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Murillo Ortiz BO, Ramírez Emiliano J, Romero Vázquez MJ, Amador Medina LF, Martínez Garza S, Ramos Rodríguez EM. Impact of iron chelation with deferasirox on telomere length and oxidative stress in hemodialysis patients: A randomized study. Nefrologia 2025; 45:68-76. [PMID: 39884801 DOI: 10.1016/j.nefroe.2025.01.003] [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: 02/12/2024] [Accepted: 06/12/2024] [Indexed: 02/01/2025] Open
Abstract
BACKGROUND Recent studies have demonstrated the effectiveness, safety, and tolerability of deferasirox in patients in peritoneal dialysis, however, its effect has not been studied in patients undergoing hemodialysis. OBJECTIVE To investigate the impact of iron chelation on telomere length, oxidative stress, and ferritin levels in patients undergoing hemodialysis. METHODS This is an open-label study, with a control group of patients undergoing hemodialysis, who will receive treatment with deferasirox 15mg/kg/day for 6 months for iron chelation. Telomere length was measured using real-time PCR. Serum ferritin levels and oxidation markers were evaluated. To evaluate the pharmacokinetics and safety of deferasirox, plasma concentrations were analyzed by HPLC. RESULTS Fifty-four patients were included to receive deferasirox, and a control group of 50 patients. Significant differences were observed in serum ferritin levels (p<0.0001), TBARS (thiobarbituric acid reactive substances) (p<0.01). Telomere length had a significant increase after chelation (p<0.001). The serum deferasirox concentration at zero time at 48h was maintained within a range of 2.67-23.78mmol/L. CONCLUSIONS Our results demonstrate that iron chelation in hemodialysis patients significantly reduces ferritin and TBARS, resulting in an increase in telomere length. Deferasirox proves to be beneficial for patients with iron overload undergoing hemodialysis.
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Affiliation(s)
- Blanca Olivia Murillo Ortiz
- Clinical Epidemiology Research Unit, OOAD Guanajuato, Mexican Institute of Social Security, León, Guanajuato, Mexico.
| | - Joel Ramírez Emiliano
- Department of Medical Sciences, Health Sciences Division, University of Guanajuato, León, Guanajuato, Mexico
| | - Marcos Javier Romero Vázquez
- Clinical Epidemiology Research Unit, OOAD Guanajuato, Mexican Institute of Social Security, León, Guanajuato, Mexico
| | - Lauro Fabián Amador Medina
- Clinical Epidemiology Research Unit, OOAD Guanajuato, Mexican Institute of Social Security, León, Guanajuato, Mexico
| | - Sandra Martínez Garza
- Clinical Epidemiology Research Unit, OOAD Guanajuato, Mexican Institute of Social Security, León, Guanajuato, Mexico
| | - Edna Montserrat Ramos Rodríguez
- Department of Hemodialysis, Hospital General Regional No. 58, Mexican Institute of Social Security, León, Guanajuato, Mexico
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Nashwan AJ, Yassin M. Lessons from Beta-Thalassemia for Improving Iron Overload Monitoring and Management in Kidney Failure. Cureus 2025; 17:e77620. [PMID: 39963620 PMCID: PMC11831958 DOI: 10.7759/cureus.77620] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/17/2025] [Indexed: 02/20/2025] Open
Abstract
Iron overload is a well-recognized complication in patients suffering from beta-thalassemia major (BTM) and end-stage renal disease (ESRD), recently known as kidney failure (KF), particularly in those who receive frequent blood transfusions or long-term iron supplementation. The mechanisms leading to iron overload differ slightly between these two conditions, but the management principles share considerable overlap. Lessons learned from monitoring and managing iron overload in patients with BTM can provide valuable insights into managing iron overload in patients with KF. This narrative review explores the parallels between these two conditions concerning iron overload, emphasizing the importance of early detection, personalized therapy, multidisciplinary care, patient education, and preventive strategies.
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Affiliation(s)
- Abdulqadir J Nashwan
- Nursing & Midwifery Research Department, Hamad Medical Corporation, Doha, QAT
- Department of Public Health, College of Health Sciences, QU Health, Qatar University, Doha, QAT
| | - Mohamed Yassin
- Department of Hematology, National Centre for Cancer Care and Research, Hamad Medical Corporation, Doha, QAT
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Nashwan AJ, Abuawwad MT, Jaradat JH, Ibraheem A, Yassin MA, Taha MJJ. Prevalence of iron overload in patients with chronic kidney disease on peritoneal dialysis: A scoping review. Health Sci Rep 2024; 7:e2255. [PMID: 39253350 PMCID: PMC11381317 DOI: 10.1002/hsr2.2255] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2024] [Revised: 06/24/2024] [Accepted: 07/03/2024] [Indexed: 09/11/2024] Open
Abstract
BACKGROUND AND AIMS Chronic kidney disease (CKD) patients undergoing peritoneal dialysis (PD) are susceptible to complications, including iron overload, which can significantly impact their prognosis and overall health. This scoping review aimed to study the prevalence and implications of iron overload in CKD patients undergoing PD. METHODS A comprehensive search was conducted across five databases, leading to the selection of 18 papers for in-depth analysis. These studies collectively involved 381 PD patients, 60.3% were males. RESULTS No consensus was reached regarding the exact diagnostic cutoff for iron overload. The investigations revealed four main aspects: (1) Seven papers identified various factors contributing to iron overload, emphasizing the role of different iron supplements and magnetic resonance imaging's capability to diagnose iron accumulation in organs; (2) Iron overload in young patients was found to hinder growth; (3) Six studies highlighted the adverse effects of iron overload, with cardiac issues being the most significant; (4) Three studies demonstrated the efficacy of iron-chelating agents, Deferoxamine and Deferasirox, in treating iron overload patients undergoing PD. Overall, the estimated prevalence of liver iron overload in CKD patients on PD ranges from approximately 10% to 28.6%, which is far lower than the prevalence of 75% elegantly shown in HD patients. CONCLUSION While iron overload was a significant concern for CKD patients undergoing PD in the past, it is less common in the current era due to advancements in treatments, such as erythropoiesis-stimulating agents. Treatment with specific chelation agents has proven beneficial, but there is also a risk of adverse effects, necessitating meticulous monitoring and timely intervention.
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Affiliation(s)
- Abdulqadir J. Nashwan
- Nursing & Midwifery Research DepartmentHamad Medical CorporationDohaQatar
- Department of Public Health, College of Health Sciences, QU HealthQatar UniversityDohaQatar
| | - Mohammad T. Abuawwad
- Clinical Medicine Department, Kasr Alainy Faculty of MedicineCairo UniversityCairoEgypt
| | | | - Anas Ibraheem
- Haematology DepartmentKing's College HospitalLondonUnited Kingdom
| | - Mohamed A. Yassin
- Hematology and Oncology Department, National Center for Cancer Care & ResearchHamad Medical CorporationDohaQatar
| | - Mohammad J. J. Taha
- Clinical Medicine Department, Kasr Alainy Faculty of MedicineCairo UniversityCairoEgypt
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Lanser L, Plaikner M, Fauser J, Petzer V, Denicolò S, Haschka D, Neuwirt H, Stefanow K, Rudnicki M, Kremser C, Henninger B, Weiss G. Tissue Iron Distribution in Anemic Patients with End-Stage Kidney Disease: Results of a Pilot Study. J Clin Med 2024; 13:3487. [PMID: 38930016 PMCID: PMC11204586 DOI: 10.3390/jcm13123487] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2024] [Revised: 06/07/2024] [Accepted: 06/11/2024] [Indexed: 06/28/2024] Open
Abstract
Background/Objectives: Anemia is a frequent multifactorial co-morbidity in end-stage kidney disease (ESKD) associated with morbidity and poor QoL. Apart from insufficient erythropoietin formation, iron deficiency (ID) contributes to anemia development. Identifying patients in need of iron supplementation with current ID definitions is difficult since no good biomarker is available to detect actual iron needs. Therefore, new diagnostic tools to guide therapy are needed. Methods: We performed a prospective cohort study analyzing tissue iron content with MRI-based R2*-relaxometry in 20 anemic ESKD patients and linked it with iron biomarkers in comparison to 20 otherwise healthy individuals. Results: ESKD patients had significantly higher liver (90.1 s-1 vs. 36.1 s-1, p < 0.001) and spleen R2* values (119.8 s-1 vs. 19.3 s-1, p < 0.001) compared to otherwise healthy individuals, while their pancreas and heart R2* values did not significantly differ. Out of the 20 ESKD patients, 17 had elevated spleen and 12 had elevated liver R2* values. KDIGO guidelines (focusing on serum iron parameters) would recommend iron supplementation in seven patients with elevated spleen and four patients with elevated liver R2* values. Conclusions: These findings highlight that liver and especially spleen iron concentrations are significantly higher in ESKD patients compared to controls. Tissue iron overload diverged from classical iron parameters suggesting need of iron supplementation. Measurement of MRI-guided tissue iron distribution might help guide treatment of anemic ESKD patients.
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Affiliation(s)
- Lukas Lanser
- Department of Internal Medicine II, Medical University of Innsbruck, 6020 Innsbruck, Austria
| | - Michaela Plaikner
- Department of Radiology, Medical University of Innsbruck, 6020 Innsbruck, Austria
| | - Josia Fauser
- Department of Internal Medicine V, Medical University of Innsbruck, 6020 Innsbruck, Austria
| | - Verena Petzer
- Department of Internal Medicine V, Medical University of Innsbruck, 6020 Innsbruck, Austria
| | - Sara Denicolò
- Department of Internal Medicine IV, Medical University of Innsbruck, 6020 Innsbruck, Austria
| | - David Haschka
- Department of Internal Medicine II, Medical University of Innsbruck, 6020 Innsbruck, Austria
| | - Hannes Neuwirt
- Department of Internal Medicine IV, Medical University of Innsbruck, 6020 Innsbruck, Austria
| | - Kiril Stefanow
- Department of Internal Medicine IV, Medical University of Innsbruck, 6020 Innsbruck, Austria
| | - Michael Rudnicki
- Department of Internal Medicine IV, Medical University of Innsbruck, 6020 Innsbruck, Austria
| | - Christian Kremser
- Department of Radiology, Medical University of Innsbruck, 6020 Innsbruck, Austria
| | - Benjamin Henninger
- Department of Radiology, Medical University of Innsbruck, 6020 Innsbruck, Austria
| | - Guenter Weiss
- Department of Internal Medicine II, Medical University of Innsbruck, 6020 Innsbruck, Austria
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Odeh D, Oršolić N, Adrović E, Bilandžić N, Sedak M, Žarković I, Lesar N, Balta V. The Impact of the Combined Effect of Inhalation Anesthetics and Iron Dextran on Rats' Systemic Toxicity. Int J Mol Sci 2024; 25:6323. [PMID: 38928030 PMCID: PMC11203443 DOI: 10.3390/ijms25126323] [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: 05/18/2024] [Revised: 06/04/2024] [Accepted: 06/05/2024] [Indexed: 06/28/2024] Open
Abstract
Disruption of any stage of iron homeostasis, including uptake, utilization, efflux, and storage, can cause progressive damage to peripheral organs. The health hazards associated with occupational exposure to inhalation anesthetics (IA) in combination with chronic iron overload are not well documented. This study aimed to investigate changes in the concentration of essential metals in the peripheral organs of rats after iron overload in combination with IA. The aim was also to determine how iron overload in combination with IA affects tissue metal homeostasis, hepcidin-ferritin levels, and MMP levels according to physiological, functional, and tissue features. According to the obtained results, iron accumulation was most pronounced in the liver (19×), spleen (6.7×), lungs (3.1×), and kidneys (2.5×) compared to control. Iron accumulation is associated with elevated heavy metal levels and impaired essential metal concentrations due to oxidative stress (OS). Notably, the use of IA increases the iron overload toxicity, especially after Isoflurane exposure. The results show that the regulation of iron homeostasis is based on the interaction of hepcidin, ferritin, and other proteins regulated by inflammation, OS, free iron levels, erythropoiesis, and hypoxia. Long-term exposure to IA and iron leads to the development of numerous adaptation mechanisms in response to toxicity, OS, and inflammation. These adaptive mechanisms of iron regulation lead to the inhibition of MMP activity and reduction of oxidative stress, protecting the organism from possible damage.
