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Alsunaid A, Spencer S, Bhandari S. Intravenous iron in chronic kidney disease without anaemia but iron deficiency: A scoping review. World J Nephrol 2025; 14:101576. [PMID: 40134647 PMCID: PMC11755244 DOI: 10.5527/wjn.v14.i1.101576] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/19/2024] [Revised: 12/30/2024] [Accepted: 01/09/2025] [Indexed: 01/20/2025] Open
Abstract
Iron deficiency (ID) is a prevalent complication of chronic kidney disease (CKD), often managed reactively when associated with anaemia. This scoping review evaluates the evidence supporting intravenous (IV) iron therapy in non-anaemic individuals with CKD and ID, focusing on safety, efficacy, and emerging therapeutic implications. Current diagnostic markers, including serum ferritin, transferrin saturation, and reticulocyte haemoglobin content, are reviewed alongside their limitations in the context of inflammation and variability. The pathophysiology of ID in CKD is explored, highlighting the roles of hepcidin, hypoxia-inducible factor pathways, and uraemic toxins. Comparative studies reveal that IV iron offers a more rapid correction of iron stores, improved compliance, and fewer gastrointestinal side effects compared to oral iron. Evidence from trials such as "iron and heart" and "iron and muscle" suggests potential benefits of IV iron on functional capacity and fatigue, though findings were statistically non-significant. Insights from heart failure trials support the safety and efficacy of IV iron in improving quality of life and reducing hospitalizations, with newer formulations like ferric derisomaltose demonstrating favourable safety profiles. This review underscores the need for standardized screening protocols for ID in CKD, even in the absence of anaemia, to facilitate earlier intervention. Future research should prioritise robust outcome measures, larger sample sizes, and person-specific treatment strategies to optimise dosing and administration frequency. Tailored approaches to IV iron therapy have the potential to significantly improve functional outcomes, quality of life, and long-term health in people with CKD.
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Affiliation(s)
- Abdulrahman Alsunaid
- Department of Medical Science, Hull York Medical School, Kingston Upon Hull HU6 7RU, United Kingdom
| | - Sebastian Spencer
- Department of Medical Science, Hull York Medical School, Kingston Upon Hull HU6 7RU, United Kingdom
- Department of Medical Science, University of Hull, Kingston Upon Hull HU6 7RU, United Kingdom
- Department of Academic Renal, Hull University Teaching Hospitals NHS Trust, Kingston Upon Hull HU3 2JZ, United Kingdom
| | - Sunil Bhandari
- Department of Medical Science, Hull York Medical School, Kingston Upon Hull HU6 7RU, United Kingdom
- Department of Academic Renal, Hull University Teaching Hospitals NHS Trust, Kingston Upon Hull HU3 2JZ, United Kingdom
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McDonnell T, Kalra PA. Iron in Chronic Kidney Disease and End-Stage Kidney Disease-Current Trends and Future Direction. Br J Hosp Med (Lond) 2025; 86:1-19. [PMID: 39998134 DOI: 10.12968/hmed.2024.0619] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/26/2025]
Abstract
Anaemia is a frequent and serious complication in chronic kidney disease (CKD), affecting both non-dialysis-dependent (NDD) and dialysis-dependent (DD) patients. While erythropoietin (EPO) deficiency is the primary cause, iron deficiency (ID) also plays a crucial role. ID in CKD can be classified as either absolute, resulting from blood loss, or functional, driven by inflammation and elevated hepcidin levels, which trap iron in macrophages and hepatocytes, preventing its use in erythropoiesis. Elevated hepcidin also reduces dietary iron absorption in the gut, making oral iron supplements ineffective, particularly in advanced CKD. This review summarises the available intravenous (IV) iron formulations, discusses diagnostic definitions and treatment thresholds for ID in NDD and DD CKD, and explores potential future therapeutic directions.
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Affiliation(s)
- Thomas McDonnell
- Donal O'Donoghue Renal Research Centre, Salford Royal Hospital, Northern Care Alliance NHS Foundation Trust, Salford, UK
- Division of Cardiovascular Sciences, Faculty of Biology Medicine and Health, University of Manchester, Manchester, UK
| | - Philip A Kalra
- Donal O'Donoghue Renal Research Centre, Salford Royal Hospital, Northern Care Alliance NHS Foundation Trust, Salford, UK
- Division of Cardiovascular Sciences, Faculty of Biology Medicine and Health, University of Manchester, Manchester, UK
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Chow K, Trollinger B, Blum M, Alasfar S, Monroy-Trujillo JM, Brown D. Implementation of a Pharmacist-Driven Protocol to Improve Screening and Treatment of Iron Deficiency in Hospitalized Patients with Chronic Kidney Disease. Hosp Pharm 2024; 60:00185787241267730. [PMID: 39558938 PMCID: PMC11569762 DOI: 10.1177/00185787241267730] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2024]
Abstract
Purpose: While intravenous (IV) iron repletion is an effective tool to treat anemia and improve outcomes in chronic kidney disease (CKD), guideline laboratory definitions of iron deficiency differ, resulting in variability in screening and repletion strategies. This study sought to describe current practices surrounding identification and treatment of iron deficiency in CKD and then implement a pharmacist-led protocol to optimize care at a tertiary medical center. Methods: This single center, retrospective, pre- and post-protocol implementation study of adults with CKD admitted to the inpatient setting first analyzed historic practices for iron deficiency screening and treatment, followed by deployment of a pharmacist-driven protocol for iron deficiency screening and treatment. Iron deficiency was defined as transferrin saturation of ≤30% and ferritin of ≤500 ng/mL. Improvement in screening and repletion rates was analyzed. Results: Historic pre-protocol practices were reviewed in 7155 admissions of which 2559 (35.8%) included screening for iron deficiency. Over the 2 months intervention (post-protocol) period, 315 admissions were included. The average age of patients in the post-protocol cohort was 64.1 years, 53.7% were female, and 26.4% were dialysis dependent. Compared to pre-protocol, patients were 2.33 (95% CI 2.20-2.47) times more likely to be screened and deficient patients were 2.05 (95% CI 1.46-2.86) times more likely to be treated, with most receiving IV iron therapy (85.4%), in the post-protocol cohort. Patients were 3.58 times (95% CI 1.97-6.48) more likely to receive IV iron versus oral alone in the post-protocol cohort compared to pre-protocol. Conclusion: The frequency of patients with CKD screened and treated with iron increased after implementation of a pharmacist-driven protocol. This study underscores the need for a systematic approach to identification/treatment of iron deficiency in this population.
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Affiliation(s)
- Karissa Chow
- The Johns Hopkins Hospital Deparment of Pharmacy, Baltimore, MD, USA
| | | | - Matthew Blum
- Johns Hopkins University School of Medicine, Department of Nephrology, Baltimore, MD, USA
| | - Sami Alasfar
- Johns Hopkins University School of Medicine, Department of Nephrology, Baltimore, MD, USA
| | | | - Dannielle Brown
- The Johns Hopkins Hospital Deparment of Pharmacy, Baltimore, MD, USA
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Kuragano T. Treatment of Anemia Associated with Chronic Kidney Disease: Plea for Considering Physiological Erythropoiesis. Int J Mol Sci 2024; 25:7322. [PMID: 39000429 PMCID: PMC11242251 DOI: 10.3390/ijms25137322] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2024] [Revised: 06/21/2024] [Accepted: 06/25/2024] [Indexed: 07/16/2024] Open
Abstract
Traditionally, the treatment of anemia associated with chronic kidney disease (CKD) involves prescribing erythropoiesis-stimulating agents (ESAs) or iron preparations. The effectiveness and safety of ESAs and iron have been established. However, several clinical issues, such as hyporesponsiveness to ESAs or defective iron utilization for erythropoiesis, have been demonstrated. Recently, a new class of therapeutics for renal anemia known as hypoxia-inducible factor (HIF)/proline hydroxylase (PH) inhibitors has been developed. Several studies have reported that HIF-PH inhibitors have unique characteristics compared with those of ESAs. In particular, the use of HIF-PH inhibitors may maintain target Hb concentration in patients treated with a high dose of ESAs without increasing the dose. Furthermore, several recent studies have demonstrated that patients with CKD with defective iron utilization for erythropoiesis had a high risk of cardiovascular events or premature death. HIF-PH inhibitors increase iron transport and absorption from the gastrointestinal tract; thus, they may ameliorate defective iron utilization for erythropoiesis in patients with CKD. Conversely, several clinical problems, such as aggravation of thrombotic and embolic complications, diabetic retinal disease, and cancer, have been noted at the time of HIF-PH inhibitor administration. Recently, several pooled analyses of phase III trials have reported the non-inferiority of HIF-PH inhibitors regarding these clinical concerns compared with ESAs. The advantages and issues of anemia treatment by ESAs, iron preparations, and HIF-PH inhibitors must be fully understood. Moreover, patients with anemia and CKD should be treated by providing a physiological erythropoiesis environment that is similar to that of healthy individuals.
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Affiliation(s)
- Takahiro Kuragano
- Division of Kidney and Dialysis, Hyogo Medical University, Hyogo 663-8501, Japan
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Zhang S, Ouyang M, Liu L. The treatment effects and cardiovascular events of high-dose intravenous iron for hemodialysis patients with renal anemia: A systematic review and meta-analysis. Chronic Illn 2024; 20:221-232. [PMID: 37282508 DOI: 10.1177/17423953231180453] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 06/08/2023]
Abstract
BACKGROUND Hemodialysis patients are common to have renal anemia in the nephrology practice. For the renal anemia, the high-dose iron from the intravenous route is an important treatment option. We can understand the treatment effects and cardiovascular events of high-dose intravenous iron reviewing the randomized clinical trials. METHODS We compared the high-dose and low-dose iron treatments to find if the high-dose intravenous iron can influence the hematological parameters more significantly than the low-dose iron. The cardiovascular events were also analyzed for the high-dose iron treatment. Six studies with a total of 2422 renal anemia patients under hemodialysis were enrolled. We focused the outcomes of hemoglobin, transferrin saturation percentage, ferritin, erythropoietin dose, and cardiovascular events. RESULTS The high-dose intravenous iron might be associated with a greater number of ferritin, transferrin saturation percentage, and hemoglobin. In addition, the erythropoietin dose was less needed to maintain the ideal hemoglobin range in the high-dose intravenous iron group. CONCLUSIONS In current meta-analysis, the high-dose intravenous iron might show the superior effects on the ferritin, transferrin saturation percentage, and hemoglobin levels and needed dose of erythropoietin when compared to low-dose iron treatment.
