Late renal toxicity of treatment for childhood malignancy: risk factors, long-term outcomes, and surveillance

Abstract

Chronic glomerular and tubular nephrotoxicity is reported in 20-50% and 20-25%, respectively, of children and adolescents treated with ifosfamide and 60-80% and 10-30%, respectively, of those given cisplatin. Up to 20% of children display evidence of chronic glomerular damage after unilateral nephrectomy for a renal tumour. Overall, childhood cancer survivors have a ninefold higher risk of developing renal failure compared with their siblings. Such chronic nephrotoxicity may have multiple causes, including chemotherapy, radiotherapy exposure to kidneys, renal surgery, supportive care drugs and tumour-related factors. These cause a wide range of chronic glomerular and tubular toxicities, often with potentially severe clinical sequelae. Many risk factors for developing nephrotoxicity, mostly patient and treatment related, have been described, but we remain unable to predict all episodes of renal damage. This implies that other factors may be involved, such as genetic polymorphisms influencing drug metabolism. Although our knowledge of the long-term outcomes of chronic nephrotoxicity is increasing, there is still much to learn, including how we can optimally predict or achieve early detection of nephrotoxicity. Greater understanding of the pathogenesis of nephrotoxicity is needed before its occurrence can be prevented.

Keywords: Glomerular toxicity; Ifosfamide; Nephrectomy; Nephrotoxicity; Platinum agents; Renal radiotherapy; Renal tubular toxicity.

Fig. 1

Relationship between cumulative dose of ifosfamide received and renal tubular threshold for phosphate/glomerular filtration rate (TmP/GFR) in 103 children and adolescents at a median of 6 months after ifosfamide treatment. Patients receiving ifosfamide as a short (3-h) infusion (+) or as a continuous infusion (■) are distinguished. Multiple regression analysis showed a highly significant inverse relationship between cumulative ifosfamide dose and TmP/GFR), a measure of phosphaturia severity. Severe proximal tubular toxicity (defined by hypophosphataemic rickets or myopathy, or by TmP/GFR ≤0.60 mmol/l at <12 months age or ≤0.50 mmol/l at ≥1 year age) was only observed in patients treated with higher doses of >80 g/m². With permission [12]

Fig. 2

Distribution of no, mild, moderate and severe ifosfamide nephrotoxicity amongst 76 children and adolescents, assessed by calculating total nephrotoxicity score. Patients are divided into five groups according to total dose of ifosfamide received. Total nephrotoxicity score was derived from measurement and scoring of glomerular filtration rate (GFR), renal tubular threshold for phosphate (TmP)/GFR, serum bicarbonate concentration and early-morning urine osmolality. These measures give an overall evaluation of clinically important glomerular, proximal and distal nephron nephrotoxicity due to ifosfamide, reflecting those aspects of toxicity with the potential to cause morbidity or require chronic treatment. Each measure was scored on a 0–4 scale, with 0 representing no, 1 mild, 2–3 moderate and 4 severe toxicity within each individual aspect of renal damage. The individual scores are summated to give a nephrotoxicity score potentially ranging from 0 to 16. No patient receiving <84 g/m² experienced severe and 20% moderate nephrotoxicity; of those receiving >119 g/m², 33% experienced severe and 40% moderate nephrotoxicity. With permission [12]