|
1
|
Cheng AN, Al-Samkari H. Impact of iron overload on incidence of diabetes mellitus, cardiac disease, and death in congenital hemolytic anemias. Blood Adv 2024; 8:5451-5457. [PMID: 39189931 PMCID: PMC11532744 DOI: 10.1182/bloodadvances.2024013666] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2024] [Revised: 07/26/2024] [Accepted: 08/07/2024] [Indexed: 08/28/2024] Open
Abstract
ABSTRACT Iron overload and its complications are recognized to be morbid and fatal in patients with congenital hemolytic anemias. In patients with iron overload caused by congenital hemolytic anemias, there has been no study evaluating the dose-response relationship between serum markers of iron overload and long-term health complications. Filling this critical gap was the aim of this study. We evaluated outcomes in a 5-hospital observational cohort study of adults with congenital hemolytic anemias diagnosed with iron overload over a 40-year period and assessed associations between depth and duration of iron overload, as well as clinical complications including diabetes, heart disease, malignancy, bone density disorders, and death. One hundred seventy patients with congenital hemolytic anemias developing iron overload were included. More years experienced of ferritin >500 ng/mL and >1000 ng/mL were associated with the development of diabetes mellitus, with adjusted odds ratios (ORs) of 2.61 per 10-year increment (P = .034) and 3.24 per 10-year increment (P = .035), respectively. More years experienced of ferritin >1000 ng/mL were associated with the development of heart disease (adjusted OR, 5.30 per 10-year increment; P = .002). Peak lifetime ferritin of >10 000 ng/mL was associated with sixfold odds of developing diabetes (P = .04) and 10-fold odds of developing heart disease (P = .007). A peak ferritin >10 000 ng/mL was associated with an increase in mortality (adjusted OR, 6.77; P = .033). In conclusion, iron overload in patients with congenital hemolytic anemias is associated with diabetes mellitus, cardiac disease, and death. Prolonged exposure to relatively modest iron overload was associated with nearly threefold increased odds of diabetes.
Collapse
Affiliation(s)
- Aaron N. Cheng
- Division of Hematology Oncology, Hospital of the University of Pennsylvania, Philadelphia, PA
| | - Hanny Al-Samkari
- Division of Hematology Oncology, Massachusetts General Hospital, Boston, MA
- Harvard Medical School, Boston, MA
| |
Collapse
|
|
2
|
García-Fariña B, Rink L, Santarini V, Westkemper M, Dohna-Schwake C, Möhlendick B. Case report: Acute liver failure during deferasirox therapy and the potential role of pharmacogenetics. Front Pharmacol 2024; 15:1477755. [PMID: 39508042 PMCID: PMC11538451 DOI: 10.3389/fphar.2024.1477755] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2024] [Accepted: 09/23/2024] [Indexed: 11/08/2024] Open
Abstract
Background and aims A number of case reports have documented the occurrence of acute hepatic and renal toxicity during treatment with deferasirox (DFX). The precise mechanisms underlying these adverse events remain unclear, with the time to toxicity varying considerably between patients-some experiencing it within weeks of treatment initiation, while others after several years. Recent studies have underscored the association of pharmacogenetic variants in genes responsible for the metabolism and clearance of DFX (ABCC2, ABCG2, and UGT1A1) in the development of toxicity. We present the case of an 8-year-old patient with beta thalassemia major who developed acute hepatic failure years after the initiation of DFX therapy. After ruling out the most likely causes, we performed a pharmacogenetic analysis, which suggested a possible link between the patient's genotype and the development of toxicity. Methods Sanger sequencing was performed for the most extensively studied single nucleotide polymorphisms (SNPs) studied associated with changes in transporter/enzyme function: ABCC2 rs717620 (c.-24C>T), rs2273697 (c.1249G>A), rs8187710 (c.4544G>A), rs369192412 (g.99781071delG); ABCG2 rs2231142 (c.421C>A); UGT1A1 *6 rs4148323 (c.211G>A), *28 rs3064744 (g.233760235TA[8]), *36 rs3064744 (g.233760235TA[6]) and *37 rs3064744 (g.233760235TA[9]). Results The patient is heterozygous for two ABCC2 variants, namely rs717620 (c.-24C>T) and rs2273697 (c.1249G>A). These variants have the potential to cause a reduction in transporter function, which could in turn result in decreased drug clearance and increased toxicity. Discussion The precise mechanism by which toxicity developed in this case remains unclear and is likely multifactorial. However, it is probable that the presence of SNPs in the gene ABCC2 played a substantial role. Our findings align with those of previously published reports of remarkably similar cases, where patients also exhibited genetic variants in the gene ABCC2.
Collapse
Affiliation(s)
- Belén García-Fariña
- Institute of Pharmacogenetics, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Lydia Rink
- Department of Pediatrics I, Neonatology, Pediatric Intensive Care, Pediatric Neurology, University Hospital Essen, Essen, Germany
| | - Virginia Santarini
- Department of Pediatrics III, Pediatric Hematology and Oncology, Cardiology, Pulmonology, University Hospital Essen, Essen, Germany
| | | | - Christian Dohna-Schwake
- Department of Pediatrics I, Neonatology, Pediatric Intensive Care, Pediatric Neurology, University Hospital Essen, Essen, Germany
| | - Birte Möhlendick
- Institute of Pharmacogenetics, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| |
Collapse
|
|
3
|
Chuansumrit A, Songdej D, Sirachainan N, Kadegasem P, Saisawat P, Sungkarat W, Kempka K, Tungbubpha N. Efficacy and Safety of a Dispersible Tablet of GPO-Deferasirox Monotherapy among Children with Transfusion-Dependent Thalassemia and Iron Overload. Hemoglobin 2024; 48:47-55. [PMID: 38369714 DOI: 10.1080/03630269.2024.2311360] [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: 10/17/2023] [Accepted: 01/23/2024] [Indexed: 02/20/2024]
Abstract
The study aimed to determine efficacy and safety of generic deferasirox monotherapy. Deferasirox was administered in transfusion-induced iron overloaded thalassemia. Efficacy was defined as responders and nonresponders by ≤ 15 reduced serum ferritin from baseline. Adverse events were also monitored. Fifty-two patients with mainly Hb E/β-thalassemia at the mean (SD) age of 8.7 (4.1) years, were enrolled. The mean (SD) daily transfusion iron load was 0.47 (0.1) mg/kg and maximum daily deferasirox was 35.0 (6.2) mg/kg. Altogether, 52, 40 and 18 patients completed the first, second and third years of study, respectively. The median baseline serum ferritin 2,383 ng/mL decreased to 1,478, 1,038 and 1,268 ng/mL at the end of first, second and third years, respectively, with overall response rate at 73.1% (38/52). Patients with baseline serum ferritin >2,500 ng/mL showed a change in serum ferritin higher than those ≤2,500 ng/mL starting from the 9th month of chelation. Adverse events were found in 5 of 52 patients (9.6%) including transaminitis (n = 2), one each of proteinuria, rash and proximal tubular dysfunction which resolved after transient stopping or decreasing the chelation dose. Generic deferasirox was effective and safe among pediatric patients with transfusion-induced iron overloaded thalassemia.
Collapse
Affiliation(s)
- Ampaiwan Chuansumrit
- Department of Pediatrics, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
| | - Duantida Songdej
- Department of Pediatrics, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
| | - Nongnuch Sirachainan
- Department of Pediatrics, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
| | - Praguywan Kadegasem
- Department of Pediatrics, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
| | - Pawaree Saisawat
- Department of Pediatrics, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
| | - Witaya Sungkarat
- Department of Radiology and Advanced Diagnostic Image Center, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
| | - Ketsuda Kempka
- Department of Pediatrics, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
| | - Noppawan Tungbubpha
- Department of Pediatrics, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
| |
Collapse
|
|
4
|
Iron Chelators in Treatment of Iron Overload. J Toxicol 2022; 2022:4911205. [PMID: 35571382 PMCID: PMC9098311 DOI: 10.1155/2022/4911205] [Citation(s) in RCA: 67] [Impact Index Per Article: 22.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2021] [Revised: 03/19/2022] [Accepted: 04/05/2022] [Indexed: 01/19/2023] Open
Abstract
Patients suffering from iron overload can experience serious complications. In such patients, various organs, such as endocrine glands and liver, can be damaged. Although iron is a crucial element for life, iron overload can be potentially toxic for human cells due to its role in generating free radicals. In the past few decades, there has been a major improvement in the survival of patients who suffer from iron overload due to the application of iron chelation therapy in clinical practice. In clinical use, deferoxamine, deferiprone, and deferasirox are the three United States Food and Drug Administration-approved iron chelators. Each of these iron chelators is well known for the treatment of iron overload in various clinical conditions. Based on several up-to-date studies, this study explained iron overload and its clinical symptoms, introduced each of the above-mentioned iron chelators, and evaluated their advantages and disadvantages with an emphasis on combination therapy, which in recent studies seems a promising approach. In numerous clinical conditions, due to the lack of accurate indicators, choosing a standard approach for iron chelation therapy can be difficult; therefore, further studies on the issue are still required. This study aimed to introduce each of these iron chelators, combination therapy, usage doses, specific clinical applications, and their advantages, toxicity, and side effects.
Collapse
|
|
5
|
Tanous O, Azulay Y, Halevy R, Dujovny T, Swartz N, Colodner R, Koren A, Levin C. Renal function in β-thalassemia major patients treated with two different iron-chelation regimes. BMC Nephrol 2021; 22:418. [PMID: 34930156 PMCID: PMC8691002 DOI: 10.1186/s12882-021-02630-5] [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: 06/08/2021] [Accepted: 11/29/2021] [Indexed: 01/19/2023] Open
Abstract
BACKGROUND Renal injury in transfusion dependent β thalassemia patients (TDT) has been attributed to iron overload, chronic anemia and iron-chelation therapy (ICT) toxicity. We studied renal function in TDT patients treated with two different ICT regimes. PATIENTS AND METHODS We studied 36 TDT patients: 26 received deferasirox (DFX) and 10 were treated with deferoxamine (DFO) +/- deferiprone (DFP). RESULTS Increased uNAG was found in 30% of the DFX group vs. 10% of the DFO+/-DFP group, the mean uNAG level in the DFX group was significantly higher than in the DFO+/-DFP group, (P < 0.05). A moderate negative correlation was found between uNAG levels and mean serum ferritin for the prior 10 years (P = 0.03), more pronounced for the DFO+/-DFP group. Twenty nine patients had had their renal function evaluated 10 years earlier; eGFR significantly declined in patients switched to DFX (P = 0.0093) but not in patients who continued DFO+/-DFP. CONCLUSIONS A high prevalence of renal tubular damage was observed in our TDT patients, particularly those treated with DFX; uNAG was negatively associated with mean 10-year serum ferritin, suggesting ICT's involvement in tubular injury. A significant decline in eGFR compared to a decade earlier was observed only in patients currently treated with DFX. Strict follow-up of renal function in TDT patients is warranted.