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Affiliation(s)
- Dyana Odeh
- Division of Animal Physiology, Faculty of Science, University of Zagreb, Rooseveltov trg 6, 10000 Zagreb, Croatia
| | - Nada Oršolić
- Division of Animal Physiology, Faculty of Science, University of Zagreb, Rooseveltov trg 6, 10000 Zagreb, Croatia
| | - Emanuela Adrović
- Division of Animal Physiology, Faculty of Science, University of Zagreb, Rooseveltov trg 6, 10000 Zagreb, Croatia
| | - Nina Bilandžić
- Laboratory for Determination of Residues, Croatian Veterinary Institute, Savska cesta 143, 10000 Zagreb, Croatia
| | - Marija Sedak
- Laboratory for Determination of Residues, Croatian Veterinary Institute, Savska cesta 143, 10000 Zagreb, Croatia
| | - Irena Žarković
- Laboratory for Analysis of Veterinary Medicinal Products, Croatian Veterinary Institute, Savska cesta 143, 10000 Zagreb, Croatia
| | - Nikola Lesar
- Division of Animal Physiology, Faculty of Science, University of Zagreb, Rooseveltov trg 6, 10000 Zagreb, Croatia
| | - Vedran Balta
- Division of Animal Physiology, Faculty of Science, University of Zagreb, Rooseveltov trg 6, 10000 Zagreb, Croatia
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Navarrete JE, Ajiboye O, Lea JI. Biochemical markers of iron status and iron accumulation in peritoneal dialysis patients treated with ferric citrate. Perit Dial Int 2024; 44:133-140. [PMID: 37691436 DOI: 10.1177/08968608231197361] [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: 09/12/2023] Open
Abstract
BACKGROUND Hyperphosphataemia is a common complication of kidney disease. Current dialysis techniques do not provide enough phosphorus clearance, hence the need to use phosphorus binders. Treatment options include calcium carbonate, calcium acetate, lanthanum carbonate, sevelamer hydrochloride and iron-based binders. Patients receiving peritoneal dialysis (PD) with sustained elevated ferritin levels exceeding 800 ng/mL are at a higher risk of death. We identify PD patients treated with iron-based binders and compare ferritin and risk of iron accumulation to patients treated with non-iron-based binders. METHODS All records of patients receiving PD at Emory dialysis centres until 30 October 2021 were reviewed for phosphorus binders. Basic demographics and laboratory data were time-referenced to the days on treatment with a particular binder. Patients were followed until discontinuation of the phosphorus binder, death, transplant, transfer to another dialysis provider or censoring at 36 months after medication was started. RESULTS Compared to calcium acetate and sevelamer, ferric citrate utilisation in PD patients resulted in a sustained increase in ferritin. The proportion of patients with a ferritin equal to or greater than 800 ng/dL and transferrin saturation greater than 40% increased over time in patients treated with ferric citrate and was higher during the second and third year of follow-up compared to baseline values and to patients treated with calcium acetate or sevelamer. Two patients (7%) treated with ferric citrate developed clinically significant haemosiderosis. CONCLUSIONS Use of ferric citrated in PD resulted in significant iron accumulation as judged by ferritin levels.
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Affiliation(s)
| | | | - Janice I Lea
- Renal Division, Emory University School of Medicine, USA
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7
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Rostoker G, Dekeyser M, Francisco S, Loridon C, Griuncelli M, Languille-Llitjos E, Boulahia G, Cohen Y. Relationship between bone marrow iron load and liver iron concentration in dialysis-associated haemosiderosis. EBioMedicine 2024; 99:104929. [PMID: 38128412 PMCID: PMC10776950 DOI: 10.1016/j.ebiom.2023.104929] [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: 06/14/2023] [Revised: 12/01/2023] [Accepted: 12/05/2023] [Indexed: 12/23/2023] Open
Abstract
BACKGROUND Iron overload due to the excessive use of parenteral iron in haemodialysis is now an increasingly recognised clinical issue. Before erythropoiesis-stimulating agents (ESA) were introduced, a specific feature of patients treated by dialysis and having iron overload was that iron levels in the bone marrow were paradoxically low in most of them, despite severe hepatosplenic siderosis. Whether or not this paradox persists in the actual ESA era was unknown until recently, when an autopsy study in 21 patients treated by haemodialysis revealed similarities between liver and bone marrow iron content. The aim of this study was to further explore these recent findings in a cohort of alive patients on dialysis and to analyse the determinants of iron bone marrow. METHODS Liver iron concentration (LIC) and vertebral T2∗ (a surrogate marker of bone marrow iron) were analysed retrospectively in 152 alive patients on dialysis (38.8% female) of whom 47.4% had iron overload by quantitative magnetic resonance imaging (MRI). FINDINGS Vertebral T2∗ differed significantly between patients classified according to liver iron content at MRI: those with mild or moderate and severe liver iron overload had increased vertebral iron content at R2∗ relaxometry MRI (mild: vertebral T2∗ = 9.9 ms (4-24.8); moderate and severe: vertebral T2∗ = 8.5 ms (4.9-22.8)) when compared to patients with normal LIC (vertebral T2∗ = 13.2 ms (6.6-30.5) (p < 0.0001 Kruskal-Wallis test)). INTERPRETATION The paradoxical discrepancy between bone marrow and liver iron-storage compartments observed in the pre-ESA era has disappeared today, as shown by a recent autopsy study and the present study in a cohort of alive patients treated by dialysis. FUNDING None.
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Affiliation(s)
- Guy Rostoker
- Division of Nephrology and Dialysis, Ramsay Santé, Hôpital Privé Claude Galien, Quincy-sous-Sénart 91480, France; Collège de Médecine des Hôpitaux de Paris, 10 Rue des Fossés Saint-Marcel, Paris 75005, France.
| | - Manon Dekeyser
- Department of Nephrology, Regional University Centre, Orléans and INSERM 1186, Gustave Roussy Institute, Paris-Saclay University, Villejuif, Paris, France
| | - Sergio Francisco
- Division of Radiology, Ramsay Santé, Hôpital Privé Claude Galien, Quincy-sous-Sénart 91480, France
| | - Christelle Loridon
- Division of Nephrology and Dialysis, Ramsay Santé, Hôpital Privé Claude Galien, Quincy-sous-Sénart 91480, France
| | - Mireille Griuncelli
- Division of Nephrology and Dialysis, Ramsay Santé, Hôpital Privé Claude Galien, Quincy-sous-Sénart 91480, France
| | - Eva Languille-Llitjos
- Division of Nephrology and Dialysis, Ramsay Santé, Hôpital Privé Claude Galien, Quincy-sous-Sénart 91480, France
| | - Ghada Boulahia
- Division of Nephrology and Dialysis, Ramsay Santé, Hôpital Privé Claude Galien, Quincy-sous-Sénart 91480, France
| | - Yves Cohen
- Division of Radiology, Ramsay Santé, Hôpital Privé Claude Galien, Quincy-sous-Sénart 91480, France
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8
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Toida T, Sato Y, Komatsu H, Fujimoto S. Association of Estimated Total Body Iron with All-Cause Mortality in Japanese Hemodialysis Patients: The Miyazaki Dialysis Cohort Study. Nutrients 2023; 15:4658. [PMID: 37960311 PMCID: PMC10649821 DOI: 10.3390/nu15214658] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2023] [Revised: 10/28/2023] [Accepted: 11/02/2023] [Indexed: 11/15/2023] Open
Abstract
Iron deficiency/excess may be associated with worse prognosis in patients undergoing hemodialysis. This study ascertained the association of the estimated total body iron (TBI) with mortality in patients receiving hemodialysis. Multicenter clinical data collected in the Miyazaki Dialysis Cohort Study from 943 patients receiving hemodialysis were analyzed after stratification into tertile categories by baseline TBI-estimated as the heme iron plus iron storage from ferritin levels. The primary outcome was a 5-year all-cause mortality; hazard ratios of the TBI-all-cause mortality association were estimated using Cox models adjusted for potential confounders, including clinical characteristics, laboratory, and drug data, wherein patients with high TBI were the reference category. The receiver operating characteristic (ROC) curve analyses of TBI, serum ferritin levels, and transferrin saturation were performed to predict all-cause mortality; a total of 232 patients died during the follow-up. The low TBI group (<1.6 g) had significantly higher hazard ratios of mortality than the high TBI group (≥2.0 g). As ROC curve analyses showed, TBI predicted mortality more accurately than either levels of serum ferritin or transferrin saturation. Lower TBI increases the mortality risk of Japanese hemodialysis patients, and further studies should examine whether iron supplementation therapy that avoids low TBI improves prognosis.
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Affiliation(s)
- Tatsunori Toida
- School of Pharmaceutical Sciences, Kyushu University of Health and Welfare, Nobeoka City 882-8508, Miyazaki, Japan
| | - Yuji Sato
- Department of Internal Medicine, Division of Nephrology, National Health Insurance Takachiho Town Hospital, Takachiho 889-1101, Miyazaki, Japan;
| | - Hiroyuki Komatsu
- Center for Medical Education and Career Development, Faculty of Medicine, University of Miyazaki, Miyazaki City 889-16095, Miyazaki, Japan;
| | - Shouichi Fujimoto
- Department of Medical Environment Innovation, Faculty of Medicine, University of Miyazaki, Miyazaki City 889-1609, Miyazaki, Japan;
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9
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Onder AM, Ansari MAY, Deng F, Grinsell MM, Patterson L, Jetton J, Fathallah-Shaykh S, Ranch D, Aviles D, Copelovitch L, Ellis E, Chadha V, Elmaghrabi A, Lin JJ, Butani L, Haddad M, Marsenic O, Brakeman P, Quigley R, Shin HS, Garro R, Raina R, Langman CB. Persistent Increase in Serum Ferritin Levels despite Converting to Permanent Vascular Access in Pediatric Hemodialysis Patients: Pediatric Nephrology Research Consortium Study. J Clin Med 2023; 12:4251. [PMID: 37445286 DOI: 10.3390/jcm12134251] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2023] [Revised: 06/19/2023] [Accepted: 06/22/2023] [Indexed: 07/15/2023] Open
Abstract
Our objective was to examine serum ferritin trends after conversion to permanent vascular access (PVA) among children who started hemodialysis (HD) using tunneled cuffed catheters (TCC). Retrospective chart reviews were completed on 98 subjects from 20 pediatric HD centers. Serum ferritin levels were collected at the creation of PVA and for two years thereafter. There were 11 (11%) arteriovenous grafts (AVG) and 87 (89%) arteriovenous fistulae (AVF). Their mean TCC use was 10.4 ± 17.3 months. Serum ferritin at PVA creation was elevated at 562.64 ± 492.34 ng/mL, increased to 753.84 ± 561.54 ng/mL (p = < 0.001) in the first year and remained at 759.60 ± 528.11 ng/mL in the second year (p = 0.004). The serum ferritin levels did not show a statistically significant linear association with respective serum hematocrit values. In a multiple linear regression model, there were three predictors of serum ferritin during the first year of follow-up: steroid-resistant nephrotic syndrome as primary etiology (p = 0.035), being from a center that enrolled >10 cases (p = 0.049) and baseline serum ferritin level (p = 0.017). Increasing serum ferritin after conversion to PVA is concerning. This increase is not associated with serum hematocrit trends. Future studies should investigate the correlation of serum transferrin saturation and ferritin levels in pediatric HD patients.
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Affiliation(s)
- Ali Mirza Onder
- Division of Pediatric Nephrology, Batson Children's Hospital of Mississippi, University of Mississippi, Jackson, MS 39216, USA
- Division of Pediatric Nephrology, Nemours Children's Hospital, Delaware, Wilmington, DE 19803, USA
| | - Md Abu Yusuf Ansari
- Department of Data Science, University of Mississippi Medical Center, Jackson, MS 39216, USA
| | - Fang Deng
- Kidney Diseases Division, Feinberg School of Medicine, Northwestern University, Ann and Robert H Lurie Children's Hospital of Chicago, Chicago, IL 60611, USA
| | - Matthew M Grinsell
- Division of Pediatric Nephrology, Primary Children's Hospital, University of Utah, Salt Lake City, UT 84112, USA
| | - Larry Patterson
- Division of Pediatric Nephrology, Children's National Health System, Washington, DC 20010, USA
| | - Jennifer Jetton
- Division of Nephrology, Dialysis and Transplantation, University of Iowa Stead Family Children's Hospital, Iowa City, IA 52242, USA
| | - Sahar Fathallah-Shaykh
- Division of Pediatric Nephrology, Children's of Alabama, University of Alabama, Birmingham, AL 35233, USA
| | - Daniel Ranch
- Division of Pediatric Nephrology, University of Texas Health Science Center, San Antonio, TX 78229, USA
| | - Diego Aviles
- Division of Pediatric Nephrology, Children's Hospital New Orleans, LSU Heath School of Medicine, New Orleans, LA 70118, USA
| | - Lawrence Copelovitch
- Division of Nephrology, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA
| | - Eileen Ellis
- Division of Pediatric Nephrology, Arkansas Children's Hospital, Little Rock, AR 72202, USA
| | - Vimal Chadha
- Division of Pediatric Nephrology, Children's Mercy Hospital, Kansas City, MO 64108, USA
| | - Ayah Elmaghrabi
- Division of Pediatric Nephrology, Children's Medical Center Dallas, UT Southwestern, Dallas, TX 75235, USA
| | - Jen-Jar Lin
- Division of Pediatric Nephrology, Brenner Children's Hospital, Wake Forest University, Winston Salem, NC 27157, USA
| | - Lavjay Butani
- Division of Pediatric Nephrology, UC Davis Children's Hospital, Sacramento, CA 95817, USA
| | - Maha Haddad
- Division of Pediatric Nephrology, UC Davis Children's Hospital, Sacramento, CA 95817, USA
| | - Olivera Marsenic
- Division of Pediatric Nephrology, Lucile Packard Children's Hospital, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Paul Brakeman
- Division of Pediatric Nephrology, UCSF Benioff Children's Hospital, San Francisco, CA 94158, USA
| | - Raymond Quigley
- Division of Pediatric Nephrology, Children's Medical Center Dallas, UT Southwestern, Dallas, TX 75235, USA
| | - H Stella Shin
- Division of Pediatric Nephrology, Children's Healthcare of Atlanta, Atlanta, GA 30322, USA
| | - Rouba Garro
- Division of Pediatric Nephrology, Children's Healthcare of Atlanta, Atlanta, GA 30322, USA
| | - Rupesh Raina
- Division of Pediatric Nephrology, Akron Children's Hospital, Akron, OH 44308, USA
| | - Craig B Langman
- Kidney Diseases Division, Feinberg School of Medicine, Northwestern University, Ann and Robert H Lurie Children's Hospital of Chicago, Chicago, IL 60611, USA
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10
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Zhabyeyev P, Sadasivan C, Shah S, Wang F, Oudit GY. Amlodipine rescues advanced iron overload cardiomyopathy in hemojuvelin knockout murine model: Clinical implications. Front Cardiovasc Med 2023; 10:1129349. [PMID: 37153462 PMCID: PMC10160373 DOI: 10.3389/fcvm.2023.1129349] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2022] [Accepted: 03/28/2023] [Indexed: 05/09/2023] Open
Abstract
Background Iron overload cardiomyopathy (IOC) is a major co-morbidity of genetic hemochromatosis and secondary iron overload with limited therapeutic options. We aim to investigate mechanisms of rescue action of amlodipine in the murine model of iron overload, characterize changes in human cardiac tissue due to IOC, and compare them to the changes in the animal model of IOC. Methods and results As an animal model, we used male hemojuvelin knockout (HJVKO) mice, which lacked hemojuvelin (a co-receptor protein for hepcidin expression). The mice were fed a high-iron diet from 4 weeks to 1 year of age. As a rescue, iron-fed mice received the Ca2+ channel blocker, amlodipine, from 9 to 12 months. Iron overload resulted in systolic and diastolic dysfunctions and changes in the cardiac tissue similar to the changes in the explanted human heart with IOC. An IOC patient (β-thalassemia) with left-ventricular ejection fraction (LVEF) 25% underwent heart transplantation. The murine model and the explanted heart showed intra-myocyte iron deposition, fibrosis, hypertrophy, oxidative stress, remodeling of Ca2+ cycling proteins, and metabolic kinases typical of heart failure. Single-myocyte contractility and Ca2+ release were diminished in the murine model. The amlodipine-treated group exhibited normalization of cellular function and reversed fibrosis, hypertrophy, oxidative stress, and metabolic remodeling. We also report a clinical case of primary hemochromatosis successfully treated with amlodipine. Conclusions The aged HJVKO murine model on the iron-rich diet reproduced many features of the human case of IOC. The use of amlodipine in the murine model and clinical case reversed IOC remodeling, demonstrating that amlodipine is effective adjuvant therapy for IOC.
