Estimation of ifosfamide/cisplatinum-induced renal toxicity by urinary protein analysis

Abstract

Ifosfamide (IFO) chemotherapy has been reported to result in deToni-Debré-Fanconi syndrome in a minority of patients only, but evaluation of tubular transport capacities has identified a substantial number of patients as having subclinical tubular dysfunction. After completion of combination chemotherapy employing IFO (n = 37) or IFO plus cisplatinum (CPL) (n = 27), glomerular and tubular function was assessed in 64 patients by the urinary excretion of transferrin, IgG, albumin, alpha 1-microglobulin (A1M) and N-acetyl-beta-D-glucosaminidase. Sodium dodecyl sulphate polyacrylamide gel electrophoresis was performed in 21 patients. The determination of urinary marker proteins was compared with the glomerular filtration rate, the fractional phosphate and percent amino acid reabsorption. A reduced glomerular filtration rate was observed in 9.8% of patients. Tubular dysfunction was frequent, with a predominance of renal amino acid (57%) and A1M (48%) loss. IFO-mediated renal toxicity was dose dependent. CPL treatment resulted in significant enhancement of tubular toxicity induced by IFO, whereas concomitant gentamicin therapy did not affect tubular function. Measurement of urinary protein cannot replace other tests for tubular dysfunction in IFO-treated patients, because the spectrum of IFO-induced nephrotoxicity includes dysfunction of different and independent transport mechanisms of the proximal tubular system. Increased urinary A1M excretion is an important indicator of impaired tubular protein reabsorption.

Ontogeny of drug elimination by the human kidney

“…Cisplatin alone can cause a biphasic polyuric response, a decrease in GFR and impaired tubular function expressed as excessive urinary excretion of magnesium [27]. The predominant manifestation of ifosfamide-induced nephrotoxicity is proximal tubular dysfunction with the occasional alteration of GFR [28]. Evidence suggests that young children up to 5 years of age may be more susceptible to ifosfamide-induced nephrotoxicity [29,30,31].…”

Acute and chronic effects of cisplatin therapy on renal magnesium homeostasis

“…It is interesting to remark that only of acute renal insufficiency was present [30]; in the other, the toxic effects of cisplatin were added to the toxic 4 of the 6 patients with chronic hypomagnesemia exhibited this finding during cisplatin therapy. Other renal ab-effects of ifosfamide [22,31,32].…”

Renal function following combination chemotherapy with ifosfamide and cisplatin in patients with osteogenic sarcoma

“…Goren et al [14] found that the ifosfamide-induced increases of both urinary NAG and urinary total protein were most closely related to the number of prior doses of cisplatin (90-100 mg/m 2 per dose). Cisplatin-related potentiation of ifosfamide nephrotoxicity, in particular proximal tubular function, was reflected by low phosphate reabsorption [15,16]. Severe renal tubular toxicity was found in 7 of 15 patients treated with moderate doses of ifosfamide (30-48 g/m 2 ).…”