Collapse
Affiliation(s)
- Osama Tanous
- Pediatric Hematology Unit, Emek Medical Center, 21 Yitzhak Rabin St, Afula, Israel.,The Ruth and Bruce Rappaport Faculty of Medicine, Technion - Institute of Technology, Haifa, Israel
| | - Yossi Azulay
- Pediatric Department B, Emek Medical Center, Afula, Israel
| | - Raphael Halevy
- Pediatric Nephrology Unit, Emek Medical Center, Afula, Israel
| | - Tal Dujovny
- Pediatric Hematology Unit, Emek Medical Center, 21 Yitzhak Rabin St, Afula, Israel
| | - Neta Swartz
- Laboratory Department, Emek Medical Center, Afula, Israel
| | - Raul Colodner
- Laboratory Department, Emek Medical Center, Afula, Israel
| | - Ariel Koren
- Pediatric Hematology Unit, Emek Medical Center, 21 Yitzhak Rabin St, Afula, Israel
| | - Carina Levin
- Pediatric Hematology Unit, Emek Medical Center, 21 Yitzhak Rabin St, Afula, Israel. .,The Ruth and Bruce Rappaport Faculty of Medicine, Technion - Institute of Technology, Haifa, Israel.
| |
Collapse
|
|
6
|
Scoglio M, Cappellini MD, D’Angelo E, Bianchetti MG, Lava SAG, Agostoni C, Milani GP. Kidney Tubular Damage Secondary to Deferasirox: Systematic Literature Review. CHILDREN 2021; 8:children8121104. [PMID: 34943300 PMCID: PMC8700300 DOI: 10.3390/children8121104] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/07/2021] [Revised: 11/26/2021] [Accepted: 11/26/2021] [Indexed: 11/16/2022]
Abstract
Deferasirox is a first-line therapy for iron overload that can sometimes cause kidney damage. To better define the pattern of tubular damage, a systematic literature review was conducted on the United States National Library of Medicine, Excerpta Medica, and Web of Science databases. Twenty-three reports describing 57 individual cases could be included. The majority (n = 35) of the 57 patients were ≤18 years of age and affected by thalassemia (n = 46). Abnormal urinary findings were noted in 54, electrolyte or acid–base abnormalities in 46, and acute kidney injury in 9 patients. Latent tubular damage was diagnosed in 11 (19%), overt kidney tubular damage in 37 (65%), and an acute kidney injury in the remaining nine (16%) patients. Out of the 117 acid–base and electrolyte disorders reported in 48 patients, normal-gap metabolic acidosis and hypophosphatemia were the most frequent. Further abnormalities were, in decreasing order of frequency, hypokalemia, hypouricemia, hypocalcemia, and hyponatremia. Out of the 81 abnormal urinary findings, renal glucosuria was the most frequent, followed by tubular proteinuria, total proteinuria, and aminoaciduria. In conclusion, a proximal tubulopathy pattern may be observed on treatment with deferasirox. Since deferasirox-associated kidney damage is dose-dependent, physicians should prescribe the lowest efficacious dose.
Collapse
Affiliation(s)
- Martin Scoglio
- Department of Pediatrics, Pediatric Institute of Southern Switzerland, Ospedale San Giovanni, 6500 Bellinzona, Switzerland; (M.S.); (M.G.B.)
| | - Maria Domenica Cappellini
- Pediatric Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy; (M.D.C.); (E.D.); (C.A.); (G.P.M.)
| | - Emanuela D’Angelo
- Pediatric Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy; (M.D.C.); (E.D.); (C.A.); (G.P.M.)
| | - Mario G. Bianchetti
- Department of Pediatrics, Pediatric Institute of Southern Switzerland, Ospedale San Giovanni, 6500 Bellinzona, Switzerland; (M.S.); (M.G.B.)
| | - Sebastiano A. G. Lava
- Pediatric Cardiology Unit, Department of Pediatrics, Centre Hospitalier Universitaire Vaudois, and University of Lausanne, 1010 Lausanne, Switzerland
- Heart Failure and Transplantation, Department of Pediatric Cardiology, Great Ormond Street Hospital, London WC1N 3JH, UK
- Correspondence:
| | - Carlo Agostoni
- Pediatric Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy; (M.D.C.); (E.D.); (C.A.); (G.P.M.)
- Department of Clinical Sciences and Community Health, Università degli Studi di Milano, 20122 Milan, Italy
| | - Gregorio P. Milani
- Pediatric Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy; (M.D.C.); (E.D.); (C.A.); (G.P.M.)
- Department of Clinical Sciences and Community Health, Università degli Studi di Milano, 20122 Milan, Italy
| |
Collapse
|
|
7
|
Pharmacological and clinical evaluation of deferasirox formulations for treatment tailoring. Sci Rep 2021; 11:12581. [PMID: 34131221 PMCID: PMC8206201 DOI: 10.1038/s41598-021-91983-w] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2021] [Accepted: 05/20/2021] [Indexed: 01/19/2023] Open
Abstract
Deferasirox (DFX) is the newest among three different chelators available to treat iron overload in iron-loading anaemias, firstly released as Dispersible Tablets (DT) and more recently replaced by Film-Coated Tablets (FCT). In this retrospective observational study, pharmacokinetics, pharmacodynamics, and safety features of DFX treatment were analyzed in 74 patients that took both formulations subsequently under clinical practice conditions. Bioavailability of DFX FCT compared to DT resulted higher than expected [Cmax: 99.5 (FCT) and 69.7 (DT) μMol/L; AUC: 1278 (FCT) and 846 (DT), P < 0.0001]. DFX FCT was also superior in scalability among doses. After one year of treatment for each formulation, no differences were observed between the treatments in the overall iron overload levels; however, DFX FCT but not DT showed a significant dose–response correlation [Spearman r (dose-serum ferritin variation): − 0.54, P < 0.0001]. Despite being administered at different dosages, the long-term safety profile was not different between formulations: a significant increase in renal impairment risk was observed for both treatments and it was reversible under strict monitoring (P < 0.002). Altogether, these data constitute a comprehensive comparison of DFX formulations in thalassaemia and other iron-loading anaemias, confirming the effectiveness and safety characteristics of DFX and its applicability for treatment tailoring.
Collapse
|
|
8
|
Yui JC, Geara A, Sayani F. Deferasirox-associated Fanconi syndrome in adult patients with transfusional iron overload. Vox Sang 2021; 116:793-797. [PMID: 33529394 DOI: 10.1111/vox.13064] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2020] [Revised: 11/12/2020] [Accepted: 12/29/2020] [Indexed: 11/29/2022]
Abstract
BACKGROUND AND OBJECTIVES Deferasirox is an oral chelator approved for iron overload, which has a potential side effect of renal Fanconi syndrome, with proximal tubular dysfunction and tubular acidosis. Monitoring of renal function is recommended, though no standard for monitoring exists. We aim to describe cases of deferasirox-associated Fanconi syndrome in adults and the renal monitoring required to detect these findings. MATERIALS AND METHODS We present a review of the literature and six cases from our institution of deferasirox-associated partial Fanconi syndrome in adult patients with transfusional iron overload secondary to β-thalassemia or Diamond Blackfan Anaemia. RESULTS While prior cases in the literature occurred at high doses of deferasirox, our series included patients on doses as low as deferasirox 10 mg/kg who had been aggressively chelated. All patients had resolution of laboratory abnormalities with drug interruption. CONCLUSION Rather than chelating to normal iron levels, this series supports prior suggestions that deferasirox dose be reduced if ferritin <500-1000 ng/ml, and also supports dose reduction if liver iron content <3 mg iron per g dry weight or for those undergoing aggressive chelation with rapid decrease in iron. Monitoring with metabolic panel and urinalysis were sufficient to detect clinically significant proximal tubular dysfunction, but should be followed up with additional studies to confirm the diagnosis while deferasirox dose is decreased or held.
Collapse
Affiliation(s)
- Jennifer C Yui
- Division of Hematology, Johns Hopkins University, Baltimore, MD, USA
| | - Abdallah Geara
- Renal-Electrolyte and Hypertension Division, University of Pennsylvania, Pennsylvania, PA, USA
| | - Farzana Sayani
- Division of Hematology and Oncology, University of Pennsylvania, Pennsylvania, PA, USA
| |
Collapse
|
|
9
|
Fraser J, Brook R, He T, Lewis D. Deferasirox-induced liver injury and Fanconi syndrome in a beta-thalassemia major male. BMJ Case Rep 2020; 13:e234542. [PMID: 32646935 PMCID: PMC7351284 DOI: 10.1136/bcr-2020-234542] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/08/2020] [Indexed: 11/03/2022] Open
Abstract
A 33-year-old male presenting with subacute abdominal pain was found to have hyperbilirubinaemia, hypokalaemia and hyponatraemia. This was in the setting of transitioning between deferasirox iron chelator formulations, from dispersible tablets to film-coated tablets for ongoing treatment of chronic iron overload secondary to transfusion requirement for beta-thalassemia major. A liver biopsy demonstrated acute cholestasis with patchy confluent hepatocellular necrosis and mild to moderate microvesicular steatosis. Based on the histological, biochemical and clinical findings, the diagnosis of hepatotoxicity and Fanconi-like syndrome was made. The patient improved clinically and biochemically with cessation of the deferasirox film-coated tablets and supportive management. To our knowledge, this is the first case report of hepatotoxicity and Fanconi-like syndrome occurring due to deferasirox film-coated tablets with previous tolerance of dispersible deferasirox tablets. It is important to raise clinical awareness of this potentially severe complication.