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Affiliation(s)
- Pavel Zhabyeyev
- Division of Cardiology, Department of Medicine, University of Alberta, Edmonton, AB, Canada
- MazankowskiAlberta Heart Institute, University of Alberta, Edmonton, AB, Canada
| | - Chandu Sadasivan
- Division of Cardiology, Department of Medicine, University of Alberta, Edmonton, AB, Canada
- MazankowskiAlberta Heart Institute, University of Alberta, Edmonton, AB, Canada
| | - Saumya Shah
- Division of Cardiology, Department of Medicine, University of Alberta, Edmonton, AB, Canada
- MazankowskiAlberta Heart Institute, University of Alberta, Edmonton, AB, Canada
| | - Faqi Wang
- Division of Cardiology, Department of Medicine, University of Alberta, Edmonton, AB, Canada
| | - Gavin Y. Oudit
- Division of Cardiology, Department of Medicine, University of Alberta, Edmonton, AB, Canada
- MazankowskiAlberta Heart Institute, University of Alberta, Edmonton, AB, Canada
- Correspondence: Gavin Y. Oudit
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11
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Nashwan AJ, Yassin MA, Abd-Alrazaq A, Shuweihdi F, Othman M, Abdul Rahim HF, Shraim M. Hepatic and cardiac iron overload quantified by magnetic resonance imaging in patients on hemodialysis: A systematic review and meta-analysis. Hemodial Int 2023; 27:3-11. [PMID: 36397717 DOI: 10.1111/hdi.13054] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2022] [Revised: 10/19/2022] [Accepted: 10/26/2022] [Indexed: 11/19/2022]
Abstract
INTRODUCTION Few studies have reported hepatic and cardiac iron overload in patients with end-stage renal disease (ESRD), and the current evidence regarding the prevalence is still scarce. AIM This review aims to estimate the prevalence of hepatic and/or cardiac iron overload quantified by magnetic resonance imaging (MRI) in patients with ESRD who receive hemodialysis (HD), peritoneal dialysis (PD), or have undergone a kidney transplant. METHODS A systematic review with meta-analysis was conducted and reported in line with PRISMA (Preferred Reporting Items for Systematic Review and Meta-Analysis) guidelines. MEDLINE and Embase bibliographic databases were searched using a comprehensive list of controlled vocabulary and keywords to identify relevant studies. All studies reporting the prevalence of hepatic and/or cardiac iron overload quantified by MRI in ESRD patients were considered. The Newcastle-Ottawa scale was used to assess the methodological quality of included studies. To investigate the heterogeneity between studies, random-effect meta-analyses for proportions were used. RESULTS The review comprised seven studies that included 339 patients. Using meta-analysis, the pooled prevalence of severe and mild to moderate hepatic iron overload quantified by MRI was 0.23 [95% CI: 0.08-0.43] and 0.52 [95% CI: 0.47-0.57], respectively. Only three studies included cardiac iron quantification, and none reported iron overload. CONCLUSIONS This review has revealed a high prevalence of severe hepatic iron overload in patients with ESRD treated by HD. Further studies with a larger sample size are needed to determine the impact of iron overload on vital organs in patients with ESRD and guide future research in this understudied field. Proper use of iron chelation and continuous monitoring will help in the early detection of unsolicited complications; however, the low renal clearance of most iron chelators limits the options for treating iron excess in patients with ESRD.
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Affiliation(s)
- Abdulqadir J Nashwan
- Department of Nursing, Hazm Mebaireek General Hospital, Hamad Medical Corporation, Doha, Qatar
- Department of Public Health, College of Health Sciences, QU Health, Qatar University, Doha, Qatar
| | - Mohamed A Yassin
- Hematology and Oncology, Hamad General Hospital, Hamad Medical Corporation, Doha, Qatar
| | - Alaa Abd-Alrazaq
- AI Center for Precision Health, Weill Cornell Medicine-Qatar, Doha, Qatar
| | - Farag Shuweihdi
- School of Medicine, Leeds Institute of Health Sciences, University of Leeds, Leeds, UK
| | - Muftah Othman
- Nephrology Section, Medicine Department, Hamad Medical Corporation, Doha, Qatar
| | - Hanan F Abdul Rahim
- Department of Public Health, College of Health Sciences, QU Health, Qatar University, Doha, Qatar
| | - Mujahed Shraim
- Department of Public Health, College of Health Sciences, QU Health, Qatar University, Doha, Qatar
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12
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Lokesh KN, Raichur AM. Bioactive nutraceutical ligands and their efficiency to chelate elemental iron of varying dynamic oxidation states to mitigate associated clinical conditions. Crit Rev Food Sci Nutr 2022; 64:517-543. [PMID: 35943179 DOI: 10.1080/10408398.2022.2106936] [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: 11/03/2022]
Abstract
The natural bioactive or nutraceuticals exhibit several health benefits, including anti-inflammatory, anti-cancer, metal chelation, antiviral, and antimicrobial activity. The inherent limitation of nutraceuticals or bioactive ligand(s) in terms of poor pharmacokinetic and other physicochemical properties affects their overall therapeutic efficiency. The excess of iron in the physiological compartments and its varying dynamic oxidation state [Fe(II) and Fe(III)] precipitates various clinical conditions such as non-transferrin bound iron (NTBI), labile iron pool (LIP), ferroptosis, cancer, etc. Though several natural bioactive ligands are proposed to chelate iron, the efficiency of bioactive ligands is limited due to poor bioavailability, denticity, and other related physicochemical properties. The present review provides insight into the relevance of studying the dynamic oxidation state of iron(II) and iron(III) in the physiological compartments and its clinical significance for selecting diagnostics and therapeutic regimes. We suggested a three-pronged approach, i.e., diagnosis, selection of therapeutic regime (natural bioactive), and integration of novel drug delivery systems (NDDS) or nanotechnology-based principles. This systematic approach improves the overall therapeutic efficiency of natural iron chelators to manage iron overload-related clinical conditions.
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Affiliation(s)
- K N Lokesh
- Department of Biotechnology, Ramaiah Institute of Technology, Bengaluru, Karnataka, India
| | - Ashok M Raichur
- Department of Materials Engineering, Indian Institute of Science, Bengaluru, Karnataka, India
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13
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Fishbane S, Ganz T, Pratt RD. Ferric pyrophosphate citrate for parenteral administration of maintenance iron: structure, mechanism of action, clinical efficacy and safety. Curr Med Res Opin 2022; 38:1417-1429. [PMID: 35726771 DOI: 10.1080/03007995.2022.2092373] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/03/2022]
Abstract
Anemia is a common complication in patients with hemodialysis-dependent chronic kidney disease (HDD-CKD). Anemia is principally the result of erythropoietin deficiency, inflammation, and iron deficiency. High molecular weight iron oxide nanoparticles (IONP) are routinely administered intravenously to replace iron losses and, although effective, there are lingering concerns about possible safety issues. Ferric pyrophosphate citrate (FPC, Triferic, Triferic AVNU [Triferic and Triferic AVNU are the proprietary name for ferric pyrophosphate citrate. Triferic and Triferic AVNU are registered trademarks of Rockwell medical Inc.]) is a complex iron salt that donates iron directly to plasma transferrin. FPC is devoid of any carbohydrate moiety and is administered via the dialysate or intravenously during each hemodialysis session to replace iron and maintain hemoglobin. Controlled clinical trials of up to 48 weeks in duration have demonstrated the efficacy of regular administration of dialysate FPC for maintaining hemoglobin levels and iron balance in HDD-CKD patients. Clinical data also suggest that dialysate FPC may reduce the dose requirements for and use of erythropoiesis-stimulating agents and IONPs in HDD-CKD patients. Safety data from clinical studies and post-marketing surveillance show that FPC is well tolerated and not associated with an increased risk of infection, inflammation, iron overload, or serious hypersensitivity reactions. FPC represents an effective and well-tolerated choice for iron replacement and maintenance of hemoglobin in the long-term management of HDD-CKD patients.
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Affiliation(s)
- Steven Fishbane
- Zucker School of Medicine at Hofstra/Northwell, Great Neck, NY, USA
| | - Tomas Ganz
- University of California Los Angeles, David Geffen School of Medicine, Los Angeles, CA, USA
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14
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Rostoker G, Lepeytre F, Merzoug M, Griuncelli M, Loridon C, Boulahia G, Cohen Y. Differential Pharmacokinetics of Liver Tropism for Iron Sucrose, Ferric Carboxymaltose, and Iron Isomaltoside: A Clue to Their Safety for Dialysis Patients. Pharmaceutics 2022; 14:pharmaceutics14071408. [PMID: 35890303 PMCID: PMC9323124 DOI: 10.3390/pharmaceutics14071408] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2022] [Revised: 06/29/2022] [Accepted: 07/02/2022] [Indexed: 01/31/2023] Open
Abstract
Anemia is a major complication of end-stage kidney disease (ESKD). Erythropoiesis-stimulating agents and intravenous (IV) iron are the current backbone of anemia treatment in ESKD. Iron overload induced by IV iron is a potential clinical problem in dialysis patients. We compared the pharmacokinetics of liver accumulation of iron sucrose, currently used worldwide, with two third-generation IV irons (ferric carboxymaltose and iron isomaltoside). We hypothesized that better pharmacokinetics of newer irons could improve the safety of anemia management in ESKD. Liver iron concentration (LIC) was analyzed in 54 dialysis patients by magnetic resonance imaging under different modalities of iron therapy. LIC increased significantly in patients treated with 1.2 g or 2.4 g IV iron sucrose (p < 0.001, Wilcoxon test), whereas no significant increase was observed in patients treated with ferric carboxymaltose or iron isomaltoside (p > 0.05, Wilcoxon-test). Absolute differences in LIC reached 25 μmol/g in the 1.2 g iron sucrose group compared with only 5 μmol/g in the 1 g ferric carboxymaltose and 1 g iron isomaltoside groups (p < 0.0001, Kruskal−Wallis test). These results suggest the beneficial consequences of using ferric carboxymaltose or iron isomaltoside on liver structure in ESKD due to their pharmacokinetic ability to minimize iron overload.
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Affiliation(s)
- Guy Rostoker
- Division of Nephrology and Dialysis, Ramsay Santé, Hôpital Privé Claude Galien, 91480 Quincy-Sous-Sénart, France; (F.L.); (M.M.); (M.G.); (C.L.); (G.B.)
- Collége de Médecine des Hôpitaux de Paris, 75005 Paris, France
- Correspondence: ; Tel.: +33-1-69-39-92-00
| | - Fanny Lepeytre
- Division of Nephrology and Dialysis, Ramsay Santé, Hôpital Privé Claude Galien, 91480 Quincy-Sous-Sénart, France; (F.L.); (M.M.); (M.G.); (C.L.); (G.B.)
| | - Myriam Merzoug
- Division of Nephrology and Dialysis, Ramsay Santé, Hôpital Privé Claude Galien, 91480 Quincy-Sous-Sénart, France; (F.L.); (M.M.); (M.G.); (C.L.); (G.B.)
| | - Mireille Griuncelli
- Division of Nephrology and Dialysis, Ramsay Santé, Hôpital Privé Claude Galien, 91480 Quincy-Sous-Sénart, France; (F.L.); (M.M.); (M.G.); (C.L.); (G.B.)
| | - Christelle Loridon
- Division of Nephrology and Dialysis, Ramsay Santé, Hôpital Privé Claude Galien, 91480 Quincy-Sous-Sénart, France; (F.L.); (M.M.); (M.G.); (C.L.); (G.B.)
| | - Ghada Boulahia
- Division of Nephrology and Dialysis, Ramsay Santé, Hôpital Privé Claude Galien, 91480 Quincy-Sous-Sénart, France; (F.L.); (M.M.); (M.G.); (C.L.); (G.B.)
| | - Yves Cohen
- Division of Radiology, Ramsay Santé, Hôpital Privé Claude Galien, 91480 Quincy-Sous-Sénart, France;
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15
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Araújo NC, Suassuna JHR, Fernandes RDCL. Transcranial sonography depicts a larger substantia nigra echogenic area in renal transplant patients on calcineurin inhibitors than on rapamycin. BMC Nephrol 2022; 23:108. [PMID: 35300603 PMCID: PMC8931960 DOI: 10.1186/s12882-022-02741-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2021] [Accepted: 03/14/2022] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND After kidney transplantation neurologic manifestations may develop, including Parkinson's disease (PD). An enlarged substantia nigra (SN) by transcranial sonography has been recognized as a marker of PD. METHODS In renal transplant recipients (RTRs = 95) and controls (n = 20), measurement of mesencephalon, SN, third ventricle, spleen and carotid intima-media thickness (cIMT) and middle cerebral artery (MCA), kidney and spleen arteries Doppler resistive index (RI) were performed. RESULTS RTRs had larger SN, third ventricle and cIMT and higher renal RI than controls. The SN was larger in the CNIs group than in controls and rapamycin group, while the third ventricle was similar between patients but larger than in controls. In RTRs, SN showed a direct linear correlation with spleen and the third ventricle with age, cIMT and RI of the MCA, kidney and spleen. In CNIs group the SN correlated positively with age and cIMT, while the third ventricle reproduced RTRs correlations. Rapamycin group showed a direct linear relationship between the third ventricle and age and RI of the MCA, kidney and spleen; SN showed no correlations. CONCLUSION RTRs on CNIs present a larger SN area than on rapamycin, probably due to the antiproliferative effect of rapamycin. This finding might be relevant when interpreting TCS in RTRs.