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Affiliation(s)
- Shanbao Zhang
- Department of Nephrology, Shanghai Pudong New District Punan Hospital, Shanghai, China Shanghai Punan Hospital, Shanghai, China
| | - Meng Ouyang
- Department of Pharmacy, The first People's Hospital of JiangXia District, Wuhan City, Hubei, China
| | - Lei Liu
- Department of Nephrology, Chongqing Three Gorges Central Hospital, Chongqing University Three Gorges Hospital, Chongqing, China
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Dubovetsky D, Tyler J, Bisceglia S. Assessing impact of an interdisciplinary erythropoiesis‐stimulating agent dosing protocol at an outpatient community hospital hemodialysis unit. JOURNAL OF THE AMERICAN COLLEGE OF CLINICAL PHARMACY 2022. [DOI: 10.1002/jac5.1675] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2022]
Affiliation(s)
| | - Joshua Tyler
- Department of Pharmacy Advent Health Orlando Florida USA
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Majoni SW, Nelson J, Germaine D, Hoppo L, Long S, Divakaran S, Turner B, Graham J, Cherian S, Pawar B, Rathnayake G, Heron B, Maple-Brown L, Batey R, Morris P, Davies J, Fernandes DK, Sundaram M, Abeyaratne A, Wong YHS, Lawton PD, Taylor S, Barzi F, Cass A. INFERR-Iron infusion in haemodialysis study: INtravenous iron polymaltose for First Nations Australian patients with high FERRitin levels on haemodialysis-a protocol for a prospective open-label blinded endpoint randomised controlled trial. Trials 2021; 22:868. [PMID: 34857020 PMCID: PMC8641231 DOI: 10.1186/s13063-021-05854-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2021] [Accepted: 11/20/2021] [Indexed: 11/14/2022] Open
Abstract
BACKGROUND The effectiveness of erythropoiesis-stimulating agents, which are the main stay of managing anaemia of chronic kidney disease (CKD), is largely dependent on adequate body iron stores. The iron stores are determined by the levels of serum ferritin concentration and transferrin saturation. These two surrogate markers of iron stores are used to guide iron replacement therapy. Most Aboriginal and/or Torres Islander Australians of the Northern Territory (herein respectfully referred to as First Nations Australians) with end-stage kidney disease have ferritin levels higher than current guideline recommendations for iron therapy. There is no clear evidence to guide safe and effective treatment with iron in these patients. We aim to assess the impact of intravenous iron treatment on all-cause death and hospitalisation with a principal diagnosis of all-cause infection in First Nations patients on haemodialysis with anaemia, high ferritin levels and low transferrin saturation METHODS: In a prospective open-label blinded endpoint randomised controlled trial, a total of 576 participants on maintenance haemodialysis with high ferritin (> 700 μg/L and ≤ 2000 μg/L) and low transferrin saturation (< 40%) from all the 7 renal units across the Northern Territory of Australia will be randomised 1:1 to receive intravenous iron polymaltose 400 mg once monthly (200 mg during 2 consecutive haemodialysis sessions) (Arm A) or no IV iron treatment (standard treatment) (Arm B). Rescue therapy will be administered when the ferritin levels fall below 700 μg/L or when clinically indicated. The primary outcome will be the differences between the two study arms in the risk of hospitalisation with all-cause infection or death. An economic analysis and several secondary and tertiary outcomes analyses will also be performed. DISCUSSION The INFERR clinical trial will address significant uncertainty on the safety and efficacy of iron therapy in First Nations Australians with CKD with hyperferritinaemia and evidence of iron deficiency. This will hopefully lead to the development of evidence-based guidelines. It will also provide the opportunity to explore the causes of hyperferritinaemia in First Nations Australians from the Northern Territory. TRIAL REGISTRATION This trial is registered with The Australian New Zealand Clinical Trials Registry (ANZCTR): ACTRN12620000705987 . Registered 29 June 2020.
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Affiliation(s)
- Sandawana William Majoni
- Division of Wellbeing and Preventable Chronic Diseases, Menzies School of Health Research, Charles Darwin University, Darwin, Northern Territory, Australia.
- Department of Nephrology, Division of Medicine, Royal Darwin Hospital, P.O. Box 41326, Casuarina, Darwin, Northern Territory, Australia.
- Flinders University and Northern Territory Medical Program, Royal Darwin Hospital Campus, Darwin, Northern Territory, Australia.
| | - Jane Nelson
- Division of Wellbeing and Preventable Chronic Diseases, Menzies School of Health Research, Charles Darwin University, Darwin, Northern Territory, Australia
| | - Darren Germaine
- Division of Wellbeing and Preventable Chronic Diseases, Menzies School of Health Research, Charles Darwin University, Darwin, Northern Territory, Australia
| | - Libby Hoppo
- Division of Wellbeing and Preventable Chronic Diseases, Menzies School of Health Research, Charles Darwin University, Darwin, Northern Territory, Australia
| | - Stephanie Long
- Division of Wellbeing and Preventable Chronic Diseases, Menzies School of Health Research, Charles Darwin University, Darwin, Northern Territory, Australia
| | - Shilpa Divakaran
- Division of Wellbeing and Preventable Chronic Diseases, Menzies School of Health Research, Charles Darwin University, Darwin, Northern Territory, Australia
- Department of Nephrology, Division of Medicine, Royal Darwin Hospital, P.O. Box 41326, Casuarina, Darwin, Northern Territory, Australia
| | - Brandon Turner
- Division of Wellbeing and Preventable Chronic Diseases, Menzies School of Health Research, Charles Darwin University, Darwin, Northern Territory, Australia
| | - Jessica Graham
- Division of Wellbeing and Preventable Chronic Diseases, Menzies School of Health Research, Charles Darwin University, Darwin, Northern Territory, Australia
| | - Sajiv Cherian
- Division of Wellbeing and Preventable Chronic Diseases, Menzies School of Health Research, Charles Darwin University, Darwin, Northern Territory, Australia
- Flinders University and Northern Territory Medical Program, Royal Darwin Hospital Campus, Darwin, Northern Territory, Australia
- Department of Nephrology, Division of Medicine, Alice Springs Hospital, Alice Springs, Northern Territory, Australia
| | - Basant Pawar
- Department of Nephrology, Division of Medicine, Alice Springs Hospital, Alice Springs, Northern Territory, Australia
| | - Geetha Rathnayake
- Flinders University and Northern Territory Medical Program, Royal Darwin Hospital Campus, Darwin, Northern Territory, Australia
- Chemical Pathology-Territory Pathology, Department of Health, Northern Territory Government, Darwin, Northern Territory, Australia
| | - Bianca Heron
- Department of Nephrology, Division of Medicine, Royal Darwin Hospital, P.O. Box 41326, Casuarina, Darwin, Northern Territory, Australia
| | - Louise Maple-Brown
- Division of Wellbeing and Preventable Chronic Diseases, Menzies School of Health Research, Charles Darwin University, Darwin, Northern Territory, Australia
- Department of Endocrinology, Division of Medicine, Royal Darwin Hospital, Darwin, Northern Territory, Australia
| | - Robert Batey
- Department of Nephrology, Division of Medicine, Alice Springs Hospital, Alice Springs, Northern Territory, Australia
- New South Wales Health, St Leonards, NSW, Australia
| | - Peter Morris
- Child Health Division, Menzies School of Health Research, Charles Darwin University, Darwin, Northern Territory, Australia
- Department of Pediatrics, Division of Women, Children and Youth, Royal Darwin Hospital, Darwin, Northern Territory, Australia
| | - Jane Davies
- Department of Infectious Diseases, Division of Medicine, Royal Darwin Hospital, Darwin, Northern Territory, Australia
- Global and Tropical Health Division, Menzies School of Health Research, Charles Darwin University, Darwin, Northern Territory, Australia
| | - David Kiran Fernandes
- Department of Nephrology, Division of Medicine, Alice Springs Hospital, Alice Springs, Northern Territory, Australia
| | - Madhivanan Sundaram
- Department of Nephrology, Division of Medicine, Royal Darwin Hospital, P.O. Box 41326, Casuarina, Darwin, Northern Territory, Australia
| | - Asanga Abeyaratne
- Division of Wellbeing and Preventable Chronic Diseases, Menzies School of Health Research, Charles Darwin University, Darwin, Northern Territory, Australia
- Department of Nephrology, Division of Medicine, Royal Darwin Hospital, P.O. Box 41326, Casuarina, Darwin, Northern Territory, Australia
- Flinders University and Northern Territory Medical Program, Royal Darwin Hospital Campus, Darwin, Northern Territory, Australia
| | - Yun Hui Sheryl Wong
- Division of Wellbeing and Preventable Chronic Diseases, Menzies School of Health Research, Charles Darwin University, Darwin, Northern Territory, Australia
- Department of Nephrology, Division of Medicine, Royal Darwin Hospital, P.O. Box 41326, Casuarina, Darwin, Northern Territory, Australia
| | - Paul D Lawton
- Division of Wellbeing and Preventable Chronic Diseases, Menzies School of Health Research, Charles Darwin University, Darwin, Northern Territory, Australia
- The Central Clinical School, Monash University & Alfred Health, Melbourne, Australia
| | - Sean Taylor
- Division of Wellbeing and Preventable Chronic Diseases, Menzies School of Health Research, Charles Darwin University, Darwin, Northern Territory, Australia
- Department of Nephrology, Division of Medicine, Royal Darwin Hospital, P.O. Box 41326, Casuarina, Darwin, Northern Territory, Australia
| | - Federica Barzi
- Division of Wellbeing and Preventable Chronic Diseases, Menzies School of Health Research, Charles Darwin University, Darwin, Northern Territory, Australia
- UQ Poche Centre for Indigenous Health, The University of Queensland, St Lucia, Queensland, 4067, Australia
| | - Alan Cass
- Division of Wellbeing and Preventable Chronic Diseases, Menzies School of Health Research, Charles Darwin University, Darwin, Northern Territory, Australia
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Gutiérrez OM. Treatment of Iron Deficiency Anemia in CKD and End-Stage Kidney Disease. Kidney Int Rep 2021; 6:2261-2269. [PMID: 34514189 PMCID: PMC8418942 DOI: 10.1016/j.ekir.2021.05.020] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2021] [Revised: 05/04/2021] [Accepted: 05/17/2021] [Indexed: 01/27/2023] Open
Abstract
Iron deficiency is common in individuals with chronic kidney disease and plays a major role in the development of anemia. Oral and intravenous iron agents are both available to replete iron in patients with chronic kidney disease diagnosed with iron deficiency. The choice of which agent to use is most often dictated by goals of therapy, tolerability, convenience, and response to prior therapy. Diminished absorption of iron in the gastrointestinal tract and a high incidence of gastrointestinal adverse effects can reduce the efficacy of oral iron agents, necessitating the use of i.v. iron formulations to treat iron deficiency anemia, particularly in patients requiring kidney replacement therapy. Newer oral agents may help to overcome these limitations and help treat iron deficiency in those not requiring kidney replacement therapy. Recent studies have provided new evidence that more aggressive repletion of iron in patients with chronic kidney disease requiring kidney replacement therapy may provide benefits with respect to anemia management and hard clinical outcomes such as cardiovascular disease and survival.
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Affiliation(s)
- Orlando M. Gutiérrez
- Division of Nephrology, Department of Medicine and Department of Epidemiology, University of Alabama at Birmingham, Birmingham, Alabama, USA
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Majoni SW, Lawton PD, Rathnayake G, Barzi F, Hughes JT, Cass A. Narrative Review of Hyperferritinemia, Iron Deficiency, and the Challenges of Managing Anemia in Aboriginal and Torres Strait Islander Australians With CKD. Kidney Int Rep 2021; 6:501-512. [PMID: 33615076 PMCID: PMC7879094 DOI: 10.1016/j.ekir.2020.10.035] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2020] [Accepted: 10/27/2020] [Indexed: 12/16/2022] Open
Abstract
Aboriginal and Torres Strait Islander Australians (Indigenous Australians) suffer some of the highest rates of chronic kidney disease (CKD) in the world. Among Indigenous Australians in remote areas of the Northern Territory, prevalence rates for renal replacement therapy (RRT) are up to 30 times higher than national prevalence. Anemia among patients with CKD is a common complication. Iron deficiency is one of the major causes. Iron deficiency is also one of the key causes of poor response to the mainstay of anemia therapy with erythropoiesis-stimulating agents (ESAs). Therefore, the effective management of anemia in people with CKD is largely dependent on effective identification and correction of iron deficiency. The current identification of iron deficiency in routine clinical practice is dependent on 2 surrogate markers of iron status: serum ferritin concentration and transferrin saturation (TSAT). However, questions exist regarding the use of serum ferritin concentration in people with CKD because it is an acute-phase reactant that can be raised in the context of acute and chronic inflammation. Serum ferritin concentration among Indigenous Australians receiving RRT is often markedly elevated and falls outside reference ranges within most national and international guidelines for iron therapy for people with CKD. This review explores published data on the challenges of managing anemia in Indigenous people with CKD and the need for future research on the efficacy and safety of treatment of anemia of CKD in patients with high ferritin and evidence iron deficiency.