Collapse
Affiliation(s)
- Jacqueline Fraser
- Gastroenterology and Hepatology Department, Austin Health, Heidelberg, Victoria, Australia
- Gastroenterology and Hepatology Department, Northern Health, Epping, Victoria, Australia
| | - Rowena Brook
- Haematology Department, Northern Health, Epping, Victoria, Australia
| | - Tony He
- Gastroenterology and Hepatology Department, Austin Health, Heidelberg, Victoria, Australia
- Gastroenterology and Hepatology Department, Northern Health, Epping, Victoria, Australia
| | - Diana Lewis
- Gastroenterology and Hepatology Department, Northern Health, Epping, Victoria, Australia
| |
Collapse
|
|
10
|
Gottwald EM, Schuh CD, Drücker P, Haenni D, Pearson A, Ghazi S, Bugarski M, Polesel M, Duss M, Landau EM, Kaech A, Ziegler U, Lundby AKM, Lundby C, Dittrich PS, Hall AM. The iron chelator Deferasirox causes severe mitochondrial swelling without depolarization due to a specific effect on inner membrane permeability. Sci Rep 2020; 10:1577. [PMID: 32005861 PMCID: PMC6994599 DOI: 10.1038/s41598-020-58386-9] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2019] [Accepted: 01/15/2020] [Indexed: 12/13/2022] Open
Abstract
The iron chelator Deferasirox (DFX) causes severe toxicity in patients for reasons that were previously unexplained. Here, using the kidney as a clinically relevant in vivo model for toxicity together with a broad range of experimental techniques, including live cell imaging and in vitro biophysical models, we show that DFX causes partial uncoupling and dramatic swelling of mitochondria, but without depolarization or opening of the mitochondrial permeability transition pore. This effect is explained by an increase in inner mitochondrial membrane (IMM) permeability to protons, but not small molecules. The movement of water into mitochondria is prevented by altering intracellular osmotic gradients. Other clinically used iron chelators do not produce mitochondrial swelling. Thus, DFX causes organ toxicity due to an off-target effect on the IMM, which has major adverse consequences for mitochondrial volume regulation.
Collapse
Affiliation(s)
| | - Claus D Schuh
- Institute of Anatomy, University of Zurich, Zurich, Switzerland
| | - Patrick Drücker
- Department of Biosystems Science and Engineering, ETH Zurich, Zurich, Switzerland
| | - Dominik Haenni
- Institute of Anatomy, University of Zurich, Zurich, Switzerland.,Center for Microscopy and Image Analysis, University of Zurich, Zurich, Switzerland
| | - Adam Pearson
- Institute of Anatomy, University of Zurich, Zurich, Switzerland
| | - Susan Ghazi
- Institute of Anatomy, University of Zurich, Zurich, Switzerland
| | - Milica Bugarski
- Institute of Anatomy, University of Zurich, Zurich, Switzerland
| | | | - Michael Duss
- Department of Chemistry, University of Zurich, Zurich, Switzerland
| | - Ehud M Landau
- Department of Chemistry, University of Zurich, Zurich, Switzerland
| | - Andres Kaech
- Center for Microscopy and Image Analysis, University of Zurich, Zurich, Switzerland
| | - Urs Ziegler
- Center for Microscopy and Image Analysis, University of Zurich, Zurich, Switzerland
| | - Anne K M Lundby
- Institute of Physiology, University of Zurich, Zurich, Switzerland
| | - Carsten Lundby
- Institute of Physiology, University of Zurich, Zurich, Switzerland
| | - Petra S Dittrich
- Department of Biosystems Science and Engineering, ETH Zurich, Zurich, Switzerland
| | - Andrew M Hall
- Institute of Anatomy, University of Zurich, Zurich, Switzerland. .,Department of Nephrology, University Hospital Zurich, Zurich, Switzerland.
| |
Collapse
|
|
11
|
Demosthenous C, Vlachaki E, Apostolou C, Eleftheriou P, Kotsiafti A, Vetsiou E, Mandala E, Perifanis V, Sarafidis P. Beta-thalassemia: renal complications and mechanisms: a narrative review. ACTA ACUST UNITED AC 2019; 24:426-438. [PMID: 30947625 DOI: 10.1080/16078454.2019.1599096] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
Abstract
OBJECTIVES Beta-thalassemias are a group of recessively autosomal inherited disorders of hemoglobin synthesis, which, due to mutations of the beta-globin gene, lead to various degrees of defective beta-chain production, an imbalance in alpha/beta-globin chain synthesis, ineffective erythropoiesis, and anemia. Improved survival in thalassemic patients has led to the emergence of previously unrecognized complications, such as renal disease. METHODS A comprehensive literature review through PubMed was undertaken to summarize the published evidence on the epidemiology and pathophysiology of renal disease in thalassemia. Literature sources published in English since 1990 were searched, using the terms beta-thalassemia, renal disease. RESULTS Renal disease is considered to be the 4th cause of morbidity among patients with transfusion dependent thalassemia. Chronic anemia, hypoxia and iron overload are the main mechanisms implicated in development of renal injury, whereas several studies also suggested a contributive role of iron chelators. DISCUSSION AND CONCLUSION Kidney disease may develop through progressive renal tubular and glomerular damage; thus, its early recognition is important in order to prevent and/or reverse deterioration. This review will provide an insight on the involved mechanisms implicated in kidney disease in thalassemic patients and will discuss the updates on diagnosis and prevention of renal complications in thalassemia.
Collapse
Affiliation(s)
- Christos Demosthenous
- a Department of Hematology and HCT Unit , General Hospital of Thessaloniki "George Papanicolaou" , Thessaloniki , Greece
| | - Efthymia Vlachaki
- b Adults Thalassemia Unit, Second Department of Internal Medicine , Aristotle University, Hippokration Hospital , Thessaloniki , Greece
| | - Chrysa Apostolou
- b Adults Thalassemia Unit, Second Department of Internal Medicine , Aristotle University, Hippokration Hospital , Thessaloniki , Greece
| | - Perla Eleftheriou
- c Department of Haematology , University College London , London , UK
| | - Aggeliki Kotsiafti
- b Adults Thalassemia Unit, Second Department of Internal Medicine , Aristotle University, Hippokration Hospital , Thessaloniki , Greece
| | - Evangelia Vetsiou
- b Adults Thalassemia Unit, Second Department of Internal Medicine , Aristotle University, Hippokration Hospital , Thessaloniki , Greece
| | - Evdokia Mandala
- d Fourth Department of Internal Medicine , Aristotle University, Hippokration Hospital , Thessaloniki , Greece
| | - Vassilios Perifanis
- e First Propedeutic Department of Internal Medicine , Aristotle University, AHEPA General Hospital of Thessaloniki , Thessaloniki , Greece
| | - Pantelis Sarafidis
- f Department of Nephrology , Hippokration Hospital, Aristotle University of Thessaloniki , Thessaloniki , Greece
| |
Collapse
|
|
12
|
De Sanctis V, Soliman AT, Elsefdy H, Soliman N, Bedair E, Fiscina B, Kattamis C. Bone disease in β thalassemia patients: past, present and future perspectives. Metabolism 2018; 80:66-79. [PMID: 28987275 DOI: 10.1016/j.metabol.2017.09.012] [Citation(s) in RCA: 42] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/30/2017] [Revised: 09/07/2017] [Accepted: 09/10/2017] [Indexed: 01/23/2023]
Abstract
Bone disorders in patients with thalassemia major (TM) and intermedia (TI) constitute complex conditions that result from various factors affecting the growing skeleton. Although much progress has been made in our understanding of the natural history, pathogenesis and clinical manifestations of β- and δβ-thalassemia, bone manifestations remain a puzzle for the clinician. In this review, we outline the key points in the current literature on the pathogenesis and management of bone disease in patients with TM and TI who were conventionally treated in recent decades with frequent blood transfusions and iron chelation. Prevention, early recognition and treatment are the most effective strategies for the management of bone disease in these patients. However, further studies are required to maintain optimal bone health for both TM and TI patients. Studying bone disease in patients with non-transfusion dependent TI, which seems to worsen considerably with age, is important to delineate the effect of the disease itself on bone health without the intervening factors of transfusions, iron intoxication and chelation.
Collapse
Affiliation(s)
- Vincenzo De Sanctis
- Pediatric and Adolescent Outpatient Clinic, Quisisana Hospital, Ferrara, Italy.
| | - Ashraf T Soliman
- Department of Pediatrics, Division of Endocrinology, Hamad General Hospital, Doha, Qatar; Department of Pediatrics, Division of Endocrinology, Alexandria University Children's Hospital, Alexandria, Egypt
| | - Heba Elsefdy
- Department of Pediatrics, Ain Shams University, Cairo, Egypt
| | - Nada Soliman
- Primary Health Care, Ministry of Health, Alexandria, Egypt
| | - Elsaid Bedair
- Department of Radiology, AlKhor Hospital, Hamad Medical Center, Doha, Qatar
| | | | - Christos Kattamis
- First Department of Paediatrics, University of Athens, Athens, Greece
| |
Collapse
|
|
13
|
Cheddani L, Leblanc T, Silve C, Tabibzadeh N, Prié D, Haymann JP, Péraldi MN, Daudon M, Meria P, Letavernier E. Iron Chelation Resulting in Renal Phosphate Wasting. Kidney Int Rep 2018; 3:1-4. [PMID: 29340306 PMCID: PMC5762934 DOI: 10.1016/j.ekir.2017.07.011] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022] Open
Affiliation(s)
- Lynda Cheddani
- Explorations Fonctionnelles Multidisciplinaires, AP-HP, Hôpital Tenon, Paris, France
| | - Thierry Leblanc
- Service d’Hématologie, AP-HP, Hôpital Saint-Louis, Paris, France
| | - Caroline Silve
- Service de Biochimie et Génétique Moléculaire, AP-HP, Hôpital Cochin, Paris, France
- INSERM U1169, Université Paris Sud, Hôpital Bicêtre, Le Kremlin Bicêtre, France
- Centre de Référence des Maladies Rares du Métabolisme du Phosphore et du Calcium, Filière de Santé Maladies Rares OSCAR, AP-HP, Paris, France
| | - Nahid Tabibzadeh
- Sorbonne Université−UPMC Paris 06, UMR S 1155, Paris, France
- INSERM, UMR S 1155, Paris, France
- Explorations Fonctionnelles Multidisciplinaires, AP-HP, Hôpital Tenon, Paris, France
| | - Dominique Prié
- Paris Descartes Université−Paris 05, Paris, France
- Service des Explorations Fonctionnelles, AP-HP, Hôpital Necker, Paris, France
| | - Jean-Philippe Haymann
- Sorbonne Université−UPMC Paris 06, UMR S 1155, Paris, France
- INSERM, UMR S 1155, Paris, France
- Explorations Fonctionnelles Multidisciplinaires, AP-HP, Hôpital Tenon, Paris, France
| | | | - Michel Daudon
- Sorbonne Université−UPMC Paris 06, UMR S 1155, Paris, France
- INSERM, UMR S 1155, Paris, France
- Explorations Fonctionnelles Multidisciplinaires, AP-HP, Hôpital Tenon, Paris, France
| | - Paul Meria
- Service d’Urologie, AP-HP, Hôpital Saint-Louis, Paris, France
| | - Emmanuel Letavernier
- Sorbonne Université−UPMC Paris 06, UMR S 1155, Paris, France
- INSERM, UMR S 1155, Paris, France
- Explorations Fonctionnelles Multidisciplinaires, AP-HP, Hôpital Tenon, Paris, France
- Correspondence: Emmanuel Letavernier, Service des Explorations Fonctionnelles, Multidisciplinaires, Hôpital Tenon, 4 rue de la Chine, 75020 Paris, France.Service des Explorations FonctionnellesMultidisciplinairesHôpital Tenon4 rue de la Chine75020 ParisFrance
| |
Collapse
|
|
14
|
Shah L, Powell JL, Zaritsky JJ. A case of Fanconi syndrome due to a deferasirox overdose and a trial of plasmapheresis. J Clin Pharm Ther 2017; 42:634-637. [DOI: 10.1111/jcpt.12553] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2016] [Accepted: 04/10/2017] [Indexed: 11/28/2022]
Affiliation(s)
- L. Shah
- Sidney Kimmel Medical College-Thomas Jefferson University School of Medicine; Philadelphia PA USA
- Alfred I. duPont Hospital for Children; Wilmington DE USA
| | - J. L. Powell
- Alfred I. duPont Hospital for Children; Wilmington DE USA
| | - J. J. Zaritsky
- Alfred I. duPont Hospital for Children; Wilmington DE USA
- Thomas Jefferson School of Medicine; Philadelphia PA USA
| |
Collapse
|
|
15
|
Abstract
This case report details a unique case of acute, reversible liver failure in a 12-year-old male with sickle cell anemia on chronic transfusion protocol and deferasirox chelation. There is substantial literature documenting deferasirox-induced renal injury, including Fanconi syndrome, but less documentation of hepatic toxicity and few reports of hepatic failure. The case highlights the importance of close monitoring of ferritin, bilirubin, and transaminases for patients on deferasirox.
