Children's Toxicology from Bench to Bed-Drug-Induced Renal Injury (2): Nephrotoxiciy Induced by Cisplatin and Ifosfamide in Children

The Journal of Toxicological Sciences (J. Toxicol. Sci.) SP251 Vol.34, Special Issue II, SP251-SP257, 2009

Children’s toxicology from bench to bed - Drug-induced Renal Injury (2): Nephrotoxiciy induced by cisplatin and ifosfamide in children

Mikiya Fujieda1, Akira Matsunaga2, Atsushi Hayashi3, Hiromichi Tauchi4, Kohsuke Chayama5 and Takashi Sekine6

1Department of Pediatrics, Kochi Medical School, Kochi University, 185-1 Kohasu, Oko-cho, Nankoku, Kochi 783-8505, Japan 2Department of Pediatrics, School of Medicine, Yamagata University, 2-2-2 Handa-nishi, Yamagata 990-9585, Japan 3Division of Pediatrics and Perinatology, Faculty of Medicine, Tottori University, 86 Nishi-mochi, Yonago, Tottori 683-8503, Japan 4Department of Pediatrics, Ehime University School of Medicine, Shitsukawa, Toon, Ehime 791-0295, Japan 5Department of Pediatrics, Okayama University Graduate School of Medicine and Dentistry, 2-5-1 Shikada-cho, Okayama 700-8558, Japan 6Department of Pediatrics, Graduate School of Medicine and Faculty of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyou-ku, Tokyo 113-8655, Japan

(Received February 17, 2009)

ABSTRACT — Cisplatin and carboplatin cause dose-dependent renal dysfunction. Electrolyte abnormalities such as hypomagnesaemia and hypokalemia are commonly reported adverse effects, in addition to increased serum creatinine and uremia. Cumulative dose, dehydration, hypoalbuminemia, and concurrent use of nephrotoxic drugs have been suggested as risk factors for cisplatin nephrotoxicity. The adverse effects of ifosfamide include proximal tubular damage, and renal wasting of electrolytes, glucose and amino acids, Fanconi syndrome, rickets and osteomalacia have also been reported with ifosfamide treatment. Risk factors for ifosfamide nephrotoxicity include the cumulative dose, young age, previous or concurrent cisplatin treatment, and unilateral nephrectomy. Ifosfamide/Carboplatin/Etoposide (ICE) combination therapy induces hypouricemia, which frequently includes renal wasting of electrolytes, and per- sistent hypouricemia has been observed in recurrent or chemotherapy-resistant patients. We retrospec- WLYHO\H[DPLQHGWKHLQFLGHQFHRIK\SRXULFHPLDDQGFOLQLFDO¿QGLQJVLQSHGLDWULFSDWLHQWVWUHDWHGZLWKDQ ICE regimen. Twenty of 28 (71.4%) pediatric patients had hypouricemia. The duration of hypouricemia was longer in the non-remission subgroup of patients, which suggests that hypouricemia may be a pre- GLFWLYHPDUNHUIRUSURJQRVLVRIPDOLJQDQWGLVHDVHDQGHI¿FDF\RIGUXJVVXFKDVLIRVIDPLGHFDUERSODWLQ and cisplatin. Nephrotoxicity induced by these drugs may also be more common in pediatric patients than in adults, but it is unclear why a young age is a risk factor and further research is required regarding the mechanism of antineoplastic drug induced-nephrotoxicity in children.

Key words: Cisplatin, Carboplatin, Ifosfamide, Nephrotoxicity, Children, Hypouremia

INTRODUCTION ic and irreversible damage. Even in children with subclinical toxicity only, the potential for morbidity in later life The severity of antineoplastic drug-induced nephro- is a serious concern, and this indicates the importance of toxicity is variable, ranging from subclinical impairment reduction of the frequency and severity of nephrotoxici- of renal function to life-threatening disease. Nephrotox- ty. There are many potential causes of acute and chronic icity may be acute and reversible in children treated for renal impairment in patients receiving treatment for can- malignant disease, but it has the potential to cause chron- cer. Chemotherapy, supportive treatment with drugs such Correspondence: Mikiya Fujieda (E-mail: [email protected])

