)A. Children with a single kidney or hydronephrosisAre ineligible to receive ifosfamide in rhabdomyosarcoma protocols. The use of ifosfamide is discouraged for all patients with a single kidney.Have greater nephrotoxicity with cisplatin than those without hydronephrosis, in spite of adjustment of doses for decreased GFR.B. Primary prevention of nephrotoxicity including adequate toincreased hydration, maintenance of normal intravascularfluid status, and avoidance of intravascular volume depletionAdequate intravascular hydration and diuresis can be enhanced by the use of 0.45% or 0.9% saline, mannitol, and diuretics.Use mannitol and diuretics to increase diuresis only after determining adequate intravascular hydration.Where possible, avoid:Nephrotoxic antimicrobials and other renal-toxic medications.The use of intravenous contrast dye for computed tomographic scanning during and after infusion of nephrotoxic chemotherapy.Prevention of bladder toxicityProvide hyperhydration to ensure increased urine output to dilute and decrease the bladder mucosal contact time of toxic oxazaphosphorine metabolites.Strongly encourage ample oral intake for the 12-24 hours preceding cyclophosphamide or ifosfamide infusion.Maintain a urine output of > 65 mL/m2/h for at least 18 hours after cyclophosphamide or ifosfamide therapy.4. Encourage the patient to void at least every 2 hours for the 24 hours after oxazaphosphorine treatment.E. Specific measures to prevent renal toxicity from renal-toxic drugs1. Hydrationa. Before infusion of high-dose methotrexate, moderate to high-dose cyclophosphamide, cisplatin, or ifosfamide, give hydration at 125 mL/m2/h (2x maintenance) for a minimum of 2 hours to increase urine output to > 100 mL/m2/h (> 3 mL/kg/h).b. Before the chemotherapy infusion, urine specific gravity should be < 1.010.c. The hydration fluid most frequently used is 596 dextrose /0.4596 NaCl + 10 mEq/L KCL.d. During infusion of these agents, in general, maintain hydration at > 125 mL/m2/h and urine output at >90 mL/m2/h.e. After the infusion of nephrotoxic chemotherapy (including high-dose melphalan), maintain urine output at 65-100 mL/m2/h (depending on agent and protocol) with oral/intravenous fluids to equal 90-125 mL/m2/h.f. Where needed to maintain isovolemic fluid balance (avoidance of over- and underhydration), diuresis can be forced (in the presence of adequate hydration) through the use of mannitol 6 g/m2 (200 mg/kg) in at least 25 mL of fluid over 15-60 minutes and/or furosemide 0.5-1 mg/kg push intravenous (IV).2. AlkalinizationBefore infusion of high-dose methotrexate, urine alkalinization of >pH 6.5 can be achieved with 40-60 rnEq NaHC03/L added to the intravenous hydration fluid.3. Uroprotectanta. Mesna has been used as a uroprotectant with high-dose cyclophosphamide and ifosfamide (oxazaphos-phorines). Mesna, which has a half-life of 90 minutes, binds the toxic oxazaphosphorine metabolite acrolein within the urinary collecting system to detoxify it. In adult patients, Mesna may not be more effective in preventing bladder toxicity than vigorous hydration.b. The dosage guidelines for Mesna vary. The majority of Children’s Cancer Group protocols recommend a total Mesna dose equivalent to the total ifosfamide dose(i.e., 1 mg of Mesna /l mg of ifosfamide) and a total Mesna dose of about 8056 of the total cyclophosphamide dose.c. Studies have shown that lower doses of Mesna may be uroprotective.4. Hypertonic salinea. The effectiveness of prevention of cisplatin nephrotoxicity by infusion in 3/6 saline is controversial.b. Prevention or diminution of nephrotoxicity associated with cisplatin is possible with hydration with normal saline, continuous infusion of cisplatin, and prophylactic supplementation with magnesium.5. Magnesiuma. During infusion of cisplatin, add mannitol in a dose of 15 g/nr (10-24 g/m2/L) and MgS04 in a dose of 20 mEq/L to the hydrating solution to prevent hypomagnesemia.b. Continue postchemotherapy hydration with 5% dextrose/0.45% NaCl + 20 mEq/L KC1 + 20 mEq/L MgS04 + mannitol 20 g/L.c. When chemotherapy includes cisplatin, routine magnesium supplementation with a minimum of 6 mEq/m2/day by mouth (PO) or IV is recommended.6. Continuous versus intermittent infusionFor cisplatin or ifosfamide, there are insufficient data to determine if continuous versus intermittent infusion or dosing by pharmacokinetic measurement of area under the curve can decrease their nephrotoxicity.Adjust the administered dose of chemotherapeutic agents according to the GFR.Limited total dose of agentMore than eight courses of ifosfamide (approximately 72 g/m2) are not recommended, as the incidence of serious nephrotoxic complications increases markedly when this dose is exceeded.Hematuria1. Microscopic hematuriaa. Transient microscopic hematuria (no more than 2 abnormal urinalyses on 2 separate days during a course of therapy); no modification of the oxazaphosphorine or Mesnab. Persistent microscopic hematuria (>2 abnormal urinalyses during a course of therapy)i. Do not modify the oxazaphosphorine dose.ii. Change the Mesna to a continuous infusion: 360 mg/m2 during oxazaphosphorine, followed by 120 mg/m2/h for 24 hours.2. Gross hematuriaEvaluate all episodes of gross hematuria by cystoscopy. Also consider further testing, such as urine culture, excretory urogram, and voiding cystogram, and perform as indicated.a. Transient gross hematuria during or after a course oftherapy (only one episode, which clears to less thangross hematuria)i. Do not modify the oxazaphosphorine dose.ii. Change the Mesna to a continuous infusion: 360 mg/m2 during oxazaphosphorine, followed by 120 mg/m2/h for 24 hours.b. Persistent gross hematuria after completion of a course of therapyi. Hold subsequent oxazaphosphorine until the urine shows less than gross hematuria.ii. Reinstitute oxazaphosphorine at full dose, with the Mesna changed to a continuous infusion: 360 mg/m2 during oxazaphosphorine, followed by 120 mg/m2/h for 24 hours after each dose of oxazaphosphorine.iii. If gross hematuria does not resolve to microscopic hematuria or less, withhold further oxazaphosphorine therapy.c. Persistent gross hematuria occurring during a course of oxazaphosphorinei. Interrupt the oxazaphosphorine.ii. Withhold further oxazaphosphorine until the next course of therapy.iii. If the gross hematuria resolves to microscopic hematuria or less, subsequent courses of oxazaphosphorine may be administered at full dose, with Mesna changed to a continuous infusion: 360 mg/m2 during oxazaphosphorine, followed by 120 mg/m2/h for 24 hours.d. Occurrence of a second episode of gross hematuria or persistence of microscopic hematuria on the continuous infusion regimeni. Continue the oxazaphosphorine when the urine shows less than gross hematuria.ii. Double the loading dose of Mesna to 720 mg/m2 and the subsequent hourly dose to 240 mg/m2/h.iii. Continue to give Mesna by continuous infusionfor 48 hours after the last dose of oxazaphosphorine.e. Persistent gross hematuria in the face of the “doubledose, continuous infusion” regimen Discontinue oxazaphosphorine.G. Renal tubular dysfunctionIf significant renal Fanconi syndrome (serum phosphate <3.5 mg/dL, potassium <3 mEq/L; 1+ glycosuria with serum glucose <150 mg/dL, bicarbonate <17 mEq/L, and ratio of urine protein/urine creatinine <0.2) develops while receiving ifosfamide, consider substituting cyclophosphamide.*36\168\2*