Collapse
|
|
16
|
Botzenhardt S, Li N, Chan EW, Sing CW, Wong ICK, Neubert A. Safety profiles of iron chelators in young patients with haemoglobinopathies. Eur J Haematol 2017; 98:198-217. [PMID: 27893170 DOI: 10.1111/ejh.12833] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/08/2016] [Indexed: 12/19/2022]
Abstract
BACKGROUND This review describes the safety of deferoxamine (DFO), deferiprone (DFP), deferasirox (DFX) and combined therapy in young patients less than 25 yr of age with haemoglobinopathies. METHODS Searches in electronic literature databases were performed. Studies reporting adverse events associated with iron chelation therapy were included. Study and reporting quality was assessed using AHRQ Risk of Bias Assessment Tool and McMaster Quality Assessment Scale of Harms. Prospective clinical studies were pooled in a random-effects meta-analysis of proportions. RESULTS Safety data of 2040 patients from 34 studies were included. Ninety-two case reports of 246 patients were identified. DFX (937 patients) and DFP (667 patients) possess the largest published safety evidence. Fewer studies on combination regimens are available. Increased transaminases were seen in all regimens (3.9-31.3%) and gastrointestinal disorders with DFP and DFX (3.7-18.4% and 5.8-18.8%, respectively). Therapy discontinuations due to adverse events were low (0-4.1%). Reporting quality was selective and poor in most of the studies. CONCLUSION Iron chelation therapy is generally safe in young patients, and published data correspond to summary of product characteristics. Each iron chelation regimen has its specific safety risks. DFO seems not to be associated with serious adverse effects in recommended doses. In DFP and DFX, rare, but serious, adverse reactions can occur. Data on combined therapy are scarce, but it seems equally safe compared to monotherapy.
Collapse
Affiliation(s)
- Sebastian Botzenhardt
- Department of Paediatrics and Adolescent Medicine, Faculty of Medicine, Friedrich-Alexander University Erlangen-Nürnberg (FAU), Erlangen, Germany
| | - Niya Li
- Department of Pharmacology and Pharmacy, Li Ka Shing Faculty of Medicine, Centre for Safe Medication Practice and Research, University of Hong Kong, Hong Kong, China.,Clinical Trials Center, The University of Hong Kong - Shenzhen Hospital, Shenzhen, China
| | - Esther W Chan
- Department of Pharmacology and Pharmacy, Li Ka Shing Faculty of Medicine, Centre for Safe Medication Practice and Research, University of Hong Kong, Hong Kong, China
| | - Chor Wing Sing
- Department of Pharmacology and Pharmacy, Li Ka Shing Faculty of Medicine, Centre for Safe Medication Practice and Research, University of Hong Kong, Hong Kong, China
| | - Ian C K Wong
- Department of Pharmacology and Pharmacy, Li Ka Shing Faculty of Medicine, Centre for Safe Medication Practice and Research, University of Hong Kong, Hong Kong, China.,Research Department of Practice & Policy, University College London School of Pharmacy, London, UK
| | - Antje Neubert
- Department of Paediatrics and Adolescent Medicine, Faculty of Medicine, Friedrich-Alexander University Erlangen-Nürnberg (FAU), Erlangen, Germany
| |
Collapse
|
|
17
|
Chuang GT, Tsai IJ, Tsau YK, Lu MY. Transfusion-dependent thalassaemic patients with renal Fanconi syndrome due to deferasirox use. Nephrology (Carlton) 2016; 20:931-5. [PMID: 26016559 DOI: 10.1111/nep.12523] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/24/2015] [Indexed: 01/30/2023]
Abstract
AIM Deferasirox is a new oral iron chelating agent with several cases reporting renal adverse events in recent years. Our aim was to identify the incidence of deferasirox-related Fanconi syndrome (FS) and its risk factors. METHODS All transfusion-dependent thalassaemic patients who received deferasirox at the outpatient department of the National Taiwan University Hospital (NTUH) from January 2006 to February 2014 were evaluated. RESULTS This cohort study included 57 patients, and mean age of deferasirox initiation was 18.2 ± 7.7 years. After 6.9 ± 1.8 years of follow-up, 5 in 57 (8.8%) thalassaemic patients had FS. Age of starting deferasirox negatively correlated with incidence of FS (correlation coefficient -0.892, P = 0.008). Other factors were not significantly associated with FS. Serum creatinine level at the start of deferasirox compared to at the end of study or onset of FS did not show significant change (P = 0.277). All the deferasirox-related FS manifested with proximal renal tubular acidosis and hypophosphataemia, which needed specific treatment or withdrawal of deferasirox use. CONCLUSIONS We recommend that children, especially of young age, who regularly use deferasirox should undergo routine urinalysis and blood testing for early detection of FS.
Collapse
Affiliation(s)
- Gwo-Tsann Chuang
- Department of Pediatrics, National Taiwan University Hospital, Taipei, Taiwan
| | - I-Jung Tsai
- Department of Pediatrics, National Taiwan University Hospital, Taipei, Taiwan
| | - Yong-Kwei Tsau
- Department of Pediatrics, National Taiwan University Hospital, Taipei, Taiwan
| | - Meng-Yao Lu
- Department of Pediatrics, National Taiwan University Hospital, Taipei, Taiwan
| |
Collapse
|
|
18
|
Bayanzay K, Alzoebie L. Reducing the iron burden and improving survival in transfusion-dependent thalassemia patients: current perspectives. J Blood Med 2016; 7:159-69. [PMID: 27540317 PMCID: PMC4982491 DOI: 10.2147/jbm.s61540] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/02/2023] Open
Abstract
Hypertransfusion regimens for thalassemic patients revolutionized the management of severe thalassemia; transforming a disease which previously led to early infant death into a chronic condition. The devastating effect of the accrued iron from chronic blood transfusions necessitates a more finely tuned approach to limit the complications of the disease, as well as its treatment. A comprehensive approach including carefully tailored transfusion protocol, continuous monitoring and assessment of total body iron levels, and iron chelation are currently the mainstay in treating iron overload. There are also indications for ancillary treatments, such as splenectomy and fetal hemoglobin induction. The main cause of death in iron overload continues to be related to cardiac complications. However, since the widespread use of iron chelation started in the 1970s, there has been a general improvement in survival in these patients.
Collapse
Affiliation(s)
- Karim Bayanzay
- Department of Hematology, Gulf Medical University, Ajman, United Arab Emirates
| | - Lama Alzoebie
- Department of Hematology, Gulf Medical University, Ajman, United Arab Emirates
| |
Collapse
|
|
19
|
Papneja K, Bhatt MD, Kirby-Allen M, Arora S, Wiernikowski JT, Athale UH. Fanconi Syndrome Secondary to Deferasirox in Diamond-Blackfan Anemia: Case Series and Recommendations for Early Diagnosis. Pediatr Blood Cancer 2016; 63:1480-3. [PMID: 27082377 DOI: 10.1002/pbc.25995] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/21/2015] [Accepted: 02/29/2016] [Indexed: 11/07/2022]
Abstract
Deferasirox is an oral iron chelator used to treat patients with transfusion-related iron overload. We report, from two institutions, two children with Diamond-Blackfan anemia who developed Fanconi syndrome secondary to deferasirox administration, along with a review of the literature. The current recommendation for the laboratory monitoring of patients receiving deferasirox does not include serum electrolytes or urine analysis. Thus, despite routine clinic visits and bloodwork, these two patients presented with life-threatening electrolyte abnormalities requiring hospitalization. Hence, we propose the inclusion of serum electrolytes and urine analysis as part of routine monitoring to facilitate the early diagnosis of Fanconi syndrome in the context of high doses of deferasirox therapy.
