End-Stage Renal Interstitial Fibrosis in an Adult Ten Years after Ifosfamide Therapy

Friedlaender, Michael M.; Haviv, Yosef S.; Rosenmann, E.; Peylan‐Ramu, Nili

doi:10.1159/000013321

Cited by 25 publications

(18 citation statements)

References 12 publications

(16 reference statements)

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“…There are several reports of the finding of renal biopsy for ifosfamide-induced late nephropathy [3,[8][9][10][11][12]. Most of reports show the chronic tubulointerstitial damage, although segmental glomerular sclerosis was also reported [8], which were also found in the present case.…”

Section: Discussionsupporting

confidence: 73%

Improvement in karyomegalic interstitial nephritis three years after ifosfamide and cisplatin therapy by corticosteroid

et al. 2014

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Long-term nephrotoxicity of ifosfamide is occasionally progressive, and, in such case, there has been no specific treatment to prevent progression. It has been reported that the presence of karyomegalic interstitial nephritis, which is rare type of interstitial nephritis, may be related to ifosfamide-induced nephropathy with poor prognosis and resistant to the immunosuppressive therapy. A 15-year-old boy presented with progressive nephrotoxicity 3 years after systemic chemotherapy with ifosfamide and cisplatin for the treatment of osteosarcoma. Renal biopsy revealed the severe tubulointerstitial nephritis with tubular atrophy and focal global and segmental glomerular sclerosis. It also showed tubular epithelial cells with variably sized nuclei, some of which were massively enlarged, abnormal hyperchromatic, irregular shaped, and bizarreappearing. These morphological changes were suggestive of the histology of karyomegalic interstitial nephritis. Corticosteroid retarded the progression of nephrotoxicity. The present case is the first report, suggesting that corticosteroid was effective against the late-onset renal toxicity by ifosfamide therapy. Our case also suggests that karyomegalic interstitial nephritis may be the result of long-term nephrotoxicity of ifosfamide. Since concurrent treatment with cisplatin is one of the risk factors for ifosfamide nephrotoxicity, there is a possibility that cisplatin may have a synergetic effect with ifosfamide for producing karyomegalic interstitial nephritis.

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Section: Discussionsupporting

confidence: 73%

Improvement in karyomegalic interstitial nephritis three years after ifosfamide and cisplatin therapy by corticosteroid

et al. 2014

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“…Ifosfamide (IFO) is an alkylating oxazaphosphorine antitumor prodrug (1,2), the clinical effectiveness of which is severely limited by a high incidence of nephrotoxicity (3)(4)(5), especially in children (6,7). Neither the biochemical mechanism(s) by which IFO damages the kidney nor the means by which other agents may reverse this damage is clearly understood.…”

Section: Introductionmentioning

confidence: 99%

“…Neither the biochemical mechanism(s) by which IFO damages the kidney nor the means by which other agents may reverse this damage is clearly understood. Both in patients and in an animal model, IFO induces a persistent Fanconi syndrome and significant proximal renal tubular dysfunction associated with a reduced glomerular filtration rate, glucosuria, aminoaciduria, phosphaturia, and bicarbonaturia (3)(4)(5)(6)(7)(8). Nephrotoxicity is a common and potentially serious complication of treatment despite coadministration of the uroprotective agent, 2-mercaptoethane sulfonic acid (MESNA; refs.…”

Section: Introductionmentioning

confidence: 99%

“…Recent reports have shown that the frequency of renal damage is remarkably higher than had been appreciated, and IFO-induced nephropathy is likely underestimated because of the inherent flaws in the evaluation methods commonly used and the time dependence of IFO-induced nephrotoxicity (6,7,9). This is especially true in cases of lateonset glomerular dysfunction (5,6,9).…”

Section: Introductionmentioning

confidence: 99%

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Ifosfamide-Induced Nephrotoxicity: Mechanism and Prevention

et al. 2006

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The efficacy of ifosfamide (IFO), an antineoplastic drug, is severely limited by a high incidence of nephrotoxicity of unknown etiology. We hypothesized that inhibition of complex I (C-I) by chloroacetaldehyde (CAA), a metabolite of IFO, is the chief cause of nephrotoxicity, and that agmatine (AGM), which we found to augment mitochondrial oxidative phosphorylation and B-oxidation, would prevent nephrotoxicity. Our model system was isolated mitochondria obtained from the kidney cortex of rats treated with IFO or IFO + AGM.

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“…There are several case reports of pediatric and adult patients who developed chronic IFO-nephrotoxicity presenting as tubulointerstitial nephritis and fibrosis [25,26,27]. The hallmarks of chronic tubulointerstitial nephritis are chronic inflammatory events and altered extracellular matrix composition, which reinforce each other [28].…”

Section: Introductionmentioning

confidence: 99%

The Nephrotoxic Ifosfamide-Metabolite Chloroacetaldehyde Interferes with Renal Extracellular Matrix Homeostasis

Benesic

Schwerdt

Hennemeier

et al. 2014

Cell Physiol Biochem

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Background/Aims: Chronic renal proximal tubule dysfunction after therapy with the antineoplastic agent ifosfamide (IFO) is often attributed to the metabolite chloroacetaldehyde (CAA). Chronic IFO-nephropathy is reported to result in tubulointerstitial fibrosis and inflammation. Methods: To elucidate possible effects of CAA on extracellular matrix homeostasis, we investigated the action of CAA on markers of extracellular matrix (ECM) homeostasis in human proximal tubule cells (RPTEC) by use of direct ELISA for extracellular collagens and gelatin zymography. Results: An increase in type III collagen and a decrease in type IV collagen abundance in the media of RPTEC could be observed after exposure to CAA in clinically relevant concentrations. CAA increased intracellular type III and decreased intracellular type IV collagen. MMP-2 activity was decreased but MMP-9 activity unchanged. The enhanced CAA-induced collagen III formation could be attenuated by the intracellular Ca²⁺-chelator BAPTA-AM, the PKA-antagonist H-89 and by extracellular acidification. CAA-induced collagen III abundance was enhanced by db-cAMP and IBMX and by protein overload. Conclusions: CAA exerts profibrotic effects on RPTEC dependent on Ca²⁺ and cAMP/PKA-signaling. These effects are enhanced by additional protein burden and attenuated by acidification.

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End-Stage Renal Interstitial Fibrosis in an Adult Ten Years after Ifosfamide Therapy

Cited by 25 publications

References 12 publications

Improvement in karyomegalic interstitial nephritis three years after ifosfamide and cisplatin therapy by corticosteroid

Improvement in karyomegalic interstitial nephritis three years after ifosfamide and cisplatin therapy by corticosteroid

Ifosfamide-Induced Nephrotoxicity: Mechanism and Prevention

The Nephrotoxic Ifosfamide-Metabolite Chloroacetaldehyde Interferes with Renal Extracellular Matrix Homeostasis

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