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Affiliation(s)
- Sandawana William Majoni
- Department of Nephrology, Division of Medicine, Royal Darwin Hospital, Darwin, Northern Territory, Australia
- Flinders University and Northern Territory Medical Program, Royal Darwin Hospital Campus, Darwin, Northern Territory, Australia
- Wellbeing and Preventable Chronic Diseases, Menzies School of Health Research, Charles Darwin University, Northern Territory, Australia
| | - Paul D. Lawton
- Department of Nephrology, Division of Medicine, Royal Darwin Hospital, Darwin, Northern Territory, Australia
- Wellbeing and Preventable Chronic Diseases, Menzies School of Health Research, Charles Darwin University, Northern Territory, Australia
| | - Geetha Rathnayake
- Flinders University and Northern Territory Medical Program, Royal Darwin Hospital Campus, Darwin, Northern Territory, Australia
- Chemical Pathology–Territory Pathology, Department of Health, Northern Territory Government, Northern Territory, Australia
| | - Federica Barzi
- Wellbeing and Preventable Chronic Diseases, Menzies School of Health Research, Charles Darwin University, Northern Territory, Australia
| | - Jaquelyne T. Hughes
- Department of Nephrology, Division of Medicine, Royal Darwin Hospital, Darwin, Northern Territory, Australia
- Wellbeing and Preventable Chronic Diseases, Menzies School of Health Research, Charles Darwin University, Northern Territory, Australia
| | - Alan Cass
- Wellbeing and Preventable Chronic Diseases, Menzies School of Health Research, Charles Darwin University, Northern Territory, Australia
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Kuragano T, Joki N, Hase H, Kitamura K, Murata T, Fujimoto S, Fukatsu A, Inoue T, Itakura Y, Nakanishi T. Low transferrin saturation (TSAT) and high ferritin levels are significant predictors for cerebrovascular and cardiovascular disease and death in maintenance hemodialysis patients. PLoS One 2020; 15:e0236277. [PMID: 32877424 PMCID: PMC7467218 DOI: 10.1371/journal.pone.0236277] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2020] [Accepted: 07/01/2020] [Indexed: 12/17/2022] Open
Abstract
Patients with high serum ferritin and low transferrin saturation (TSAT) levels could be considered as presenting with dysutilization of iron for erythropoiesis. However, the long-term safety of iron administration in these patients has not been well established. An observational multicenter study was performed over 3 years. In 805 patients undergoing maintenance hemodialysis (MHD), we defined dysutilization of iron for erythropoiesis in patients with lower TSAT (<20%) and higher ferritin (≥100 ng/mL) levels. A time-dependent Cox hazard model was used for the evaluation of the association between dysutilization of iron for erythropoiesis and adverse events and survival. Patients with low TSAT levels showed an increased risk of cerebrovascular and cardiovascular disease (CCVD) and death compared to patients with normal or higher TSAT levels. Patients with low ferritin and high TSAT levels had a significantly lower risk of CCVD and death compared with patients with high ferritin and low TSAT levels. Higher TSAT levels were associated with male gender, age, the absence of diabetes, low levels of high-sensitivity CRP, and low β2 microglobulin levels, but not with intravenous iron administration or ferritin levels. Although patients with low TSAT levels had a significantly higher risk of CCVD or death, high TSAT levels were not linked with iron administration. Patients, who were suspected of dysutilization of iron for erythropoiesis, had a higher risk of CCVD and death. The administration of iron should be performed cautiously for improving TSAT levels, as iron administration could sustain TSAT levels for a short term.
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Affiliation(s)
- Takahiro Kuragano
- Department of Internal Medicine, Division of Kidney and Dialysis, Hyogo College of Medicine, Nisinomiya, Japan
- * E-mail:
| | - Nobuhiko Joki
- Department of Nephrology, Toho University Ohashi Medical Center, Tokyo, Japan
| | - Hiroki Hase
- Department of Nephrology, Toho University Ohashi Medical Center, Tokyo, Japan
| | - Kenichiro Kitamura
- The Third Department of Internal Medicine Faculty of Medicine, The University of Yamanashi, Yamanashi, Japan
| | - Toshiaki Murata
- Department of Nephrology, Murakami karin dou Hospital, Fukuoka, Japan
| | - Shouichi Fujimoto
- Department of Hemovascular Medicine and Artificial Organs, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan
| | - Atushi Fukatsu
- Department of Nephrology, Hekinan Municipal Hospital, Hekinan, Japan
| | - Toru Inoue
- Department of Internal Medicine, Yuseikai Clinic, Osaka, Japan
| | | | - Takeshi Nakanishi
- Department of Internal Medicine, Division of Kidney and Dialysis, Hyogo College of Medicine, Nisinomiya, Japan
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11
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The Impact of Iron Supplementation for Treating Anemia in Patients with Chronic Kidney Disease: Results from Pairwise and Network Meta-Analyses of Randomized Controlled Trials. Pharmaceuticals (Basel) 2020; 13:ph13050085. [PMID: 32365757 PMCID: PMC7281268 DOI: 10.3390/ph13050085] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2020] [Revised: 04/26/2020] [Accepted: 04/28/2020] [Indexed: 12/11/2022] Open
Abstract
After relative erythropoietin deficiency, iron deficiency is the second most important contributing factor for anemia in chronic kidney disease (CKD) patients. Iron supplementation is a crucial part of the treatment of anemia in CKD patients, and intravenous (IV) iron supplementation is considered to be superior to per os (PO) iron supplementation. The differences between the available formulations are poorly characterized. This report presents results from pairwise and network meta-analyses carried out after a comprehensive search in sources of published and unpublished studies, according to the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) recommendations (International prospective register of systematic reviews PROSPERO reference ID: CRD42020148155). Meta-analytic calculations were performed for the outcome of non-response to iron supplementation (i.e., hemoglobin (Hgb) increase of <0.5–1.0 g/dL, or initiation/intensification of erythropoiesis-stimulating agent (ESA) therapy, or increase/change of iron supplement, or requirements of blood transfusion). A total of 34 randomized controlled trials (RCT) were identified, providing numerical data for analyses covering 93.7% (n = 10.097) of the total study population. At the network level, iron supplementation seems to have a more protective effect against the outcome of non-response before the start of dialysis than once dialysis is initiated, and some preparations seem to be more potent (e.g., ferumoxytol, ferric carboxymaltose), compared to the rest of iron supplements assessed (surface under the cumulative ranking area (SUCRA) > 0.8). This study provides parameters for adequately following-up patients requiring iron supplementation, by presenting the most performing preparations, and, indirectly, by making it possible to identify good responders among all patients treated with these medicines.
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Besarab A, Drueke TB. The problem with transferrin saturation as an indicator of iron 'sufficiency' in chronic kidney disease. Nephrol Dial Transplant 2020; 36:1377-1383. [PMID: 32301986 DOI: 10.1093/ndt/gfaa048] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2019] [Accepted: 02/06/2020] [Indexed: 02/07/2023] Open
Abstract
After a brief review of physiological iron metabolism, we describe diagnostic tests for iron status and iron deficiency anemia in patients without chronic kidney disease (CKD) or inflammation. Thereafter we review the dysregulation of iron metabolism in CKD. Specific emphasis is placed on the role of the 'inflammatory' state that develops with the progression of CKD. It invokes changes in iron metabolism that are the exact opposite of those occurring during pure iron deficiency. As a result, transferrin saturation (TSAT) becomes a poorer index of iron availability to the bone marrow and serum ferritin no longer represents iron that can be used during erythropoiesis. We argue that serum iron may provide more information to guide iron therapy than TSAT. In other words, the emphasis on TSAT is misplaced. With the development of a number of hypoxia-inducible factor prolyl hydroxylase inhibitors, which restore iron metabolism toward the 'physiologic state', the iron indices indicating sufficient iron availability to avoid functional iron deficiency during therapy of CKD-associated anemia are likely to change. We summarize these changes in the section 'A peek into things to come!', citing the available data.
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Affiliation(s)
- Anatole Besarab
- Stanford University School of Medicine, Stanford University, Stanford, CA, USA
| | - Tilman B Drueke
- INSERM U1018, Team 5, CESP, Paris Saclay University, Paris-Sud Univ, UVSQ, Villejuif, France
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13
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Abstract
PURPOSE OF REVIEW We will examine the current and future options in management of anemia in dialysis patients focusing on recent trials in iron supplementation and alternatives to erythropoietin-stimulating agents (ESAs). RECENT FINDINGS We review the literature on Erythropoietin (EPO)-stimulating agents, focusing on the risk benefits of various options available. We review the recent practice changing trial in iron supplementation in dialysis patients with chronic kidney disease and movements in the research on alternatives to EPO-stimulating agents primarily hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHIs). SUMMARY ESAs constitute the mainstay of treatment of anemia in dialysis and evidence does not support the preference of any one type over the other. But concerns exist about the cardiovascular safety of supra-physiological ESA levels. Iron supplementation has been shown to be a well tolerated method to decrease ESA doses while maintaining hemoglobin levels and recent evidence should result in a revisiting of the guidelines for iron supplementation. HIF-PHIs are potentially safe alternatives to ESAs that correct and maintain hemoglobin while maintaining physiological levels of erythropoietin. Ongoing phase III trials for these drugs will likely answer questions of long-term safety regarding these drugs.
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Batchelor EK, Kapitsinou P, Pergola PE, Kovesdy CP, Jalal DI. Iron Deficiency in Chronic Kidney Disease: Updates on Pathophysiology, Diagnosis, and Treatment. J Am Soc Nephrol 2020; 31:456-468. [PMID: 32041774 PMCID: PMC7062209 DOI: 10.1681/asn.2019020213] [Citation(s) in RCA: 167] [Impact Index Per Article: 33.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Anemia is a complication that affects a majority of individuals with advanced CKD. Although relative deficiency of erythropoietin production is the major driver of anemia in CKD, iron deficiency stands out among the mechanisms contributing to the impaired erythropoiesis in the setting of reduced kidney function. Iron deficiency plays a significant role in anemia in CKD. This may be due to a true paucity of iron stores (absolute iron deficiency) or a relative (functional) deficiency which prevents the use of available iron stores. Several risk factors contribute to absolute and functional iron deficiency in CKD, including blood losses, impaired iron absorption, and chronic inflammation. The traditional biomarkers used for the diagnosis of iron-deficiency anemia (IDA) in patients with CKD have limitations, leading to persistent challenges in the detection and monitoring of IDA in these patients. Here, we review the pathophysiology and available diagnostic tests for IDA in CKD, we discuss the literature that has informed the current practice guidelines for the treatment of IDA in CKD, and we summarize the available oral and intravenous (IV) iron formulations for the treatment of IDA in CKD. Two important issues are addressed, including the potential risks of a more liberal approach to iron supplementation as well as the potential risks and benefits of IV versus oral iron supplementation in patients with CKD.
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Affiliation(s)
| | - Pinelopi Kapitsinou
- Feinberg Cardiovascular and Renal Research Institute and
- Division of Nephrology and Hypertension, Northwestern University Feinberg School of Medicine, Chicago, Illinois
| | - Pablo E Pergola
- Renal Associates PA, Division of Nephrology, University of Texas Health Science Center at San Antonio, San Antonio, Texas; and
| | - Csaba P Kovesdy
- Division of Nephrology, University of Tennessee Health Science Center, Memphis, Tennessee
| | - Diana I Jalal
- Division of Nephrology, University of Iowa Hospitals and Clinics, Iowa City, Iowa;
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Salim SA, Cheungpasitporn W, Elmaraezy A, Jawafi O, Rahman M, Aeddula NR, Tirupathi R, Fülöp T. Infectious complications and mortality associated with the use of IV iron therapy: a systematic review and meta-analysis. Int Urol Nephrol 2019; 51:1855-1865. [PMID: 31485910 DOI: 10.1007/s11255-019-02273-4] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2019] [Accepted: 08/29/2019] [Indexed: 12/22/2022]
Abstract
BACKGROUND Parental iron is used to optimize hemoglobin and enhance erythropoiesis in end-stage renal disease along with erythropoietin-stimulating agents. Safety of iron has been debated extensively and there is no definite evidence whether parenteral iron increases the risk of infections and mortality. We performed this meta-analysis to evaluate the incidence of infectious complications, hospitalizations and mortality with use of parenteral iron. METHODS Medical electronic databases [PubMed, EMBASE, Scopus, Web of Science, and cochrane central register for controlled clinical trials (CENTRAL)] were queried for studies that investigated the association between intravenous iron administration and infection in hemodialysis patients. 24 studies (8 Randomized control trials (RCTs) and 16 observational studies) were considered for qualitative and quantitative analysis. RESULTS All-cause mortality Data from 6 RCTs show that high-dose IV iron conferred 17% less all-cause mortality compared to controls; however, this outcome was not statistically significant (OR = 0.83, CI [0.7, 1.01], p = 0.07). Nine observational studies were pooled under the random effects model due to significant heterogeneity (I2 = 83%, p < 0.001). The overall HR showed increased risk of all-cause mortality in the high-dose group but was statistically non-significant (HR = 1.1, CI [1, 1.22], p = 0.06). Infections Four RCTs with no heterogeneity among their data (I2 = 0%, p = 0.61). Under the fixed effect model, there was no difference in the infection rate between high-dose iron and control group (OR = 0.97, CI [0.82, 1.16], p = 0.77); eight observational studies with significant heterogeneity and utilizing random effects model. Summary HR showed increased yet non-significant risk of infection in the high-dose group (HR = 1.13, CI [0.99, 1.28], p = 0.07) Hospitalization 1 RCT and six observational studies provided data for the rate of all-cause hospitalization. There was marked heterogeneity among observational studies. RCT showed no significant difference between high-dose iron and controls in the rate of hospitalization (OR = 1.03, CI [0.87, 1.23], p = 0.71). Summary HR for observational data showed increased rate of hospitalization in the high-dose group; however, this effect was not statistically significant (HR = 1.11, CI [0.99, 1.24], p = 0.07). Cardiovascular events One RCT compared the rate of adverse cardiovascular events between high-dose and low-dose iron. No significant difference was observed between the two groups (22.3% vs 25.6%, p = 0.12). Six heterogeneous observational studies (I2 = 65%, p < 0.001) reported on the rate of cardiovascular events. No significant difference was observed between high-dose iron and controls (HR = 1.18, CI [0.89, 1.57], p = 0.24). CONCLUSION High-dose parenteral iron does not seem to be associated with higher risk of infection, all-cause mortality, increased hospitalization or increased cardiovascular events on analysis of RCTs. Observational studies show increased risk for all-cause mortality, infections and hospitalizations that were not statistically significant and were associated with significant heterogeneity.
