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Children (Basel, Switzerland) Dec 2021Deferasirox 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)
Review
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 ( = 35) of the 57 patients were ≤18 years of age and affected by thalassemia ( = 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.
PubMed: 34943300
DOI: 10.3390/children8121104 -
BMC Nephrology Dec 2021Renal injury in transfusion dependent β thalassemia patients (TDT) has been attributed to iron overload, chronic anemia and iron-chelation therapy (ICT) toxicity. We... (Comparative Study)
Comparative Study
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.
Topics: Adolescent; Adult; Child; Child, Preschool; Deferasirox; Deferoxamine; Female; Humans; Iron Chelating Agents; Kidney; Male; Middle Aged; Retrospective Studies; Young Adult; beta-Thalassemia
PubMed: 34930156
DOI: 10.1186/s12882-021-02630-5 -
Saudi Journal of Biological Sciences Apr 2022Ferritin, which includes twenty-four light and heavy chains in varying proportions in different tissues, is primarily responsible for maintaining the body's iron... (Review)
Review
Ferritin, which includes twenty-four light and heavy chains in varying proportions in different tissues, is primarily responsible for maintaining the body's iron metabolism. Its normal value is between 10 and 200 ngmL in men and between 30 and 300 ngmL in women. Iron is delivered to the tissue via them, and they act as immunomodulators, signaling molecules, and inflammatory markers. When ferritin level exceeds 1000 µgL, the patient is categorized as having hyperferritinemia. Iron chelators such as deferiprone, deferirox, and deferoxamine are currently FDA approved to treat iron overload. The inflammation cascade and poor prognosis of COVID-19 may be attributed to high ferritin levels. Critically ill patients can benefit from deferasirox, an iron chelator administered orally at 20-40 mgkg once daily, as well as intravenous deferoxamine at 1000 mg initially followed by 500 mg every 4 to 12 h. It can be combined with monoclonal antibodies, antioxidants, corticosteroids, and lactoferrin to make iron chelation therapy effective for COVID-19 victims. In this article, we analyze the antiviral and antifibrotic activity of iron chelators, thereby promoting iron depletion therapy as a potentially innovative treatment strategy for COVID-19.
PubMed: 34924800
DOI: 10.1016/j.sjbs.2021.11.061 -
World Journal of Hepatology Nov 2021Chelation is the mainstay of therapy in certain pediatric liver diseases. Copper and iron related disorders require chelation. Wilson's disease (WD), one of the common... (Review)
Review
Chelation is the mainstay of therapy in certain pediatric liver diseases. Copper and iron related disorders require chelation. Wilson's disease (WD), one of the common causes of cirrhosis in children is treated primarily with copper chelating agents like D-penicillamine and trientine. D-Penicillamine though widely used due its high efficacy in hepatic WD is fraught with frequent adverse effects resulting discontinuation. Trientine, an alternative drug has comparable efficacy in hepatic WD but has lower frequency of adverse effects. The role of ammonium tetra-thiomolybdate is presently experimental in hepatic WD. Indian childhood cirrhosis is related to excessive copper ingestion, rarely seen in present era. D-Penicillamine is effective in the early part of this disease with reversal of clinical status. Iron chelators are commonly used in secondary hemochromatosis of liver in hemolytic anemias. There are strict chelation protocols during bone marrow transplant. The role of iron chelation in neonatal hemochromatosis is presently not in vogue due to its poor efficacy and availability of other modalities of therapy. Hereditary hemochromatosis is rare in children and the use of iron chelators in this condition is limited.
PubMed: 34904029
DOI: 10.4254/wjh.v13.i11.1552 -
OTO Open 2021
PubMed: 34870066
DOI: 10.1177/2473974X211061408 -
Mediterranean Journal of Hematology and... 2021Patients with transfusion-dependent thalassemia TDT risk iron overload and require iron chelation therapy. Second-line therapy is warranted for patients demonstrating...
Long-Term Effectiveness, Safety, and Tolerability of Twice-Daily Dosing with Deferasirox in Children with Transfusion-Dependent Thalassemias Unresponsive to Standard Once-Daily Dosing.
BACKGROUND
Patients with transfusion-dependent thalassemia TDT risk iron overload and require iron chelation therapy. Second-line therapy is warranted for patients demonstrating poor chelation responses.
PATIENTS AND METHODS
We retrospectively studied the serum-ferritin (SF), and liver-iron-concentration (LIC) outcomes of patients with TDT treated with twice-daily dosing of deferasirox (TDD-DFX) > 24 months, after failing to respond to once-daily deferasirox (OD-DFX).
RESULTS
We enrolled 22 OD-DFX nonresponders (14 males and eight females; median age, 9.2 [3-15.5] years). The median blood transfusion was 216 (206-277) ml/kg/year. The median TDD-DFX treatment period was 30 (24-35) months. Before initiating TDD-DFX, the median SF level was 2,486 (1,562-8,183) ng/ml, while the median LIC was 6.6 (3.2-19) mg/g dry wt. There were 18 TDD-DFX responders (81.8%) and 4 TDD-DFX nonresponders. The median SF-level change was -724 (-4,916 to 1,490) ng/mL. The median LIC change was -2.14 (-13.7 to 6.8) mg/g dry wt. The 1-year and 2-year SF levels and LICs were statistically significant (SF, = 0.006/0.005; and LIC, 0.006/0.005, respectively). There were no treatment interruptions secondary to adverse events. In the follow-up of the TDD-DFX responder group, 11 of the 18 had a reduced dose, whereas the remaining seven continued with the same dose.
