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

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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 abnor- malities such as hypomagnesaemia and hypokalemia are commonly reported adverse effects, in addition to increased serum creatinine and uremia. Cumulative dose, dehydration, hypoalbuminemia, and concur- rent 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 treat- ment. Risk factors for ifosfamide nephrotoxicity include the cumulative dose, young age, previous or concurrent cisplatin treatment, and unilateral nephrectomy. Ifosfamide/Carboplatin/Etoposide (ICE) com- bination 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 subclin- ical 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]) Vol. 34 Special Issue II SP252 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 prox- imal 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- Vol. 34 Special Issue II SP253 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
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