Collapse
Affiliation(s)
- Koyelle Papneja
- Division of Pediatric Hematology/Oncology, Department of Pediatrics, McMaster Children's Hospital, McMaster University, Hamilton, Ontario, Canada
| | - Mihir D Bhatt
- Division of Pediatric Hematology/Oncology, Department of Pediatrics, McMaster Children's Hospital, McMaster University, Hamilton, Ontario, Canada
| | - Melanie Kirby-Allen
- Division of Pediatric Hematology/Oncology, Department of Pediatrics, The Hospital for Sick Children, Toronto, Ontario, Canada
| | - Steven Arora
- Division of Nephrology, Department of Pediatrics, McMaster Children's Hospital, McMaster University, Hamilton, Ontario, Canada
| | - John T Wiernikowski
- Division of Pediatric Hematology/Oncology, Department of Pediatrics, McMaster Children's Hospital, McMaster University, Hamilton, Ontario, Canada
| | - Uma H Athale
- Division of Pediatric Hematology/Oncology, Department of Pediatrics, McMaster Children's Hospital, McMaster University, Hamilton, Ontario, Canada
| |
Collapse
|
|
20
|
Rémy P, Audard V, Galactéros F. [Kidney and hemoglobinopathy]. Nephrol Ther 2016; 12:117-29. [PMID: 26947986 DOI: 10.1016/j.nephro.2016.01.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
Sickle-cell disease (SCD), one of the most common severe monogenic disorders into the world, is associated with an increased frequency of chronic kidney disease. SCD is caused by a point mutation in the gene encoding β globin gene which leads to the formation of hemoglobin S that polymerises after deoxygenation. HbS polymerisation is associated with erythrocyte rigidity and vaso-occlusive episodes that play a central role into SCD pathogenesis. The spectrum of renal diseases during SCD is broad and includes various renal manifestations which become more apparent with increasing age. Underlying pathophysiological processes involved in sickle cell nephropathy are multifactorial but endothelial dysfunction related to chronic hemolysis is a key factor contributing to renal involvement. Our review focuses on the pathogenesis and on the spectrum of renal manifestations occurring in SCD patients.
Collapse
Affiliation(s)
- Philippe Rémy
- Service de néphrologie-dialyse-transplantation, hôpital Henri-Mondor, 51, avenue du Maréchal-de-Lattre-de-Tassigny, 94010 Créteil cedex, France.
| | - Vincent Audard
- Service de néphrologie-dialyse-transplantation, hôpital Henri-Mondor, 51, avenue du Maréchal-de-Lattre-de-Tassigny, 94010 Créteil cedex, France
| | - Frédéric Galactéros
- Service de néphrologie-dialyse-transplantation, hôpital Henri-Mondor, 51, avenue du Maréchal-de-Lattre-de-Tassigny, 94010 Créteil cedex, France
| |
Collapse
|
|
21
|
Saliba AN, El Rassi F, Taher AT. Clinical monitoring and management of complications related to chelation therapy in patients with β-thalassemia. Expert Rev Hematol 2015; 9:151-68. [DOI: 10.1586/17474086.2016.1126176] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
|
|
22
|
Borgna-Pignatti C, Marsella M. Iron Chelation in Thalassemia Major. Clin Ther 2015; 37:2866-77. [PMID: 26519233 DOI: 10.1016/j.clinthera.2015.10.001] [Citation(s) in RCA: 41] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2015] [Revised: 10/01/2015] [Accepted: 10/02/2015] [Indexed: 01/19/2023]
Abstract
PURPOSE Iron chelation has improved survival and quality of life of patients with thalassemia major. there are currently 3 commercially available iron-chelating drugs with different pharmacokinetic and pharmacodynamic activity. The choice of adequate chelation treatment should be tailored to patient needs and based on up-to-date scientific evidence. METHODS A review of the most recent literature was performed. FINDINGS The ability of the chelators to bind the redox active component of iron, labile plasma iron, is crucial for protecting the cells. Chelation therapy should be guided by magnetic resonance imaging that permits the tailoring of therapy according to the needs of the patient because different chelators preferentially clear iron from different sites. Normal levels of body iron seem to decrease the need for hormonal and cardiac therapy. IMPLICATIONS The 3 chelators currently available have different benefits, different safety profiles, and different acceptance on the part of the patients. Good-quality, well-designed, randomized, long-term clinical trials continue to be needed.
Collapse
Affiliation(s)
| | - Maria Marsella
- Pediatrics and Adolescentology Unit, Maternal and Child Health Department, "G. Rummo" Hospital, Benevento, Italy
| |
Collapse
|
|
23
|
Bergeron RJ, Bharti N, McManis JS, Wiegand J. Metabolically programmed iron chelators. Bioorg Med Chem 2015; 23:5954-71. [PMID: 26231739 DOI: 10.1016/j.bmc.2015.06.059] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2015] [Revised: 06/15/2015] [Accepted: 06/23/2015] [Indexed: 01/19/2023]
Abstract
Extensive structure activity relationship (SAR) studies focused on the desferrithiocin [DFT, (S)-4,5-dihydro-2-(3-hydroxy-2-pyridinyl)-4-methyl-4-thiazolecarboxylic acid] pharmacophore have led to three different DFT analogs being evaluated clinically for the treatment of iron overload diseases, for example, thalassemia. The SAR work revealed that the lipophilicity of a ligand, as determined by its partition between octanol and water, logP(app), could have a profound effect on the drug's iron clearing efficiency (ICE), organ distribution, and toxicity profile. While within a given structural family the more lipophilic a chelator the better the ICE, unfortunately, the more lipophilic ligands are often more toxic. Thus, a balance between lipophilicity, ICE, and toxicity must be achieved. In the current study, we introduce the concept of 'metabolically programmed' iron chelators, that is, highly lipophilic, orally absorbable, effective deferration agents which, once absorbed, are quickly converted to their nontoxic, hydrophilic counterparts.
Collapse
Affiliation(s)
- Raymond J Bergeron
- JHMHC, Department of Medicinal Chemistry, University of Florida, Box 100485, Gainesville, FL 32610-0485, United States.
| | - Neelam Bharti
- JHMHC, Department of Medicinal Chemistry, University of Florida, Box 100485, Gainesville, FL 32610-0485, United States
| | - James S McManis
- JHMHC, Department of Medicinal Chemistry, University of Florida, Box 100485, Gainesville, FL 32610-0485, United States
| | - Jan Wiegand
- JHMHC, Department of Medicinal Chemistry, University of Florida, Box 100485, Gainesville, FL 32610-0485, United States
| |
Collapse
|
|
24
|
Bergeron RJ, Wiegand J, McManis JS, Bharti N. Desferrithiocin: a search for clinically effective iron chelators. J Med Chem 2014; 57:9259-91. [PMID: 25207964 PMCID: PMC4255733 DOI: 10.1021/jm500828f] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2014] [Indexed: 01/19/2023]
Abstract
The successful search for orally active iron chelators to treat transfusional iron-overload diseases, e.g., thalassemia, is overviewed. The critical role of iron in nature as a redox engine is first described, as well as how primitive life forms and humans manage the metal. The problems that derive when iron homeostasis in humans is disrupted and the mechanism of the ensuing damage, uncontrolled Fenton chemistry, are discussed. The solution to the problem, chelator-mediated iron removal, is clear. Design options for the assembly of ligands that sequester and decorporate iron are reviewed, along with the shortcomings of the currently available therapeutics. The rationale for choosing desferrithiocin, a natural product iron chelator (a siderophore), as a platform for structure-activity relationship studies in the search for an orally active iron chelator is thoroughly developed. The study provides an excellent example of how to systematically reengineer a pharmacophore in order to overcome toxicological problems while maintaining iron clearing efficacy and has led to three ligands being evaluated in human clinical trials.
Collapse
Affiliation(s)
- Raymond J. Bergeron
- Department of Medicinal Chemistry, University of Florida, Box 100485 JHMHC, Gainesville, Florida 32610-0485, United States
| | - Jan Wiegand
- Department of Medicinal Chemistry, University of Florida, Box 100485 JHMHC, Gainesville, Florida 32610-0485, United States
| | - James S. McManis
- Department of Medicinal Chemistry, University of Florida, Box 100485 JHMHC, Gainesville, Florida 32610-0485, United States
| | - Neelam Bharti
- Department of Medicinal Chemistry, University of Florida, Box 100485 JHMHC, Gainesville, Florida 32610-0485, United States
| |
Collapse
|
|
25
|
Kontoghiorghe CN, Andreou N, Constantinou K, Kontoghiorghes GJ. World health dilemmas: Orphan and rare diseases, orphan drugs and orphan patients. World J Methodol 2014; 4:163-188. [PMID: 25332915 PMCID: PMC4202455 DOI: 10.5662/wjm.v4.i3.163] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/29/2014] [Revised: 04/05/2014] [Accepted: 06/27/2014] [Indexed: 02/06/2023] Open
Abstract
According to global annual estimates hunger/malnutrition is the major cause of death (36 of 62 million). Cardiovascular diseases and cancer (5.44 of 13.43 million) are the major causes of death in developed countries, while lower respiratory tract infections, human immunodeficiency virus infection/acquired immunodeficiency syndrome, diarrhoeal disease, malaria and tuberculosis (10.88 of 27.12 million) are the major causes of death in developing countries with more than 70% of deaths occurring in children. The majority of approximately 800 million people with other rare diseases, including 100000 children born with thalassaemia annually receive no treatment. There are major ethical dilemmas in dealing with global health issues such as poverty and the treatment of orphan and rare diseases. Of approximately 50000 drugs about 10% are orphan drugs, with annual sales of the latter approaching 100 billion USD. In comparison, the annual revenue in 2009 from the top 12 pharmaceutical companies in Western countries was 445 billion USD and the top drug, atorvastatin, reached 100 billion USD. In the same year, the total government expenditure for health in the developing countries was 410 billion USD with only 6%-7% having been received as aid from developed countries. Drugs cost the National Health Service in the United Kingdom more than 20 billion USD or 10% of the annual health budget. Uncontrollable drug prices and marketing policies affect global health budgets, clinical practice, patient safety and survival. Fines of 5.3 billion USD were imposed on two pharmaceutical companies in the United States, the regulatory authority in France was replaced and clinicians were charged with bribery in order to overcome recent illegal practises affecting patient care. High expenditure for drug development is mainly related to marketing costs. However, only 2 million USD was spent developing the drug deferiprone (L1) for thalassaemia up to the stage of multicentre clinical trials. The criteria for drug development, price levels and use needs to be readdressed to improve drug safety and minimise costs. New global health policies based on cheaper drugs can help the treatment of many categories of orphan and rare diseases and millions of orphan patients in developing and developed countries.