CONCLUSIONS
TDD-DFX appears to be an alternative treatment approach for patients refractory to OD-DFX, with a favorable long-term safety profile. Further studies with larger groups and pharmacogenetic analyses of OD-DFX responders are warranted to determine the efficacy and safety profile of TDD-DFX.
PubMed: 34804439
DOI: 10.4084/MJHID.2021.065 -
Transplantation and Cellular Therapy Feb 2022The negative effects of iron overload caused by repetitive blood transfusions and iron release during cytotoxic chemotherapy might be ameliorated by early treatment with... (Observational Study)
Observational Study
The negative effects of iron overload caused by repetitive blood transfusions and iron release during cytotoxic chemotherapy might be ameliorated by early treatment with an iron chelator. However, in the setting of allogeneic hematopoietic stem cell transplantation (HSCT), chelation therapy is often postponed until the late post-transplantation period because of potential drug interactions. Therefore we systematically investigated the influence of iron chelation with deferasirox on the pharmacokinetics of intravenous busulfan in adult patients in the context of routine therapeutic drug monitoring (TDM) before HSCT. We conducted a single-center, prospective, observational study in 25 adult patients with planned allogeneic HSCT after myeloablative, busulfan-based, TDM-guided conditioning chemotherapy. Busulfan was administered intravenously over 3 hours with an initial dose of 3.2 mg/kg once daily (based on adjusted ideal body weight [AIBW] in overweight patients). Four consecutive dosages were planned to achieve a cumulative area under the curve (AUC) of 80 mg · h/L. Patients received deferasirox for transfusional iron overload as per approval from the start of conditioning until day 3 after transplantation. Model-based calculation of the busulfan AUC was carried out by means of Bayesian prediction based on a population pharmacokinetic model after the first or second dose of busulfan, and dose adjustments were performed accordingly. Calculated median cumulative AUC before dose adjustment was 93.7 mg · h/L (65.1-151.4 mg · h/L), which was considerably above the target AUC of 80 mg · h/L ± 10%. Median dose adjustment was -17.1% (-50.0% to 18.2%), and patients ultimately received busulfan with a median cumulative dose of 10.60 mg/kg (6.38 - 15.62) mg/kg. A busulfan dose reduction was necessary in 19 patients (76%) whereas a dose increase was only needed in 1 patient. After dose adjustment the median AUC was 79.7 mg/L · h (62.5 - 84.2 mg/L · h). Median busulfan clearance was 0.134 L/h/kg (0.084 - 0.203 L/h/kg), which is significantly lower than the average clearance of 0.2 L/h/kg reported in the literature, whereas volume of distribution was not altered. We were able to demonstrate, that TDM is the key point to facilitate a safe co-administration of both medications, because the intake of deferasirox leads to a considerable increase in the busulfan AUC of about 35% to 40%. The reason for the increase in busulfan AUC is a reduction in busulfan clearance by about one third; therefore a lower initial dose of busulfan followed by TDM could be considered in patients with comedication with deferasirox.
Topics: Adult; Area Under Curve; Bayes Theorem; Busulfan; Deferasirox; Hematopoietic Stem Cell Transplantation; Humans; Iron Chelating Agents; Iron Overload; Prospective Studies
PubMed: 34775147
DOI: 10.1016/j.jtct.2021.11.003 -
Frontiers in Medicine 2021The treatment of sickle cell disease (SCD) is mainly supportive, except for a minority, who receive bone marrow transplantation (BMT). Serum ferritin (SF) is routinely...
Iron Overload in Patients With Heavily Transfused Sickle Cell Disease-Correlation of Serum Ferritin With Cardiac T2 MRI (CMRTools), Liver T2 MRI, and R2-MRI (Ferriscan®).