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Affiliation(s)
- Sohail Abdul Salim
- Department of Internal Medicine, Division of Nephrology, University of Mississippi Medical Center, 2500 North State Street, Jackson, MS, 39216-4505, USA.
| | - Wisit Cheungpasitporn
- Department of Internal Medicine, Division of Nephrology, University of Mississippi Medical Center, 2500 North State Street, Jackson, MS, 39216-4505, USA
| | | | - Omar Jawafi
- Computational and Data-Enabled Science, Jackson State University, Jackson, MS, USA
| | - Md Rahman
- Computational and Data-Enabled Science, Jackson State University, Jackson, MS, USA
| | | | | | - Tibor Fülöp
- Division of Nephrology, Department of Internal Medicine, Medical University of South Carolina, Charleston, SC, USA.,Raph H. Johnson VA Medical Center, Charleston, SC, USA
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Pergola PE, Fishbane S, Ganz T. Novel Oral Iron Therapies for Iron Deficiency Anemia in Chronic Kidney Disease. Adv Chronic Kidney Dis 2019; 26:272-291. [PMID: 31477258 DOI: 10.1053/j.ackd.2019.05.002] [Citation(s) in RCA: 48] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2019] [Revised: 05/06/2019] [Accepted: 05/12/2019] [Indexed: 12/26/2022]
Abstract
Iron deficiency anemia (IDA) is a frequent complication of chronic kidney disease (CKD) and is associated with adverse outcomes in these patients. Patients with CKD and IDA remain largely undertreated. Conventional oral iron agents are insufficiently effective due to poor absorption and cause gastrointestinal side effects; thus, novel oral iron preparations are needed. This article covers current treatment guidelines for patients with anemia and CKD and clinical trial data for iron-repletion agents currently in use, as well as for novel oral iron therapies in development. Ferric citrate, a novel oral iron-repletion agent approved for patients with non-dialysis-dependent CKD and IDA, demonstrated improvements in hemoglobin levels and iron parameters, with good tolerability in patients with non-dialysis-dependent CKD. When used as a phosphate binder, ferric citrate also improves hemoglobin and iron parameters in dialysis-dependent CKD, but additional trials are needed to evaluate its efficacy as an iron-repletion agent in this setting. Other novel oral iron preparations in development for IDA in patients with CKD include ferric maltol, which is approved in Europe and the United States for IDA in adult patients, and sucrosomial iron, which has been evaluated in IDA associated with CKD and several other clinical settings.
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Collister D, Tangri N. Post-PIVOTAL Iron Dosing with Maintenance Hemodialysis. Clin J Am Soc Nephrol 2019; 14:1533-1535. [PMID: 31182556 PMCID: PMC6777601 DOI: 10.2215/cjn.02300219] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Affiliation(s)
- David Collister
- Division of Nephrology, Department of Medicine, McMaster University, Hamilton, Ontario, Canada.,Population Health Research Institute, Hamilton, Ontario, Canada
| | - Navdeep Tangri
- Section of Nephrology, Department of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada; and .,Chronic Disease Innovation Center, Winnipeg, Manitoba, Canada
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HIF stabilizers in the management of renal anemia: from bench to bedside to pediatrics. Pediatr Nephrol 2019; 34:365-378. [PMID: 29569190 PMCID: PMC6349802 DOI: 10.1007/s00467-017-3849-3] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/20/2017] [Revised: 10/28/2017] [Accepted: 10/31/2017] [Indexed: 02/06/2023]
Abstract
Anemia is a common complication of chronic kidney disease (CKD) in adult and pediatric patients. It has traditionally been treated with erythropoietin therapy and iron supplementation, with great success. With the discovery of the major transcription factor hypoxia inducible factor (HIF) for the erythropoietin gene in 1992, molecules were created that inhibit the HIF prolyl-hydroxylase enzyme. This new class of drug-called HIF stabilizers, or HIF prolyl-hydroxylase inhibitors-prevents the proteasomal degradation of HIF-α, thereby inducing upregulation of the erythropoietin gene. This new strategy for treating CKD anemia is already in phase III clinical trials in adults, and the potential advantages of this therapy are that it is orally active (thereby avoiding injections), and patients are exposed to lower circulating levels of erythropoietin. The long-term safety of this strategy, however, requires elucidation in these trials, particularly since there are many other hypoxia-sensitive genes, notably, angiogenic factors such as vascular endothelial growth factors (VEGF), as well as glycolytic enzymes. As with all new therapies, it is only once a positive benefit: risk profile has been ascertained in adults that the treatment will translate across into pediatrics. Specific issues in the pediatric CKD population are discussed in this review.
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20
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Varas J, Ramos R, Aljama P, Pérez-García R, Moreso F, Pinedo M, Ignacio Merello J, Stuard S, Canaud B, Martín-Malo A. Relationships between iron dose, hospitalizations and mortality in incident haemodialysis patients: a propensity-score matched approach. Nephrol Dial Transplant 2018; 33:160-170. [PMID: 28992120 DOI: 10.1093/ndt/gfx209] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2017] [Accepted: 04/15/2017] [Indexed: 01/01/2023] Open
Abstract
Background Intravenous iron management is common in the haemodialysis population. However, the safest dosing strategy remains uncertain, in terms of the risk of hospitalization and mortality. We aimed to determine the effects of cumulative monthly iron doses on mortality and hospitalization. Methods This multicentre observational retrospective propensity-matched score study included 1679 incident haemodialysis patients. We measured baseline demographic variables, haemodialysis clinical parameters and laboratory analytical values. We compared outcomes among quartiles of cumulative iron dose (mg/kg/month). We implemented propensity-score matching (PSM) to reduce confounding due to indication. In the PSM cohort (330 patients), we compared outcomes between groups that received cumulative iron doses above and below 5.66 mg/kg/month. Results Kaplan-Meier analyses showed that the high iron dose group had significantly worse survival than the low iron dose group. A univariate analysis indicated that the monthly iron dose could significantly predict mortality. However, a multivariate regression did not confirm that finding. The multivariate regression analysis revealed that iron doses >5.58 mg/kg/month were not associated with elevated mortality risk, but they were associated with elevated risks of all-cause and cardiovascular-related hospitalizations. These results were ratified in the PSM population. Conclusions Intravenous iron administration is advisable for maintaining haemoglobin levels in patients that receive haemodialysis. Our data suggested that large monthly iron doses, adjusted for body weight, were associated with more hospitalizations, but not with mortality or infection-related hospitalizations.
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Affiliation(s)
- Javier Varas
- Medical Department, Fresenius Medical Care, Madrid, Spain
| | - Rosa Ramos
- Medical Department, Fresenius Medical Care, Madrid, Spain
| | - Pedro Aljama
- Nephrology Department, Hospital Universitario Reina Sofía, Universidad de Córdoba, Córdoba, Spain
| | | | | | - Miguel Pinedo
- Medical Department, Fresenius Medical Care, Madrid, Spain
| | | | - Stefano Stuard
- Clinical & Therapeutical Governance, Care Value Management EMEA, Fresenius Medical Care Deutschland GmbH, Bad Homburg, Germany
| | - Bernard Canaud
- Center of Excellence Medical EMEA, Fresenius Medical Care Deutschland GmbH, Bad Homburg, Germany
| | - Alejandro Martín-Malo
- Nephrology Department, Hospital Universitario Reina Sofía, Universidad de Córdoba, Córdoba, Spain
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Cunha GJL, Rocha BML, Menezes Falcão L. Iron deficiency in chronic and acute heart failure: A contemporary review on intertwined conditions. Eur J Intern Med 2018; 52:1-7. [PMID: 29680173 DOI: 10.1016/j.ejim.2018.04.013] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/13/2018] [Revised: 04/11/2018] [Accepted: 04/12/2018] [Indexed: 12/13/2022]
Abstract
Iron Deficiency (ID) is increasingly recognized as a prevalent comorbid condition in Heart Failure (HF). Despite this, the pathophysiological mechanisms for progressive ID in either chronic or acute HF are still poorly understood. Beyond the traditional factors for iron deficit in the general population, we ought to review the specificities of such paucity in the HF patient, particularly focusing on the interplay between heightened inflammation, overactivity of the sympathetic nervous system and the so-called cardio-renal-anaemia-ID syndrome. Currently, ID constitutes not only an independent prognostic marker but also a novel safe therapeutic target. Particularly, in selected stable HF patients with reduced left ventricular ejection fraction, intravenous (IV) iron improves symptomatic burden and reduces hospitalizations due to worsening HF. On this topic, the main trials of IV iron with either iron sucrose (Toblli et al., FERRIC-HF and IRON-HF) or ferric carboxymaltose (FAIR-HF, CONFIRM-HF and EFFECT-HF) will be summarized and discussed. Finally, we debate the gaps in knowledge of ID in special populations, namely the unreliability of routine plasmatic surrogate markers to assess iron status in acute and advanced HF, the challenging patient with both HF and Chronic Kidney Disease, as well as efficacy and safety concerns in these settings and the potential role of iron correction in cardiac resynchronization therapy candidates.
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Affiliation(s)
| | | | - Luiz Menezes Falcão
- Department of Internal Medicine, Hospital Santa Maria, Lisbon, Portugal; Faculty of Medicine, University of Lisbon, Lisbon, Portugal.
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22
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Hougen I, Collister D, Bourrier M, Ferguson T, Hochheim L, Komenda P, Rigatto C, Tangri N. Safety of Intravenous Iron in Dialysis: A Systematic Review and Meta-Analysis. Clin J Am Soc Nephrol 2018; 13:457-467. [PMID: 29463597 PMCID: PMC5967668 DOI: 10.2215/cjn.05390517] [Citation(s) in RCA: 54] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2017] [Accepted: 11/22/2017] [Indexed: 12/14/2022]
Abstract
BACKGROUND AND OBJECTIVES The safety of intravenous iron dosing in dialysis is uncertain. Higher-dose intravenous iron may be associated with a higher risk of infections, cardiovascular events, hospitalizations, and mortality. This systematic review aimed to determine the safety of higher-dose versus lower-dose intravenous iron, oral iron, or no iron supplementation in adult patients treated with dialysis. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS We searched Medline, EMBASE, Cochrane library, and CINAHL from inception to January 6, 2017 for randomized, controlled trials and observational studies comparing higher-dose intravenous iron with lower-dose intravenous iron, oral iron, or no iron in patients treated with dialysis that had all-cause mortality, infection, cardiovascular events, or hospitalizations as outcomes. RESULTS Of the 2231 eligible studies, seven randomized, controlled trials and 15 observational studies met inclusion criteria. The randomized, controlled trials showed no association between higher-dose intravenous iron (>400 mg/mo for most studies) and mortality (six studies; n=970; pooled relative risk, 0.93; 95% confidence interval, 0.47 to 1.84; follow-up ranging from 35 days to 26 months) or infection (four studies; n=743; relative risk, 1.02; 95% confidence interval, 0.74 to 1.41). The observational studies showed no association between higher-dose intravenous iron (>200 mg/mo for most studies) and mortality (eight studies; n=241,408; hazard ratio, 1.09; 95% confidence interval, 0.98 to 1.21; follow-up ranging from 3 to 24 months), infection (eight studies; n=135,532; pooled hazard ratio, 1.13; 95% confidence interval, 0.99 to 1.28), cardiovascular events (seven studies; n=135,675; hazard ratio, 1.18; 95% confidence interval, 0.90 to 1.56), or hospitalizations (five studies; n=134,324; hazard ratio, 1.08; 95% confidence interval, 0.97 to 1.19). CONCLUSIONS Higher-dose intravenous iron does not seem to be associated with higher risk of mortality, infection, cardiovascular events, or hospitalizations in adult patients on dialysis. Strength of this finding is limited by small numbers of participants and events in the randomized, controlled trials and statistical heterogeneity in observational studies.