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M. Fujieda et al. as aminoglycoside antibiotics, surgery, immature trans- is the S3 segment of the outer medulla. The cisplatin con- porter function, and wasting by antineoplastic drugs may FHQWUDWLRQLQWXEXODUHSLWKHOLDOFHOOVLV¿YHWLPHVLQH[FHVV all cause nephrotoxicity. Among such drugs, cisplatin and of that found in plasma (Finkel et al., 2007). The plasma ifosfamide are particularly associated with nephrotoxicity. decay curve for platinum showed a biphasic pattern with

Mammalian nephrons consist of a glomerulus, proxi- a terminal t1/2 of 58.5-73 hr, with clearance mainly in the mal tubule, loop of Henle, and distal tubule draining into a urine with 15-75% as the unchanged drug (Li et al., 2007). collecting duct. The proximal nephron includes the proximal tubule and the loop of Henle, and the distal nephron Carboplatin comprises the distal tubule and collecting duct. Glomer- Carboplatin is a second-generation platinum agent XODU¿OWUDWLRQOHDGVWRIRUPDWLRQRIDQXOWUD¿OWUDWHZKLFK that has similar efficacy and less nephrotoxicity com- then enters the proximal nephron where it is progressively pared with cisplatin when each drug is given in combina- PRGL¿HGE\WXEXODUUHDEVRUSWLRQDQGVHFUHWLRQRIHOHFWUR- tion with other agents in treatment of pediatric organ can- lytes, amino acids, glucose, uric acid and other small mol- cer. After intravenous administration, most carboplatin HFXOHVVXFKDVȕPLFURJOREXOLQ7XEXODUVHFUHWLRQHOLP- is bound to protein and only free platinum causes cyto- inates endogenous and exogenous toxic substances, and toxicity. Approximately 70% of the administered dose is VXEVHTXHQWDFLGL¿FDWLRQDQGFRQFHQWUDWLRQRIWKHXOWUD¿O- cleared through the kidneys, with 32% of the dose excret- trate occur in the distal nephron with formation of urine. ed as unchanged carboplatin within 24 hr after adminis- Cisplatin nephrotoxicity mainly affects the S3 segment tration (Li et al., 2007; Koeller et al., 1986). Dose adjust- of the proximal tubule in the outer medulla, while ifos- ment is required in patients with renal dysfunction. famide nephrotoxicity appears to affect all of the nephron Calvert’s formula (carboplatin dose in milligrams = A tar- segments. The mechanisms of cisplatin- and ifosfamide- get area under the concentration curve (AUC) × (glomer- induced nephrotoxicity in children are not completely XODU¿OWUDWLRQUDWH *)5 LVZLGHO\XVHGIRUFDUER- clear, and an improved understanding could lead to novel platin dosing based on the GFR. AUC of 5-7 mg/ml·min renoprotective interventions. is recommended for the formula. GFR is set to zero for patients with end-stage renal disease. Cisplatin and carboplatin metabolism Mechanisms of cisplatin nephrotoxicity Cisplatin An overview of the pathophysiological events in cispl- Organic cation transporters (OCTs) have been impli- atin nephrotoxicity is shown in Fig. 1. Exposure of tubu- cated in cisplatin uptake based on the higher toxicity in lar cells to cisplatin activates molecules and signaling Madin-Darby canine kidney (MDCK) cells following pathways that promote cell death, including reactive oxy- application of cisplatin to the basolateral side compared gen species (ROS), the mitogen-activated protein kinase to the apical side (Ludwig et al., 2004). These results (MAPK) pathway, and P53 or cytoprotective p21. Cis- suggest that cisplatin-induced tubular cell injury may be SODWLQLQGXFHVWXPRUQHFURVLVIDFWRUĮ 71)Į SURGXF- related to basolateral organic cation transport, and this is WLRQLQWXEXODUFHOOVZKLFKUHVXOWVLQDUREXVWLQÀDPPD- supported by the partial prevention of cisplatin-induced tory response and further contributes to tubular cell injury cytotoxicity by cimetidine, an OCT inhibitor. In addi- and death. Cisplatin may also induce injury in the renal tion, Ciarimboli et al. (2005) reported that OCT2, which vasculature, leading to ischemic tubular cell death and a is mainly expressed in the kidney, is the critical OCT decreased GFR, and resulting in acute renal failure (Pabla responsible for cisplatin uptake in the kidney. In contrast, and Dong, 2008) cisplatin does not interact with OCT1, which is mainly Renal tubular cell death via apoptosis and necrosis is expressed in the liver. Therefore, expression of OCTs in a common histopathological feature of cisplatin nephro- GLIIHUHQWWLVVXHVPLJKWDFFRXQWIRUWKHRUJDQVSHFL¿FWR[- toxicity. Apoptosis of renal tubular cells has been a recent icity of cisplatin, and it is also of note that less nephrotox- focus in mechanistic investigation of cisplatin nephro- ic analogs of cisplatin such as carboplatin and oxaliplatin toxicity. Cisplatin activates both the intrinsic mitochon- do not interact with OCT2 (Ciarimboli et al., 2005). drial pathway and extrinsic death receptors in apopto- After entry into cells, cisplatin may react with various VLVLQFOXGLQJ)DVDQG71)ĮUHFHSWRU 71)5 DQG molecules. In the kidney, it has been suggested that the 5HFHQWVWXGLHVKDYHVKRZQWKDW71)ĮLVSURGXFHGPDLQ- nephrotoxicity of cisplatin may depend on metabolic activa- ly from resident kidney cells, rather than infiltrating WLRQYLDDSDWKZD\LQFOXGLQJȖJOXWDP\OWUDQVSHSWLGDVHDQG immune cells, and may trigger tubular cell death directly F\VWHLQH6FRQMXJDWHȕO\DVH7KHPDMRUVLWHRIUHQDOLQMXU\ YLD71)5DVZHOODVLQGLUHFWO\WKURXJKDQLQÀDPPDWR-