The treatment of sickle cell disease (SCD) is mainly supportive, except for a minority, who receive bone marrow transplantation (BMT). Serum ferritin (SF) is routinely available but is notoriously unreliable as a tool for iron-overload assessment since it is an acute-phase reactant. Although blood transfusion is one of the most effective ways to deal with specific acute and chronic complications of SCD, this strategy is often associated with alloimmunization, iron overload, and hemolytic reactions. This study, thus, aims to evaluate iron overload in patients with SCD on chronic blood transfusions and specifically, correlate SF with the current standard of care of iron-overload assessment using MRI-based imaging techniques. Amongst a historic cohort of 58 chronically transfused patients with SCD, we were able to evaluate 44 patients who are currently alive and had multiple follow-up testing. Their mean age (±SD) was 35 (9) years and comprised of 68.2% of women. The studied iron-overload parameters included cardiac T2 MRI, liver iron concentration (LIC) by Liver T2 MRI, and serial SF levels. Additionally, in a smaller cohort, we also studied LIC by FerriScan R2-MRI. Chronic blood transfusions were necessary for severe vaso-occlusive crisis (VOC) (38.6%), severe symptomatic anemia (38.6%), past history of stroke (15.9%), and recurrent acute chest syndrome (6.9%). About 14 (24%) patients among the original cohort died following SCD-related complications. Among the patients currently receiving chelation, 26 (96%) are on Deferasirox (DFX) [Jadenu® (24) or Exjade® (2)], with good compliance and tolerance. However, one patient is still receiving IV deferoxamine (DFO), in view of the significantly high systemic iron burden. In this evaluable cohort of 44 patients, the mean SF (±SD) reduced marginally from 4,311 to 4,230 ng/ml, mean Liver T2 MRI dropped from 12 to 10.3 mg/gm dry weight, while the mean cardiac T2MRI improved from 36.8 to 39.5 ms. There was a mild to moderate correlation between the baseline and final values of SF ng/ml, = 0.33, = 0.01; Cardiac T2 MRI ms, = 0.3, = 0.02 and Liver T2 MRI mg/kg dry weight, = 0.6, < 0.001. Overall, there was a positive correlation between SF and Liver T2 MRI (Pearson's = 0.78, < 0.001). Cardiac T2MRI increased with the decreasing SF concentration, showing a negative correlation which was statistically significant (Pearson's = -0.6, < 0.001). Furthermore, there was an excellent correlation between SF ng/ml and LIC by FerriScan R2-MRI mg/g or mmol/kg (Spearmen's rho = -0.723, < 0.008) in a small subset of patients ( = 14) who underwent the procedure. In conclusion, our study demonstrated a good correlation between serial SF and LIC by either Liver MRI T2 or by FerriScan R2-MRI, even though SF is an acute-phase reactant. It also confirms the cardiac sparing effect in patients with SCD, even with the significant transfusion-related iron burden. About 14 (24%) patients of the original cohort died over the past 15 years, indicative of a negative impact of iron overload on disease morbidity and mortality.
PubMed: 34760898
DOI: 10.3389/fmed.2021.731102 -
Frontiers in Oncology 2021Iron chelation therapy (ICT) has become a mainstay in heavily transfused hematological patients, with the aim to reduce iron overload (IOL) and prevent organ damage.... (Review)
Review
Iron chelation therapy (ICT) has become a mainstay in heavily transfused hematological patients, with the aim to reduce iron overload (IOL) and prevent organ damage. This therapeutic approach is already widely used in thalassemic patients and in low-risk Myelodysplastic Syndrome (MDS) patients. More recently, ICT has been proposed for high-risk MDS, especially when an allogeneic bone marrow transplantation has been planned. Furthermore, other hematological and hereditary disorders, characterized by considerable transfusion support to manage anemia, could benefit from this therapy. Meanwhile, data accumulated on how iron toxicity could exacerbate anemia and other clinical comorbidities due to oxidative stress radical oxygen species (ROS) mediated by free iron species. Taking all into consideration, together with the availability of approved oral iron chelators, we envision a larger use of ICT in the near future. The aim of this review is to better identify those non-thalassemic patients who can benefit from ICT and give practical tips for management of this therapeutic strategy.
PubMed: 34692534
DOI: 10.3389/fonc.2021.752192 -
Andes Pediatrica : Revista Chilena de... Aug 2021Treatment with iron chelators is essential for patients with iron overload secondary to repeated trans fusions. Deferasirox is the first once-daily oral active iron...
INTRODUCTION
Treatment with iron chelators is essential for patients with iron overload secondary to repeated trans fusions. Deferasirox is the first once-daily oral active iron chelator. As a result, therapeutic adherence has improved, reducing the complications of iron overload, especially heart failure. However, it is not exempt from possible side effects, such as kidney involvement, which is more frequent in children.
OBJECTIVE
To report 2 patients with Diamond-Blackfan anemia (DBA) who developed impaired renal function secondary to the administration of Deferasirox.
CLINICAL CASES
Case 1. A 15-year-old adolescent diagnosed with DBA undergoing treatment with periodic transfusions and Deferasirox. During an acute gastroenteritis, she developed acute renal failure along with complex proximal tubu- lopathy. Case 2. A 5-year-old boy diagnosed with DBA receiving periodic transfusions and treatment with Deferasirox. He presented polyuria with laboratory abnormalities compatible with acute renal failure and proximal tubular dysfunction. In both cases, they were adequately hydrated and Deferasi rox was temporarily suspended, improving renal function.
CONCLUSION
Based on these cases, close monitoring of renal and tubular function, as well as ferritin levels, is recommended in patients recei ving Deferasirox. In the presence of intercurrent processes, adequate hydration should be performed, and an early dose reduction or drug administration interruption should be considered in cases of kidney involvement.
Topics: Acute Kidney Injury; Adolescent; Anemia, Diamond-Blackfan; Benzoates; Child, Preschool; Deferasirox; Female; Humans; Iron Chelating Agents; Iron Overload; Kidney; Male; Triazoles
PubMed: 34652377
DOI: 10.32641/andespediatr.v92i4.3154