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Affiliation(s)
- Ingrid Hougen
- Chronic Disease Innovation Center, Seven Oaks General Hospital, Winnipeg, Manitoba, Canada; and
| | - David Collister
- Chronic Disease Innovation Center, Seven Oaks General Hospital, Winnipeg, Manitoba, Canada; and
- Section of Nephrology, Department of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada
| | - Mathieu Bourrier
- Chronic Disease Innovation Center, Seven Oaks General Hospital, Winnipeg, Manitoba, Canada; and
| | - Thomas Ferguson
- Chronic Disease Innovation Center, Seven Oaks General Hospital, Winnipeg, Manitoba, Canada; and
- Section of Nephrology, Department of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada
| | - Laura Hochheim
- Chronic Disease Innovation Center, Seven Oaks General Hospital, Winnipeg, Manitoba, Canada; and
| | - Paul Komenda
- Chronic Disease Innovation Center, Seven Oaks General Hospital, Winnipeg, Manitoba, Canada; and
- Section of Nephrology, Department of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada
| | - Claudio Rigatto
- Chronic Disease Innovation Center, Seven Oaks General Hospital, Winnipeg, Manitoba, Canada; and
- Section of Nephrology, Department of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada
| | - Navdeep Tangri
- Chronic Disease Innovation Center, Seven Oaks General Hospital, Winnipeg, Manitoba, Canada; and
- Section of Nephrology, Department of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada
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23
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Wish JB, Aronoff GR, Bacon BR, Brugnara C, Eckardt KU, Ganz T, Macdougall IC, Núñez J, Perahia AJ, Wood JC. Positive Iron Balance in Chronic Kidney Disease: How Much is Too Much and How to Tell? Am J Nephrol 2018; 47:72-83. [PMID: 29439253 DOI: 10.1159/000486968] [Citation(s) in RCA: 53] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2017] [Accepted: 01/15/2018] [Indexed: 12/12/2022]
Abstract
BACKGROUND Regulation of body iron occurs at cellular, tissue, and systemic levels. In healthy individuals, iron absorption and losses are minimal, creating a virtually closed system. In the setting of chronic kidney disease and hemodialysis (HD), increased iron losses, reduced iron absorption, and limited iron availability lead to iron deficiency. Intravenous (IV) iron therapy is frequently prescribed to replace lost iron, but determining an individual's iron balance and stores can be challenging and imprecise, contributing to uncertainty about the long-term safety of IV iron therapy. SUMMARY Patients on HD receiving judicious doses of IV iron are likely to be in a state of positive iron balance, yet this does not appear to confer an overt risk for clinically relevant iron toxicity. The concomitant use of iron with erythropoiesis-stimulating agents, the use of maintenance iron dosing regimens, and the reticuloendothelial distribution of hepatic iron deposition likely minimize the potential for iron toxicity in patients on HD. Key Messages: Because no single diagnostic test can, at present, accurately assess iron status and risk for toxicity, clinicians need to take an integrative approach to avoid iron doses that impose excessive exposure while ensuring sufficient replenishment of iron stores capable of overcoming hepcidin blockade and allowing for effective erythropoiesis.
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Affiliation(s)
- Jay B Wish
- Division of Nephrology, Indiana University Health, Indianapolis, Indiana, USA
| | - George R Aronoff
- Department of Medicine, University of Louisville School of Medicine, Louisville, Kentucky, USA
- DaVita Kidney Care, Denver, Colorado, USA
| | - Bruce R Bacon
- Division of Gastroenterology and Hepatology, Saint Louis University School of Medicine, St. Louis, Missouri, USA
| | - Carlo Brugnara
- Department of Laboratory Medicine, Boston Children's Hospital and Department of Pathology, Harvard Medical School, Boston, Massachusetts, USA
| | - Kai-Uwe Eckardt
- Department of Nephrology and Medical Intensive Care, Charité - Universitätsmedizin, Berlin, Germany
| | - Tomas Ganz
- Department of Medicine, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, California, USA
| | - Iain C Macdougall
- Department of Renal Medicine, King's College Hospital, Denmark Hill, London, United Kingdom
| | - Julio Núñez
- Cardiology Service, Hospital Clínico Universitario, INCLIVA, CIBERCV and University of Valencia, Valencia, Spain
| | - Adam J Perahia
- NorthStar Strategic Consulting, LLC, Gladstone, New Jersey, USA
| | - John C Wood
- Division of Cardiology, Children's Hospital Los Angeles, Los Angeles, California, USA
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Abstract
Dysregulated iron homeostasis plays a central role in the development of anemia of chronic kidney disease (CKD) and is a major contributor toward resistance to treatment with erythropoiesis-stimulating agents. Understanding the underlying pathophysiology requires an in-depth understanding of normal iron physiology and regulation. Recent discoveries in the field of iron biology have greatly improved our understanding of the hormonal regulation of iron trafficking in human beings and how its alterations lead to the development of anemia of CKD. In addition, emerging evidence has suggested that iron homeostasis interacts with bone and mineral metabolism on multiple levels, opening up new avenues of investigation into the genesis of disordered iron metabolism in CKD. Building on recent advances in our understanding of normal iron physiology and abnormalities in iron homeostasis in CKD, this review characterizes how anemia related to disordered iron metabolism develops in the setting of CKD. In addition, this review explores our emerging recognition of the connections between iron homeostasis and mineral metabolism and their implications for the management of altered iron status and anemia of CKD.
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Affiliation(s)
- Bhupesh Panwar
- Department of Medicine, University of Alabama at Birmingham, Birmingham, AL.
| | - Orlando M Gutiérrez
- Department of Medicine, University of Alabama at Birmingham, Birmingham, AL; Department of Epidemiology, University of Alabama at Birmingham, Birmingham, AL
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25
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Abstract
Iron deficiency is common in patients on chronic dialysis, and most require iron-replacement therapy. In addition to absolute iron deficiency, many patients have functional iron deficiency as shown by a suboptimal response to the use of erythropoietin-stimulating agents. Both absolute and functional iron-deficiency anemia have been shown to respond to intravenous (IV) iron replacement. Although parenteral iron is an efficacious method and superior to standard doses of oral iron in patients on hemodialysis, there are ongoing safety concerns about repeated exposure potentially enhancing infection risk and cardiovascular disease. Each IV iron product is composed of an iron core with a carbohydrate shell. The avidity of iron binding and the type of carbohydrate shell play roles in the safe maximal dose and the frequency and severity of acute infusion reactions. All IV iron products are taken up into the reticuloendothelial system where the shell is metabolized and the iron is stored within tissue ferritin or exported to circulating transferrin. IV iron can be given as large intermittent doses (loading therapy) or in smaller doses at frequent intervals (maintenance dosing regimen). Limited trial data and observational data suggest that a maintenance dosing regimen is more efficacious and possibly safer than loading therapy. There is no consensus regarding the preferred method of iron repletion in patients on peritoneal dialysis, although small studies comparing oral and parenteral iron regimens in these patients have shown the latter to be more efficacious. Use of IV iron in virtually all hemodialysis and many peritoneal dialysis patients remains the standard of care.
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Abstract
Iron supplementation is an important aspect of treatment for hemodialysis patients, with most administration by an intravenous route. As with any drug, decisions as to treatment are most meaningful when benefits and risks are weighed in the context of the individual patient's clinical characteristics. In this article, knowledge of benefits and risks of intravenous iron are reviewed.
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Alabdan N, AlRuthia Y, Yates MED, Sales I, Finch CK, Hudson JQ. Predictors of adherence to a new erythropoiesis-stimulating agent inpatient ordering policy: A cross-sectional study. PLoS One 2017; 12:e0188390. [PMID: 29182650 PMCID: PMC5705120 DOI: 10.1371/journal.pone.0188390] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2017] [Accepted: 11/06/2017] [Indexed: 11/19/2022] Open
Abstract
Background Erythropoiesis-stimulating agents (ESAs) are recommended for treating anemia in patients with chronic kidney disease and end-stage renal disease. However, misappropriate and over-use of these agents can be costly and unnecessary in some settings. Objective The primary aim was to identify predictors of adherence to a newly approved ESA inpatient ordering policy. The secondary aims were to evaluate the impact of a 5-day delay in the initiation of ESA therapy on ESA usage, hemoglobin (Hb) levels, and costs. Methods This retrospective observational record review included a sample of adult patients admitted to four tertiary care hospitals from November 1, 2013 to August 31, 2014. Multivariable logistic and linear regression analyses were used to calculate the odds of adherence to the new ESA inpatient ordering policy and the impact of this policy on discharge Hb level, respectively. Results A total of 242 patients were included. The majority of the prescribers (77%) adhered to the new ESA ordering policy. Hemoglobin (OR = 1.306; 95% CI: 1.03–1.65) and ferritin (OR = 3.91; 95% CI: 1.23–12.51) levels at admission and length of hospital stay were positively correlated with the odds of patients receiving ESAs after day 5 (OR = 1.12; 95% CI:1.05–1.20). Furthermore, adherence to the new policy did not have a significant impact on discharge Hb level (β = 0.02349; P = 0.895). Conclusions Prescribers were adherent to a 5-day delay in the initiation of ESA therapy policy which resulted in a reduction in ESA usage, did not impact the discharge Hb levels, and was proven to be cost effective.
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Affiliation(s)
- Numan Alabdan
- Department of Pharmacy Practice, King Abdulaziz Medical City, Riyadh, Saudi Arabia
| | - Yazed AlRuthia
- Department of Clinical Pharmacy, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia
- * E-mail:
| | - Mary E. D. Yates
- Department of Clinical Pharmacy, College of Pharmacy, University of Tennessee Health Science Center, Memphis, Tennessee, United States of America
- Department of Pharmacy, Methodist Germantown Hospital, Germantown, Tennessee, United States of America
| | - Ibrahim Sales
- Department of Clinical Pharmacy, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia
| | - Christopher K. Finch
- Department of Clinical Pharmacy, College of Pharmacy, University of Tennessee Health Science Center, Memphis, Tennessee, United States of America
- Department of Pharmacy, Methodist University Hospital, Memphis, Tennessee, United States of America
| | - Joanna Q. Hudson
- Department of Clinical Pharmacy, College of Pharmacy, University of Tennessee Health Science Center, Memphis, Tennessee, United States of America
- Department of Medicine, Division of Nephrology, Methodist University Hospital, Memphis, Tennessee, United States of America
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29
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Berns JS. Interpretation of the Kidney Disease: Improving Global Outcomes guidelines for iron therapy: commentary and emerging evidence. Clin Kidney J 2017; 10:i3-i8. [PMID: 29225817 PMCID: PMC5716187 DOI: 10.1093/ckj/sfx042] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2017] [Accepted: 04/05/2017] [Indexed: 12/12/2022] Open
Abstract
The ‘Kidney Disease: Improving Global Outcomes’ (KDIGO) Clinical Practice Guideline for Anaemia in Chronic Kidney Disease includes detailed recommendations for the use of iron therapy in a variety of clinical circumstances. However, the evidence base regarding the use of iron therapy in patients with chronic kidney disease was relatively incomplete at the time the guideline was developed. As a result, there has been significant debate as to the appropriate use of iron therapy in this population. In this article, the KDIGO guidelines are discussed in the context of recently published commentary pieces and additional research to provide a richer context in which to interpret and understand the guidelines.