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Nephrotoxiciy induced by cisplatin and ifosfamide in children

Cisplatin nephrotoxicity

Cisplatin

Cisplatin uptake by renal tubular cells Vascular injury

TNF-D ROS P53 p21 Ischemia MAPK

inflammation Renal tubular cell death

Renal tissue damage

Decrease in GFR

[Pabla, et al. (2008), modified]

Fig. 1. Overview of pathophysiological events in cisplatin nephrotoxicity. 526UHDFWLYHR[\JHQVSHFLHV0$3.PLWRJHQDFWLYDWHGSURWHLQNLQDVH71)ĮWXPRUQHFURVLVIDFWRUĮ*)5JORPHUXODU ¿OWUDWLRQUDWH ry response via TNFR2 (Zhang et al., 2007). In addition, FLVSODWLQLVFRPPRQZLWKDVLJQL¿FDQWHOHYDWLRQRIXUL- endoplasmic reticulum (ER)-stress may also be induced QDU\ȕPLFURJOREXOLQGXULQJWKH¿UVWZHHNRIHDFKF\FOH and activation of these pathways leads to caspase-depend- with a subsequent decline during the next cycle. Signif- ent or -independent apoptosis (Pabla and Dong, 2008) icant increases in urinary excretion of albumin and IgG (Fig. 2). KDYHEHHQIRXQGRQGD\RIWKH¿UVWFKHPRWKHUDS\F\FOH (Daugaard et al., 1988), and a mean reduction in GFR of &OLQLFDO¿QGLQJVLQFLVSODWLQDQGFDUERSODWLQ 8% per cycle was shown in measurement of renal function nephrotoxicity in 22 pediatric patients (age 1.3 to 10 years old) receiving cisplatin 100 mg/m2 every 21 to 28 days for neuroblasto- Cisplatin ma or malignant germ cell tumors (Womer et al., 1985). Cumulative dose, dehydration, hypoalbuminemia, and concurrent use of nephrotoxic drugs have been sug- Carboplatin gested as risk factors for cisplatin nephrotoxicity. The A mean reduction of GFR of 22 ml/min/1.73m2 was mean cumulative dose of cisplatin precipitating persist- found in 23 pediatric patients (age 0.4 to 15 years old) ent hypomagnesemia in 10 of 22 pediatric patients (age receiving a median cumulative dose of carboplatin of 1 to 15 years old) treated with various cisplatin-contain- 2,590 mg/m2, with a mean reduction of 0.17 mmol in ing chemotherapy regimens was 500 mg/m2 (Ariceta et the serum magnesium level following treatment. These al., 1997). Increased magnesuria and a decreased serum FKDQJHVRFFXUUHGPDLQO\GXULQJWKH¿UVWPRQWKIROORZ- magnesium level were detected soon after administration ing carboplatin administration and post-treatment changes of cisplatin in all 22 patients. In a study of 18 patients fol- in GFR and serum magnesium did not markedly improve lowed for a mean of 2.3 years after discontinuation of cis- or worsen in 24-month follow-up (English et al., 1999). platin, chronic hypomagnesemia accompanied by moder- Acute renal failure occurred in 4 of 16 pediatric patients ately elevated serum creatinine levels was detected in 6 (age 16 months to 14 years old) receiving carboplatin patients, chronic hypocalciuria in 5 patients, and hypoka- 1,000 mg/m2, melphalan 180 mg/m2, vincristine 1.5 mg/ lemia in 1 patient. m2, and etoposide 250 mg/m2 prior to autologous bone A 20-40% reduction of GFR following treatment with marrow transplantation, and an increase in serum creati-

