Chapter 11. Chemotherapy and Kidney Injury † † Ilya G. Glezerman, MD,* and Edgar A. Jaimes, MD* *Renal Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York; and †Department of Medicine, Weill Cornell Medical College, New York, New York INTRODUCTION cell apoptosis and production of ROS (3). Cisplatin is excreted and concentrated in the kidneys entering re- By January 1, 2011, 4,594,732 people in the United nal tubular cells via organic cation transporter 2, States carried the diagnosis of invasive malignancy. which is kidney specific(3). On the other hand, with significant advances in Initialrenaltoxicitymanifestsasadecreaseinrenal anticancer therapies, the 5-year survival for cancer blood flow and subsequent decline in GFR within patients has increased from 48.9% in 1975–1979 to 3hoursofcisplatinadministration.Thesechangesare 68.5% in 2006 (1). These statistics show that a sig- probably due to increased vascular resistance sec- nificant percentage of the population is likely to be ondary to tubulo-glomerular feedback and increased exposed to chemotherapy and suffer various short- sodium chloride delivery to macula densa. The term and, in case of survivors, long-term adverse decline in GFR appears to be dose dependent. In effects of treatment. a group of patients who received four cycles of Kidneys are vulnerable to the development of drug 100 mg/m2,the51Cr-EDTA–measured GFR de- toxicity due to their role in the metabolism and clined by 11.7%, whereas in patients who received excretion of toxic agents. The kidneys receive close to three cycles of 200 mg/m2, the mean decline was 25% of cardiac output, and the renal tubules and 35.7%. This effect was noted to be lasting, as GFR proximal segment in particular have significant capa- was still 30% below baseline at 2 years (4). Acute city for uptake of drugs via endocytosis or transporter tubular toxicity of cisplatin causes mitochondrial proteins. The high rate of delivery and uptake results dysfunction, decreased ATPase activity, impaired in high intracellular concentration of various sub- solute transport, and altered cation balance. As a re- stances that then undergo extensive metabolism, sult, sodium and water reabsorption is decreased, leading to formation of potentially toxic metabolites and salt and water excretion is increased, leading and reactive oxygen species (ROS) (2). Numerous to polyuria (3). Cisplatin also causes dose-dependent chemotherapy agents have been associated with renal magnesium wasting. various renal toxicities including tubulointerstitial Tubulointerstitial injury is a predominant find- damage, glomerular disease, electrolyte abnormal- ing on pathologic examination of human kidneys ities, hypertension, and proteinuria (Table 1). affected by cisplatin toxicity. Both proximal and distal tubules are affected, and in patients with AKI, there is usually acute tubular necrosis. Long-term AGENTS WITH PREDOMONANLTY cisplatin exposure may also cause cyst formation TUBULAR TOXICITY and interstitial fibrosis (Figure 1) (3). Patients with cisplatin toxicity typically present Platinum compounds with progressive azotemia in the setting of bland Cisplatin (cis-dichlorodiammineplatinum)–platinum urinalysis and minimal proteinuria. Although renal coordination complex is an effective chemotherapy function improves in most patients, a subgroup of against a wide spectrum of tumors such as testicular, patients developed permanent renal impairment. head and neck, ovarian, lung, cervical, and bladder Hypomagnesemia is common and may be present in cancers. Nephrotoxicity is the dose-limiting toxicity of cisplatin. Cisplatin induces the production of ROS and inhibits several antioxidant enzymes, leading to Correspondence: Ilya G. Glezerman, Memorial Sloan Kettering oxidative stress injury. It increases renal expression of Cancer Center, 1275 York Ave., New York, New York 10024. tumor necrosis factor a,leadingtoincreasedtubular Copyright © 2016 by the American Society of Nephrology American Society of Nephrology Onco-Nephrology Curriculum 1 Table 1. Nephrotoxicity of common chemotherapy drugs Agent Common pathologic finding Clinical syndromes Drugs with tubular toxicity Cisplatin ATN AKI, hypomagnesemia, renal sodium Chronic interstitial fibrosis and cyst formation wasting, CKD Ifosfamide ATN Fanconi syndrome (partial or complete) AKI ESRD Methotrexate Crystal nephropathy Nonoliguric AKI Pemetrexed ATN AKI AIN CKD Tubular atrophy and interstitial fibrosis Nephrogenic diabetes insipidus Ipilimumab AIN AKI Drugs with glomerular toxicity Gemcitabine Thrombotic microangiopathy AKI MAHA Hypertension Mitomycin Thrombotic microangiopathy Dose dependent: AKI, MAHA Hypertension Bevacizumab Thrombotic microangiopathy Proteinuria Hypertension Less common: Nephrotic syndrome AKI, MAHA VEGFR mTKI Thrombotic microangiopathy Proteinuria Sunitinib MCD/cFSGS Hypertension Sorafenib Less common: Nephrotic syndrome Axitinib AKI, MAHA Pazopanib Drugs causing electrolyte abnormalities EGFR antibody Inhibition of TRMP6 in distal Hypomagnesemia Cetuximab convoluted tubule Panitumumab Imatinib Unknown Hypophosphatemia ATN, acute tubular necrosis; AIN, acute interstitial nephritis; MAHA, microangiopathic hemolytic anemia; VEGFR mTKI, vascular endothelial growthfactormul- titarget tyrosine kinase inhibitors; MCD/cFSGS, minimal change disease and/or collapsing-like focal segmental glomerulosclerosis; EGFR, epithelial growth factor receptor; TRMP, transient receptor potential cation channel, subfamily M, member 6. 42%–100% of patients depending on total cisplatin dose and Numerous compounds have been studied to prevent cisplatin length of exposure. Hypomagnesemia and renal magnesium nephrotoxicity but only amifostine is US Food and Drug Ad- wasting may persist for up to 6 years after initial dose (5). ministration (FDA) approved for protection against cumulative Renal salt wasting syndrome has been reported in up to 10% nephrotoxicity from cisplatin therapy. Amifostine is protective of patients, manifesting as hyponatremia and severe ortho- by increasing the binding of ROS to thiol groups. Side effects, static hypotension in the setting of high urinary sodium cost, and concerns that it also diminishes antitumor effect have concentration. This syndrome may present 2–4 months after limited its use in clinical practice (3). A recent study in a murine initiation of cisplatin therapy (6). Rare cases of thrombotic model showed that magnesium supplementation during cis- microangiopathy have been reported in patients who were platin therapy may attenuate renal damage; however, further also receiving bleomycin with cisplatin (4). Syndrome of in- studies in humans are needed to validate these findings (9). appropriate antidiuretic hormone secretion (SIADH) has Carboplatin is also a platinum-based agent with a lower po- been documented in patients receiving vigorous hydration tential for nephrotoxicity compared with cisplatin but can be (7) but is less common now as cisplatin-associated nausea is nephrotoxic at myeloablative doses of .800 mg/m2 (10). Ox- treated with new-generation antiemetics, diminishing the aliplatin, another platinum compound, has no nephrotoxic stimulus for antidiuretic hormone secretion. potential. Vigorous hydration has been shown to reduce the incidence of AKI in patients receiving cisplatin. Both mannitol and loop Ifosfamide diuretics have also been used to ameliorate toxicity; however, Ifosfamide is an alkylating agent used in the treatment of a randomized studies have not shown a clear benefit(8). varietyof childhoodand adult malignancies. Its use, however, is 2 Onco-Nephrology Curriculum American Society of Nephrology and secreted by the kidneys. It is a weak organic acid and is poorly soluble in acidic urine (18). Although it is administered over a large therapeutic range, only high-dose methotrexate (HDMTX) therapy of .1g/m2 has the potential for nephrotoxicity. MTX renal toxicity is pre- sumed to be due to direct precipitation of the drug, as well to direct toxic effects on renal tubules. In a large clinical trial of 3,887 patients treated with HDMTX, renal dysfunction occurred in 1.8% of the subjects and was associated with a 4.4% mortality in this group (19). Affected patients usually develop nonoliguric and in more severe cases oliguric AKI shortly after the admin- istration of HDMTX. Urinalysis is generally bland and without proteinuria. Because MTX is excreted in the urine, renal im- pairment affects the clearance of the drug. Prolonged expo- sure to toxic levels of MTX (.10 mmol/L at 24 hours; .1 mmol/L at 48 hours, and .0.1 mmol/L at 72 hours) may lead Figure 1. Cisplatin-induced acute tubular injury and necrosis to life-threatening nonrenal toxicities such as prolonged cy- (ATI/ATN). Light microscopy of the kidney biopsy specimen re- topenias, mucositis, neurotoxicity, and hepatic dysfunction. veals dilated tubules with flattened epithelium. There is also apical MTX solubility is 10-fold higher in urine with a pH of 7.5 blebbing of tubular cells and drop out of tubular cells from the basement membrane. than in acidic urine, and therefore urinary alkalinization and aggressive hydration (2.5–3.5 L/m2 per 24 hours starting 12 hours prior to chemotherapy administration) are important associated with a significant risk for nephrotoxicity. Because it steps to establish brisk diuresis and prevent methotrexate pre- is commonly used in children, most of the data pertaining to cipitation in the tubules. Probenecid, penicillins, salicylates, nephrotoxicity