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Affiliation(s)
- Nordeval Cavalcante Araújo
- Division of Nephrology, University of the State of Rio de Janeiro, Boulevard 28 de Setembro, 77 - Vila Isabel, Rio de Janeiro-RJ, 20551-030, Brazil.
| | - José Hermógenes Rocco Suassuna
- Division of Nephrology, University of the State of Rio de Janeiro, Boulevard 28 de Setembro, 77 - Vila Isabel, Rio de Janeiro-RJ, 20551-030, Brazil
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16
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Pramod S, Goldfarb DS. Challenging patient phenotypes in the management of anaemia of chronic kidney disease. Int J Clin Pract 2021; 75:e14681. [PMID: 34331826 PMCID: PMC9285529 DOI: 10.1111/ijcp.14681] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/15/2020] [Revised: 05/12/2021] [Accepted: 07/25/2021] [Indexed: 12/17/2022] Open
Abstract
BACKGROUND Chronic kidney disease (CKD) is often complicated by anaemia, which is associated with disease progression and increased hospital visits, decreased quality of life, and increased mortality. METHODS A comprehensive literature search of English language peer-reviewed articles in PubMed/MedLine published between 1998 and 2020 related to the treatment of anaemia of CKD was conducted. The United States Renal Database System and Dialysis Outcomes and Practice Patterns Study (DOPPS) data reports, the Centers for Disease Control and Prevention and the US Food and Drug Administration websites, and published congress abstracts in 2020 were surveyed for relevant information. RESULTS Subgroups of patients with anaemia of CKD present a clinical challenge throughout the disease spectrum, including those with end-stage kidney disease, advanced age or resistance to or ineligibility for current standards of care (ie, oral or intravenous iron supplementation, erythropoietin-stimulating agents and red blood cell transfusions). In addition, those with an increased risk of adverse events because of comorbid conditions, such as cardiovascular diseases or diabetes, comprise special populations of patients with an unmet need for interventions to improve clinical outcomes. These comorbidities must be managed in parallel and may have a synergistic effect on overall disease severity. CONCLUSIONS Several therapies provide promising opportunities to address gaps with a standard of care, including hypoxia-inducible factor prolyl hydroxylase inhibitors, which stimulate haematopoiesis through promoting modest increases in serum erythropoietin and improved iron homeostasis. The critical issues in the management of anaemia of CKD in these challenging phenotypes and the clinical utility of new therapeutic agents in development for the treatment of anaemia of CKD should be assessed and the information should be made available to healthcare providers.
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Affiliation(s)
- Sheena Pramod
- Department of Internal MedicineDivision of NephrologyMarshall University School of MedicineHuntingtonWest VirginiaUSA
| | - David S. Goldfarb
- Department of MedicineDivision of NephrologyNYU School of MedicineNew YorkNew YorkUSA
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17
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Lu R, Zhang X, Cai X, Wang X, Li H, Wang L, Zhou Y, Shen J, Liu Q, Zhang H, Ni Z. Efficacy and safety of polysaccharide iron complex capsules compared with iron sucrose in hemodialysis patients: study protocol for a randomized, open-label, positive control, multicenter trial (IHOPE). Trials 2021; 22:691. [PMID: 34629085 PMCID: PMC8503988 DOI: 10.1186/s13063-021-05663-1] [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: 06/02/2021] [Accepted: 09/27/2021] [Indexed: 11/25/2022] Open
Abstract
Background Anemia is one of the main complications of chronic kidney disease especially kidney failure, which includes treatment with erythropoiesis-stimulating agents and iron supplementation, including intravenous and oral iron. However, intravenous iron may pose limitations, such as potential infusion reactions. Oral iron is mainly composed of divalent iron, which can excessively stimulate the gastrointestinal tract. Iron polysaccharide complex capsules are a novel oral iron trivalent supplement with higher iron content and lower gastrointestinal irritation. However, since high-quality evidence-based medicinal support is lacking, it is necessary to conduct clinical studies to further evaluate the effectiveness and safety of oral iron polysaccharide complex in chronic kidney disease patients. Methods This randomized controlled trial uses an open-label, parallel group design, where the efficacy and safety of maintenance hemodialysis (MHD) participants is evaluated. The experimental group is assigned erythropoietins and iron polysaccharide complex (two capsules each time, bid), and the control group is assigned erythropoietin and sucrose iron (100mg, 2w) injection. Participants (aged 18–75 years) undergoing maintenance hemodialysis were considered for screening. Inclusion criteria included hemoglobin (Hb) ≥110g/L and < 130g/L, transferrin saturation (TSAT) > 20% and < 50%, and serum ferritin (SF) > 200μg/L and < 500μg/L. Exclusion criteria included acute or chronic bleeding, serum albumin < 35g/L, hypersensitive C-reactive protein (HsCRP) > 10 mg/L, and severe secondary hyperparathyroidism (iPTH ≥ 800 pg/mL). Full inclusion and exclusion criteria are described in the “Methods” section. The primary endpoint is TSAT of the participants at week 12. Secondary endpoints include Hb, SF, hematocrit (Hct), HsCRP, pharmacoeconomic evaluation, drug costs, quality of life, and indicators of oxidative stress. The treatment will last for 24 weeks with a follow-up visit at baseline (within 7 days prior to initial treatment) and weeks 4, 8, 12, 16, 20, and 24 after initial treatment. This clinical research includes 9 hemodialysis centers in mainland China and plans to enroll 186 participants. Discussion It is expected that it will provide strong evidence to reveal the clinical efficacy and safety of oral iron in the treatment of chronic CKD-related anemia in MHD patients through this clinical trial. Trial registration Chinese Clinical Trial Registry ChiCTR2000031166. Registered on March 23, 2020
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Affiliation(s)
- Renhua Lu
- Department of Nephrology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, 160 Pujian Road, Shanghai, China
| | - Xu Zhang
- Department of Nephrology, Taixing People's Hospital, Taizhou, Jiangsu, China
| | - Xudong Cai
- Department of Nephrology, Ningbo Hospital of Traditional Chinese Medicine, Ningbo, Zhejiang, China
| | - Xiaoxia Wang
- Department of Nephrology, Tongren Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Hua Li
- Department of Nephrology, Sir Run Shaw Hospital affiliated to Zhejiang University School of Medicine, Zhejiang, Hangzhou, China
| | - Li Wang
- Department of Nephrology, Shandong Qianfoshan Hospital, Jinan, Shandong, China
| | - Yijun Zhou
- Department of Nephrology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, 160 Pujian Road, Shanghai, China
| | - Jianxiao Shen
- Department of Nephrology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, 160 Pujian Road, Shanghai, China
| | - Qian Liu
- Department of Nephrology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, 160 Pujian Road, Shanghai, China
| | - Haifen Zhang
- Department of Nephrology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, 160 Pujian Road, Shanghai, China
| | - Zhaohui Ni
- Department of Nephrology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, 160 Pujian Road, Shanghai, China.
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18
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Al-Mashdali A, Alyafei T, Yassin M. The Superiority of T2*MRI Over Serum Ferritin in the Evaluation of Secondary Iron Overload in a Chronic Kidney Disease Patient: A Case Report. J Blood Med 2021; 12:665-670. [PMID: 34345192 PMCID: PMC8324975 DOI: 10.2147/jbm.s319591] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2021] [Accepted: 07/15/2021] [Indexed: 11/23/2022] Open
Abstract
Secondary iron overload is increasingly encountered in chronic kidney disease (CKD) patients because of the frequent use of parenteral iron products, especially in hemodialysis patients. Serum ferritin has been commonly used to monitor iron overload in these patients; however, other conditions can be associated with the high serum ferritin, like infections and inflammatory conditions. Currently, T2*MRI of the heart and liver is the preferred investigation for evaluating liver iron concentration (LIC) and cardiac iron concentration, which reflect the state of iron overload. Few studies observe a positive correlation between serum iron and LIC in CKD patients and postulate that serum ferritin exceeding 290 mcg/L should indicate significant iron overload and necessitates further MRI evaluation. However, here, we present a patient with a history of ESRD for which she underwent renal transplantation twice referred to our clinic due to persistent elevation in serum ferritin level (>1000 mcg/L) for several years. T2*MRI of the heart and liver revealed the absence of iron overload. Our objective of this case is to demonstrate the accuracy of T2*MRI over serum ferritin in evaluating iron overload and questioning the positive correlation between serum ferritin and LIC in CKD patients.
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Affiliation(s)
| | - Tahiya Alyafei
- Department of Clinical Imaging, Hamad Medical Corporation, Doha, Qatar
| | - Mohamed Yassin
- National Center for Cancer Care and Research, Department of Oncology, Hematology and BMT Section, Hamad Medical Corporation, Doha, Qatar
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19
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Guedes M, Muenz DG, Zee J, Bieber B, Stengel B, Massy ZA, Mansencal N, Wong MMY, Charytan DM, Reichel H, Waechter S, Pisoni RL, Robinson BM, Pecoits-Filho R. Serum Biomarkers of Iron Stores Are Associated with Increased Risk of All-Cause Mortality and Cardiovascular Events in Nondialysis CKD Patients, with or without Anemia. J Am Soc Nephrol 2021; 32:2020-2030. [PMID: 34244326 PMCID: PMC8455257 DOI: 10.1681/asn.2020101531] [Citation(s) in RCA: 44] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2020] [Accepted: 04/29/2021] [Indexed: 01/07/2023] Open
Abstract
BACKGROUND Approximately 30%-45% of patients with nondialysis CKD have iron deficiency. Iron therapy in CKD has focused primarily on supporting erythropoiesis. In patients with or without anemia, there has not been a comprehensive approach to estimating the association between serum biomarkers of iron stores, and mortality and cardiovascular event risks. METHODS The study included 5145 patients from Brazil, France, the United States, and Germany enrolled in the Chronic Kidney Disease Outcomes and Practice Patterns Study, with first available transferrin saturation (TSAT) and ferritin levels as exposure variables. We used Cox models to estimate hazard ratios (HRs) for all-cause mortality and major adverse cardiovascular events (MACE), with progressive adjustment for potentially confounding variables. We also used linear spline models to further evaluate functional forms of the exposure-outcome associations. RESULTS Compared with patients with a TSAT of 26%-35%, those with a TSAT ≤15% had the highest adjusted risks for all-cause mortality and MACE. Spline analysis found the lowest risk at TSAT 40% for all-cause mortality and MACE. Risk of all-cause mortality, but not MACE, was also elevated at TSAT ≥46%. Effect estimates were similar after adjustment for hemoglobin. For ferritin, no directional associations were apparent, except for elevated all-cause mortality at ferritin ≥300 ng/ml. CONCLUSIONS Iron deficiency, as captured by TSAT, is associated with higher risk of all-cause mortality and MACE in patients with nondialysis CKD, with or without anemia. Interventional studies evaluating the effect on clinical outcomes of iron supplementation and therapies for alternative targets are needed to better inform strategies for administering exogenous iron.
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Affiliation(s)
- Murilo Guedes
- Pontificia Universidade Catolica do Parana, Curitiba, Brazil.,Arbor Research Collaborative for Health, Ann Arbor, Michigan
| | - Daniel G Muenz
- Arbor Research Collaborative for Health, Ann Arbor, Michigan
| | - Jarcy Zee
- Arbor Research Collaborative for Health, Ann Arbor, Michigan
| | - Brian Bieber
- Arbor Research Collaborative for Health, Ann Arbor, Michigan
| | | | - Ziad A Massy
- Université Paris Saclay, Villejuif, France.,Service de Néphrologie et Dialyse, Assistance Publique Hôpitaux de Paris, Hôpital Universitaire Ambroise Paré, Boulogne Billancourt, France
| | - Nicolas Mansencal
- Service de Cardiologie Assistance Publique Hôpitaux de Paris, Hôpital Universitaire Ambroise Paré, Boulogne Billancourt, France
| | - Michelle M Y Wong
- Department of Medicine, University of British Columbia, Vancouver, Canada
| | | | | | | | - Ronald L Pisoni
- Arbor Research Collaborative for Health, Ann Arbor, Michigan
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20
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Richardson L, Gardner K, Eberhardt S, Thompson W. A case of hepatic splenosis in the setting of iron overload; multimodal and literature review. Radiol Case Rep 2021; 16:2499-2504. [PMID: 34257788 PMCID: PMC8259227 DOI: 10.1016/j.radcr.2021.05.037] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2021] [Revised: 05/10/2021] [Accepted: 05/11/2021] [Indexed: 11/29/2022] Open
Abstract
Hepatic splenosis, a rare entity, is the ectopic implantation of splenic tissue into the hepatic parenchyma, most often incidentally seen in patients with a history of splenic trauma and splenectomy. We present a unique case of hepatic splenosis in a patient with hemosiderosis and splenectomy following the incidental finding of hepatic masses on pretransplant imaging. Final diagnosis was made based on cross-sectional imaging characteristics matching that of the left upper quadrant splenules alone. We discuss common characteristics of hepatic splenosis on multiple modalities, the effect of iron deposition on the imaging characteristics of hepatic and splenic tissue and how that impacts the differential and diagnosis. This case highlights the unique imaging characteristics hepatic splenosis can have particularly in the setting of hemosiderosis. Hepatic splenosis imaging diagnosis has a significant advantage over tissue diagnosis in terms of decreased risk, time and cost.