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Apoptotic pathway of cisplatin nephrotoxicity

[Pabla HWDO. (2008), modified]

OCT2

Caspase-12 Caspase- Caspase-9 Caspase-8 activation independent activation activation

Fig. 2. Cisplatin activates both the intrinsic mitochondrial pathway and extrinsic death receptors in apoptosis, such as the tumor QHFURVLVIDFWRUĮUHFHSWRU,QDGGLWLRQHQGRSODVPLFUHWLFXOXPVWUHVVPD\EHLQGXFHG$FWLYDWLRQRIWKHVHSDWKZD\VOHDGVWR caspase-dependent or -independent apoptosis. ER: endoplasmic reticulum, AIF: apoptosis induced factor. nine was noted within 24 hr of chemotherapy in 4 of the Mechanisms of ifosfamide nephrotoxicity 16 patients. Three of the 4 patients with acute renal fail- The pathophysiological mechanisms of ifosfamide ure required dialysis. GFR was reduced by a mean of 24% nephrotoxicity remain to be elucidated. Depletion of ade- in 10 patients evaluated 7 months after transplantation nosine triphosphate (ATP) by binding of toxic metabolites (Corbett et al., 1992). to mitochondrial DNA or blockage of cell regeneration by binding to nuclear DNA have been proposed, and recent- Ifosfamide metabolism ly Patzer et al. (2006) reported that the ifosfamide metab- Ifosfamide is transformed to its active metabolites pri- olites chloracetaldehyde, 4-hydroperoxylifosfamide and marily by hepatic enzymes such as cytochrome P450. ifosfamide mustard are able to inhibit sodium-dependent Urinary excretion of ifosfamide occurs predominantly as phosphate co-transport in kidney cells. The ifosfamide inactive metabolites and acrolein, with unchanged ifos- mustard effect occurs via internalization and reduction of famide accounting for 20% of the administered dose (Li de novo synthesis of the type IIa sodium-dependent phos- et al., 2007). Ifosfamide exerts its antineoplastic effect phate transporter (NaPi-IIa). only when hydroxylated to its active alkylating metabolites, ifosfamide mustard and acrolein, and acrolein is &OLQLFDO¿QGLQJVRILIRVIDPLGHQHSKURWR[LFLW\ responsible for hemorrhagic cystitis in ifosfamide ther- A cumulative dose exceeding 45 g/m2, an age young- apy. Introduction of the uroprotective thiol compound er than 3 years old, previous or concurrent cisplatin treat- MESNA (sodium 2-mercaptoethanesulfonate) has virtu- ment, and unilateral nephrectomy are the most impor- ally eliminated urotoxicity. In addition to hydroxylation, tant risk factors for ifosfamide nephrotoxicity (Loebstein the oxazaphosphorine ring of ifosfamide undergoes side et al., 1999; Skinner et al., 2003). Ifosfamide may cause chain dealkylation (about 50%) that results in formation chronic glomerular, proximal or distal tubular toxic- of non-toxic 2- and 3-dechloroethylifosfamide and equi- ity with a wide range of severity. The main features of molar amounts of chloracetaldehyde, which is thought to ifosfamide nephrotoxicity are shown in Table 1 (Skinner, be responsible for ifosfamide nephrotoxicity. 2003; Kintzel et al., 2001; Skinner et al., 2000; Rossi et al., 1999). An incidence of 1.4 to 30% has been report-