Collapse
|
|
26
|
Díaz-García JD, Gallegos-Villalobos A, Gonzalez-Espinoza L, Sanchez-Niño MD, Villarrubia J, Ortiz A. Deferasirox nephrotoxicity-the knowns and unknowns. Nat Rev Nephrol 2014; 10:574-86. [PMID: 25048549 DOI: 10.1038/nrneph.2014.121] [Citation(s) in RCA: 52] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/30/2023]
Abstract
In 2005, the oral iron chelator deferasirox was approved by the FDA for clinical use as a first-line therapy for blood-transfusion-related iron overload. Nephrotoxicity is the most serious and frequent adverse effect of deferasirox treatment. This nephrotoxicity can present as an acute or chronic decrease in glomerular filtration rate (GFR). Features of proximal tubular dysfunction might also be present. In clinical trials and observational studies, GFR is decreased in 30-100% of patients treated with deferasirox, depending on dose, method of assessment and population studied. Nephrotoxicity is usually nonprogressive and/or reversible and rapid iron depletion is one of several risk factors. Scarce data are available on the molecular mechanisms of nephrotoxicity and the reasons for the specific proximal tubular sensitivity to the drug. Although deferasirox promotes apoptosis of cultured proximal tubular cells, the trigger has not been well characterized. Observational studies are required to track current trends in deferasirox prescription, assess the epidemiology of deferasirox nephrotoxicity in routine clinical practice, explore the effect on outcomes of various monitoring and dose-adjustment protocols and elucidate the long-term consequences of the different features of nephrotoxicity. Deferasirox nephrotoxicity can be more common in the elderly; thus, specific efforts should be dedicated to investigate the effect of deferasirox use in this group of patients.
Collapse
Affiliation(s)
- Juan Daniel Díaz-García
- Escuela Superior de Medicina del Instituto Politécnico Nacional, Avenida Salvador Díaz Mirón s/n, 11340 Ciudad de México, México
| | | | | | | | - Jesus Villarrubia
- Hospital Ramon y Cajal, Carretera de Colmenar Viejo km. 9,100, 28034 Madrid, Spain
| | - Alberto Ortiz
- Unidad de Diálisis, Fundación Jiménez Díaz-IRSIN, Avenida Reyes Católicos 2, 28040 Madrid, Spain
| |
Collapse
|
|
27
|
Staikou C, Stavroulakis E, Karmaniolou I. A narrative review of peri-operative management of patients with thalassaemia. Anaesthesia 2014; 69:494-510. [DOI: 10.1111/anae.12591] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/20/2013] [Indexed: 01/19/2023]
Affiliation(s)
- C. Staikou
- Department of Anaesthesia; Aretaieio University Hospital; Athens Greece
| | - E. Stavroulakis
- Department of Anaesthesia; Aretaieio University Hospital; Athens Greece
| | - I. Karmaniolou
- Department of Anaesthesia; Royal National Orthopaedic Hospital; Stanmore UK
| |
Collapse
|
|
28
|
Abstract
Red blood cell transfusions are increasingly used in the management of various anemias, including thalassemia and sickle cell disease. Because the body lacks physiologic mechanisms for removing excess iron, transfusional iron overload is a common complication in children receiving regular transfusions. Iron chelation is necessary to remove the excess iron that causes injury to the heart, liver, and endocrine organs. Three chelators, deferoxamine, deferasirox, and deferiprone, are currently available in the United States. When choosing a chelator regimen, patients, parents, and providers may consider a variety of factors, including the severity of iron overload, administration schedule, and adverse effect profile.
Collapse
Affiliation(s)
- Hannah M Ware
- Division of Hematology, Department of Pediatrics, Children's Hospital of Philadelphia, University of Pennsylvania, 34th Street, Civic Center Boulevard, Philadelphia, PA 19104, USA
| | | |
Collapse
|
|
29
|
Kontoghiorghe CN, Kolnagou A, Kontoghiorghes GJ. Potential clinical applications of chelating drugs in diseases targeting transferrin-bound iron and other metals. Expert Opin Investig Drugs 2013; 22:591-618. [PMID: 23586878 DOI: 10.1517/13543784.2013.787408] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
Abstract
INTRODUCTION Iron is essential for normal, neoplasmic and microbial cells. Transferrin (Tf) is responsible for iron transport and its interactions with chelators are of physiological and toxicological importance and could lead to new therapeutic applications. AREAS COVERED Differential interactions of Tf with chelators such as deferiprone (L1) could be used to modify toxicity and disease pathways in relation to iron and other metal metabolism. Iron mobilization by L1 could achieve normal body iron stores in thalassemia patients. Iron mobilization from the reticuloendothelial system by L1 and exchange with Tf could be used to increase the production of hemoglobin in the anemia of chronic disease. Iron accumulation is pathogenic in neurodegenerative, acute kidney and other diseases and could be removed by L1 with therapeutic implications. Deprivation of iron from neoplasmic and microbial cells by chelators could increase the prospect of improved treatments in cancer and infectious diseases. Other applications include metal detoxification and inhibition of oxidative stress-related conditions. EXPERT OPINION Specific mechanisms apply in the interactions of chelators with Tf, which could be used in the design of targeted therapeutic strategies in many conditions. In each case specific chelator protocols have to be designed for achieving optimum therapeutic activity.
Collapse
Affiliation(s)
- Christina N Kontoghiorghe
- Postgraduate Research Institute of Science, Technology, Environment and Medicine, Limassol CY 3021, Cyprus.
| | | | | |
Collapse
|
|
30
|
Bentley A, Gillard S, Spino M, Connelly J, Tricta F. Cost-utility analysis of deferiprone for the treatment of β-thalassaemia patients with chronic iron overload: a UK perspective. PHARMACOECONOMICS 2013; 31:807-22. [PMID: 23868464 PMCID: PMC3757270 DOI: 10.1007/s40273-013-0076-z] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/05/2023]
Abstract
BACKGROUND Patients with β-thalassaemia major experience chronic iron overload due to regular blood transfusions. Chronic iron overload can be treated using iron-chelating therapies such as desferrioxamine (DFO), deferiprone (DFP) and deferasirox (DFX) monotherapy, or DFO-DFP combination therapy. OBJECTIVES This study evaluated the relative cost effectiveness of these regimens over a 5-year timeframe from a UK National Health Service (NHS) perspective, including personal and social services. METHODS A Markov model was constructed to evaluate the cost effectiveness of the treatment regimens over 5 years. Based on published randomized controlled trial evidence, it was assumed that all four treatment regimens had a comparable effect on serum ferritin concentration (SFC) and liver iron concentration (LIC), and that DFP was more effective for reducing cardiac morbidity and mortality. Published utility scores for route of administration were used, with subcutaneously administered DFO assumed to incur a greater quality of life (QoL) burden than the oral chelators DFP and DFX. Healthcare resource use, drug costs (2010/2011 costs), and utilities associated with adverse events were also considered, with the effect of varying all parameters assessed in sensitivity analysis. Incremental costs and quality-adjusted life-years (QALYs) were calculated for each treatment, with cost effectiveness expressed as incremental cost per QALY. Assumptions that DFP conferred no cardiac morbidity, mortality, or morbidity and mortality benefit were also explored in scenario analysis. RESULTS DFP was the dominant strategy in all scenarios modelled, providing greater QALY gains at a lower cost. Sensitivity analysis showed that DFP dominated all other treatments unless the QoL burden associated with the route of administration was greater for DFP than for DFO, which is unlikely to be the case. DFP had >99 % likelihood of being cost effective against all comparators at a willingness-to-pay threshold of £20,000 per QALY. CONCLUSIONS In this analysis, DFP appeared to be the most cost-effective treatment available for managing chronic iron overload in β-thalassaemia patients. Use of DFP in these patients could therefore result in substantial cost savings.
Collapse
Affiliation(s)
- Anthony Bentley
- Abacus International, 6 Talisman Business Centre, Talisman Road, Bicester, Oxfordshire, OX26 6HR, UK.
| | | | | | | | | |
Collapse
|
|
31
|
Dell'Orto VG, Bianchetti MG, Brazzola P. Hyperchloraemic metabolic acidosis induced by the iron chelator deferasirox: a case report and review of the literature. J Clin Pharm Ther 2013; 38:526-7. [DOI: 10.1111/jcpt.12095] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2013] [Accepted: 07/29/2013] [Indexed: 11/28/2022]
Affiliation(s)
- V. G. Dell'Orto
- Integrated Department of Pediatrics; Ente Ospedaliero Cantonale Ticinese; University of Berne; Berne Switzerland
| | - M. G. Bianchetti
- Integrated Department of Pediatrics; Ente Ospedaliero Cantonale Ticinese; University of Berne; Berne Switzerland
| | - P. Brazzola
- Integrated Department of Pediatrics; Ente Ospedaliero Cantonale Ticinese; University of Berne; Berne Switzerland
| |
Collapse
|
|
32
|
Wong P, Fuller PJ, Gillespie MT, Kartsogiannis V, Strauss BJ, Bowden D, Milat F. Thalassemia bone disease: the association between nephrolithiasis, bone mineral density and fractures. Osteoporos Int 2013; 24:1965-71. [PMID: 23291906 DOI: 10.1007/s00198-012-2260-y] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/06/2012] [Accepted: 12/12/2012] [Indexed: 01/19/2023]
Abstract
UNLABELLED Thalassemia bone disease is well described, but the prevalence of nephrolithiasis has not been characterized. The association between nephrolithiasis, reduced bone density, and increased fractures has been demonstrated through this retrospective study of 166 participants with transfusion-dependent thalassemia. The findings support the need for increased vigilance of kidney and bone disease in this cohort. INTRODUCTION Previous studies have revealed that thalassemia is associated with reduced bone mineral density (BMD) and fractures. Many causes are implicated including hypogonadism, growth hormone deficiency, marrow expansion, and iron overload. Nephrolithiasis is associated with reduced BMD and increased fractures in the general population. However, the prevalence of nephrolithiasis and its association with bone density and fractures have not been characterized in thalassemia. METHODS We have addressed this question by performing a retrospective cohort study of 166 participants with transfusion-dependent thalassemia who had undergone dual-energy X-ray absorptiometry between 2009 and 2011. Logistic regression modeling was used to adjust for potential confounders. RESULTS We found a high prevalence of kidney stones (18.1 %) which was greater in males compared to females (28.7 vs 9.7 %, respectively). Renal stones were associated with reduced femoral neck Z-score and fractures in men after adjusting for potential confounders. These results indicate that nephrolithiasis is highly prevalent in patients with transfusion-dependent thalassemia and is significantly associated with reduced BMD and increased fractures. CONCLUSIONS The findings from this study strongly support the need for ongoing surveillance of BMD, fractures, and nephrolithiasis in the management of transfusion-dependent thalassemia.