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Affiliation(s)
- Jeffrey S Berns
- Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, USA
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Macdougall IC. Intravenous iron therapy in patients with chronic kidney disease: recent evidence and future directions. Clin Kidney J 2017; 10:i16-i24. [PMID: 29225819 PMCID: PMC5716151 DOI: 10.1093/ckj/sfx043] [Citation(s) in RCA: 44] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2017] [Accepted: 02/15/2017] [Indexed: 12/18/2022] Open
Abstract
Current recommendations for the use of intravenous iron therapy in the management of anaemia in patients with chronic kidney disease (CKD) are based on limited clinical evidence. Since the publication of the Kidney Disease: Improving Global Outcomes (KDIGO) Clinical Practice Guideline for Anaemia in Chronic Kidney Disease in 2012, a number of randomized clinical trials [notably, the Ferinject Assessment in Patients with Iron Deficiency Anaemia (FIND-CKD) and Randomized Trial to Evaluate IV and Oral Iron in Chronic Kidney Disease (REVOKE) trials] and observational studies have been completed, and a further large clinical trial—Proactive IV Iron Therapy in Dialysis Patients (PIVOTAL)—is currently underway. In this article, the implications of the findings from these recent studies are discussed and the critical evidence gaps that remain to be addressed are highlighted.
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Robinson BM, Larkina M, Bieber B, Kleophas W, Li Y, Locatelli F, McCullough KP, Nolen JG, Port FK, Pisoni RL. Evaluating the effectiveness of IV iron dosing for anemia management in common clinical practice: results from the Dialysis Outcomes and Practice Patterns Study (DOPPS). BMC Nephrol 2017; 18:330. [PMID: 29121874 PMCID: PMC5679150 DOI: 10.1186/s12882-017-0745-9] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2017] [Accepted: 10/20/2017] [Indexed: 12/16/2022] Open
Abstract
Background Anemia management protocols in hemodialysis (HD) units differ conspicuously regarding optimal intravenous (IV) iron dosing; consequently, patients receive markedly different cumulative exposures to IV iron and erythropoiesis-stimulating agents (ESAs). Complementary to IV iron safety studies, our goal was to gain insight into optimal IV iron dosing by estimating the effects of IV iron doses on Hgb, TSAT, ferritin, and ESA dose in common clinical practice. Methods 9,471 HD patients (11 countries, 2009-2011) in the DOPPS, a prospective cohort study, were analyzed. Associations of IV iron dose (3-month average, categorized as 0, <300, ≥300 mg/month) with 3-month change in Hgb, TSAT, ferritin, and ESA dose were evaluated using adjusted GEE models. Results Relative change: Monotonically positive associations between IV iron dose and Hgb, TSAT, and ferritin change, and inverse associations with ESA dose change, were observed across multiple strata of prior Hgb, TSAT, and ferritin levels. Absolute change: TSAT, ferritin, and ESA dose changes were nearest zero with IV iron <300 mg/month, rather than 0 mg/month or ≥300 mg/month by maintenance or replacement dosing. Findings were robust to numerous sensitivity analyses. Conclusions Though residual confounding cannot be ruled out in this observational study, findings suggest that IV iron dosing <300 mg/month, as commonly seen with maintenance dosing of 100-200 mg/month, may be a more effective approach to support Hgb than the higher IV iron doses (300-400 mg/month) often given in many European and North American hemodialysis clinics. Alongside studies supporting the safety of IV iron in 100-200 mg/month dose range, these findings help guide the rational dosing of IV iron in anemia management protocols for everyday hemodialysis practice. Electronic supplementary material The online version of this article (10.1186/s12882-017-0745-9) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Bruce M Robinson
- Arbor Research Collaborative for Health, 340 E. Huron, Suite 300, Ann Arbor, MI, 48104, USA. .,University of Michigan, 1415 Washington Heights, Ann Arbor, MI, 48109, USA.
| | - Maria Larkina
- Arbor Research Collaborative for Health, 340 E. Huron, Suite 300, Ann Arbor, MI, 48104, USA
| | - Brian Bieber
- Arbor Research Collaborative for Health, 340 E. Huron, Suite 300, Ann Arbor, MI, 48104, USA
| | - Werner Kleophas
- Dialysezentrum Karlstrasse, Karlstraße 17-19, 40210, Düsseldorf, Germany
| | - Yun Li
- Arbor Research Collaborative for Health, 340 E. Huron, Suite 300, Ann Arbor, MI, 48104, USA.,University of Michigan, 1415 Washington Heights, Ann Arbor, MI, 48109, USA
| | - Francesco Locatelli
- Department of Nephrology, Alessandro Manzoni Hospital, Via dell'Eremo, 9/11, 23900, Lecco, LC, Italy
| | - Keith P McCullough
- Arbor Research Collaborative for Health, 340 E. Huron, Suite 300, Ann Arbor, MI, 48104, USA
| | - Jackie G Nolen
- Vifor Pharma, Flughofstrasse 61, 8152, Glattbrugg, Switzerland
| | - Friedrich K Port
- Arbor Research Collaborative for Health, 340 E. Huron, Suite 300, Ann Arbor, MI, 48104, USA
| | - Ronald L Pisoni
- Arbor Research Collaborative for Health, 340 E. Huron, Suite 300, Ann Arbor, MI, 48104, USA
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Del Vecchio L, Locatelli F. Clinical practice guidelines on iron therapy: A critical evaluation. Hemodial Int 2017; 21 Suppl 1:S125-S131. [PMID: 28436206 DOI: 10.1111/hdi.12562] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2017] [Revised: 03/17/2017] [Indexed: 12/14/2022]
Abstract
Anemia is common among patients with chronic kidney disease (CKD) and it is managed primarily with erythropoiesis-stimulating agents (ESA) and iron therapy. Following concerns around ESA therapy and economic constraints, IV iron is more and more administered worldwide. Several guidelines or position papers, which give indications on iron therapy in CKD patients, have been issued in Nephrology. Unfortunately, the field is characterized by a lack of evidence. As a result, the recommendations/suggestions are not uniform. There is general consensus to prescribe iron therapy to patients who are clearly iron deficient. In addition, iron therapy may increase Hb values, delay the start of ESA therapy in ESA-naïve patients and reduce ESA dose in ESA-treated patients. However, there is debate on the safety and efficacy of IV iron therapy when given in the presence of already high serum ferritin levels. In addition, not all the guidelines/position papers differentiate between non-dialysis/dialysis patients and between the presence/absence of ESA therapy. Many international Bodies or Societies suggest caution when administering IV iron during infections. A trial of oral iron should be considered as a first step, especially in the ND-CKD population. Finally, recommendations on the prevention of anaphylactic reactions following IV iron therapy are given by several bodies. There is consensus that IV iron is to be administered in the presence of resuscitative facilities (including medications) and personnel trained for emergencies.
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Affiliation(s)
- Lucia Del Vecchio
- Department of Nephrology and Dialysis, Alessandro Manzoni Hospital, Lecco, Italy
| | - Francesco Locatelli
- Department of Nephrology and Dialysis, Alessandro Manzoni Hospital, Lecco, Italy
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Li X, Kshirsagar AV, Brookhart MA. Safety of intravenous iron in hemodialysis patients. Hemodial Int 2017; 21 Suppl 1:S93-S103. [PMID: 28370957 DOI: 10.1111/hdi.12558] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Among end-stage renal disease patients maintained by hemodialysis, anemia has been managed primarily through erythropoiesis-stimulating agents (ESAs) and intravenous (IV) iron. Following concerns about the cardiovascular (CV) safety of ESAs and changes in the reimbursement policies in Medicare's ESRD program, the use of IV iron has increased. IV iron supplementation promotes hemoglobin production and reduces ESA requirements, yet there exists relatively little evidence on the long-term safety of iron supplementation in hemodialysis patients. Labile iron can induce oxidative stress and is also essential in bacterial growth, leading to concerns about IV iron use and risk of CV events and infections in hemodialysis patients. Existing randomized controlled trials provide little evidence about safety due to insufficient power and short follow-up; recent observational studies have been inconsistent, but some have associated iron exposure with increased risk of infections and CV events. Given the widespread use and potential safety concerns related to IV iron, well-designed large prospective studies are needed to assess to identify optimal strategies for iron administration that maximize its benefits while avoiding potential risks.
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Affiliation(s)
- Xiaojuan Li
- Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.,UNC Kidney Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
| | - Abhijit V Kshirsagar
- UNC Kidney Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
| | - M Alan Brookhart
- Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
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Abstract
Anemia is one of the main comorbidities related to chronic kidney disease (CKD). Until the advent of erythropoiesis stimulating agents (ESA), endogenous erythropoietin deficiency has been thought to be the main culprit of anemia in CKD patients. The use of ESAs has shed new light on the physiology of CKD anemia, where iron homeostasis plays an increasingly important role. Disorders of iron homeostasis occurring in CKD turn the anemia management in those patients into a complex multifactorial therapeutic task, where ESA and Iron dose must be properly balanced to achieve the desired outcome without exposing the patients to the risk of serious adverse events. This review covers diagnostic markers traditionally used for quantifying iron status in CKD patients, such as serum ferritin and transferrin saturation, new ones, such as reticulocyte hemoglobin content and percent hypochromic red cells (HRC), as well as experimental ones, such as hepcidin and soluble transferrin receptor (sTfR). Each marker is presented in terms of their diagnostic performance, followed by biological and analytical variability data. Advantages and disadvantages of each marker are briefly discussed. Although serum ferritin and transferrin saturation are easily available, they exhibit large biological variability and require caution when used for diagnosing iron status in CKD patients. Reticulocyte hemoglobin content and the percentage of HRC are more powerful, but their widespread use is hampered by the issue of sample stability in storage. sTfR and hepcidin show promise, but require further investigation as well as the development of standardized, low-cost assay platforms.
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Affiliation(s)
- Adam E Gaweda
- Department of Medicine, University of Louisville, Louisville, Kentucky, USA
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35
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Assessing the Association between Serum Ferritin, Transferrin Saturation, and C-Reactive Protein in Northern Territory Indigenous Australian Patients with High Serum Ferritin on Maintenance Haemodialysis. Int J Nephrol 2017; 2017:5490963. [PMID: 28243472 PMCID: PMC5294373 DOI: 10.1155/2017/5490963] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2016] [Revised: 12/29/2016] [Accepted: 01/09/2017] [Indexed: 01/16/2023] Open
Abstract
Objective. To determine the significance of high serum ferritin observed in Indigenous Australian patients on maintenance haemodialysis in the Northern Territory, we assessed the relationship between ferritin and transferrin saturation (TSAT) as measures of iron status and ferritin and C-reactive protein (CRP) as markers of inflammation. Methods. We performed a retrospective cohort analysis of data from adult patients (≥18 years) on maintenance haemodialysis (>3 months) from 2004 to 2011. Results. There were 1568 patients. The mean age was 53.9 (11.9) years. 1244 (79.3%) were Indigenous. 44.2% (n = 693) were male. Indigenous patients were younger (mean age [52.3 (11.1) versus 57.4 (15.2), p < 0.001]) and had higher CRP [14.7 mg/l (7–35) versus 5.9 mg/l (1.9–17.5), p < 0.001], higher median serum ferritin [1069 µg/l (668–1522) versus 794.9 µg/l (558.5–1252.0), p < 0.001], but similar transferrin saturation [26% (19–37) versus 28% (20–38), p = 0.516]. We observed a small positive correlation between ferritin and TSAT (r2 = 0.11, p < 0.001), no correlation between ferritin and CRP (r2 = 0.001, p < 0.001), and positive association between high serum ferritin and TSAT (p < 0.001), Indigenous ethnicity (p < 0.001), urea reduction ratio (p = 0.001), and gender (p < 0.001) after adjustment in mixed regression analysis. Conclusion. Serum ferritin and TSAT may inadequately reflect iron status in this population. The high ferritin was poorly explained by inflammation.
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36
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Deak AT, Troppan K, Rosenkranz AR. Anemia management in cancer patients with chronic kidney disease. Eur J Intern Med 2016; 36:13-19. [PMID: 27640913 DOI: 10.1016/j.ejim.2016.08.036] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/31/2016] [Revised: 08/06/2016] [Accepted: 08/19/2016] [Indexed: 12/27/2022]
Abstract
Anemia is a common complication of cancer and chronic kidney disease (CKD) associated with decreased physical performance as well as poor prognosis for life expectancy. Renal and cancer-induced anemia share common features regarding pathogenesis and therapeutic strategies. It is typically treated with iron substitution, erythropoiesis-stimulating agents (ESA) and in refractory cases with red blood cell transfusions. However, studies of the past few years unveiled numerous setbacks in the use of ESAs. These included a higher risk of cerebrovascular events and increased mortality without the improvement of cardiovascular outcomes in patients with CKD. Moreover, particularly negative results were observed in patients with previous cancer history under ESA therapy. These unfavorable findings have forced the clinicians to reevaluate the management of renal anemia. This led to decrease of ESA usage, while iron substitution and alternative therapeutic options gained more significance. Iron supplementation is also accompanied with certain risks ranging from gastrointestinal complications to severe allergic reactions and increased rate of infections. Furthermore, the evaluation of the long-term safety of excessive iron therapy is still lacking, especially in CKD patients with cancer. In the absence of these clinical studies, this review aims to summarize the currently available therapeutic strategies in anemia management of CKD patients with concomitant cancer.