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HGIRUVLJQL¿FDQWFKURQLFJORPHUXODUWR[LFLW\LQFKLOGUHQ mg/dl) and Fanconi syndrome soon after ICE administra- and chronic proximal tubular toxicity is very common, tion of ICE therapy for 7 months. Based on this case, we ranging from subclinical glycosuria in about 90% of chil- retrospectively examined the incidence of hypouricemia dren to hypophosphatemic rickets and/or proximal renal DQGFOLQLFDO¿QGLQJVLQSHGLDWULFSDWLHQWVWUHDWHGZLWKDQ tubular acidosis in over 25%. Urinary excretion of ami- ICE regimen. no acids showed a marked increase in 28% of patients. Fanconi syndrome occurs in 1 to 7% of children receiv- Patients and methods ing repeated doses of ifosfamide and impairment of renal Twenty-eight pediatric patients were enrolled in the phosphate reabsorption is found in 20 to 30%. An appar- study, including 25 with a solid tumor (20 with a brain ent reduction in urinary concentrating ability may occur tumor, 2 with Wilms’ tumor, 2 with osteosarcoma, and 1 in up to 30% of children, but severe distal tubular toxicity with rhabdmyosarcoma), 2 with Hodgkin disease, and 1 is rare. Chronic tubular dysfunction persisting over a peri- with non-Hodgkin disease. The median age was 8 years od of 5 years has been found in 47% (7 of 16) and 25% old (range: 1 to 19 years old) and the median follow-up (4 of 16) of pediatric patients with severe and moderate period was 14 months (range: 2 to 54 months). Hypou- ifosfamide nephrotoxicity, respectively (Loebstein et al., ULFHPLDZDVGH¿QHGDVDVHUXPOHYHORIXULFDFLG 1999). mg/dl for over 1 week. Statistical analyses were per- formed using a non-parametric Mann-Whitney U-test Ifosfamide/Carboplatin(or Cisplatin)/Etoposide or chi-square test as appropriate. Calculations were per- (ICE) combination therapy and hypouricemia formed using Statview 5.0 (Abacus Concepts, Berkeley, &$86$ 7KHOHYHORIVLJQL¿FDQFHZDV'DWDDUH Background expressed as means ± S.D.. We experienced a 14-year-old Japanese girl with recurrent Wilms’ tumor who developed hypouricemia (< 2.0 RESULTS

The 28 subjects were divided into those with hypou- Table 1. Clinical features of ifosfamidenephrotoxicity ricemia (group H, n = 20, 71.4%) and those with normal Glomerulartoxicity (1.4-30%) serum levels of uric acid (group N, n = 8, 28.6%). The Acute renal failure mean lowest levels of serum uric acid were 0.9 ± 0.4 and Chronic renal failure (CRF) 3.2 ± 0.8 mg/dl in groups H and N, respectively, and these OHYHOVZHUHVLJQL¿FDQWO\GLIIHUHQW S &XPXODWLYH Proximal tubular toxicity doses of ifosfamide and carboplatin or cisplatin did not Aminoaciduria (28%) GLIIHUVLJQL¿FDQWO\EHWZHHQWKHWZRJURXSV7KHLQFLGHQF- Glycosuria (90%) es of hypomagnesemia, hypophosphatemia, hypocalcine- /RZPROHFXODUZHLJKWSURWHLQXULD ȕ0*Į0*et al.) mia, hypokalemia, glucosuria, and proteinuria were high- Fanconi syndrome (1-7%) er in group H compared to group N, but there were no Hypophosphatemia and hypophosphatemic rickets (HR) VLJQL¿FDQWGLIIHUHQFHV 7DEOH 7KHUHZDVDVLJQL¿FDQW Proximal renal tubular acidosis (RTA) correlation (p < 0.05) between the lowest uric acid lev- Hypokalemia el in serum and peripheral white blood cell count (Fig. 3), Impairment of phosphate reabsorption (20-30%) but hypouricemia persisted despite recovery of the periph- Calciuria, magnesiuria, natriuria (rarely) eral white blood count (> 1,500 /mm2) (data not shown). :HDOVRFRPSDUHGFOLQLFDO¿QGLQJVDQGVHUXPOHYHOV Distal tubular toxicity of uric acid in a remission subgroup (n = 17) and a non- Subclinical impairment of urinary concentration (30%) remission subgroup (n = 3) in subjects in group H. There Distal RTA ZHUHQRVLJQL¿FDQWGLIIHUHQFHVEHWZHHQWKHVHVXEJURXSV Nephrogenicdiabetes insipidus but the duration of hypouricemia was longer in the non- remission subgroup (117 ± 35 days) compared with the Renal toxicity remission subgroup (41 ± 19 days). The cumulative doses Proteinuria of ifosfamide and carboplatin in the non-remission sub- Hypertension group (35.0 ± 7.5 g/m2 and 4.0 ± 2.1 g/m2, respectively) Growth failure (related CRF, HR, and/or RTA) were higher than those in the remission subgroup (22.1 ± ( ) indicates the incidence rate. 9.9 g/m2 and 2.5 ± 1.2 g/m2, respectively) (Table 3). There

