Nephrotoxicity of Cancer Treatment in Children

Roderick Skinner

Disclosures

Pediatr Health. 2010;4(5):519-538. 

In This Article

Prevention

Prevention of nephrotoxicity is clearly preferable to treatment, especially given the long life expectancy of survivors of childhood malignancy. General measures to reduce renal damage often include the use of hydration protocols, as well as the reduction or ideally avoidance of concurrent or sequential use of other potentially nephrotoxic drugs. In clinical practice, strategies to reduce nephrotoxicity due to specific drugs are usually based on the avoidance of established risk factors, such as high doses. However, effective prevention of nephrotoxicity ideally requires a full understanding of its pathogenesis, but this is not available for most agents.

Reduction of the risk of ifosfamide nephrotoxicity is based on the avoidance of cumulative doses over 80 g/m2,[7] and limitation (where possible) of its use in children younger than 5 years[174] or in patients previously given cisplatin or with poor renal function. Separate studies using rat or cell culture models have suggested that concurrent administration of glutathione,[175] melatonin[176] or N-acetylcysteine[177] may reduce ifosfamide nephrotoxicity by an antioxidant effect. Glycine appears to reduce nephrotoxicity in rats treated with ifosfamide, but the mechanism of protection is not fully understood.[62] Preliminary work in rats has also suggested that carnitine supplementation may reduce ifosfamide nephrotoxicity by maintaining mitochondrial tricarboxylic acid cycle metabolism.[178] However, the efficacy of these or similar approaches in humans has not yet been confirmed in clinical trials. Although mesna prevents the urinary tract toxicity (hemorrhagic cystitis) of ifosfamide, there is no evidence that it reduces the risk or severity of nephrotoxicity.

Cisplatin is likely to remain an important component of pediatric oncology protocols until improved analogs are introduced, in view of its major role in the treatment of many solid malignancies. Many strategies have attempted to prevent or reduce its nephrotoxicity.[179,180] Early experience suggested that the administration of cisplatin by prolonged continuous infusion and saline hyperhydration, with or without frusemide or mannitol osmotic diuresis, reduces nephrotoxicity.[179] Although contemporary protocols invariably employ hyperhydration and many use low-dose rates of cisplatin, it is clear that nephroprotection is not complete.[84] Hydration reduces the risk of nephrotoxicity with high-dose carboplatin[181] but appears unnecessary with conventional doses of 400–600 mg/m2. The consequences of tubular toxicity may be ameliorated by prophylactic intravenous magnesium supplements in hydration fluid to reduce the frequency and severity of hypomagnesemia.[182]

Many pharmacological agents that may ameliorate cisplatin nephrotoxicity have been investigated,[180] but none have found widespread acceptance yet owing to uncertainty about the mechanism of toxicity, and the lack of clear evidence to demonstrate improvements in the therapeutic index of cisplatin. Amongst many others, the drugs studied have included a variety of sulfur-containing compounds, such as sodium thiosulfate, WR-2721 (amifostine), DDTC (sodium diethyldithiocarbamate), mesna, biotin, cephalexin and sulfathiazole, all of which probably react with nephrotoxic cisplatin metabolites to form less toxic products.[180,183] The dephosphorylation of amifostine to the active free thiol metabolite (WR-1065) by membrane-bound alkaline phosphatase is reduced in tumor cells compared with normal cells, therefore allowing healthy tissues (e.g., kidneys and bone marrow) a degree of selective protection against cisplatin toxicity.[184] Based on data from adult studies, guidelines from the American Society of Clinical Oncology suggest that its use may be considered for protection against cisplatin nephrotoxicity.[185] Although there is some experience of the use of amifostine to prevent cisplatin ototoxicity in children,[184] only anecdotal case reports exist of its use to prevent cisplatin nephrotoxicity.[186] A randomised controlled trial of amifostine found no evidence of reduction of cisplatin ototoxicity or tubular nephrotoxicity in the amifostine group but did not report any measures of glomerular function.[187] Furthermore, the value of amifostine may be limited by side effects, including nausea, vomiting, flushing and infusion-related hypotension.[185] Animal studies have also suggested that cisplatin nephrotoxicity may be reduced by a variety of antioxidants including capsaicin, glutamine, melatonin, N-acetylcysteine and selenium.[18]

Additional pharmacological approaches to the reduction of cisplatin nephrotoxicity have involved the development of platinum analogs (e.g., nedaplatin, ormaplatin, oxaliplatin and zeniplatin) and complexes (e.g., with alginates, methionine and procaine hydrochloride) with pharmacokinetic and pharmacodynamic properties that may reduce nephrotoxicity whilst retaining cytotoxic efficacy.[18,188] Liposomal and microsphere preparations have been designed to improve the therapeutic index of platinum compounds. Although a Phase I clinical study of liposomal cisplatin in children demonstrated reduced renal toxicity, cisplatin appeared to be retained within the liposomes, thereby compromising efficacy.[189] Additional protective strategies proposed have included a blockade of possible mediators of renal vasoconstriction, including aminophylline (to inhibit adenosine) and BN-52063 (to antagonize platelet-activating factor),[104,105] and inhibition of cisplatin metabolism by procainamide.[190] Other strategies to selectively reduce nephrotoxicity by inhibition of tubular cisplatin transport, for example with probenecid (organic anion) or cimetidine (organic cation transport), have been investigated, but the uncertainty concerning which renal tubular pathways are responsible for cisplatin transport has limited the value of this approach.[191,192]

The risk of significant methotrexate nephrotoxicity is reduced greatly by prophylactic intravenous fluid and alkalinization regimens to prevent tubular precipitation.[124] Specific preventive strategies are not currently available for other nephrotoxic drugs.

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