A total of 2141 patients underwent randomization (1093 patients to the high-dose group and 1048 to the low-dose group). The median follow-up was 2.1 years. Patients in the high-dose group received a median monthly iron dose of 264 mg (interquartile range [25th to 75th percentile], 200 to 336), as compared with 145 mg (interquartile range, 100 to 190) in the low-dose group. The median monthly dose of an erythropoiesis-stimulating agent was 29,757 IU in the high-dose group and 38,805 IU in the low-dose group (median difference, -7539 IU; 95% confidence interval [CI], -9485 to -5582). A total of 320 patients (29.3%) in the high-dose group had a primary end-point event, as compared with 338 (32.3%) in the low-dose group (hazard ratio, 0.85; 95% CI, 0.73 to 1.00; P<0.001 for noninferiority; P=0.04 for superiority). In an analysis that used a recurrent-events approach, there were 429 events in the high-dose group and 507 in the low-dose group (rate ratio, 0.77; 95% CI, 0.66 to 0.92). The infection rate was the same in the two groups.

Conclusions: Among patients undergoing hemodialysis, a high-dose intravenous iron regimen administered proactively was superior to a low-dose regimen administered reactively and resulted in lower doses of erythropoiesis-stimulating agent being administered. (Funded by Kidney Research UK; PIVOTAL EudraCT number, 2013-002267-25 .).
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http://dx.doi.org/10.1056/NEJMoa1810742DOI Listing
January 2019
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