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Table 2. Clinical features in pediatric pateintstreated with an ICE regimen Hypouricemia (n = 20) Non-hypouricemia (n = 8) Age (years old) 8.1 ± 3.8 9.3 ± 6.0 Ifosfamide (g/m2) 25.5 ± 4.6 25.9 ± 7.9 Carboplatin (g/m2) 2.3 ± 1.6 (n = 17) 2.5 ± 0.6 Cisplatin (g/m2) 0.3 ± 0.1 (n = 3) Not available Lowest serum level of uric acid (mg/dl) 0.9 ± 0.4 3.2 ± 0.8 p < 0.01 Hypomagnesemia (< 1.9 mg/dl) 5/12 (41.7%) 1/4 (25.0%) Hypophosphatemia (< 2.9 mg/dl) 9/17 (52.9%) 1/4 (25.0%) Hypocalcemia (< 8.0 mg/dl) 3/20 (15.0%) 1/8 (12.5%) Hypokalemia (< 3.3 mmol/l) 7/20 (35.0%) 0/8 (0%) *OXFRVXULD ! 6/20 (30.0%) 0/8 (0%) 3URWHLQXULD ! 8/20 (40.0%) 0/8 (0%)

Fig. 3. Correlation between serum lowest uric acid level and peripheral white blood cell count (WBC) in patients treated with an ICE regimen. ICE: ifosfamide, carboplatin (or cisplatin), and etoposide combination therapy.

ZDVQRVLJQL¿FDQWGLIIHUHQFHLQWKHLQFLGHQFHRIHOHFWUR UHQDOWXEXODUG\VIXQFWLRQ7KHUHZDVDVLJQL¿FDQWGLIIHU lyte abnormalities and glycosuria between the subgroups ence of the lowest serum level of urate between groups (data not shown). H and N, although cumulative dose of antineoplastic GUXJVDQGWKHDJHGLGQRWGLIIHUVLJQL¿FDQWO\EHWZHHQWZR DISCUSSION groups. The exact reason is obscure, but these findings might be explained by different tubular function of uptake Hypouricemia has been recognized frequently in pedi- and/or excretion of these drugs, or by different metaboliz- atric patients treated with an ICE regimen, in addition to able function between two groups. electrolyte abnormalities and glycosuria, probably due to The duration of hypouricemia was longer in the non-

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Table 3. Clinical features in the non-remission and remission subgroups Non-remission (n = 3) Remission (n = 17) Lowest serum levelof uric acid (mg/dl) 0.9 ± 0.3 1.0 ± 0.4 Duration of hypouricemia (days) 117 ± 35 41 ± 19 Ifosfamide (g/m2) 35.0 ± 7.5 22.1 ± 9.9 Carboplatin (g/m2) 4.0 ± 2.1 2.5 ± 1.2 (n = 14)