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Zakrocka I, Baranowicz-Gąszczyk I, Załuska W. Haemochromatosis in a kidney transplant recipient: a case report. BMC Nephrol 2021; 22:201. [PMID: 34051741 PMCID: PMC8164756 DOI: 10.1186/s12882-021-02416-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2021] [Accepted: 05/24/2021] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Iron overload is inevitably related to chronic kidney disease (CKD) treatment. Haemochromatosis leads to multiorgan damage and is associated with increased mortality. Primary haemochromatosis is the most common autosomal recessive disease in white populations. In most cases, the classic form of hereditary haemochromatosis is caused by mutations, mainly C282Y and H63D, in the haemochromatosis gene (HFE). Secondary haemochromatosis can be triggered by iron administration and blood transfusions. Haemochromatosis is rarely reported in kidney transplant recipients. Atypical factors may evoke haemochromatosis in patients without HFE mutations or other standard risk factors. CASE PRESENTATION In the current study, we present a patient who started to have haemochromatosis symptoms after kidney transplantation. A 37-year-old man after kidney transplantation from a deceased donor was admitted to the hospital due to high serum ferritin levels and impaired graft function. The patient's past medical history included arterial hypertension, embolization of both renal arteries and necrosis of the left femoral head. Glomerulonephritis was suspected as a cause of CKD; however, severe kidney failure was diagnosed, kidney biopsy was not performed, and the patient started intermittent haemodialysis. While on dialysis to treat anaemia, the patient had received erythropoietin and iron intravenously, and the maximal serum ferritin level was 2115 ng/ml. After kidney transplantation, ferritin levels started to increase rapidly, with a maximum level of 9468 ng/ml one and a half years after surgery. His genetic study showed HFE C282Y heterozygosity. Symptoms of haemochromatosis, such as skin hyperpigmentation, elevated activity of aminotransferases, impaired glucose tolerance and heart failure, were observed. Therapeutic phlebotomy was started, and 36 procedures were performed. After treatment, graft function significantly improved, most haemochromatosis symptoms resolved, and the serum ferritin level significantly decreased. CONCLUSIONS Haemochromatosis can occur in heterozygotic HFE patients after kidney transplantation. Iron administration, infections, type of immunosuppression and liver dysfunction should be considered potential triggers of haemochromatosis in this group of patients.
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Affiliation(s)
- Izabela Zakrocka
- Department of Nephrology, Medical University of Lublin, Jaczewskiego street 8, 20-090, Lublin, Poland.
| | - Iwona Baranowicz-Gąszczyk
- Department of Nephrology, Medical University of Lublin, Jaczewskiego street 8, 20-090, Lublin, Poland
| | - Wojciech Załuska
- Department of Nephrology, Medical University of Lublin, Jaczewskiego street 8, 20-090, Lublin, Poland
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22
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Luo D, Zhong Z, Qiu Y, Wang Y, Li H, Lin J, Chen W, Yang X, Mao H. Abnormal iron status is associated with an increased risk of mortality in patients on peritoneal dialysis. Nutr Metab Cardiovasc Dis 2021; 31:1148-1155. [PMID: 33618923 DOI: 10.1016/j.numecd.2020.12.018] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/15/2020] [Accepted: 12/12/2020] [Indexed: 10/22/2022]
Abstract
BACKGROUND AND AIMS Iron deficiency is prevalent, but there is limited data about the relationship between iron status and poor outcomes in chronic kidney disease patients undergoing peritoneal dialysis (PD). We aimed to investigate the association between iron status and mortality in PD patients. METHODS AND RESULTS This retrospective study was conducted on incident PD patients from January 2006 to December 2016 and followed up until December 2018. Patients were categorized into four groups according to baseline serum transferrin saturation (percent) and ferritin levels (ng/ml): reference (20-30%, 100-500 ng/ml), absolute iron deficiency (<20%, <100 ng/ml), function iron deficiency (FID) (<20%, >100 ng/ml), and high iron (>30%, >500 ng/ml). Among the 1173 patients, 77.5% had iron deficiency. During a median follow-up period of 43.7 months, compared with the reference group, the FID group was associated with increased risk for all-cause [adjusted hazard ratio (aHR) 1.87, 95% confidence interval (95% CI) 1.05-3.31, P = 0.032], but not cardiovascular (CV) mortality. Additionally, the high iron group had a more than four-fold increased risk of both all-cause and CV mortality [aHR 4.32 (95% CI 1.90-9.81), P < 0.001; aHR 4.41 (95% CI 1.47-13.27), P = 0.008; respectively]. CONCLUSION FID and high iron predict worse prognosis of patients on PD.
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Affiliation(s)
- Dan Luo
- Department of Nephrology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China; Key Laboratory of Nephrology, National Health Commission and Guangdong Province, Guangzhou, Guangdong, China
| | - Zhong Zhong
- Department of Nephrology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China; Key Laboratory of Nephrology, National Health Commission and Guangdong Province, Guangzhou, Guangdong, China
| | - Yagui Qiu
- Department of Nephrology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China; Key Laboratory of Nephrology, National Health Commission and Guangdong Province, Guangzhou, Guangdong, China
| | - Yating Wang
- Department of Nephrology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China; Key Laboratory of Nephrology, National Health Commission and Guangdong Province, Guangzhou, Guangdong, China
| | - Hongyu Li
- Department of Nephrology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China; Key Laboratory of Nephrology, National Health Commission and Guangdong Province, Guangzhou, Guangdong, China
| | - Jianxiong Lin
- Department of Nephrology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China; Key Laboratory of Nephrology, National Health Commission and Guangdong Province, Guangzhou, Guangdong, China
| | - Wei Chen
- Department of Nephrology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China; Key Laboratory of Nephrology, National Health Commission and Guangdong Province, Guangzhou, Guangdong, China
| | - Xiao Yang
- Department of Nephrology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China; Key Laboratory of Nephrology, National Health Commission and Guangdong Province, Guangzhou, Guangdong, China
| | - Haiping Mao
- Department of Nephrology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China; Key Laboratory of Nephrology, National Health Commission and Guangdong Province, Guangzhou, Guangdong, China.
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23
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Upadhyay B, Green SD, Khanal N, Antony AC. Clinical conundrum: managing iron overload after renal transplantation. BMJ Case Rep 2021; 14:14/2/e239568. [PMID: 33547097 PMCID: PMC7871264 DOI: 10.1136/bcr-2020-239568] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Iatrogenic iron overload, which is not uncommon in patients undergoing long-term haemodialysis, arises from a combination of multiple red cell transfusions and parenteral iron infusions that are administered to maintain a haemoglobin concentration of approximately 10 g/dL. Although iron overload due to genetic haemochromatosis is conventionally managed by phlebotomy, patients with haemoglobinopathies and chronic transfusion-induced iron overload are treated with iron-chelation therapy. However, the management of iron overload in our patient who presented with hepatic dysfunction and immunosuppressive drug-induced mild anaemia in the post-renal transplant setting posed unique challenges. We report on the decision-making process used in such a case that led to a successful clinical resolution of hepatic iron overload through the combined use of phlebotomy and erythropoiesis stimulating agents, while avoiding use of iron-chelating agents that could potentially compromise both hepatic and renal function.
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Affiliation(s)
- Binayak Upadhyay
- Internal Medicine, AMITA Health Saint Francis Hospital Evanston, Evanston, Illinois, USA
| | - Steven D Green
- Division of Hematology-Oncology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - Nabin Khanal
- Division of Hematology-Oncology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - Aśok C Antony
- Division of Hematology-Oncology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA,Medicine Service (Hematology-Oncology Section), Richard L Roudebush Veterans Affairs Medical Center, Indianapolis, Indiana, USA
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24
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Alageeli AA, Alqahtany FS, Algahtani FH. The Role of Reticulocyte Hemoglobin Content for the Diagnosis of Functional Iron Deficiency in Hemodialyzed patients. Saudi J Biol Sci 2021; 28:50-54. [PMID: 33424282 PMCID: PMC7783634 DOI: 10.1016/j.sjbs.2020.08.030] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2020] [Revised: 08/17/2020] [Accepted: 08/17/2020] [Indexed: 11/26/2022] Open
Abstract
The effectiveness of reticulocyte hemoglobin content (CHr) had been reported to detect early functional iron deficiency especially among Chronic kidney disease (CKD) patients. CHr is more superior to classic biochemical indices in reflecting transient iron-deficiency status, therefore improving diagnosis and treatment. This study was conducted to determine the sensitivity of CHr in the diagnosis of functional iron deficiency (FID) in hemodialyzed patients. One hundred hemodialyzed patients along with 60 healthy controls were recruited and blood specimens were collected. Venous blood was used for hematological and biochemical investigations collected via 3 ml lavender-top tubes for hematological tests including CBC, blood film, ESR and CHr, and red-top tube for biochemical tests including TIBC, SF and CRP. A statistically significant decrease was noted in CHr values between hemodialysis patients and the control group (24.8 ± 2.0 pg vs. 30.9 ± 1.3 pg, p<0.001). CHr values showed a significant correlations with RBCs, Hb- hemoglobin, Hct- hematocrit level, MCV- mean corpuscular volume, MCH- mean corpuscular hemoglobin, MCHC, RDW- red cell distribution width , SI-Serum Iron, TIBC- Total iron binding capacity and TSAT- Transferrin saturation. The present study showed that CHr in comparison to the conventional hematological and biochemical markers commonly used to diagnose iron deficiency.
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Affiliation(s)
- Ali A. Alageeli
- Department of Clinical Laboratory Sciences, College of Applied Medical Science, King Saud University, Riyadh, Saudi Arabia
| | - Fatmah S. Alqahtany
- Department of Pathology, Hematopathology Unit, College of Medicine, King Saud University, King Saud University Medical City, Riyadh, Saudi Arabia
| | - Farjah H. Algahtani
- Department of Medicine, Division of Oncology/Hematology, College of Medicine, King Saud University, King Saud University Medical City, Riyadh, Saudi Arabia
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25
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Fertrin KY. Diagnosis and management of iron deficiency in chronic inflammatory conditions (CIC): is too little iron making your patient sick? HEMATOLOGY. AMERICAN SOCIETY OF HEMATOLOGY. EDUCATION PROGRAM 2020; 2020:478-486. [PMID: 33275757 PMCID: PMC7727593 DOI: 10.1182/hematology.2020000132] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/20/2023]
Abstract
While iron deficiency remains the most common cause of anemia worldwide, low iron stores are associated with symptoms regardless of the presence of typical microcytic, hypochromic anemia and may be hard to recognize in patients with concurrent inflammation. Diagnosing and treating iron deficiency become more of a challenge because markers of iron status are influenced by low-grade inflammation present in common conditions, such as chronic kidney disease, cirrhosis, or heart failure. Here I present a pragmatic way of interpreting diagnostic lab tests to help clinicians recognize patients who are most likely to benefit from iron supplementation, choose between oral and parenteral administration, and make personalized decisions when patients do not fit usual guidelines.
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26
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Kassianides X, Hazara AM, Bhandari S. Improving the safety of intravenous iron treatments for patients with chronic kidney disease. Expert Opin Drug Saf 2020; 20:23-35. [PMID: 33203251 DOI: 10.1080/14740338.2021.1853098] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Introduction: Iron-deficiency anemia in chronic kidney disease (CKD) is common and has prognostic, financial, and quality of life implications. Intravenous (IV) iron is a key intervention for optimal management, however, ongoing safety concerns exist. Area covered: The potential side effects associated with IV iron use are addressed as we review the most recent studies. Hypersensitivity reactions and true anaphylaxis are indeed rare with a greater understanding of the nature of labile iron and 'Fishbane' reactions. Hypophosphatemia appears commoner with certain IV iron preparations, however its significance in CKD requires exploration. The long-standing questions regarding oxidative stress and the potential susceptibility to infections and worsening cardiovascular morbidity are discussed. Iron overload secondary to repeat IV iron infusions is plausible, however, a number of guidelines limit and strictly guide prescription. Expert opinion: The past decade has improved our understanding of IV iron administration safety in patients with CKD. Third generation IV iron compounds have minimized hypersensitivity reactions while allowing high doses to be administered safely and rapidly in non-dialysis-dependent CKD patients. However, differences in safety profiles such as hypophosphatemia require further study and therapy should be tailored to the individual. Clinicians should feel confident in using IV iron therapy.
