Ifosfamide nephrotoxicity

The susceptibility factors associated with chronic ifosfamide nephrotoxicity up to 28 months after treatment have been studied in 23 children. The authors concluded that cumulative doses of 100 g/m or higher should be avoided in children with cancers (11). 

Boddy AV, Enghsh M, Pearson AD, Idle JR, Skinner R. Ifosfamide nephrotoxicity limited influence of metabolism and mode of administration during repeated therapy in paediatrics. Eur J Cancer 1996 32A(7) 1179-84. 

Skinner R, Pearson AD, English MW, Price L, Wyllie RA, Coulthard MG, Craft AW. Risk factors for ifosfamide nephrotoxicity in children. Lancet 1996 348(9027) 578-80. 

Skinner R (2003) Chronic ifosfamide nephrotoxicity in children. Med Pediatr Oncol 41 190-197... 

Chen N, Aleska K, Woodland C, Rieder MJ, Koren G (2007) Prevention of ifosfamide nephrotoxicity by N-acetylcysteine clinical pharmacokinetic considerations. Can J Clin Pharmacol 14 e246-e250... 

Hanly L, Chen N, Rieder M, Koren G (2009) Ifosfamide nephrotoxicity in children a mechanistic base for pharmacological prevention. Expert Opin Drug Saf 8 155-168... 

Martinez F, Deray G, Cacoub P, Beaufils H, Jacobs C. Ifosfamide nephrotoxicity deleterious effect of previous cisplatin administration. Lancet (1996) 348,1100-1. 

Aleksa K, Matsell D, Krausz K, Gelboin H, Ito S, Koren G. 2005. Cytochrome P450 3A and 2B6 in the developing kidney imph-cations for ifosfamide nephrotoxicity. Pediatr Nephrol 20(7) 872-885. 

Benesic, A. Schwerdt, G. Mildenberger, S. Freudinger, R. Gordjani, N. Gekle, M. Disturbed Ca -signaUng by chloroacetaldehyde a possible cause for cbronic ifosfamide nephrotoxicity. Kidney Int. 2005, 68, 2029-2041. 

Ifosfamide—adequate hydration is necessary to prevent nephrotoxicity... 

IFOSFAMIDE CISPLATIN t risk of neurotoxicity, haematotoxicity and tubular nephrotoxicity of ifosfamide due to t plasma concentrations of ifosfamide Cisplatin tends to cause renal damage, which results in impaired clearance of ifosfamide Do renal function tests before initiating therapy and during concurrent therapy, and adjust dosage based on creatinine clearance values. Advise patients to drink plenty of water -vigorous hydration - and consider mesna therapy for renal protection... 

It has been thought that the metabolism of ifosfamide to chloroacetaldehyde is the mechanism whereby ifosfamide causes renal damage. However, this was not confirmed in a study of repeated doses of 6-9 g/m in 15 children, in whom there was no correlation between the pharmacokinetics of ifosfamide or its metabolites and either acute renal toxicity or chronic renal toxicity at either 1 or 6 months after treatment (8). However, there were changes in the metabolism of ifosfamide with time, particularly a reduction in dechloroethylation, which correlated with the risk of chronic nephrotoxicity. 

Goren MP, Pratt CB, Viar MJ. Tubular nephrotoxicity during long-term ifosfamide and mesna therapy. Cancer Chemother Pharmacol 1989 25(l) 70-2. 

Hartmann JT, Fels LM, Franzke A, Knop S, Renn M, Maess B, Panagiotou P, Lampe H, Kanz L, Stolte H, Bokemeyer C. Comparative study of the acute nephrotoxicity from standard dose cisplatin + - ifosfamide and high-... 

Hartmarm JT, Fels LM, Knop S, Stolt H, Kattz L, Bokemeyer C. A randomized trial comparing the nephrotoxicity of cisplatin/ifosfamide-based combination chemotherapy with or without amifostine in patients with solid tumors. Invest New Drugs 2000 18(3) 281-9. 

