Assessment of chemotherapy-associated nephrotoxicity in children with cancer

Abstract

Assessment of the toxicity caused by chemotherapy in children with cancer has become more important as the number of long-term survivors has continued to increase. It is vital to monitor both acute life-threatening adverse effects and long-term toxicity that may impair the child's development and cause permanent morbidity. Renal damage may follow treatment with cytotoxic drugs, especially cisplatin or ifosfamide, and lead to glomerular, proximal tubular or distal tubular impairment or to any combination of these. Greater understanding of nephrotoxicity and of its prevention may enable the use of more intensive schedules or of higher doses of potentially nephrotoxic chemotherapy. However, the evaluation of cytotoxic drug-induced nephrotoxicity has frequently depended mainly on measurement of the plasma creatinine concentration, which may remain normal despite substantial glomerular impairment or severe tubular dysfunction. Detailed assessment of nephrotoxicity depends on an understanding of normal renal physiology and requires evaluation of all aspects of function. A comprehensive but simple investigatory protocol that enables assessment of the nature and severity of nephrotoxicity in children is described, which can be performed without admission to hospital. Glomerular function is assessed by measurement of the glomerular filtration rate from the plasma clearance of [51Cr]-ethylenediaminetetraacetic acid ([51Cr]-EDTA). Proximal nephron function is evaluated in three ways: by measurement of the concentration of calcium, magnesium, phosphate, glucose and urate in blood and urine along with calculations of their fractional excretion and of the renal threshold for phosphate; by determination of the excretion in urine of low-molecular-weight proteins (e.g. retinol-binding protein); and by investigation of urinary bicarbonate excretion in patients who are acidotic. Distal nephron function is initially investigated by examination of the concentration (osmolality) and acidification (pH) of an early morning sample of urine. Finally, a group of general investigations is performed, including quantitation of urinary excretion of renal tubular enzymes (e.g. N-acetylglucosaminidase) and measurement of blood pressure.