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Affiliation(s)
- Xenophon Kassianides
- Academic Renal Medicine, Hull University Teaching Hospitals NHS Trust , Kingston upon Hull, UK
| | - Adil Mohammad Hazara
- Academic Renal Medicine, Hull University Teaching Hospitals NHS Trust , Kingston upon Hull, UK
| | - Sunil Bhandari
- Academic Renal Medicine, Hull University Teaching Hospitals NHS Trust , Kingston upon Hull, UK
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27
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Li P, Xia C, Liu P, Peng Z, Huang H, Wu J, He Z. Neutrophil-to-lymphocyte ratio and platelet-to-lymphocyte ratio in evaluation of inflammation in non-dialysis patients with end-stage renal disease (ESRD). BMC Nephrol 2020; 21:511. [PMID: 33238906 PMCID: PMC7690201 DOI: 10.1186/s12882-020-02174-0] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2019] [Accepted: 11/17/2020] [Indexed: 12/22/2022] Open
Abstract
Background Neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) have been reported to be associated with inflammation in end-stage renal disease (ESRD) receiving dialysis. However, the value of NLR and PLR in non-dialysis patients with ESRD remains unclear. Methods Among 611 non-dialysis patients with ESRD in The First Affiliated Hospital of University of South China (2012–2018), we compared NLR and PLR in patients with high-sensitivity C-reactive protein (hs-CRP) levels of ≤3 mg/L vs. > 3 mg/L. Correlation of NLR and PLR to hs-CRP, PCT, ferritin were analyzed. Receiver operating characteristics (ROC) analysis was used for estimating sensitivity and specificity of NLR and PLR. Results NLR was higher in the patients with high hs-CRP levels (> 3 mg/L), compared to patients with low hs-CRP levels (≤ 3 mg/L) [5.74 (3.54–9.01) vs. 3.96 (2.86–5.85), p < 0.0001]. Additionally, PLR was higher in high hs-CRP group than in low group [175.28 (116.67–252.26) vs. 140.65 (110.51–235.17), p = 0.022]. In the current study, NLR and PLR were both positively correlated with hs-CRP (rs = 0.377, p = 0.000 for NLR; rs = 0.161, p = 0.001 for PLR), PCT, leukocytes, neutrophils, platelets, and age. NLR or PLR with a cut-off value of 5.07 or 163.80 indicated sensitivity and specificity were 65.67 and 66.37% (AUC = 0.69) or 57.21 and 57.52% (AUC = 0.55), respectively. Conclusions NLR or PLR was positively correlated with hs-CRP in non-dialysis patients with ESRD. NLR might be better for identifying inflammation than PLR in this population.
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Affiliation(s)
- Peiyuan Li
- Department of Gastroenterology, The First Affiliated Hospital of University of South China, Hengyang, 421001, PR China
| | - Chenqi Xia
- Department of Nephrology, The First Affiliated Hospital of University of South China, Hengyang, Hunan Province, 421001, PR China
| | - Peng Liu
- Department of Nephrology, The First Affiliated Hospital of University of South China, Hengyang, Hunan Province, 421001, PR China
| | - Zhong Peng
- Department of Gastroenterology, The First Affiliated Hospital of University of South China, Hengyang, 421001, PR China
| | - Hong Huang
- Institute of Clinical Medicine, The First Affiliated Hospital of University of South China, Hengyang, 421001, PR China
| | - Juan Wu
- Department of Gastroenterology, The First Affiliated Hospital of University of South China, Hengyang, 421001, PR China
| | - Zhangxiu He
- Department of Nephrology, The First Affiliated Hospital of University of South China, Hengyang, Hunan Province, 421001, PR China.
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28
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Rund D. Intravenous iron: do we adequately understand the short- and long-term risks in clinical practice? Br J Haematol 2020; 193:466-480. [PMID: 33216989 DOI: 10.1111/bjh.17202] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2020] [Accepted: 09/28/2020] [Indexed: 12/31/2022]
Abstract
Intravenous (IV) iron as a therapeutic agent is often administered but not always fully understood. The benefits of IV iron are well proven in many fields, particularly in nephrology. IV iron is beneficial not only for true iron deficiency but also for iron-restricted anaemia (functional iron deficiency). Yet, the literature on intravenous iron has many inconsistencies regarding its adverse effects. Over the last several years, newer forms of iron have been developed, leading to the more regular use of iron and in larger doses. This review will summarize some of the older and newer literature regarding the differences among iron products, including the mechanisms and frequency of their adverse events (AEs). The pathway and frequency of an underrecognized adverse event (hypophosphataemia) will be discussed. Recent insights on infection risk and iron handling by macrophages are examined. Potential but presently unproven risks of iron overload due to IV iron are discussed. The impact of these on the risk:benefit ratio and dosing of intravenous iron are considered in different clinical settings, including pregnancy and cancer. IV iron is an essential component of the therapy of anaemia and understanding these issues will enable more informed treatment decisions and knowledgeable use of these drugs.
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Affiliation(s)
- Deborah Rund
- Hebrew University-Hadassah Medical Organization, Ein Kerem, Jerusalem, Israel
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29
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Wu J, Meng QH. Current understanding of the metabolism of micronutrients in chronic alcoholic liver disease. World J Gastroenterol 2020; 26:4567-4578. [PMID: 32884217 PMCID: PMC7445863 DOI: 10.3748/wjg.v26.i31.4567] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/04/2020] [Revised: 06/22/2020] [Accepted: 07/30/2020] [Indexed: 02/06/2023] Open
Abstract
Alcoholic liver disease (ALD) remains an important health problem worldwide. Perturbation of micronutrients has been broadly reported to be a common characteristic in patients with ALD, given the fact that micronutrients often act as composition or coenzymes of many biochemical enzymes responsible for the inflammatory response, oxidative stress, and cell proliferation. Mapping the metabolic pattern and the function of these micronutrients is a prerequisite before targeted intervention can be delivered in clinical practice. Recent years have registered a significant improvement in our understanding of the role of micronutrients on the pathogenesis and progression of ALD. However, how and to what extent these micronutrients are involved in the pathophysiology of ALD remains largely unknown. In the current study, we provide a review of recent studies that investigated the imbalance of micronutrients in patients with ALD with a focus on zinc, iron, copper, magnesium, selenium, vitamin D and vitamin E, and determine how disturbances in micronutrients relates to the pathophysiology of ALD. Overall, zinc, selenium, vitamin D, and vitamin E uniformly exhibited a deficiency, and iron demonstrated an elevated trend. While for copper, both an elevation and deficiency were observed from existing literature. More importantly, we also highlight several challenges in terms of low sample size, study design discrepancies, sample heterogeneity across studies, and the use of machine learning approaches.
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Affiliation(s)
- Jing Wu
- Department of Critical Care Medicine of Liver Disease, Beijing You-An Hospital, Capital Medical University, Beijing 100069, China
| | - Qing-Hua Meng
- Department of Critical Care Medicine of Liver Disease, Beijing You-An Hospital, Capital Medical University, Beijing 100069, China
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30
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Iron deficiency and iron therapy in heart failure and chronic kidney disease. Curr Opin Nephrol Hypertens 2020; 29:508-514. [PMID: 32701598 DOI: 10.1097/mnh.0000000000000630] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
PURPOSE OF REVIEW Iron deficiency is common and associated with adverse outcomes in heart failure, regardless of anemia. Iron deficiency, absolute and functional, with and without anemia, is associated with adverse outcomes in chronic kidney disease (CKD). Heart failure and CKD frequently occur together. Intravenous iron therapy has been shown to reduce heart failure symptoms and improve physical function in heart failure with reduced ejection fraction with iron deficiency. In CKD, intravenous or oral iron therapy are often used for management of anemia, along with erythropoiesis stimulating agents, yet the risks and benefits of intravenous iron use is controversial. In this review, we survey available evidence and ongoing studies of iron deficiency and iron supplementation in heart failure, and integrate with recent evidence on effectiveness and safety of intravenous iron therapy in CKD. RECENT FINDINGS Intravenous iron therapy improves heart failure symptoms and physical function in heart failure with reduced ejection fraction and iron deficiency, regardless of anemia, and may reduce heart failure hospitalizations and cardiovascular mortality. Sustained intravenous iron therapy regardless of hemoglobin level in selected patients with end-stage kidney disease receiving hemodialysis improves outcomes, and does not appear to cause infectious complications. SUMMARY Iron therapy has important effects in heart failure and CKD, and appears safe in the short term. Ongoing trials will provide additional important information.
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31
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Aldwairi MM, Yassin MA. Iatrogenic Iron Overload in an End Stage Renal Disease Patient. Case Rep Oncol 2020; 13:760-763. [PMID: 32774272 PMCID: PMC7383200 DOI: 10.1159/000507979] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2020] [Accepted: 04/18/2020] [Indexed: 01/30/2023] Open
Abstract
Iron overload is a common complication in patients with chronic renal failure treated with dialysis prior to the availability of recombinant human erythropoietin therapy. Iron overload was the result of hypoproliferative erythroid marrow function coupled with the need for frequent red blood cell transfusions to manage symptomatic anemia. The repetitive use of intravenous iron with or without the use of red blood cell transfusions also contributed to iron loading and was associated with iron deposition in liver parenchymal and reticuloendothelial cells. Here we report a 56-year-old female with end-stage renal failure who underwent kidney transplant twice and found to have iatrogenic iron overload with excess intravenous iron treated conservatively.
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Affiliation(s)
- Majd M Aldwairi
- Department of Internal Medicine/Hamad Medical Corporation, Doha, Qatar
| | - Mohamed A Yassin
- Department of Medical Oncology, National Center for Cancer Care and Research, Doha, Qatar
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32
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Histological Scores Validate the Accuracy of Hepatic Iron Load Measured by Signal Intensity Ratio and R2* Relaxometry MRI in Dialysis Patients. J Clin Med 2019; 9:jcm9010017. [PMID: 31861625 PMCID: PMC7019535 DOI: 10.3390/jcm9010017] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2019] [Revised: 12/14/2019] [Accepted: 12/17/2019] [Indexed: 01/02/2023] Open
Abstract
Almost all haemodialysis patients are treated with parenteral iron to compensate for blood loss and to allow the full therapeutic effect of erythropoiesis-stimulating agents. Iron overload is an increasingly recognised clinical situation diagnosed by quantitative magnetic resonance imaging (MRI). MRI methods have not been fully validated in dialysis patients. We compared Deugnier’s and Turlin’s histological scoring of iron overload and Scheuer’s classification (with Perls’ stain) with three quantitative MRI methods for measuring liver iron concentration (LIC)—signal intensity ratio (SIR), R2* relaxometry, and R2* multi-peak spectral modelling (Iterative Decomposition of water and fat with Echo Asymmetry and Least-squares estimation (IDEAL-IQ®)) relaxometry—in 16 haemodialysis patients in whom a liver biopsy was formally indicated for medical follow-up. LIC MRI with these three different methods was highly correlated with Deugnier’s and Turlin’s histological scoring (SIR: r = 0.8329, p = 0.0002; R2* relaxometry: r = −0.9099, p < 0.0001; R2* relaxometry (IDEAL-IQ®): r = −0.872, p = 0.0018). Scheuer’s classification was also significantly correlated with these three MRI techniques. The positive likelihood ratio for the diagnosis of abnormal LIC by Deugnier’s histological scoring was > 62 for the three MRI methods. This study supports the accuracy of quantitative MRI methods for the non-invasive diagnosis and follow-up of iron overload in haemodialysis patients.
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Sousa L, Oliveira MM, Pessôa MTC, Barbosa LA. Iron overload: Effects on cellular biochemistry. Clin Chim Acta 2019; 504:180-189. [PMID: 31790701 DOI: 10.1016/j.cca.2019.11.029] [Citation(s) in RCA: 64] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2019] [Revised: 11/19/2019] [Accepted: 11/20/2019] [Indexed: 02/07/2023]
Abstract
Iron is an essential element for human life. However, it is a pro-oxidant agent capable of reacting with hydrogen peroxide. An iron overload can cause cellular changes, such as damage to the plasma membrane leading to cell death. Effects of iron overload in cellular biochemical processes include modulating membrane enzymes, such as the Na, K-ATPase, impairing the ionic transport and inducing irreversible damage to cellular homeostasis. To avoid such damage, cells have an antioxidant system that acts in an integrated manner to prevent oxidative stress. In addition, the cells contain proteins responsible for iron transport and storage, preventing its reaction with other substances during absorption. Moreover, iron is associated with cellular events coordinated by iron-responsive proteins (IRPs) that regulate several cellular functions, including a process of cell death called ferroptosis. This review will address the biochemical aspects of iron overload at the cellular level and its effects on important cellular structures.
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Affiliation(s)
- Leilismara Sousa
- Laboratório de Bioquímica Celular, Universidade Federal de São João del Rei, Campus Centro-Oeste Dona Lindu, Divinópolis, MG, Brazil
| | - Marina M Oliveira
- Laboratório de Bioquímica Celular, Universidade Federal de São João del Rei, Campus Centro-Oeste Dona Lindu, Divinópolis, MG, Brazil
| | - Marco Túlio C Pessôa
- Laboratório de Bioquímica Celular, Universidade Federal de São João del Rei, Campus Centro-Oeste Dona Lindu, Divinópolis, MG, Brazil
| | - Leandro A Barbosa
- Laboratório de Bioquímica Celular, Universidade Federal de São João del Rei, Campus Centro-Oeste Dona Lindu, Divinópolis, MG, Brazil.
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34
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Issad B, Griuncelli M, Verger C, Rostoker G. What do we learn about the “Anemia Module” of the French language Peritoneal Dialysis ? Interest and Results. BULLETIN DE LA DIALYSE À DOMICILE 2019. [DOI: 10.25796/bdd.v2i3.20983] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2022] Open
Abstract
Background: Anemia is commonly observed in patients with chronic kidney disease (CKD) as soon as the glomerular filtration rate falls below than 30 ml/min. CKD patients frequently have iron deficiency. The use of both erythropoiesis-stimulating agents (ESA) and iron therapy is the backbone of anemia management in CKD. For this reason, an adequate iron supply is mandatory to achieve the optimal therapeutic benefit of erythropoiesis stimulating agents (ESAs). Many groups agree that anemia in peritoneal dialysis (PD) patients is less severe than in hemodialysis (HD) patients and that there are important differences in treatment practices for anemia between PD and HD patients.
Methods: Analysis of the Anemia module of the French Language Peritoneal Dialysis Registry (RDPLF) register from the database set up in 2005 with a study of the period 2010-2017.