Hartmann JT, Knop S, Fels LM, van Vangerow A, Stolte H, Kanz L, Bokemeyer C. The use of reduced doses of amifostine to ameliorate nephrotoxicity of cisplatin/ifosfamide-based chemotherapy in patients with solid tumors. Anticancer Drugs 2000 ll(l) l-6. 

Beta-lactam induced renal toxicity can results from their use in monotherapy or when used in combination with other nephrotoxic drugs such as aminoglycosides, amphotericin B, cisplatin, cyclosporine, furosemide, ifosfamide, vancomycin and nephrotoxic p-lactams. While the risk of nephrotoxic injury from monotherapy with p-lactams is relatively low, this risk is substantially increased when multiple drug combinations are required. 

Experience with ifosfamide-contain-ing regimens has revealed a consistent clinical pattern of nephrotoxicity. Fanco-ni syndrome, which is characterized by acid, sodium, potassium, magnesium, and small molecular weight proteins, occurs in 1-5% of the children who have received repeated treatments of ifosfamide [94] [95]. In fact the development of rickets secondary to Fanconi syndrome has been reported following treatment with ifosfamide [96]. Patients who have received therapy with cisplatin or carboplatin in addition to ifosfamide may be at greater risk for development of Fanconi syndrome [97]. Hemorrhagic cystitis is a significant toxicity that occurs with ifosfamide administration [98,... 

Skinner R, Sharkey IM, Pearson ADJ, et al. Ifosfamide, Mesnaand nephrotoxicity in children. J Clin Oncol 11 173-190,1993. 

Major risk factors for renal toxicity in cancer patients include nephrotoxic chemotherapy drugs, age, nutritional status, concurrent use of other nephrotoxic drugs (e.g., aminoglycoside antibiotics), and preexisting renal dysfunction. Drugs with a high risk for renal toxicity include cisplatin, ifosfamide,... 

In the case of ifosfamide, the mechanism ofifosfamide-induced nephrotoxicity has been the topic of intense study which has yielded important clues as pathophysiology [54, 76-82], As noted above, ifosfamide is a prodrug that must undergo activation to ifosfamide mustard to exert its anticancer effects (Fig. 6). Ifosfamide metabolism can produce either ifosfamide mustard by ring hydrox-ylation or chloracetaldehyde by side chain oxidation [71, 77, 79], It has been demonstrated that chloracetaldehyde produced by intrarenal metabolism can act as a potent renal toxin, both in vitro and in vivo [76, 77, 80], It has also been clearly demonstrated that the use of concurrent antioxidant therapy—in the case of ifosfamide with 27-acetylcysteine—can prevent ifosfamide-induced renal injury, again both in vitro and in vivo [79-81], This approach has been shown in a small number of case reports to be effective in children with cancer [82],... 

Loebstein R, Koren G (1998) Ifosfamide -induced nephrotoxicity in children critical review of predictive risk factors. Pediatr 10LE8-E12... 

Aleksa K, Ito S, Koren G (2004) Renal-tubule metabolism of ifosfamide to the nephrotoxic chloroacetaldehyde pharmacokinetic modeling for estimation of intracellular levels. J Lab Clin Med 143 159-162... 

Hanly LN, Chen N, Aleksa K et al (2011) N-acetylcysteine as a Novel Prophylactic Treatment for Ifosfamide-induced Nephrotoxicity in Children Translational Pharmacokinetics. J Clin Pharmacol 52(l) 55-64... 

Foxall, P.J. Singer, J.M. Hartley, J.M. Neild, G.H. Lapsley, M. Nicholson, J.K. Urinary Proton Magnetic Resonance Studies of Early Ifosfamide-induced Nephrotoxicity and Encephalopathy, Clin. Cancer Res. 3(9), 1507-1518 (1997). 

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