Chronic Ifosfamide Toxicity: Kidney Pathology and Pathophysiology

Akilesh, Shreeram; Juaire, Noemie; Duffield, Jeremy S.; Smith, Kelly D.

doi:10.1053/j.ajkd.2013.11.028

Cited by 18 publications

(5 citation statements)

References 37 publications

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“…Notably, coadministration of 2-mercaptoethanesulfonic acid prevents haemorrhagic cystitis and allows an increase of the administrated ifosfamide dose, but may facilitate ifosfamide nephrotoxicity. Histological descriptions of ifosfamide nephrotoxicity in adults are uncommon, and light microscopy analysis usually shows non-specific proximal tubular atrophy (TA), proximal tubular basement membrane denudation, proximal tubular cell vacuolation, nuclear atypia and a moderate monomorphic interstitial infiltrate [ 26 , 27 ], which is consistent with our findings. Our ultrastructural analysis performed in only three patients showed mitochondrial changes may suggest specific toxicity, including irregular mitochondria, mitochondrial enlargement and disappearance of some mitochondrial ridges.…”

Section: Discussionsupporting

confidence: 90%

Ifosfamide nephrotoxicity in adult patients

Ensergueix

Pallet

Joly³

et al. 2019

Clinical Kidney Journal

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Background Ifosfamide, a widely prescribed antineoplasic agent, is frequently associated with kidney dysfunction. Its nephrotoxicity is well documented in children, but data are lacking in adult patients. Methods The aim of this retrospective study was to describe the clinical, biological and histological characteristics of ifosfamide nephrotoxicity. Results We report 34 patients (median age: 41 years) admitted in six French nephrology departments for kidney failure and/or tubular dysfunction. Fifteen patients (44.1%) received cisplatin as part of their chemotherapy. In 6 patients (17.7%), ifosfamide nephrotoxicity was revealed by a proximal tubular dysfunction (PTD), in 5 patients (14.4%) by an acute kidney injury (AKI), in 6 patients (17.7%) by a chronic kidney disease (CKD) and in 17 patients (49.7%) by an association of PTD and AKI. Fourteen renal biopsies (41.2%) were performed and revealed acute tubular necrosis (85.7%), vacuolation (78.6%) and nuclear atypias (71.4%) of renal epithelial cells, interstitial inflammation (71.4%) and fibrosis (57.1%). Electron microscopy showed mitochondrial enlargement and dysmorphic changes suggestive of mitochondrial toxicity. Ten patients (29.4%) progressed to Stage 5 CKD, six (17.6%) required haemodialysis and six patients died during a median follow-up period of 31 months. Risk factors for Stage 5 CKD were age and cisplatin co-administration.

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Section: Discussionsupporting

confidence: 90%

Ifosfamide nephrotoxicity in adult patients

Ensergueix

Pallet

Joly³

et al. 2019

Clinical Kidney Journal

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“…The mean eGFR fell from 82 to 67 mL/min/1.73 m 2 after 5 years; most of this reduction occurred during the course of chemotherapy (likely reflecting AKI), although renal function continued to decline thereafter. So the reduction in kidney function associated with ifosfamide administration occurs in a minority of patients, is permanent and progressive and can also occur long after exposure to ifosfamide [ 19 ].…”

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confidence: 99%

The growing pains of ifosfamide

Sprangers

Lapman

2020

Clinical Kidney Journal

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Ifosfamide is a commonly used chemotherapeutic known to have numerous adverse kidney manifestations. In this issue of Clinical Kidney Journal, Ensergueix et al. report a multicentric observational retrospective French study on 34 adult patients with tubular dysfunction and /or kidney dysfunction following ifosfamide treatment. Of these patients, 18% had isolated proximal tubular dysfunction, 14% had isolated acute kidney injury (AKI), 18% had isolated chronic kidney disease (CKD) and 50% had a combination of proximal tubular dysfunction and AKI. Concomitant treatment with cisplatin was identified as a risk factor for the development of AKI, and cisplatin and age were associated with estimated glomerular filtration rate at last follow-up. Interestingly, the cumulative dose of ifosfamide was not associated with renal outcomes. This report highlights the need for additional studies on the prevalence, spectrum and management of ifosfamide-associated nephrotoxicity and clearly demonstrates that patients who received ifosfamide should be followed long term to detect proximal tubular dysfunction and CKD early.

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“…The example of a non-nephrotoxic compound that may be toxic to other organs was ketoprofen, which induces oxidative stress ( Cheng et al., 2014 ) through effects on the mitochondria ( van Leeuwen et al., 2012 ), and has its main toxic effect in the gastrointestinal tract. Examples of nephrotoxicants included puromycin, cisplatin, gentamicin, cidofovir, and ifosfamide ( Ho et al., 2000 ; Barnett and Cummings, 2018 ; Akilesh et al., 2014 ).…”

Section: Resultsmentioning

confidence: 99%