Results: Data from 568 patients who participated in the Anemia module were analysed during the 2010-2017 follow-up period. Their median age were 71 years, 42% were female, median dialysis vintage was 13 months, 40,5% of patients had diabetes mellitus, 74% of patients were treated with ESA, 23% were on oral iron and only 11% have received intravenous iron. In terms of biological assessment, the average hemoglobin level was close to 12 g/dl and median CRP was close to 5 mg/l. For the iron balance, ferritin reached an average level of 270 µg/l in 2013 and stabilized in 2017 at 200 µg/l. The transferrin saturation coefficient always fluctuated between 23 % and 25 % from year 2010 to year 2017.
Conclusion: The results of the Anemia module of RDPLF register appear to be in line with the target values of the ERA-EDTA latest European guideline on anemia (ERBP 2013) and show the low use of intravenous iron in PD (usually as second line therapy).
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Rostoker G, Vaziri ND. Risk of iron overload with chronic indiscriminate use of intravenous iron products in ESRD and IBD populations. Heliyon 2019; 5:e02045. [PMID: 31338466 PMCID: PMC6627982 DOI: 10.1016/j.heliyon.2019.e02045] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2018] [Revised: 03/14/2019] [Accepted: 07/03/2019] [Indexed: 01/19/2023] Open
Abstract
The routine use of recombinant erythropoiesis-stimulating agents (ESA) over the past three decades has enabled the partial correction of anaemia in most patients with end-stage renal disease (ESRD). Since ESA use frequently leads to iron deficiency, almost all ESA-treated haemodialysis patients worldwide receive intravenous iron (IV) to ensure sufficient available iron during ESA therapy. Patients with inflammatory bowel disease (IBD) are also often treated with IV iron preparations, as anaemia is common in IBD. Over the past few years, liver magnetic resonance imaging (MRI) has become the gold standard method for non-invasive diagnosis and follow-up of iron overload diseases. Studies using MRI to quantify liver iron concentration in ESRD have shown a link between high infused iron dose and risk of haemosiderosis in dialysis patients. In September 2017, the Pharmacovigilance Committee (PRAC) of the European Medicines Agency (EMA) considered convergent publications over the last few years on iatrogenic haemosiderosis in dialysis patients and requested that companies holding marketing authorization for iron products should investigate the risk of iron overload, particularly in patients with end-stage renal disease on dialysis and, by analogy, patients with IBD. We present a narrative review of data supporting the views and decision of the EMA, and then give our expert opinion on this controversial field of anaemia therapeutics.
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Affiliation(s)
- Guy Rostoker
- Division of Nephrology and Dialysis, Hôpital Privé Claude Galien, Ramsay-Générale de Santé, Quincy-sous-Sénart, France
| | - Nosratola D Vaziri
- Division of Nephrology and Hypertension, University of California, Irvine, USA
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Li X, Cole SR, Kshirsagar AV, Fine JP, Stürmer T, Brookhart MA. Safety of Dynamic Intravenous Iron Administration Strategies in Hemodialysis Patients. Clin J Am Soc Nephrol 2019; 14:728-737. [PMID: 30988164 PMCID: PMC6500950 DOI: 10.2215/cjn.03970318] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2018] [Accepted: 03/06/2019] [Indexed: 12/17/2022]
Abstract
BACKGROUND AND OBJECTIVES Intravenous iron therapy for chronic anemia management is largely driven by dosing protocols that differ in intensity with respect to dosing approach (i.e., dose, frequency, and duration). Little is known about the safety of these protocols. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS Using clinical data from a large United States dialysis provider linked to health care utilization data from Medicare, we constructed a cohort of patients with ESKD aged ≥65 years who initiated and continued center-based hemodialysis for ≥90 days between 2009 and 2012, and initiated at least one of the five common intravenous iron administration strategies; ranked by intensity (the amount of iron given at moderate-to-high iron indices), the order of strategies was 3 (least intensive), 2 (less intensive), 1 (reference), 4 (more intensive), and 5 (most intensive). We estimated the effect of continuous exposure to these strategies on cumulative risks of mortality and infection-related events with dynamic Cox marginal structural models. RESULTS Of 13,249 eligible patients, 1320 (10%) died and 1627 (12%) had one or more infection-related events during the 4-month follow-up. The most and least commonly initiated strategy was strategy 2 and 5, respectively. Compared with the reference strategy 1, more intensive strategies (4 and 5) demonstrated a higher risk of all-cause mortality (e.g., most intensive strategy 5: 60-day risk difference: 1.3%; 95% confidence interval [95% CI], 0.8% to 2.1%; 120-day risk difference: 3.1%; 95% CI, 1.0% to 5.6%). Similarly, higher risks were observed for infection-related morbidity and mortality among more intensive strategies (e.g., strategy 5: 60-day risk difference: 1.8%; 95% CI, 1.2% to 2.6%; 120-day risk difference: 4.3%; 95% CI, 2.2% to 6.8%). Less intensive strategies (2 and 3) demonstrated lower risks of all-cause mortality and infection-related events. CONCLUSIONS Among dialysis patients surviving 90 days, subsequent intravenous iron administration strategies promoting more intensive iron treatment at moderate-to-high iron indices levels are associated with higher risks of mortality and infection-related events.
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Affiliation(s)
- Xiaojuan Li
- Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina,University of North Carolina Kidney Center, Division of Nephrology and Hypertension, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina,Department of Population Medicine, Harvard Medical School and Harvard Pilgrim Health Care Institute, Boston, Massachusetts
| | - Stephen R Cole
- Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
| | - Abhijit V Kshirsagar
- University of North Carolina Kidney Center, Division of Nephrology and Hypertension, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
| | - Jason P Fine
- Department of Biostatistics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
| | - Til Stürmer
- Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
| | - M Alan Brookhart
- Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
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Mikhail AI, Schön S, Simon S, Brown C, Hegbrant JBA, Jensen G, Moore J, Lundberg LDI. A prospective observational study of iron isomaltoside in haemodialysis patients with chronic kidney disease treated for iron deficiency (DINO). BMC Nephrol 2019; 20:13. [PMID: 30630452 PMCID: PMC6327585 DOI: 10.1186/s12882-018-1159-z] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2018] [Accepted: 11/28/2018] [Indexed: 12/21/2022] Open
Abstract
Background Iron deficiency is frequent in haemodialysis (HD) patients with chronic kidney disease (CKD), and intravenous iron is an established therapy for these patients. This study assessed treatment routine, effectiveness, and safety of iron isomaltoside (IIM) 5% (Diafer®) in a HD cohort. Methods This prospective observational study included 198 HD patients converted from iron sucrose (IS) and treated with IIM according to product label and clinical routine. Data for IIM were compared to historic data for IS in 3-month intervals. The primary endpoint was to show non-inferiority for IIM versus IS in haemoglobin (Hb) maintenance. Results Most patients (> 60%) followed a fixed low-dose iron treatment protocol. Three minutes were required for preparation and administration of IIM. Erythropoiesis-stimulating agent (ESA) was used in > 80% of patients during both IIM and IS phases. The maintenance of Hb was similar with both iron drugs; the mean Hb level was 11 g/dL, and the mean change of 0.3 g/dL (95% confidence interval: 0.1, 0.5) for IIM 0–3 months compared to IS demonstrated non-inferiority. Nine adverse drug reactions were reported in 2% of patients administered IIM. All patients had uneventful recoveries. The frequency of metallic taste was higher with IS compared to IIM (34% versus 0.5%, p < 0.0001). Conclusions IIM is effective and well tolerated by CKD patients on HD. IIM was non-inferior to IS in maintenance of Hb, and had similar ESA requirements. The fast-push injection of IIM may enable logistical benefits in clinical practice, and the low frequency of metallic taste contributes to patient convenience. Trial registration ClinicalTrials.gov identifier NCT02301026, study registered November 25, 2014.
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Affiliation(s)
| | | | - Sylvia Simon
- Medical Department, Pharmacosmos A/S, Holbaek, Denmark
| | | | | | - Gert Jensen
- Department of Molecular and Clinical Medicine/Nephrology, The Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Jason Moore
- Renal Unit, Royal Devon and Exeter Hospital NHS Foundation Trust, Exeter, UK
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Abstract
There are several options available for intravenous application of iron supplements, but they all have a similar structure:—an iron core surrounded by a carbohydrate coating. These nanoparticles require processing by the reticuloendothelial system to release iron, which is subsequently picked up by the iron-binding protein transferrin and distributed throughout the body, with most of the iron supplied to the bone marrow. This process risks exposing cells and tissues to free iron, which is potentially toxic due to its high redox activity. A new parenteral iron formation, ferric pyrophosphate citrate (FPC), has a novel structure that differs from conventional intravenous iron formulations, consisting of an iron atom complexed to one pyrophosphate and two citrate anions. In this study, we show that FPC can directly transfer iron to apo-transferrin. Kinetic analyses reveal that FPC donates iron to apo-transferrin with fast binding kinetics. In addition, the crystal structure of transferrin bound to FPC shows that FPC can donate iron to both iron-binding sites found within the transferrin structure. Examination of the iron-binding sites demonstrates that the iron atoms in both sites are fully encapsulated, forming bonds with amino acid side chains in the protein as well as pyrophosphate and carbonate anions. Taken together, these data demonstrate that, unlike intravenous iron formulations, FPC can directly and rapidly donate iron to transferrin in a manner that does not expose cells and tissues to the damaging effects of free, redox-active iron.
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Cernaro V, Tripepi G, Visconti L, Lacquaniti A, Montalto G, Romeo A, Cimadoro D, Costantino G, Torre F, Santoro D, Buemi M. Convective Dialysis Reduces Mortality Risk: Results From a Large Observational, Population-Based Analysis. Ther Apher Dial 2018; 22:457-468. [DOI: 10.1111/1744-9987.12684] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2017] [Revised: 03/08/2018] [Accepted: 03/12/2018] [Indexed: 11/27/2022]
Affiliation(s)
- Valeria Cernaro
- Department of Clinical and Experimental Medicine; University of Messina; Messina Italy
| | - Giovanni Tripepi
- CNR-IFC, Clinical Epidemiology and Physiopathology of Renal Diseases and Hypertension; Reggio Calabria Italy
| | - Luca Visconti
- Department of Clinical and Experimental Medicine; University of Messina; Messina Italy
| | - Antonio Lacquaniti
- Department of Clinical and Experimental Medicine; University of Messina; Messina Italy
| | - Gaetano Montalto
- Department of Clinical and Experimental Medicine; University of Messina; Messina Italy
| | - Adolfo Romeo
- Department of Clinical and Experimental Medicine; University of Messina; Messina Italy
| | - Domenica Cimadoro
- Department of Clinical and Experimental Medicine; University of Messina; Messina Italy
| | - Giuseppe Costantino
- Department of Clinical and Experimental Medicine; University of Messina; Messina Italy
| | - Francesco Torre
- Department of Clinical and Experimental Medicine; University of Messina; Messina Italy
| | - Domenico Santoro
- Department of Clinical and Experimental Medicine; University of Messina; Messina Italy
| | - Michele Buemi
- Department of Clinical and Experimental Medicine; University of Messina; Messina Italy
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Wilson RJ, Jones B, Marelli C. Iron parameters in patients with end-stage renal disease receiving lanthanum carbonate or other non-iron-based phosphate binders: Results from a phase 3, randomized open-label study. SAGE Open Med 2018; 6:2050312118786161. [PMID: 30013785 PMCID: PMC6041850 DOI: 10.1177/2050312118786161] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2018] [Accepted: 05/30/2018] [Indexed: 11/26/2022] Open
Abstract
OBJECTIVES The recent availability of iron-based phosphate binders has raised some concerns about iron overload in patients with end-stage renal disease. This study evaluated iron parameters in patients with end-stage renal disease receiving lanthanum carbonate or other non-iron-based phosphate binders. METHODS This analysis used 2-year follow-up data from an open-label, multicentre, randomized, active-controlled, parallel-group, phase 3 trial of lanthanum carbonate (SPD405-307). After a washout period, if patients' serum phosphate levels exceeded 5.9 mg/dL, they were randomized 1:1 to receive lanthanum carbonate (375-3000 mg/day) or non-iron-based standard therapy during a 6-week dose titration period. Patients achieving control of serum phosphate levels (⩽5.9 mg/dL) received maintenance therapy with lanthanum carbonate or standard therapy for up to 24 months. RESULTS No clinically relevant changes in mean (standard deviation) iron parameters between the treatment groups (lanthanum carbonate, n = 682; standard therapy, n = 677) from baseline to month 24/final visit were observed: iron (µg/dL), -1.1 (41.8) versus 1.0 (38.7); ferritin (ng/mL), 208.4 (445.1) versus 262.4 (505.5); transferrin saturation (%), 2.8 (18.0) versus 2.8 (17.3); and haemoglobin (g/dL), 0.4 (1.9) versus 0.3 (1.7), respectively (all, p > 0.1). There were no clinically relevant changes in the percentage of patients receiving any anti-anaemic preparation in either treatment group (pre- vs post-randomization: lanthanum carbonate, 94.9% vs 97.8%; standard therapy, 95.1% vs 98.8%, respectively). This is in contrast to the study by Lewis and colleagues, which found significant increases in ferritin and transferrin saturation levels in patients receiving ferric citrate versus active control (calcium acetate and/or sevelamer carbonate) after 52 weeks of therapy. Although serum ferritin and transferrin saturation are the recommended iron indices by the Kidney Disease Outcome Quality Initiative, they are indirect indicators of iron status. Longer-term studies are required to understand fully the potential risks associated with iron overload. CONCLUSION No evidence of iron accumulation was found in patients with end-stage renal disease receiving lanthanum carbonate or other non-iron-based binders.