remission subgroup of patients, which suggests that Drug Safety, 24, 19-38. hypouricemia may be a predictive marker for prognosis Koeller, J.M., Trump, D.L., Tutsch, K.D., Earhart, R.H., Davis, T. E. and Tormey, D.C. (1986): Phase I clinical trial and pharma- RIPDOLJQDQWGLVHDVHDQGHI¿FDF\RIGUXJVVXFKDVLIRV- cokinetics of carboplatin (NSC 241240) by single monthly 30- famide, carboplatin and cisplatin. A large scale prospec- minute infusion. Cancer, 57, 222-225. tive study in both adult and pediatric patients is required Li, Y.F., Fu, S., Hu, W., Liu, J.H., Finkels, K.W., Gershenson, D.M. WRGHWHUPLQHLIWKHVH¿QGLQJVDUHVSHFL¿FDOO\FKDUDFWHULV- and Kavanagh, J.J. (2007): Systemic anticancer therapy in gyne- tic of pediatric patients. cological cancer patients with renal dysfunction. Int. J. Gynecol. Cancer, 17, 739-763. In conclusion, nephrotoxicity induced by antineoplas- Loebstein, R., Atanackovic, G., Bishai, R., Wolpin, J., Khattak, tic drugs may be more common in pediatric patients than S., Hashemi, G., Gobrial, M., Baruchel, S., Ito, S. and Koren, adults, but it is unclear why a young age is a risk factor G. (1999): Risk factors for long-term outcome of ifosfamide- and further research is required, including examination of induced nephrotoxicity in children. J. Clin. Pharmacol., 39, 454- transporter function in pediatric patients (Loebstein et al., 461. Ludwig, T., Riethmuller, C. and Gekle, M. (2004): Nephrotoxici- 1999; Skinner et al., 2003). ty of platinum complexes is related to basolateral organic cation transport. Kidney Int., 66, 196-202. ACKNOWLEDGMENT Pabla, N. and Dong, Z. (2008): Cisplatin nephrotoxicity: Mecha- nisms and renoprotective strategies. Kidney Int., 73, 994-1007. Patzer, L., Hernando, N., Ziegler, U., Beck-Schimmer, B., Biber, J. This peer-reviewed article is based upon a lecture pre- and Murer, H. (2006): Ifosfamide metabolites CAA, 4-OH-Ifo sented at the 35th Annual Meeting of Japanese Socie- and Ifo-mustard reduce apical phosphate transport by changing ty of Toxicology, June 2008 in Tokyo under the theme of NaPi-IIa in OK cells. Kidney Int., 70, 1725-1734. “Children's Toxicology”, June 2008 in Tokyo. Rossi, R., Kleta, R. and Ehrich, J.H. (1999): Renal involvement in children with malignancies. Pediatr. Nephrol., 13, 153-162. Skinner, R. (2003): Chronic ifosfamide nephrotoxicity in children. REFERENCES Med. Pediatr. Oncol., 41, 190-197. Skinner, R., Cotterill, S.J. and Stevens, M.C. (2000): Risk fac- Ariceta, G., Rodriguez-Soriano, J., Vallo, A. and Navajas, A. (1997): tors for nephrotoxicity after ifosfamide treatment in children: a Acute and chronic effects of cisplatin therapy on renal magnesi- UKCCSG Late Effect Group study. United Kingdom Children's um homeostasis. Med. Pediatr. Oncol., 28, 35-40. Cancer Study Group. Br. J. Cancer, 82, 1636-1645. Ciarimboli, G., Ludwig, T., Lang, D., Pavenstädt, H., Koepsell, H., Womer, R.B., Pritchard, J. and Barratt, T.M. (1985): Renal toxicity Piechota, H.J., Haier, J., Jaehde, U., Zisowsky, J. and Schlatter, of cisplatin in children. J. Pediatr., 106, 659-663. E. (2005): Cisplatin nephrotoxicity is critically mediated via the Zhang, B., Ramesh, G., Norbury, C.C. and Reeves, W.B. (2007): human organic cation transporter 2. Am. J. Pathol., 167, 1477- Cisplatin-induced nephrotoxicity is mediated by tumor necrosis 1484. factor-alpha produced by renal parenchymal cells. Kidney Int., Corbett, R., Pinkerton, R., Pritchard, J., Meller, S., Lawis, I., 72, 37-44. Kingston, J. and McElwain, T. (1992): Pilot study of high-dose vincristine, etoposide, carboplatin and melphalan with autologous bone marrow rescue in advanced neuroblastoma. Eur. J. Cancer, 28A, 1324-1328. Daugaard, G., Rossing, N. and Rorth, M. (1988): Effects of cisplatin on different measures of glomerular function in the human kidney with special emphasis on high-dose. Cancer Chemother. Pharmacol., 21, 163-167. English, M.W., Skinner, R., Pearson, A.D., Price, L., Wyllie, R. and Craft, A.W. (1999): Dose-related nephrotoxicity of carboplatin in children. Br. J. Cancer, 81, 336-341. Finkel, K.W. and Foringer, J.R. (2007): Renal disease in patients with cancer. Nat. Clin. Pract. Nephrol., 3, 669-678. Kintzel, P.E. (2001): Anticancer drug-induced kidney disorders.

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