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Affiliation(s)
- Andras T Deak
- Clinical Division of Nephrology, Department of Internal Medicine, Medical University of Graz, Auenbruggerplatz 27, 8036 Graz, Austria
| | - Katharina Troppan
- Clinical Division of Haematology, Department of Internal Medicine, Medical University of Graz, Auenbruggerplatz 38, 8036 Graz, Austria
| | - Alexander R Rosenkranz
- Clinical Division of Nephrology, Department of Internal Medicine, Medical University of Graz, Auenbruggerplatz 27, 8036 Graz, Austria.
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Shiohira S, Tsuchiya K, Kataoaka H, Okazaki M, Komatsu M, Naganuma T, Kawaguchi H, Nitta K. Relationship between variations in time-dependent response to erythropoiesis-stimulating agents and mortality in hemodialysis patients: a single-center study. RENAL REPLACEMENT THERAPY 2016. [DOI: 10.1186/s41100-016-0020-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
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Wish JB. What are the Considerations in Balancing Benefits and Risks in Iron Treatment?: The Benefits of Intravenous Iron. Semin Dial 2016; 30:20-22. [PMID: 27679413 DOI: 10.1111/sdi.12552] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
Affiliation(s)
- Jay B Wish
- Division of Nephrology, Indiana University Health, Indianapolis, Indiana
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Abstract
Dialysis patients have absolute and functional iron deficiencies. Traditionally, oral iron preparations have been insufficient to maintain iron stores to support erythropoiesis, especially in the setting of the ubiquitous use of erythropoiesis-stimulating agents. This has led to the widespread adoption of intravenous iron protocols designed to maintain iron stores at levels that are much higher than for patients not on dialysis. These protocols are often developed by dialysis providers and may be largely independent of the treating nephrologist. Concerns about multiple risks associated with the use of intravenous iron persist. Despite this, mean ferritin levels in the United States have risen, partly due to more intravenous iron use and partly due to reduced erythropoiesis-stimulating agent use. Questions about the relationship of intravenous iron to infection, cardiac, and hepatobiliary risks remain. The failure of oral iron preparations to maintain iron stores continues to prompt the use of intravenous iron. Recently, studies with oral ferric citrate as a phosphate binder have shown improved iron stores and maintenance of hemoglobin, and studies with soluble ferric pyrophosphate added to dialysate have shown both maintenance of iron stores and hemoglobin. With new iron options that affect iron stores in dialysis patients, the use of intravenous iron and its potential risks may wane.
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Affiliation(s)
- Jamie P Dwyer
- Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee
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40
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Macdougall IC, Bircher AJ, Eckardt KU, Obrador GT, Pollock CA, Stenvinkel P, Swinkels DW, Wanner C, Weiss G, Chertow GM, Adamson JW, Akizawa T, Anker SD, Auerbach M, Bárány P, Besarab A, Bhandari S, Cabantchik I, Collins AJ, Coyne DW, de Francisco ÁL, Fishbane S, Gaillard CA, Ganz T, Goldsmith DJ, Hershko C, Jankowska EA, Johansen KL, Kalantar-Zadeh K, Kalra PA, Kasiske BL, Locatelli F, Małyszko J, Mayer G, McMahon LP, Mikhail A, Nemeth E, Pai AB, Parfrey PS, Pecoits-Filho R, Roger SD, Rostoker G, Rottembourg J, Singh AK, Slotki I, Spinowitz BS, Tarng DC, Tentori F, Toblli JE, Tsukamoto Y, Vaziri ND, Winkelmayer WC, Wheeler DC, Zakharova E. Iron management in chronic kidney disease: conclusions from a “Kidney Disease: Improving Global Outcomes” (KDIGO) Controversies Conference. Kidney Int 2016; 89:28-39. [DOI: 10.1016/j.kint.2015.10.002] [Citation(s) in RCA: 167] [Impact Index Per Article: 18.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2015] [Revised: 09/22/2015] [Accepted: 09/29/2015] [Indexed: 12/21/2022]
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[Use of intravenous iron supplementation in chronic kidney disease: Interests, limits, and recommendations for a better practice]. Nephrol Ther 2015; 11:531-42. [PMID: 26498106 DOI: 10.1016/j.nephro.2015.04.009] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2015] [Revised: 04/19/2015] [Accepted: 04/20/2015] [Indexed: 11/23/2022]
Abstract
Iron deficiency is an important clinical concern in chronic kidney disease (CKD), giving rise to iron-deficiency anaemia, and various impaired cellular functions. Oral supplementation, in particular with ferrous salts, is associated with a high rate of gastro-intestinal side effects and is poorly absorbed, a problem that is avoided with intravenous (IV) irons. Recently, with the approval of the European Medicines Agency's Committee for Medicinal Products for Human Use, the French Agence nationale de sécurité du médicament et des produits de santé (ANSM) took adequate measures to minimize the risk of allergic reactions, by correction on the summary of intravenous iron products characteristics. All IV iron products should be prescribed, administered and injected, inside public or private hospitals exclusively, and a clinical follow-up after the infusion for at least 30 minutes is mandatory. The most stable intravenous iron complexes (low molecular weight iron dextran, ferric carboxymaltose, and iron isomaltoside 1000 [under agreement]) can be given in higher single doses and more rapidly than less recent preparations such as iron sucrose (originator or similars). Test doses are advisable for conventional low molecular weight iron dextrans, but are no more mandatory. Iron supplementation is recommended for all CKD patients with iron-deficiency anaemia and those who receive erythropoiesis-stimulating agents, whether or not they require dialysis. Intravenous iron is the preferred route of administration in haemodialysis patients, with randomized trials showing a significantly greater increase in haemoglobin levels for intravenous versus oral iron and a low rate of treatment-related adverse events during these trials. According ANSM, physicians should apply the product's label recommendations especially the posology. In the non-dialysis CKD population, the erythropoietic response is also significantly higher using intravenous versus oral iron, and tolerability is at least as good. Moreover in some non-dialysis patients, intravenous iron supplementation might avoid or at least delay the need for erythropoiesis-stimulating agents. Following the new ANSM's recommendations, we now have the ability to achieve iron stores replenishment correctly and conveniently in dialysis dependent and non-dialysis dependent CKD patients without compromising safety using the various pharmaceutical forms of iron products especially intravenous compounds.
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Umanath K, Jalal DI, Greco BA, Umeukeje EM, Reisin E, Manley J, Zeig S, Negoi DG, Hiremath AN, Blumenthal SS, Sika M, Niecestro R, Koury MJ, Ma KN, Greene T, Lewis JB, Dwyer JP. Ferric Citrate Reduces Intravenous Iron and Erythropoiesis-Stimulating Agent Use in ESRD. J Am Soc Nephrol 2015; 26:2578-87. [PMID: 25736045 PMCID: PMC4587699 DOI: 10.1681/asn.2014080842] [Citation(s) in RCA: 67] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2014] [Accepted: 12/09/2014] [Indexed: 11/03/2022] Open
Abstract
Ferric citrate (FC) is a phosphate binder with shown efficacy and additional effects on iron stores and use of intravenous (iv) iron and erythropoiesis-stimulating agents (ESAs). We provide detailed analyses of changes in iron/hematologic parameters and iv iron/ESA use at time points throughout the active control period of a phase 3 international randomized clinical trial. In all, 441 subjects were randomized (292 to FC and 149 to sevelamer carbonate and/or calcium acetate [active control (AC)]) and followed for 52 weeks. Subjects on FC had increased ferritin and transferrin saturation (TSAT) levels compared with subjects on AC by week 12 (change in ferritin, 114.1±29.35 ng/ml; P<0.001; change in TSAT, 8.62%±1.57%; P<0.001). Change in TSAT plateaued at this point, whereas change in ferritin increased through week 24, remaining relatively stable thereafter. Subjects on FC needed less iv iron compared with subjects on AC over 52 weeks (median [interquartile range] dose=12.9 [1.0-28.9] versus 26.8 [13.4-47.6] mg/wk; P<0.001), and the percentage of subjects not requiring iv iron was higher with FC (P<0.001). Cumulative ESA over 52 weeks was lower with FC than AC (median [interquartile range] dose=5303 [2023-9695] versus 6954 [2664-12,375] units/wk; P=0.04). Overall, 90.3% of subjects on FC and 89.3% of subjects on AC experienced adverse events. In conclusion, treatment with FC as a phosphate binder results in increased iron parameters apparent after 12 weeks and reduces iv iron and ESA use while maintaining hemoglobin over 52 weeks, with a safety profile similar to that of available binders.
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Affiliation(s)
- Kausik Umanath
- Division of Nephrology and Hypertension, Henry Ford Hospital, Detroit, Michigan;
| | - Diana I Jalal
- Renal Diseases and Hypertension, University of Colorado, Denver, Colorado
| | - Barbara A Greco
- Western New England Renal and Transplant Associates, Baystate Medical Center, Springfield, Massachusetts
| | | | - Efrain Reisin
- Section of Nephrology and Hypertension, Louisiana State University Health Science Center, New Orleans, Louisiana
| | - John Manley
- Mountain Kidney and Hypertension Associates, Asheville, North Carolina
| | - Steven Zeig
- Pines Clinical Research, Pembroke Pines, Florida
| | - Dana G Negoi
- Division of Nephrology, University of Vermont, Burlington, Vermont
| | | | | | | | | | - Mark J Koury
- Hematology and Oncology, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Khe-Ni Ma
- Department of Population Health Sciences, University of Utah, Salt Lake City, Utah
| | - Tom Greene
- Department of Population Health Sciences, University of Utah, Salt Lake City, Utah
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Rodby RA, Umanath K, Niecestro R, Bond TC, Sika M, Lewis J, Dwyer JP. Ferric Citrate, an Iron-Based Phosphate Binder, Reduces Health Care Costs in Patients on Dialysis Based on Randomized Clinical Trial Data. Drugs R D 2015; 15:271-9. [PMID: 26239948 PMCID: PMC4561055 DOI: 10.1007/s40268-015-0103-y] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023] Open
Abstract
BACKGROUND Patients with end-stage renal disease (ESRD) require phosphate binders for hyperphosphatemia and erythropoiesis-stimulating agents (ESAs) and intravenous (i.v.) iron for anemia. Ferric citrate (FC) is a novel, iron-based phosphate binder that increases iron stores and decreases i.v. iron and ESA usage while maintaining hemoglobin levels, and may decrease the cost of ESRD care. The study objectives were to (1) quantify differences in ESA and i.v. iron usage among ESRD patients receiving FC compared with active control (AC) (sevelamer carbonate and/or calcium acetate) on the basis of data from a 52-week phase III clinical trial and (2) standardize trial data to the general United States (US) ESRD population and calculate the potential impact of FC on ESRD cost/patient/year in the USA. STUDY DESIGN The study was a randomized, controlled clinical trial. SETTING AND POPULATION A total of 441 adult subjects with ESRD who received FC or AC for 52 weeks were included. MODEL, PERSPECTIVE, AND TIMELINE Differences in ESA and i.v. iron usage between the treatment groups were modeled over time using generalized linear mixed models and zero-inflated Poisson models. Trends were modeled via logarithmic curves, and utilization patterns were applied to the general dialysis population to estimate expected resource savings. OUTCOMES Study outcomes were costs saved/patient/year using FC versus AC (US dollars). RESULTS Our model suggests an annual decrease of 129,106 U of ESAs and 1960 mg of i.v. iron per patient in the second year after a switch from AC to FC. Applying 2013 Medicare pricing, this would save $1585 in ESAs and $516 in i.v. iron: a total of $2101/patient/year; these savings would be expected to double for managed care plans. LIMITATIONS The projections were made on 1 year of trial data. CONCLUSIONS Phosphate binding with FC reduces i.v. iron and ESA usage. Given the high cost burden of ESRD, our model demonstrates significant potential cost savings. TRIAL REGISTRATION ClinicalTrials.gov (NCT01191255) http://clinicaltrials.gov/ct2/show/NCT01191255 .