Collapse
Affiliation(s)
- P Wong
- Prince Henry's Institute, P.O. Box 5152, Clayton, VIC 3168, Australia.
| | | | | | | | | | | | | |
Collapse
|
|
33
|
Pennell DJ, Udelson JE, Arai AE, Bozkurt B, Cohen AR, Galanello R, Hoffman TM, Kiernan MS, Lerakis S, Piga A, Porter JB, Walker JM, Wood J. Cardiovascular function and treatment in β-thalassemia major: a consensus statement from the American Heart Association. Circulation 2013; 128:281-308. [PMID: 23775258 DOI: 10.1161/cir.0b013e31829b2be6] [Citation(s) in RCA: 285] [Impact Index Per Article: 23.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
Abstract
This aim of this statement is to report an expert consensus on the diagnosis and treatment of cardiac dysfunction in β-thalassemia major (TM). This consensus statement does not cover other hemoglobinopathies, including thalassemia intermedia and sickle cell anemia, in which a different spectrum of cardiovascular complications is typical. There are considerable uncertainties in this field, with a few randomized controlled trials relating to treatment of chronic myocardial siderosis but none relating to treatment of acute heart failure. The principles of diagnosis and treatment of cardiac iron loading in TM are directly relevant to other iron-overload conditions, including in particular Diamond-Blackfan anemia, sideroblastic anemia, and hereditary hemochromatosis. Heart failure is the most common cause of death in TM and primarily results from cardiac iron accumulation. The diagnosis of ventricular dysfunction in TM patients differs from that in nonanemic patients because of the cardiovascular adaptation to chronic anemia in non-cardiac-loaded TM patients, which includes resting tachycardia, low blood pressure, enlarged end-diastolic volume, high ejection fraction, and high cardiac output. Chronic anemia also leads to background symptomatology such as dyspnea, which can mask the clinical diagnosis of cardiac dysfunction. Central to early identification of cardiac iron overload in TM is the estimation of cardiac iron by cardiac T2* magnetic resonance. Cardiac T2* <10 ms is the most important predictor of development of heart failure. Serum ferritin and liver iron concentration are not adequate surrogates for cardiac iron measurement. Assessment of cardiac function by noninvasive techniques can also be valuable clinically, but serial measurements to establish trends are usually required because interpretation of single absolute values is complicated by the abnormal cardiovascular hemodynamics in TM and measurement imprecision. Acute decompensated heart failure is a medical emergency and requires urgent consultation with a center with expertise in its management. The first principle of management of acute heart failure is control of cardiac toxicity related to free iron by urgent commencement of a continuous, uninterrupted infusion of high-dose intravenous deferoxamine, augmented by oral deferiprone. Considerable care is required to not exacerbate cardiovascular problems from overuse of diuretics or inotropes because of the unusual loading conditions in TM. The current knowledge on the efficacy of removal of cardiac iron by the 3 commercially available iron chelators is summarized for cardiac iron overload without overt cardiac dysfunction. Evidence from well-conducted randomized controlled trials shows superior efficacy of deferiprone versus deferoxamine, the superiority of combined deferiprone with deferoxamine versus deferoxamine alone, and the equivalence of deferasirox versus deferoxamine.
Collapse
|
|
34
|
Dubourg L, Laurain C, Ranchin B, Pondarré C, Hadj-Aïssa A, Sigaudo-Roussel D, Cochat P. Deferasirox-induced renal impairment in children: an increasing concern for pediatricians. Pediatr Nephrol 2012; 27:2115-2122. [PMID: 22527533 DOI: 10.1007/s00467-012-2170-4] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/04/2011] [Revised: 03/22/2012] [Accepted: 03/26/2012] [Indexed: 01/19/2023]
Abstract
BACKGROUND Deferasirox (DFX) is an oral iron chelator with an established dose-dependent efficacy in transfusion-related iron overload. Whereas emerging long-term data confirm the safety of the drug, with transient moderate elevation of serum creatinine level, several authors have reported renal tubular dysfunction. The aim of this study was to evaluate tubular and glomerular function before and after the initiation of DFX therapy in a pediatric patient population. METHODS Ten children (4 girls, mean age 12.4 ± 3.9 years) enrolled in a routine blood transfusion program were treated with 24.8 ± 9.6 mg/kg per day of DFX, and renal function was assessed before and 17.2 ± 8.9 months after the initiation of DFX therapy. RESULTS Prior to treatment with DFX, all patients had a normal glomerular function rate (GFR) (125 ± 15 ml/min per 1.73 m(2)) and normal tubular function. Following the initiation of DFX therapy, the GFR decreased by approximately 20 % with one patient with a GFR of <80 mL/min per 1.73 m(2) and seven patients with a GFR of <100 mL/min per 1.73 m(2). Two patients experienced a generalized proximal tubular dysfunction whereas nine patients presented at least one sign of proximal tubular dysfunction. CONCLUSIONS Renal toxicity is a frequent adverse event of DFX treatment, presenting as both glomerular and proximal dysfunction. A routine renal assessment is therefore required to prevent chronic kidney disease that may result from prolonged tubular injury.
Collapse
Affiliation(s)
- Laurence Dubourg
- Centre de Référence des Maladies Rénales Rares, Service de Néphrologie et Rhumatologie Pédiatriques, Hôpital Femme Mère Enfant, Hospices Civils de Lyon, Bron, France. .,Exploration Fonctionnelle Rénale et Métabolique, Hospices Civils de Lyon, Lyon, France. .,Université Claude Bernard, Lyon I, France. .,FRE CNRS 3310, Université Claude Bernard, Lyon I, France. .,Exploration Fonctionnelle Rénale et Métabolique, Pavillon P-Hôpital Edouard Herriot, 5 place d'Arsonval, 69437, Lyon cedex 03, France.
| | - Céline Laurain
- Centre de Référence des Maladies Rénales Rares, Service de Néphrologie et Rhumatologie Pédiatriques, Hôpital Femme Mère Enfant, Hospices Civils de Lyon, Bron, France
| | - Bruno Ranchin
- Centre de Référence des Maladies Rénales Rares, Service de Néphrologie et Rhumatologie Pédiatriques, Hôpital Femme Mère Enfant, Hospices Civils de Lyon, Bron, France
| | - Corinne Pondarré
- Université Claude Bernard, Lyon I, France.,Institut d'Hématologie et d'Oncologie Pédiatrique et Centre de Références des Thalassémies, Hospices Civils de Lyon, Lyon, France
| | - Aoumeur Hadj-Aïssa
- Exploration Fonctionnelle Rénale et Métabolique, Hospices Civils de Lyon, Lyon, France.,Université Claude Bernard, Lyon I, France
| | | | - Pierre Cochat
- Centre de Référence des Maladies Rénales Rares, Service de Néphrologie et Rhumatologie Pédiatriques, Hôpital Femme Mère Enfant, Hospices Civils de Lyon, Bron, France.,Université Claude Bernard, Lyon I, France.,FRE CNRS 3310, Université Claude Bernard, Lyon I, France
| |
Collapse
|
|
35
|
Bhandari S, Galanello R. Renal aspects of thalassaemia a changing paradigm. Eur J Haematol 2012; 89:187-97. [DOI: 10.1111/j.1600-0609.2012.01819.x] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/05/2012] [Indexed: 01/19/2023]
Affiliation(s)
- Sunil Bhandari
- Department of Renal Medicine; Hull & East Yorkshire Hospitals NHS Trust & Hull York Medical School; East Yorkshire; UK
| | - Renzo Galanello
- Clinica Pediatrica, Ospedale Regionale Microcitemie ASL8; Università degli Studi di Cagliari; Cagliari; Italy
| |
Collapse
|
|
36
|
Chueh HW, Sung KW, Lee SH, Yoo KH, Koo HH, Kim JY, Cho EJ. Iron chelation treatment with deferasirox prior to high-dose chemotherapy and autologous stem cell transplantation may reduce the risk of hepatic veno-occlusive disease in children with high-risk solid tumors. Pediatr Blood Cancer 2012; 58:441-7. [PMID: 21638755 DOI: 10.1002/pbc.23198] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/13/2010] [Accepted: 04/19/2011] [Indexed: 11/08/2022]
Abstract
BACKGROUND We evaluated whether iron chelation treatment during induction chemotherapy could safely reduce serum iron levels and thereby reduce the frequency of hepatic veno-occlusive disease (VOD) during high-dose chemotherapy and autologous stem cell transplantation (HDCT/autoSCT) in children with high-risk solid tumors. PROCEDURE Children diagnosed with high-risk solid tumors between August 2008 and July 2009 were enrolled. Deferasirox treatment (25 mg/kg/day) was initiated when serum ferritin levels increased to more than 1,000 ng/ml during induction chemotherapy. Patients who were diagnosed with the same disease between April 2005 and June 2007 and treated in the same way without any iron chelation treatment formed the control group. Efficacy and toxicity of deferasirox treatment were compared between the two groups. RESULTS Eighteen of 20 patients enrolled received deferasirox treatment. Deferasirox treatment was completed as scheduled in 11 (61.1%) of them without dose reduction or discontinuation. The serum ferritin levels prior to HDCT/autoSCT were lower in the deferasirox group than in the control group (median 1,268 ng/ml vs. 1,828 ng/ml, P < 0.001), although there was no difference in the RBC transfusion amount between the two groups. While 7 (17.9%) VODs developed during 39 HDCT/autoSCTs in the control group, there was no VOD during 40 HDCT/autoSCTs in the deferasirox group (P = 0.005). However, renal dysfunction (38.9%) including Fanconi syndrome (16.7%) was a frequently observed adverse effect of deferasirox treatment. CONCLUSIONS Deferasirox treatment during induction chemotherapy reduces the frequency of VOD during HDCT/autoSCT. The development of renal dysfunction should be closely monitored during deferasirox treatment.
