Transport of iron chelators and chelates across MDCK cell monolayers: implications for iron excretion during chelation therapy

Huang, Xi‐Ping; Thiessen, Jake J.; Spino, Michael; Templeton, Douglas M.

doi:10.1007/s12185-010-0510-3

Cited by 6 publications

(5 citation statements)

References 57 publications

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“…It is well-known that iron is involved in a large number of processes which are critical for cellular energy production via mitochondrial electron transport. So, its depletion can cause damage in renal tubular and glomerular cells, yielding renal failure [29,30]. A routine renal assessment before and during DFX therapy for all TM patients and special attention and closer monitoring are required for TM patients with lower iron burden.…”

Section: Discussionmentioning

confidence: 99%

Insidious Renal Damage in Patients with Thalassemia Major: Is it More Serious than Appreciated?

Gökçe¹

2014

J Hematol Thrombo Dis

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Aim: To investigate early renal injury in thalassemia major patients by using novel serum markers and demonstrate the factors leading to renal injury. Material and Methods: Seventy-one thalassemia major patients (37 males) who were on regular transfusion and chelation programme with deferasirox have been enrolled in this study. Thirty-five healthy children of the same age served as a control group. Serum urea-creatinine, electrolytes, cystatin C and glomerular filtration rate were all noted in our cohort and compared with the control group. Proteinuria was also investigated by calculating UPr/UCr ratio. Results: The median serum creatinine level was 0.4 mg/dL (range; 0.2-0.76 mg/dL) and the median glomerular filtration rate level was 192 mL/min/1.73 m 2 (range; 106-308 mL/min/1.73 m 2) in patients. More than half of the patients had glomerular hyperfiltration (n=48, 67.6%). Hyperfiltration was prominent in thalassemia group (66.2% vs. 19.4%) (p=0.0001). Mean serum cystatin C levels were found to be statistically elevated in patient group comparing with controls (p=0.0001). Serum cystatin C level was above >1 mg/L in 46 patients (64.7%) whereas only three in controls (p=0.0001). Sex, age, hemoglobin level and cardiac T2* MRI results were not related to the elevated cystatin C levels. On the other hand, liver iron burden and serum ferritin levels were noted to be statistically correlated to elevated cystatin C level (p=0.024 and p=0.04). Deferasirox dose below 25 mg/kg/day was also found in relation with elevated cystatin C levels. Conclusion: Renal injury is multifactorial, insidious but progressive in thalassemia patients. High index of suspicion and routine use of novel markers are required for detection of renal injury during the follow up of thalassemia patients.

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Section: Discussionmentioning

confidence: 99%

Insidious Renal Damage in Patients with Thalassemia Major: Is it More Serious than Appreciated?

Gökçe¹

2014

J Hematol Thrombo Dis

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“…Indeed, in cultured proximal tubular cells, polarized transport of chelates suggests that the kidney is involved in reabsorption of iron bound to chelators and that active transporters are involved. 77 In the presence of chelators, iron leaves tubular cells mainly through the basolateral membrane. Deferasirox does not behave differently from other chelators.…”

Section: Accumulation In Kidneymentioning

confidence: 99%

Deferasirox nephrotoxicity—the knowns and unknowns

et al. 2014

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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.

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“…To prevent iron reuptake in the renal tubules, conventional iron chelators could potentially be used; however, these agents often cause tubular dysfunction in patients, probably by dramatically decreasing or increasing iron levels in the kidney. [117][118][119] Filterable, nonabsorbable iron chelators based on endogenous iron carrier proteins are potentially more suitable for this purpose than chemical ironchelating agents. For example, a patent has been granted for the use of mutant NGAL proteins as novel urinary iron chelators.…”

Section: Treatment Of Iron-related Kidney Injurymentioning

confidence: 99%

Iron metabolism in the pathogenesis of iron-induced kidney injury

et al. 2013

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In the past 8 years, there has been renewed interest in the role of iron in both acute kidney injury (AKI) and chronic kidney disease (CKD). In patients with kidney diseases, renal tubules are exposed to a high concentration of iron owing to increased glomerular filtration of iron and iron-containing proteins, including haemoglobin, transferrin and neutrophil gelatinase-associated lipocalin (NGAL). Levels of intracellular catalytic iron may increase when glomerular and renal tubular cells are injured. Reducing the excessive luminal or intracellular levels of iron in the kidney could be a promising approach to treat AKI and CKD. Understanding the role of iron in kidney injury and as a therapeutic target requires insight into the mechanisms of iron metabolism in the kidney, the role of endogenous proteins involved in iron chelation and transport, including hepcidin, NGAL, the NGAL receptor and divalent metal transporter 1, and iron-induced toxic effects. This Review summarizes emerging knowledge, which suggests that complex mechanisms of iron metabolism exist in the kidney, modulated directly or indirectly by cellular iron content, inflammation, ischaemia and oxidative stress. The potential exists for prevention and treatment of iron-induced kidney injury by customized iron removal or relocation, aided by detailed insight into the underlying pathological mechanisms.

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Transport of iron chelators and chelates across MDCK cell monolayers: implications for iron excretion during chelation therapy

Cited by 6 publications

References 57 publications

Insidious Renal Damage in Patients with Thalassemia Major: Is it More Serious than Appreciated?

Insidious Renal Damage in Patients with Thalassemia Major: Is it More Serious than Appreciated?

Deferasirox nephrotoxicity—the knowns and unknowns

Iron metabolism in the pathogenesis of iron-induced kidney injury

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