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Diagnosis of hyperferritinemia in routine clinical practice. Presse Med 2017; 46:e329-e338. [PMID: 29150231 DOI: 10.1016/j.lpm.2017.09.028] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/22/2017] [Accepted: 09/06/2017] [Indexed: 01/29/2023] Open
Abstract
The discovery of hyperferritinemia is often fortuitous, revealed in results from a laboratory screening or follow-up test. The aim of the diagnostic procedure is therefore to identify its cause and to identify or rule out hepatic iron overload, in a three-stage process. In the first step, clinical findings and several simple laboratory tests are sufficient to detect four of the most frequent causes of high ferritin concentrations: alcoholism, inflammatory syndrome, cytolysis, and metabolic syndrome. None of these causes is associated with substantial hepatic iron overload. If transferrin saturation is high (> 50%), hereditary hemochromatosis will be considered in priority. In the second phase, rarer diseases will be sought. Among them, only chronic hematologic diseases (acquired or congenital) and excessive iron intake or infusions (patients on chronic dialysis and high-level athletes) are at risk of iron overload. In the third stage, if a doubt persists about the cause or if the ferritin concentration is very high or continues to rise, it is essential to verify the hepatic iron concentration to rule out overload. The principal examination to guide diagnosis and treatment is hepatic MRI to assess its iron concentration. It is essential to remember that more than 40% of patients with hyperferritinemia have several causes simultaneously present.
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Iatrogenic iron overload and its potential consequences in patients on hemodialysis. Presse Med 2017; 46:e312-e328. [PMID: 29153377 DOI: 10.1016/j.lpm.2017.10.014] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/20/2017] [Revised: 10/03/2017] [Accepted: 10/10/2017] [Indexed: 12/13/2022] Open
Abstract
Iron overload was considered rare in hemodialysis patients until recently, but its clinical frequency is now increasingly recognized. The liver is the main site of iron storage and the liver iron concentration (LIC) is closely correlated with total iron stores in patients with secondary hemosiderosis and genetic hemochromatosis. Magnetic resonance imaging (MRI) is now the gold standard method for estimating and monitoring LIC. Studies of LIC in hemodialysis patients by magnetic susceptometry thirteen years ago and recently by quantitative MRI have demonstrated a relation between the risk of iron overload and the use of intravenous (IV) iron products prescribed at doses determined by the iron biomarker cutoffs contained in current anemia management guidelines. These findings have challenged the validity of both iron biomarker cutoffs and current clinical guidelines, especially with respect to recommended IV iron doses. Moreover, three recent long-term observational studies suggested that excessive IV iron doses might be associated with an increased risk of cardiovascular events and death in hemodialysis patients. It has been hypothesized that iatrogenic iron overload in the era of erythropoiesis-stimulating agents might silently increase complications in dialysis patients without creating obvious, clinical signs and symptoms. High hepcidin-25 levels were recently linked to fatal and nonfatal cardiovascular events in dialysis patients. It has been postulated that the main pathophysiological pathway leading to these events might involve the pleiotropic master hormone hepcidin, which regulates iron metabolism, leading to activation of macrophages in atherosclerotic plaques and then to clinical cardiovascular events. Thus, the potential iron overload toxicity linked to chronic administration of IV iron therapy is now becoming one of the most controversial topics in the management of anemia in hemodialysis patients.
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Paisant A, d'Assignies G, Bannier E, Bardou-Jacquet E, Gandon Y. MRI for the measurement of liver iron content, and for the diagnosis and follow-up of iron overload disorders. Presse Med 2017; 46:e279-e287. [PMID: 29133084 DOI: 10.1016/j.lpm.2017.10.008] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/23/2017] [Revised: 10/04/2017] [Accepted: 10/04/2017] [Indexed: 01/19/2023] Open
Abstract
MRI is now the reference method for detecting and quantifying hepatic and extrahepatic iron overload, regardless of its cause. The decrease of the hepatic signal is proportional to the amount of iron in the tissues. It is more pronounced with T2*-weighted gradient echo sequences. It increases proportionally with the strength of the magnetic field. Thus a 3-T MRI is be more sensitive and probably more accurate to detect a slight iron overload, as seen in dysmetabolic hepatosiderosis. Conversely, a 1.5-T MRI better estimates a high overload. Quantification can be done with the calculation of T2* (or R2*) or by using the liver to muscle signal intensity ratio (SIR). Today with a single multi-echo gradient-echo sequence, obtained in a unique apnea, the two methods can be used simultaneously. An associated quantification of steatosis is also obtained. This same type of sequence is proposed for quantification of iron in other tissues and in particular for the myocardium.
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Affiliation(s)
- Anita Paisant
- CHU de Rennes, service de radiologie, 35033 Rennes, France
| | | | - Elise Bannier
- CHU de Rennes, service de radiologie, 35033 Rennes, France
| | | | - Yves Gandon
- CHU de Rennes, service de radiologie, 35033 Rennes, France.
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Oral Ferric Citrate Hydrate Associated With Less Oxidative Stress Than Intravenous Saccharated Ferric Oxide. Kidney Int Rep 2017; 3:364-373. [PMID: 29725640 PMCID: PMC5932126 DOI: 10.1016/j.ekir.2017.10.016] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2017] [Revised: 10/17/2017] [Accepted: 10/30/2017] [Indexed: 11/25/2022] Open
Abstract
Introduction A recent study suggested that orally dosed ferric citrate hydrate (FC) corrects renal anemia in patients on hemodialysis (HD), suggesting biological differences in effects of iron supplementation using different routes of administration. To address this issue, the present study compared oral FC with i.v. saccharated ferric oxide (FO) in stable HD patients. Methods Participants comprised 6 patients administered 3 consecutive protocols in the first HD session of the week in a fasting state: nothing given, as control (C); oral load of FC (480 mg iron), and 5 minutes of i.v. FO (40 mg iron). Iron dynamics in the body and biological impact on redox-inflammation status during the study (6 hours) were examined. Results Significant increases in serum iron and transferrin saturation were seen with both FC and FO. Regarding total iron-binding capacity as the sum of serum iron and unsaturated iron-binding capacity, no changes were found in FC, whereas significant increases were seen in FO (appearance of non–transferrin-binding iron [NTBI]), despite the lower serum iron levels in FO. Compared with C, increases were seen in serum myeloperoxidase (oxidative marker) with accompanying significant decreases in thioredoxin (antioxidant) in FO, whereas no changes were found in FC. Conclusion Oral FC differs from i.v. FO in areas such as less NTBI generation and less induction of oxidative stress. The result indicates potential clinical benefits of oral FC in terms of iron supplementation for renal anemia in HD patients.
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Issad B, Ghali N, Beaudreuil S, Griuncelli M, Cohen Y, Rostoker G. Hepatic Iron Load at Magnetic Resonance Imaging Is Normal in Most Patients Receiving Peritoneal Dialysis. Kidney Int Rep 2017; 2:1219-1222. [PMID: 29270530 PMCID: PMC5733676 DOI: 10.1016/j.ekir.2017.07.005] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2017] [Revised: 06/26/2017] [Accepted: 07/17/2017] [Indexed: 01/12/2023] Open
Affiliation(s)
- Belkacem Issad
- Division of Nephrology and Dialysis, Groupe Hospitalier Pitié-Salpêtrière, Paris, France
| | - Nasredine Ghali
- Division of Nephrology and Dialysis, Centre Hospitalier Marc Jacquet, Melun, France
| | - Séverine Beaudreuil
- Division of Nephrology, Dialysis and Transplantation, Centre Hospitalier Universitaire Bicêtre, Kremlin-Bicêtre, France
| | - Mireille Griuncelli
- Division of Nephrology and Dialysis, RAMSAY-Générale de Santé, Hôpital Privé Claude Galien, Quincy-sous-Sénart, France
| | - Yves Cohen
- Division of Radiology, RAMSAY-Générale de Santé, Hôpital Privé Claude Galien, Quincy-sous-Sénart, France
| | - Guy Rostoker
- Division of Nephrology and Dialysis, RAMSAY-Générale de Santé, Hôpital Privé Claude Galien, Quincy-sous-Sénart, France
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Stefanova D, Raychev A, Arezes J, Ruchala P, Gabayan V, Skurnik M, Dillon BJ, Horwitz MA, Ganz T, Bulut Y, Nemeth E. Endogenous hepcidin and its agonist mediate resistance to selected infections by clearing non-transferrin-bound iron. Blood 2017; 130:245-257. [PMID: 28465342 PMCID: PMC5520472 DOI: 10.1182/blood-2017-03-772715] [Citation(s) in RCA: 101] [Impact Index Per Article: 12.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2017] [Accepted: 04/29/2017] [Indexed: 12/27/2022] Open
Abstract
The iron-regulatory hormone hepcidin is induced early in infection, causing iron sequestration in macrophages and decreased plasma iron; this is proposed to limit the replication of extracellular microbes, but could also promote infection with macrophage-tropic pathogens. The mechanisms by which hepcidin and hypoferremia modulate host defense, and the spectrum of microbes affected, are poorly understood. Using mouse models, we show that hepcidin was selectively protective against siderophilic extracellular pathogens (Yersinia enterocolitica O9) by controlling non-transferrin-bound iron (NTBI) rather than iron-transferrin concentration. NTBI promoted the rapid growth of siderophilic but not nonsiderophilic bacteria in mice with either genetic or iatrogenic iron overload and in human plasma. Hepcidin or iron loading did not affect other key components of innate immunity, did not indiscriminately promote intracellular infections (Mycobacterium tuberculosis), and had no effect on extracellular nonsiderophilic Y enterocolitica O8 or Staphylococcus aureus Hepcidin analogs may be useful for treatment of siderophilic infections.
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Affiliation(s)
- Deborah Stefanova
- Molecular, Cellular, and Integrative Physiology Graduate Program and
| | - Antoan Raychev
- Department of Medicine, David Geffen School of Medicine, University of California Los Angeles (UCLA), Los Angeles, CA
| | - Joao Arezes
- Medical Research Council (MRC) Human Immunology Unit, MRC Weatherall Institute for Molecular Medicine, University of Oxford, Oxford, United Kingdom
| | - Piotr Ruchala
- Department of Medicine, David Geffen School of Medicine, University of California Los Angeles (UCLA), Los Angeles, CA
| | - Victoria Gabayan
- Department of Medicine, David Geffen School of Medicine, University of California Los Angeles (UCLA), Los Angeles, CA
| | - Mikael Skurnik
- Department of Bacteriology and Immunology, University of Helsinki, Helsinki, Finland; and
| | - Barbara J Dillon
- Department of Medicine, David Geffen School of Medicine, University of California Los Angeles (UCLA), Los Angeles, CA
| | - Marcus A Horwitz
- Department of Medicine, David Geffen School of Medicine, University of California Los Angeles (UCLA), Los Angeles, CA
| | - Tomas Ganz
- Department of Medicine, David Geffen School of Medicine, University of California Los Angeles (UCLA), Los Angeles, CA
- Department of Pathology and
| | - Yonca Bulut
- Department of Pediatrics, David Geffen School of Medicine, UCLA, Los Angeles, CA
| | - Elizabeta Nemeth
- Department of Medicine, David Geffen School of Medicine, University of California Los Angeles (UCLA), Los Angeles, CA
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Rostoker G, Griuncelli M, Cohen Y. HFE gene mutations are not risk factors for iron overload in European hemodialysis patients. Hemodial Int 2017; 21:440-442. [PMID: 28332280 DOI: 10.1111/hdi.12552] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/01/2022]
Affiliation(s)
- Guy Rostoker
- Division of Nephrology and Dialysis, Hôpital Privé Claude Galien, Ramsay Générale de Santé, Quincy sous Sénart 91480, France
| | - Mireille Griuncelli
- Division of Nephrology and Dialysis, Hôpital Privé Claude Galien, Ramsay Générale de Santé, Quincy sous Sénart 91480, France
| | - Yves Cohen
- Division of Radiology, Hôpital Privé Claude Galien, Ramsay Générale de Santé, Quincy sous Sénart 91480, France
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Rostoker G, Vaziri ND. Impact of iatrogenic iron overload on the course of hepatitis C in the dialysis population: A plea for caution. Hemodial Int 2017; 21 Suppl 1:S68-S77. [PMID: 28332306 DOI: 10.1111/hdi.12557] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
About 2.5% of the world population, corresponding to about 177 million individuals, are infected by hepatitis C virus (HCV), a small, single-stranded RNA virus. The prevalence of HCV infection among dialysis patients in Japan, Europe, and North America during the 2012 to 2015 period was found to be 8.7% in the DOPPS study. Nosocomial HCV spread in hemodialysis facilities still occurs. Increased hepatic tissue iron has been shown to play a deleterious role in the course of hepatitis C, favor development of fibrosis and cirrhosis and possibly increase the risk of liver cancer in the general population. Regular loss of blood in the hemodialysis circuit, in routine blood sampling for laboratory tests (for uremia monitoring), and in gut due to uremic enteropathy, invariably results in iron deficiency for which patients are commonly treated with intravenous (IV) iron preparations. Data on the effects of IV iron in hemodialysis patients with hepatitis C are limited (2 studies) and strongly suggest that parenteral iron may contribute to hepatocellular injury. Iatrogenic iron overload is extremely prevalent among hemodialysis population worldwide. Iron overload and toxicity has emerged as one of the most controversial topic in the management of anemia in dialysis patients. Given the known impact of iron in promoting growth and virulence of HCV and the associated liver disease, it is necessary to use iron therapy cautiously and closely monitor plasma markers of iron metabolism and liver iron stores non-invasively by means of MRI to avoid iron overload in this vulnerable population.
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Affiliation(s)
- Guy Rostoker
- Division of Nephrology and Dialysis, Hôpital Privé Claude Galien, Ramsay-Générale de Santé, Quincy sous Sénart, France
| | - Nosratola D Vaziri
- Division of Nephrology and Hypertension, University of California, Irvine, California, USA
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