Collapse
Affiliation(s)
- Hee Won Chueh
- Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, 50 Irwon-dong, Gangnam-gu, Seoul, Republic of Korea
| | | | | | | | | | | | | |
Collapse
|
|
37
|
Milat F, Wong P, Fuller PJ, Johnstone L, Kerr PG, Doery JCG, Strauss BJ, Bowden DK. A case of hypophosphatemic osteomalacia secondary to deferasirox therapy. J Bone Miner Res 2012; 27:219-22. [PMID: 21956684 DOI: 10.1002/jbmr.522] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/24/2011] [Revised: 07/13/2011] [Accepted: 08/25/2011] [Indexed: 01/30/2023]
Abstract
Patients with β-thalassemia major require iron-chelation therapy to avoid the complication of iron overload. Until recently, deferoxamine (DFO) was the major iron chelator used in patients requiring chronic hypertransfusion therapy, but DFO required continuous subcutaneous therapy. The availability of deferasirox (Exjade®), an orally active iron chelator, over the past 4 years represented a necessary alternative for patients requiring chelation therapy. However, there have been increasing reports of proximal renal tubular dysfunction and Fanconi syndrome associated with deferasirox in the literature. We report a case of hypophosphataemic osteomalacia secondary to deferasirox therapy.
Collapse
Affiliation(s)
- Frances Milat
- Prince Henry's Institute and Department of Endocrinology, Melbourne, Australia
| | | | | | | | | | | | | | | |
Collapse
|
|
38
|
Galanello R, Campus S, Origa R. Deferasirox: pharmacokinetics and clinical experience. Expert Opin Drug Metab Toxicol 2011; 8:123-34. [DOI: 10.1517/17425255.2012.640674] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
|
|
39
|
Kwiatkowski JL. Management of transfusional iron overload - differential properties and efficacy of iron chelating agents. J Blood Med 2011; 2:135-49. [PMID: 22287873 PMCID: PMC3262345 DOI: 10.2147/jbm.s13065] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2011] [Indexed: 01/19/2023] Open
Abstract
Regular red cell transfusion therapy ameliorates disease-related morbidity and can be lifesaving in patients with various hematological disorders. Transfusion therapy, however, causes progressive iron loading, which, if untreated, results in endocrinopathies, cardiac arrhythmias and congestive heart failure, hepatic fibrosis, and premature death. Iron chelation therapy is used to prevent iron loading, remove excess accumulated iron, detoxify iron, and reverse some of the iron-related complications. Three chelators have undergone extensive testing to date: deferoxamine, deferasirox, and deferiprone (although the latter drug is not currently licensed for use in North America where it is available only through compassionate use programs and research protocols). These chelators differ in their modes of administration, pharmacokinetics, efficacy with regard to organ-specific iron removal, and adverse-effect profiles. These differential properties influence acceptability, tolerability and adherence to therapy, and, ultimately, the effectiveness of treatment. Chelation therapy, therefore, must be individualized, taking into account patient preferences, toxicities, ongoing transfusional iron intake, and the degree of cardiac and hepatic iron loading.
Collapse
Affiliation(s)
- Janet L Kwiatkowski
- The Children's Hospital of Philadelphia, Division of Hematology and University of Pennsylvania School of Medicine, Philadelphia, PA, USA
| |
Collapse
|
|
40
|
Cao A, Moi P, Galanello R. Recent advances in β-thalassemias. Pediatr Rep 2011; 3:e17. [PMID: 21772954 PMCID: PMC3133499 DOI: 10.4081/pr.2011.e17] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/08/2011] [Revised: 04/15/2011] [Accepted: 04/15/2011] [Indexed: 01/25/2023] Open
Abstract
β-thalassemias are heterogeneous hereditary anemias characterized by a reduced output of β-globin chains. The disease is most frequent in the temperate regions of the world, where it represents an important health problem. In the last decades, several programs, aimed at controlling the birth rate of thalassemia newborns by screening and prenatal diagnosis of populations with high risk of β-thalassemia, have been successful accomplished. Bone marrow transplantation has offered a definitive cure for the fraction of patients with available donors. In the same time, steady improvements were made in the traditional clinical management of β-thalassemia patients. The introduction of the oral iron chelators deferiprone that preferentially chelates hearth iron and the development of novel NMR diagnostic methods has led to reduced morbility, increased survival and improved quality of life. More recently, major advances have being made in the discovery of critical modifier genes, such as Myb and especially BCL11A (B cell lymphoma 11A), a master regulator of HbF (fetal hemoglobin) and hemoglobin switching. Polimorphysms of BCL11A, Myb and γ-globin genes account for most of the variability in the clinical phenotypes in β-thalassemia and sickle cell anemia patients. Finally, the year 2010 has brought in the first successful experiment of gene therapy in a β-thalassemia patient, opening up the perspective of a generalized cure for all β- thalassemia patients.
Collapse
Affiliation(s)
- Antonio Cao
- Biomedical and Biotechnology Department, University of Cagliari, Cagliari, Italy
| | | | | |
Collapse
|
|
41
|
Iron chelation with deferasirox in adult and pediatric patients with thalassemia major: efficacy and safety during 5 years' follow-up. Blood 2011; 118:884-93. [PMID: 21628399 DOI: 10.1182/blood-2010-11-316646] [Citation(s) in RCA: 151] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023] Open
Abstract
Patients with β-thalassemia require lifelong iron chelation therapy from early childhood to prevent complications associated with transfusional iron overload. To evaluate long-term efficacy and safety of once-daily oral iron chelation with deferasirox, patients aged ≥ 2 years who completed a 1-year, phase 3, randomized trial entered a 4-year extension study, either continuing on deferasirox (deferasirox cohort) or switching from deferoxamine to deferasirox (crossover cohort). Of 555 patients who received ≥ 1 deferasirox dose, 66.8% completed the study; 43 patients (7.7%) discontinued because of adverse events. In patients with ≥ 4 years' deferasirox exposure who had liver biopsy, mean liver iron concentration significantly decreased by 7.8 ± 11.2 mg Fe/g dry weight (dw; n = 103; P < .001) and 3.1 ± 7.9 mg Fe/g dw (n = 68; P < .001) in the deferasirox and crossover cohorts, respectively. Median serum ferritin significantly decreased by 706 ng/mL (n = 196; P < .001) and 371 ng/mL (n = 147; P < .001), respectively, after ≥ 4 years' exposure. Investigator-assessed, drug-related adverse events, including increased blood creatinine (11.2%), abdominal pain (9.0%), and nausea (7.4%), were generally mild to moderate, transient, and reduced in frequency over time. No adverse effect was observed on pediatric growth or adolescent sexual development. This first prospective study of long-term deferasirox use in pediatric and adult patients with β-thalassemia suggests treatment for ≤ 5 years is generally well tolerated and effectively reduces iron burden. This trial was registered at www.clinicaltrials.gov as #NCT00171210.
Collapse
|
|
42
|
Bergeron RJ, Wiegand J, Bharti N, McManis JS, Singh S. Desferrithiocin analogue iron chelators: iron clearing efficiency, tissue distribution, and renal toxicity. Biometals 2011; 24:239-58. [PMID: 21103911 PMCID: PMC3329216 DOI: 10.1007/s10534-010-9389-y] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2010] [Accepted: 10/25/2010] [Indexed: 01/19/2023]
Abstract
The current solution to iron-mediated damage in transfusional iron overload disorders is decorporation of excess unmanaged metal, chelation therapy. The clinical development of the tridentate chelator deferitrin (1, Table 1) was halted due to nephrotoxicity. It was then shown by replacing the 4'-(HO) of 1 with a 3,6,9-trioxadecyloxy group, the nephrotoxicity could be ameliorated. Further structure-activity relationship studies have established that the length and the position of the polyether backbone controlled: (1) the ligand's iron clearing efficiency (ICE), (2) chelator tissue distribution, (3) biliary ferrokinetics, and (4) tissue iron reduction. The current investigation compares the ICE and tissue distribution of a series of (S)-4,5-dihydro-2-[2-hydroxy-4-(polyether)phenyl]-4-methyl-4-thiazolecarboxylic acids (Table 1, 3-5) and the (S)-4,5-dihydro-2-[2-hydroxy-3-(polyether)phenyl]-4-methyl-4-thiazolecarboxylic acids (Table 1, 8-10). The three most effective polyether analogues, in terms of performance ratio (PR), defined as mean ICE(primate)/ICE(rodent), are 3 (PR 1.1), 8, (PR 1.5), and 9, now in human trials, (PR 2.2). At the onset of the clinical trial on 9, no data were available for ligand 3 or 8. This is unfortunate, as 3 has many advantages over 9, e.g., the ICE of 3 in rats is 2.5-fold greater than that of 9 and analogue 3 achieves very high levels in the liver, pancreas, and heart, the organs most affected by iron overload. Finally, the impact of 3 on the urinary excretion of kidney injury molecule-1 (Kim-1), an early diagnostic biomarker for monitoring acute kidney toxicity, has been carried out in rats; no evidence of nephrotoxicity was found. Overall, the results suggest that 3 would be a far superior clinical candidate to 9.
Collapse
Affiliation(s)
- Raymond J Bergeron
- Department of Medicinal Chemistry, University of Florida, JHMHC, Box 100485, Gainesville, FL 32610-0485, USA.
| | | | | | | | | |
Collapse
|
|
43
|
Heli H, Mirtorabi S, Karimian K. Advances in iron chelation: an update. Expert Opin Ther Pat 2011; 21:819-56. [PMID: 21449664 DOI: 10.1517/13543776.2011.569493] [Citation(s) in RCA: 60] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
Abstract
INTRODUCTION Oxidative stress (caused by excess iron) can result in tissue damage, organ failure and finally death, unless treated by iron chelators. The causative factor in the etiology of a variety of disease states is the presence of iron-generated reactive oxygen species (ROS), which can result in cell damage or which can affect the signaling pathways involved in cell necrosis-apoptosis or organ fibrosis, cancer, neurodegeneration and cardiovascular, hepatic or renal dysfunctions. Iron chelators can reduce oxidative stress by the removal of iron from target tissues. Equally as important, removal of iron from the active site of enzymes that play key roles in various diseases can be of considerable benefit to the patients. AREAS COVERED This review focuses on iron chelators used as therapeutic agents. The importance of iron in oxidative damage is discussed, along with the three clinically approved iron chelators. EXPERT OPINION A number of iron chelators are used as approved therapeutic agents in the treatment of thalassemia major, asthma, fungal infections and cancer. However, as our knowledge about the biochemistry of iron and its role in etiologies of seemingly unrelated diseases increases, new applications of the approved iron chelators, as well as the development of new iron chelators, present challenging opportunities in the areas of drug discovery and development.
Collapse
Affiliation(s)
- Hossein Heli
- Islamic Azad University, Science and Research Branch, Department of Chemistry, Fars, 7348113111, Iran
| | | | | |
Collapse
|
|
44
|
|