Effects of deferasirox on renal function and renal epithelial cell death

Sánchez-González, Penélope; López‐Hernández, Francisco J.; Morales, Ana Isabel; Macías-Núñez, Juan F.; López‐Novoa, José M.

doi:10.1016/j.toxlet.2011.03.018

Cited by 31 publications

(21 citation statements)

References 32 publications

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“…In this regard, our observations differ from a previous report that DFX led to increased urinary protein and glucose excretion, and increased tubular damage markers in Wistar rats. 34 The differences between these results may depend on differences in the experimental protocol. Sánchez-González et al 34 provided high dose of DFX intraperitoneally in normal rats for 1 week, whereas we gave CKD rats three doses of DFX in chow for 3 weeks and moderate dose of DFX in chow for 8 weeks.…”

Section: Discussionmentioning

confidence: 99%

“…34 The differences between these results may depend on differences in the experimental protocol. Sánchez-González et al 34 provided high dose of DFX intraperitoneally in normal rats for 1 week, whereas we gave CKD rats three doses of DFX in chow for 3 weeks and moderate dose of DFX in chow for 8 weeks. Since they evaluated renal toxicological effects of DFX in normal rats, the dose of DFX in their experiments (75 mg kg − 1 day − 1 ) was higher Iron and renal fibrosis Y Naito et al than the current experiments (15,30 and 60 mg kg − 1 day − 1 ) and the usual doses in patients (20 mg kg − 1 day − 1 ).…”

Section: Discussionmentioning

confidence: 99%

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Association between renal iron accumulation and renal interstitial fibrosis in a rat model of chronic kidney disease

et al. 2015

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Iron accumulation is associated with the pathophysiology of chronic kidney disease (CKD). Renal fibrosis is a final common feature that contributes to the progression of CKD; however, little is known about the association between renal iron accumulation and renal interstitial fibrosis in CKD. Here we investigate the effects of iron chelation on renal interstitial fibrosis in a rat model of CKD. CKD was induced by 5/6 nephrectomy in Sprague-Dawley rats. At 8 weeks after operation, 5/6 nephrectomized rats were administered an oral iron chelator, deferasirox (DFX), in chow for 8 weeks. Other CKD rats were given a normal diet. Sham-operative rats given a normal diet served as a control. CKD rats exhibited hypertension, glomerulosclerosis and renal interstitial fibrosis. Iron chelation with DFX did not change hypertension and glomerulosclerosis; however, renal interstitial fibrosis was attenuated in CKD rats. Consistent with these findings, renal gene expression of collagen type III and transforming growth factor-β was increased in CKD rats compared with the controls, while iron chelation suppressed these increments. In addition, a decrease in vimentin along an increase in E-cadherin in renal gene expression was observed in CKD rats with iron chelation. CKD rats also showed increased CD68-positive cells in the kidney, whereas its increase was attenuated by iron deprivation. Similarly, increased renal gene expression of CD68, tumor necrosis factor-α and monocyte chemoattractant protein-1 was suppressed in CKD rats with iron chelation. Renal iron accumulation seems to be associated with renal interstitial fibrosis in a rat model of CKD.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Association between renal iron accumulation and renal interstitial fibrosis in a rat model of chronic kidney disease

et al. 2015

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“…However, this hypothesis is not fully supported by the data. The nephrotoxic potential of deferasirox was documented in preclinical studies in experimental animals and importantly in cultured tubular cells, 78 which rules out haemodynamic changes as major triggers of nephrotoxicity. Furthermore, Fanconi syndrome is not a known consequence of altered renal haemodynamics.…”

Section: Haemodynamic Changesmentioning

confidence: 99%

“…42 In rats, 1 week of daily parenteral administration of deferasirox increased urinary protein, albumin and glucose excretion and promoted tubular necrosis and apoptosis, despite normal glomerular function. 78 Cultured murine tubular proximal cells are more sensi tive to deferasirox toxicity than are human cells. Deferasirox significantly induced apoptosis of murine tubular cells within 24 h in a dose-dependent manner whereas no toxicity was observed in human cells.…”

Section: Haemodynamic Changesmentioning

confidence: 99%

“…Deferasirox significantly induced apoptosis of murine tubular cells within 24 h in a dose-dependent manner whereas no toxicity was observed in human cells. 78 Sublethal or lethal tubular cell injury might explain some manifestations of deferasirox nephrotoxicity, such as the Fanconi syndrome features, the lack of return to baseline renal function or the lag time of days to return thereto, and the severe deterioration of renal function requiring dialysis.…”

Section: Haemodynamic Changesmentioning

confidence: 99%

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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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