Prevention of cisplatin nephrotoxicity

AKImedium

A 76-year-old man with stage 3 non-small cell lung cancer is evaluated for increased serum creatinine after initiating cisplatin therapy. He denies shortness of breath, edema, or hematuria. On exam, BP is 110/64 mm Hg and heart rate is 72/min without orthostatic changes. There is trace pretibial edema bilaterally. Laboratory data: WBC count 3200/µL (reference 4000–11,000); hemoglobin 9.6 g/dL (14–18); platelet count 162,000/µL (150,000–450,000); serum sodium 137 mEq/L (136–145); potassium 3.9 mEq/L (3.5–5.0); creatinine 1.7 mg/dL (baseline, 0.7) (0.7–1.3); magnesium 1.3 mEq/L (1.6–2.6); urine protein-to-creatinine ratio 0.6 mg/mg (baseline, 0.2) (<0.2). Urinalysis with microscopy is unremarkable, and urine output is 1200 mL/day. Which ONE of the following is the MOST appropriate intervention to limit cisplatin-associated AKI?

  1. A.Mannitol
  2. B.Isotonic salineCorrect
  3. C.Isotonic saline plus furosemide
  4. D.Magnesium

Explanation

Infusion of isotonic saline before chemotherapy is the most effective way to minimize cisplatin-associated nephrotoxicity. The alkylating agent cisplatin causes kidney injury by several mechanisms, including direct proximal tubular toxicity, renal arteriolar vasoconstriction, and inflammation. Cisplatin is filtered and secreted by organic cation transporters in the proximal tubule, and increased concentrations cause tubular injury in the S3 segment. The risk of cisplatin nephrotoxicity rises as the cumulative dose increases. Carboplatin has less nephrotoxicity and is sometimes substituted for cisplatin when possible. Toxicity may manifest as AKI, Fanconi syndrome, or thrombotic microangiopathy, especially when combined with agents such as bleomycin or gemcitabine. Furosemide and mannitol do not prevent toxicity, although furosemide may be useful in patients with hypervolemia. A single, underpowered trial showed that pretreatment with magnesium IV decreased cisplatin-associated AKI in patients with ovarian cancer; this result has not been replicated in larger trials. Separately, hypomagnesemia from urinary magnesium wasting is commonly observed with cisplatin, and this deficit may exacerbate cisplatin nephrotoxicity. Magnesium supplementation would be appropriate in this patient but would not preclude administration of isotonic saline. Isotonic saline infusion and forced diuresis with saline followed by furosemide or mannitol were compared in a randomized controlled trial for preventing cisplatin nephrotoxicity. There was a trend toward increased toxicity in the mannitol arm and no difference in the isotonic saline alone versus isotonic saline plus furosemide arms. Therefore, the current standard of care to prevent cisplatin-associated AKI is isotonic saline only.

Why each option

A.
Mannitol forced diuresis showed a trend toward more nephrotoxicity than saline alone and is not recommended for cisplatin prophylaxis.
B.
Correct. Isotonic saline before and after cisplatin dilutes tubular drug concentration and is the only consistently supported measure to limit cisplatin nephrotoxicity.
C.
Adding furosemide to saline did not reduce nephrotoxicity compared with saline alone in a randomized trial; reserve it for hypervolemia.
D.
Magnesium repletion is appropriate for cisplatin-induced wasting, but evidence for preventing AKI is limited and it does not replace saline hydration.

Reference: Santoso JT, Cancer Chemother Pharmacol 2003 (saline, mannitol, and furosemide hydration in preventing cisplatin nephrotoxicity); Perazella MA, Clin J Am Soc Nephrol 2012 (onco-nephrology: renal toxicities of chemotherapeutic agents)

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