Cisplatin dose rate as a risk factor for nephrotoxicity in children

Abstract

Summary The purpose of the study was to evaluate the incidence, risk factors and changes in severity with time of cisplatin nephrotoxicity in children. A total of 35 children underwent measurement of glomerular filtration rate (GFR) and tubular function after completion of cisplatin chemotherapy. No child received ifosfamide. A clinically relevant 'nephrotoxicity score' was derived from GFR and serum magnesium. Followup studies were performed in 16 children at 1 year and in 15 at 2 years after cisplatin. Considerable interpatient variability in nephrotoxicity was observed. Treatment was modified in three patients because of nephrotoxicity. GFR was low in 18 out of 31 patients. Proximal nephron toxicity caused hypomagnesaemia in ten patients and hypocalcaemia in five patients. Elevated urinary N-acetylglucosaminidase excretion was seen in 22 out of 30 children, indicating subclinical tubular toxicity. Nephrotoxicity was less severe in children who received cisplatin courses at a dose rate of 40 mg m-2 dar' than in those who received higher dose rates (P < 0.005), but there was no correlation with total dose received. Follow-up studies revealed partial recovery of GFR (P < 0.05). Glomerular and proximal nephron toxicity are common in children treated with cisplatin, and more severe at higher dose rates. Despite partial recovery of GFR, the long-term outcome of nephrotoxicity remains unknown and careful monitoring of chronic toxicity is necessary.Keywords: cisplatin; nephrotoxicity; children The use of combination chemotherapy has led to dramatic improvements in the survival rates from many childhood malignancies during the last three decades. However, cytotoxic drugs may also cause severe and chronic side-effects, leading to permanent ill-health, disability or even premature death (Morris Jones and Craft, 1990). The development of effective strategies to prevent these adverse events depends on careful evaluation of toxicity both during and after treatment.In view of its established efficacy, cisplatin has retained an important role in the treatment of several childhood solid tumours, including neuroblastoma, osteosarcoma, hepatic and brain tumours, despite the increasing use of its apparently less nephrotoxic analogue carboplatin. Indeed, recent evidence has suggested that cisplatin may be more active than carboplatin in some germ cell tumours in adolescents and adults (Bajorin et al, 1993). However, even with the use of hyperhydration and other protective measures, nephrotoxicity is still a common and potentially serious adverse effect of cisplatin in both adults (Madias and Harrington, 1978;Schilsky et al, 1982;Daugaard and Abildgaard, 1989) and children (Womer et al, 1985;Brock et al, 1991). Despite numerous publications concerning cisplatin nephrotoxicity in adults, there is less information and no clear consensus on the importance of patient-and treatment-related risk factors for the development of nephrotoxicity in children. Furthermore, as there are few data concerning the long-term outcome of cisplatin nep...

Long–Term Renal Outcomes after Cisplatin Treatment

“…Whether patient age at the time of onset of cisplatin treatment correlates with the incidence of AKI and long-term renal function is not well established. Some studies report a negative correlation between age and renal function (12,24,25), and others show no relationship (26). A possible explanation for this finding is that older patients had more subclinical renal injury that was not detected by SCr values compared with younger ones or that they may have other comorbidities that made them more susceptible to AKI from cisplatin.…”

Nephrotoxicity of platinum derivatives in children – a review of the literature

“…The dysfunction in glomerular filtration was, in a majority of cases, persistent, but it generally did not present signs of progression in long-term observation [31]. In contrast, in the report published by Skinner et al, after a year of clinical observation, renal filtration activity radically improved: the mean GFR (corrected for body surface areast, BSA) was significantly higher than the GFR value measured at the moment of the termination of antineoplastic therapy (92 ±10 ml/min/1.73 m 2 BSA) [14]. Similar observations were published by Brock and Gomez Campdera [21,33].…”

“…Risk factors that increase kidney impairment after CDDP administration include previous or concomitant renal diseases, solitary kidney (nephrectomy), combined anticancer treatment with IFO and MTX, concurrent treatment with other nephrotoxic agents such as aminoglycosides and amphotericin B, the cumulative dose of CDDP (≥ 200 mg/m 2 ), radiation impacting the kidney (renal radiation dose ≥ 15 Gy), diabetes mellitus, hypertension, dehydration and hypoalbuminaemia [2,14,15].…”

“…Hypomagnesaemia and decreased GFR are the most common clinical manifestations of CDDP nephrotoxicity [2]. The grading of CDDP nephrotoxicity first proposed by Skinner in 1998 is widely used in clinical practice [14]. The scale is based on GFR and serum magnesium concentration (Table 1).…”

“…The T Ta ab bl le e 1 1. . Grading of cisplatin (CDDP) nephrotoxicity in children [14] N Ne ep ph hr ro ot to ox xi ic ci it ty y G GF FR R M Mg g < < 2 2 y ye ea ar rs s M Mg g ≥ 2 2 y ye ea ar rs s g gr ra ad de e (10), 1677-82 [14], with permission main mechanism of its protective action is the removal of free radicals [37]. Additionally, amifostine breaks the binding of CDDP to DNA, binds metabolites of cytotoxic agents, reduces apoptosis and activates tumour-suppressor gene p53.…”