Anticancer Drugs and the Kidney

Cisplatin

Cisplatin, a platinum-based compound, is used widely as first-line chemotherapy for a variety of solid tumors. After intravenous administration, more than 90% of cisplatin is protein bound, and only 30% is eliminated by the kidneys in the first 24 hours via glomerular filtration and tubular secretion. Nephrotoxicity is its dose-limiting side effect. The S3 segment of the proximal tubule in the corticomedullary region is the most common site of cisplatin nephrotoxicity in rats. More distal sites also may be affected in humans, whereas glomeruli remain unaffected.

Cisplatin causes decreases in renal function in a dose-dependent fashion. Single doses less than 50 mg/m ² rarely cause clinically significant AKI. Acute nonoliguric renal failure occurs with higher doses usually 3 to 5 days after exposure and is associated with minimal proteinuria (<0.5 g/day). Function usually returns to baseline within 2 to 4 weeks, although recovery may be delayed for several months. CKD also may develop after prolonged exposure, but few patients progress to end-stage renal disease.

Cisplatin-induced renal salt wasting may result in significant morbidity, including severe hyponatremia, orthostatic hypotension, mental status changes, and prerenal azotemia. This syndrome develops 2 to 4 months after starting cisplatin and is treated with normal saline hydration and oral sodium supplementation where feasible.

Magnesium-wasting is present in virtually all patients treated with multiple courses of cisplatin. Cisplatin impairs magnesium reabsorption in the ascending limb of loop of Henle and distal tubules resulting in hypermagnesiuria despite low serum magnesium concentrations. Hypomagnesemia also may be exacerbated by coadministration of aminoglycosides, amphotericin, loop diuretics, foscarnet, and others. Cisplatin-induced hypomagnesemia may persist for up to a number of years and can be associated with hypokalemia and hypocalcemia.

Vigorous saline diuresis and fractionated or continuous infusion of the total cisplatin dose have been effective in reducing cisplatin nephrotoxicity. Recent studies showed that osmotic and loop diuretics given do not significantly attenuate kidney toxicity of cisplatin and cannot be recommended at this time.

Although numerous compounds have been tested to prevent cisplatin nephrotoxicity, only amifostine, an inorganic thiophosphate, has been approved for prevention of cisplatin-induced kidney damage. It likely acts via free radical scavenging mechanism and intracellular binding of the drug, but concerns that amifostine also diminishes antitumor effect have limited its use in clinical practice.

Carboplatin

Carboplatin is another platinum-containing antineoplastic agent. Its dose-limiting toxicity is myelosuppression with the maximum tolerated dose of 1200 mg/m ² . Higher doses (up to 2.1 g/m ² ) require stem cell transplant rescue and may lead to nephrotoxicity. High-dose carboplatin-induced renal toxicity is a transient but frequent complication occasionally requiring renal replacement therapy, although irreversible renal failure is infrequent.

Methotrexate

Methotrexate (MTX) is a folic acid antagonist antimetabolite that is effective against many malignancies. When given at doses that exceed 1 g/m ² MTX has a tendency to precipitate in the renal tubules, especially in an acidic pH. This may lead to crystal-induced nonoliguric, nonproteinuric renal failure 1 to 2 days after initial exposure. Because MTX is excreted by the kidney, renal failure leads to toxic MTX blood levels. The accumulation of MTX places patients at risk for prolonged myelosuppression, severe mucositis, and hepatitis. Vigorous intravenous saline and, when necessary, loop diuretics are administered to maintain high urine flow during infusion and afterward until nontoxic levels of MTX (<0.1 µmol/L) are achieved. Sodium bicarbonate is infused concomitantly to alkalinize the urine and inhibit crystal formation. When appropriate preventative measures are employed, MTX-induced AKI is relatively rare. Only 1.8% of patients treated with high-dose MTX for osteosarcoma develop grade 2 or greater nephrotoxicity. However, once AKI develops, mortality is 4.4%.

Because AKI is usually self-limited and resolves in 12 +/- 7 (mean +/- SD) days, the goal of therapy is to prevent extrarenal MTX toxicity. Intravenous leucovorin is given as an antidote at doses ranging from 100 to 1000 mg/m ² every 3 to 6 hours depending on MTX level and until such level is below the toxic threshold. Glucarpidase (carboxipeptidase-G ₂ ) selectively hydrolyzes MTX to inactive metabolites and lowers MTX levels by a median of 97% (range 73%–99%) within 15 minutes of administration. Although a number of studies showed rapid rates of MTX removal in patients with HDMTX nephrotoxicity, none had a control group, and true clinical impact of glucarpidase is difficult to assess. Time to renal recovery in most studies was similar to that of the leucovorin rescue case series. Glucarpidase affects only extracellular levels of MTX, which may explain the delay in renal recovery after MTX removal from circulation. The use of glucarpidase is limited by its high cost (>$100,000/patient), and therefore it should be considered only after standard supportive measures are maximized.

Hemodialysis, high-flux hemodialysis, charcoal-based hemoperfusion, and hemofiltration have been used also to remove MTX in patients with AKI. High-flux hemodialysis appears to be most effective with a median MTX reduction ratio of 75.5% (42%–94%). All modalities exhibited significant postprocedure rebound. Patients who develop MTX renal toxicity can be rechallenged successfully once renal failure resolves.