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Malkinska M. Outcomes Associated with Conventional Accelerated Versus Once-Weekly IV Iron Therapy in Outpatients Undergoing Hemodialysis. Can J Hosp Pharm 2015; 68:304-310. [PMID: 26327704 PMCID: PMC4552231] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/04/2023]
Abstract
BACKGROUND Although parenteral iron replacement is a key aspect of managing anemia in patients who are undergoing hemodialysis, studies evaluating novel iron dosing regimens are scarce. OBJECTIVE To compare the effectiveness of a once-weekly IV iron dosing strategy with that of a conventional accelerated iron dosing regimen in patients undergoing hemodialysis. METHODS In this retrospective cohort study, patient-specific information was collected for individuals undergoing hemodialysis who received IV iron between June 1, 2010, and June 30, 2012, at a community hospital in southwestern Ontario. The primary outcomes were hemoglobin level and utilization of an erythropoiesis-stimulating agent for 2 groups of patients: those receiving iron according to a once-weekly IV regimen and those receiving iron by a conventional accelerated IV regimen. RESULTS Of the 148 patients who met the inclusion criteria, 99 (66.9%) received iron by a conventional accelerated regimen and 49 (33.1%) by a once-weekly IV regimen. Generalized estimating equations developed from 313 observations obtained from these 148 patients suggested that average transferrin saturation percentage and iron concentration were both significantly higher in the group that received iron once weekly than in the group that received iron by the conventional accelerated regimen (p = 0.014 and 0.008, respectively). The mean weekly dose of erythropoiesis-stimulating agent was significantly lower in the once-weekly administration group than in the conventional administration group (7419 versus 10 706 units; p = 0.041). The 2 groups did not differ significantly in terms of hemoglobin concentration (p = 0.46) or ferritin level (p = 0.13). CONCLUSIONS The findings of this study suggest that a once-weekly iron dosing regimen may be superior to a conventional accelerated dosing regimen for managing iron deficiency anemia in patients who are undergoing hemodialysis.
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Affiliation(s)
- Marta Malkinska
- Address correspondence to: Marta Malkinska, Department of Nephrology, Sunnybrook Health Sciences Centre, 2075 Bayview Avenue, Toronto ON M4N 3M5, e-mail:
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Charytan DM, Pai AB, Chan CT, Coyne DW, Hung AM, Kovesdy CP, Fishbane S. Considerations and challenges in defining optimal iron utilization in hemodialysis. J Am Soc Nephrol 2015; 26:1238-47. [PMID: 25542967 PMCID: PMC4446883 DOI: 10.1681/asn.2014090922] [Citation(s) in RCA: 66] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023] Open
Abstract
Trials raising concerns about erythropoiesis-stimulating agents, revisions to their labeling, and changes to practice guidelines and dialysis payment systems have provided strong stimuli to decrease erythropoiesis-stimulating agent use and increase intravenous iron administration in recent years. These factors have been associated with a rise in iron utilization, particularly among hemodialysis patients, and an unprecedented increase in serum ferritin concentrations. The mean serum ferritin concentration among United States dialysis patients in 2013 exceeded 800 ng/ml, with 18% of patients exceeding 1200 ng/ml. Although these changes are broad based, the wisdom of these practices is uncertain. Herein, we examine influences on and trends in intravenous iron utilization and assess the clinical trial, epidemiologic, and experimental evidence relevant to its safety and efficacy in the setting of maintenance dialysis. These data suggest a potential for harm from increasing use of parenteral iron in dialysis-dependent patients. In the absence of well powered, randomized clinical trials, available evidence will remain inadequate for making reliable conclusions about the effect of a ubiquitous therapy on mortality or other outcomes of importance to dialysis patients. Nephrology stakeholders have an urgent obligation to initiate well designed investigations of intravenous iron in order to ensure the safety of the dialysis population.
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Affiliation(s)
| | - Amy Barton Pai
- Pharmacy Practice, Brigham & Women's Hospital, Boston, Massachusetts; Albany College of Pharmacy and Health Sciences, Albany, New York
| | - Christopher T Chan
- Renal Division and Toronto General Hospital, University Health Network, Ontario, Canada
| | - Daniel W Coyne
- Renal Division and Washington University, Saint Louis, Missouri
| | - Adriana M Hung
- Nephrology Division, Departments of Medicine and Vanderbilt University Medical Center, Nashville, Tennessee
| | - Csaba P Kovesdy
- Nephrology Division, Departments of Medicine and University of Tennessee Health Science Center, Memphis, Tennessee; and
| | - Steven Fishbane
- Renal Division and Hofstra North Shore-LIJ School of Medicine, Great Neck, New York
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Abstract
The practice of intravenous iron supplementation has grown as nephrologists have gradually moved away from the liberal use of erythropoiesis-stimulating agents as the main treatment for the anemia of CKD. This approach, together with the introduction of large-dose iron preparations, raises the future specter of inadvertent iatrogenic iron toxicity. Concerns have been raised in original studies and reviews about cardiac complications and severe infections that result from long-term intravenous iron supplementation. Regarding the iron preparations specifically, even though all the currently available preparations appear to be relatively safe in the short term, little is known regarding their long-term safety. In this review we summarize current knowledge of iron metabolism with an emphasis on the sources and potentially harmful effects of labile iron, highlight the approaches to identifying labile iron in pharmaceutical preparations and body fluids and its potential toxic role as a pathogenic factor in the complications of CKD, and propose methods for its early detection in at-risk patients.
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Affiliation(s)
- Itzchak Slotki
- Division of Adult Nephrology, Shaare Zedek Medical Center and Hadassah Hebrew University of Jerusalem, Jerusalem, Israel; and
| | - Zvi Ioav Cabantchik
- Department of Biological Chemistry, Alexander Silberman Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem, Israel
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Del Vecchio L, Locatelli F. Anemia in chronic kidney disease patients: treatment recommendations and emerging therapies. Expert Rev Hematol 2015; 7:495-506. [PMID: 25025373 DOI: 10.1586/17474086.2014.941349] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Erythropoiesis-stimulating agents (ESA) and iron have been available since decades to treat anemia of chronic kidney disease (CKD). However, many grey areas surround the field. The optimal hemoglobin (Hb) target to aimed at with ESA, the general safety of ESA and boundaries to not be exceeded with iron supplementation are still to be clearly defined. New strategies to stimulate erythropoiesis and new iron molecules have been developed; the most promising approach is the manipulation of the hypoxia-inducible transcription factor (HIF) system. The regulation of activin A pathway is another option with good potential, also considering the additional advantage of increasing bone mass. New iron molecule for intravenous administration may be useful to reduce the number of doses to be administered.
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Affiliation(s)
- Lucia Del Vecchio
- Department of Nephrology and Dialysis, A. Manzoni Hospital, Lecco, Italy
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Effect of aggressively driven intravenous iron therapy on infectious complications in end-stage renal disease patients on maintenance hemodialysis. Am J Ther 2015; 21:250-3. [PMID: 22832501 DOI: 10.1097/mjt.0b013e31825425bd] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
For treating end-stage renal disease-associated anemia, various strategies to achieve optimal hemoglobin levels with lower erythropoiesis stimulating agent doses are being tried. One of these involves the use of a high dose [transferrin saturation (TSAT) >30%] of intravenous (IV) iron supplementation. However, due to in vitro effects of iron on stimulating bacterial growth, there are concerns of increased risk of infection. The safety of higher iron targets with respect to infectious complications (bacteremias, pneumonias, soft tissue infections, and osteomyelitis) is unknown. This was a retrospective study of patients on maintenance hemodialysis from a single, urban dialysis center to assess the long-term impact of the higher cumulative use of IV iron, on the incidence of clinically important infections. Our iron protocol was modified in June 2010 to aim for TSAT >30% unless serum ferritin levels were >1200 ng/mL. Data from only those patients who had been on dialysis for the whole duration between June 2009 and May 2011 were included. A total of 140 patients with end-stage renal disease on hemodialysis patients were found to be eligible for the study. There was a statistically significant increase in the mean TSAT and mean serum ferritin with the new anemia management protocol with a significant decrease in the mean erythropoiesis stimulating agent dose requirement. There was no statistically significant increase in the incidence of infectious complications. Although in vitro effects of iron are known to stimulate bacterial growth, a higher IV dose of iron may not increase the risk of infection in such patients.
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Gillespie IA, Macdougall IC, Richards S, Jones V, Marcelli D, Froissart M, Eckardt KU. Factors precipitating erythropoiesis-stimulating agent responsiveness in a European haemodialysis cohort: case-crossover study. Pharmacoepidemiol Drug Saf 2015; 24:414-26. [PMID: 25690434 PMCID: PMC5024014 DOI: 10.1002/pds.3755] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2014] [Revised: 12/01/2014] [Accepted: 12/18/2014] [Indexed: 01/05/2023]
Abstract
Purpose Hyporesponsiveness to erythropoiesis‐stimulating agents (ESAs) is clinically and economically important in the treatment of anaemia in chronic kidney disease (CKD) patients. Previous studies focused on baseline predictors of ESA hyporesponsiveness, rather than factors associated with the transition to this state. Reversibility of ESA hyporesponsiveness has also not been studied previously. Methods Case‐crossover methodology was applied to a cohort of 6645 European CKD patients undergoing haemodialysis and prescribed ESAs. Ninety‐day ESA exposure periods were defined, haemoglobin (Hb) response was calculated using the last 30 days of one period and the first 30 days of the next, and periods were classified based on a median ESA dose (80.8 IU/kg/week) and a 10 g/dL Hb threshold. Clinical, dialysis and laboratory data from patients' first hyporesponsive ‘case’ period was compared with the preceding responsive ‘control’ period using conditional logistic regression. A similar approach was applied to hyporesponsiveness reversal. Results Of the patients, 672 experienced hyporesponsiveness periods with preceding responsive periods; 711 reversed to normality from hyporesponsiveness periods. Transition to hyporesponsiveness was associated with hospitalization, vascular access changes or worsening inflammation, with these factors accounting for over two‐thirds of transitions. Findings were largely insensitive to alternative ESA doses and Hb thresholds. Continued hospitalization, catheter insertion and uncontrolled secondary hyperparathyroidism were associated with a lack of regain of responsiveness. Conclusions Transition to hyporesponsiveness is linked to the development of conditions such as hospitalization events, vascular access issues or episodes of systemic inflammation. However, a third of hyporesponsive episodes remain unexplained. © 2015 The Authors. Pharmacoepidemiology and Drug Safety published by John Wiley & Sons Ltd.
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Affiliation(s)
- Iain A Gillespie
- Center for Observational Research (CfOR), Amgen Ltd, Uxbridge, UK
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Rodby R, Umanath K, Niecestro R, Jackson JH, Sika M, Lewis JB, Dwyer JP. Phosphorus binding with ferric citrate is associated with fewer hospitalizations and reduced hospitalization costs. Expert Rev Pharmacoecon Outcomes Res 2014; 15:545-50. [PMID: 25495878 DOI: 10.1586/14737167.2015.995169] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
BACKGROUND Ferric citrate (FC) is a new phosphorus binder shown to increase serum iron stores while reducing intravenous iron and erythropoiesis-stimulating agent usage. Such reductions could lower hospitalization rates and associated costs. METHODS Hospitalizations during a Phase III trial were compared between FC and active control (AC). Hospitalization costs were estimated using the 2013 US Renal Data System Annual Data Report. RESULTS 34.6% of FC patients were hospitalized at least once versus 45.6% of the AC group (risk reduction 24.2%; p = 0.02). There were 181 unique hospitalizations in the FC group versus 239 in the AC group, for a difference of 58 hospitalizations. Total potential savings was US$ 867,622 in hospitalization costs in the FC group. If the hospitalization reduction in our study was applied to the general end-stage renal disease population, this could translate into a savings of US$ 3002/patient/year. CONCLUSIONS Patients receiving FC experienced fewer hospitalizations with the potential for significant savings.
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Affiliation(s)
- Roger Rodby
- Rush University, 1426 W. Washington Blvd, Chicago, IL 60607, USA
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