Renal function abnormalities after ifosfamide treatment in children

Abstract

Renal function was evaluated in 12 children (aged 2.5-17.5 years) who received ifosfamide as part of their chemotherapy for different malignancies. A blood and urine analysis evaluating renal glomerular and tubular function and an isotopic determination of glomerular filtration were carried out four months or later after treatment had been stopped. Three patients had several biochemical abnormalities suggesting a significant degree of proximal renal dysfunction (increased urinary excretion of calcium, glucose, beta 2-microglobulin, amino acids (three patients) and decreased tubular reabsorption of phosphate (one patient)). The tubular dysfunction in these patients was associated with a diminished glomerular filtration. These patients could be characterized by their younger age at treatment and a higher dose of ifosfamide received if calculated per kg body weight.

The influence of ifosfamide scheduling on acute nephrotoxicity in children

“…Both RBP and B2 microglobulin have been found to be sensitive measures of ifosfamide-induced renal tubular damage (Al Sheyyab et al, 1993;De Schepper et al, 1993). Some patients were already on treatment when this study started and had already received large cumulative doses of ifosfamide.…”

“…Acute changes in renal function were compared in 16 children receiving 9 g m-2 of ifosfamide as a 72-h continuous infusion on one occasion and, on another course, divided into three 1 -h infusions on consecutive days. Subclinical acute nephrotoxicity was demonstrated with both schedules, but there were no significant differences in severity.Keywords: ifosfamide; nephrotoxicity; ifosfamide administration Subclinical renal damage has been reported in most children treated with ifosfamide (Skinner et al, 1990;Heney et al, 1991), and in some series between 20% and 40% of children have required some form of mineral replacement therapy because of inappropriate renal tubular loss of phosphate and bicarbonate (Skinner et al, 1990;Caron et al, 1992;De Schepper et al, 1993). Renal failure may occur acutely and prevent the delivery of planned chemotherapy, however it is more often a chronic problem with severely affected children suffering from hypophosphataemic rickets, renal tubular acidosis and occasionally nephrogenic diabetes insipidus.…”

“…Impairment of growth may result from renal tubular acidosis and rickets (De Schepper et al, 1991;Rossi et al, 1992;Skinner et al, 1992). Higher cumulative dose of ifosfamide, younger patient age at treatment (Suarez et al, 1991;Skinner et al, 1992;Al Sheyyab et al, 1993;De Schepper et al, 1993), prior nephrectomy and pre-existing renal impairment, including that caused by prior or concomitant treatment with cisplatin, have all been reported as being associated with an increased risk of ifosfamide-induced nephropathy (Pratt et al, 1991;Suarez et al, 1991;Caron et al, 1992;Skinner et al, 1992;Al Sheyyab et al, 1993;De Schepper et al, 1993), Marina et al, 1993;Tournade, 1993; Rossi et al, 1994a,b).A further possible risk factor is the method of administration of the drug. Schedules of administration in children have varied from short infusions over 15 min to continuous infusion over 3 or more days.…”

True

“…Although early studies failed to reveal any evidence of nephrotoxicity in children receiving ifosfamide (de Kraker and Voute, 1984;Gasparini, 1986;Biron et al, 1987;Kellie et al, 1988;Demeocq et al, 1989), subsequent reports described a characteristic pattern of proximal renal tubular damage, often accompanied by glomerular and sometimes by distal tubular impairment (Smeitink et al, 1988;Burk et al, 1990;Skinner et al, 1990;Pratt et al, 1991;Suarez et al, 1991;Caron et al, 1992;Shore et al, 1992;De Schepper et al, 1993;Arndt et al, 1994;Ashraf et al, 1994). Such toxicity persisted long after discontinuation of ifosfamide treatment in many patients, often presenting with clinical manifestations due to the Fanconi syndrome (Skinner et al, 1993).…”

“…The reported incidence of severe chronic nephrotoxicity in children has varied widely from 1.4% (Pratt et al, 1991) to about 30% (De Schepper et al, 1993), probably depending on the distribution of risk factors amongst different patient groups and on the sensitivity of the methods used to detect renal damage. The commonest clinical sequelae of ifosfamide nephrotoxicity include hypophosphatemia, which may lead to rickets (Moncrieff and Foot, 1989;Burk et al, 1990;Skinner et al, 1990;De Schepper et al, 1991;Pratt et al, 1991;Suarez et al, 1991;De Schepper et al, 1993), and renal tubular acidosis (Heney et al, 1989;Suarez et al, 1991), both of which may impair growth (De Schepper et al, 1991).…”