Cisplatin

The introduction of cisplatin to the clinic highlighted the hazards that follow failure to understand the renal complications of cytotoxic agents.²⁸ Effectively overcoming this principal toxicity of cisplatin has allowed significant benefit to patients with many types of cancer. Development of platinum analogs has, in part, been motivated by the renal toxicity associated with cisplatin. However, cisplatin continues to be widely used as a major cancer drug because of its differential antitumor activity when compared with the available analogues. The study of cisplatin, the modification of its delivery, and the anticipation of and screening for nephrotoxicity, provide a paradigm for the study of nephrotoxic agents in general.

The principal excretion route of cisplatin is renal. However, only a small portion of the total cisplatin dose can be recovered in the urine in the first few days after therapy.²⁹ Much of the drug is irreversibly bound to protein, but active metabolites, the aquated diammino derivative, as well as the parent dichlorodiammineplatinum, are found in the ultrafiltrable plasma fraction. This plasma clearance is triphasic with nearly all the drug gone in 4 h, but it has a terminal half-life of over 24 h. The primary lesion of cisplatin toxicity is necrosis of the proximal convoluted tubules. The severity of the nephrotoxicity can be modified by hydration. The strong emetic effects of cisplatin can, however, produce dehydration. These dual side effects—severe nausea and vomiting and primary nephrotoxicity exaggerated by dehydration—have been largely overcome with hydration schedules and the aggressive use of new antiemetics.^30,31

Reduction in glomerular filtration rate (GFR) is the primary cisplatin-induced injury that is measured clinically. Other complications include hypomagnesemia and modest amounts of proteinuria. The proteinuria associated with cisplatin nephrotoxicity is attributed to a tubular defect.³² Hemolytic uremic syndrome has also been described, especially when cisplatin is combined with bleomycin.³³ Sequential measurement of the GFR is essential for monitoring of cisplatin toxicity. An accurate urine collection for inulin clearance is superior to 24-h urine collection for creatinine clearance, but we have used the serum creatinine concentration and calculation of the creatinine clearance. Assay of electrolytes, including calcium, magnesium, and phosphorus, has also been routinely made. For patients treated at the University of Texas M.D. Anderson Cancer Center (UTMDACC) in the Department of Genitourinary Medical Oncology, electrolytes, BUN, and creatinine are monitored prior to each dose of therapy. There is a minimum interval of 7 days between cisplatin doses. This interval is important because maximal nephrotoxicity frequently does not manifest itself in less than 7 days. A significant decline in the creatinine clearance, as measured by the Cockroft formula, should result in a delay of therapy (Table 151-6).

Table 151-6

Cockroft Formula.

Prevention of toxicity is important in patient care. Empirical observations, both in the laboratory and the clinic, demonstrate that hydration with the use of mannitol or hypertonic saline has significantly reduced the cisplatin-induced decline in renal function.^30,31 Although hypertonic saline is not commonly used, normal saline is important to provide abundant chloride ions. This diminishes the formation of the aquated species by mass action, thereby lessening the impact on renal function. Minimum urine flow should be sustained at 100 mL/h before cisplatin administration. Multiple clinical trials have demonstrated the effectiveness of using mannitol in different schedules. Conflicting reports exist regarding use of furosemide (Lasix) and its ability to affect cisplatin's nephrotoxicity. Its use has generally been avoided at the UTMDACC.^34,35 More recently, amifostine (phosphorylated aminothiol prodrug) has been used in the prevention of nephrotoxicity by cisplatin. Amifostine is metabolized to WR-1065 and WR-33278, which reduce formation of deoxyribonucleic acid (DNA)-DNA cross-links,³⁶ reverse platinum-DNA adducts,³⁷ and bind to oxygen free radicals. Several studies show that amifostine decreases the number of patients with a greater than 40% reduction in creatinine clearance, or with glomerular filtration secondary to cisplatin nephrotoxicity, from 30% to 40% to approximately 10%.^38–40 It has been noted that amifostine does not affect the response to chemotherapy. Certain chemotherapeutic agents and other nephrotoxic drugs can impact significantly on nephrotoxicity. Cisplatin is used frequently in combination with other agents, such as ifosfamide and methotrexate. The side effects seem to be greatly diminished by adequate hydration. Paclitaxel in combination with cisplatin has been associated with elevation of serum creatinine in the treatment of gynecologic cancers.⁴¹ Concurrent aminoglycoside antibiotics have been reported to result in a significantly greater reduction of renal function.⁴² Meticulous attention to detail, adequate hydration, and avoidance of these interactions is important.

Methotrexate

Methotrexate (MTX), an agent dependent on renal glomerular filtration as its principal excretory route, can also induce renal toxicity.^43,44 Renal toxicity can be particularly devastating because prolonged exposure to MTX at elevated levels substantially increases toxicity in the bone marrow and the oral cavity of the alimentary canal. The renal toxicity of MTX is a dose-dependent phenomenon. Renal failure has often been implicated in deaths associated with the use of this agent.

The nephrotoxicity of MTX is manifested primarily in the renal tubule, where extensive necrosis of the convoluted tubules occurs. The lesion has been termed crystalline hydronephrosis and has been attributed to deposition of the agent. The precipitation of MTX and its less-soluble principal metabolite, 7-hydroxy MTX, in the renal tubule, results in changes in preglomerular vascular pressure and a direct decrease in glomerular filtration.

Avoidance of MTX nephrotoxicity can be accomplished by selecting patients with normal renal function, ensuring adequate hydration, and alkalinizing the urine to pH 7 or higher. Prior to administration of MTX at doses of 100 mg/m² or greater (and some doses are 100 to 200 times this amount) adequate renal function should be ensured by normal serum creatinine and minimum urinary flow of 100 mL/h. Urine should have a pH of 7 or higher, and leucovorin can be administered after MTX. Methotrexate is highly protein bound, and it is not readily removed by dialysis.³³ Specific attention to interaction with other agents is important when administering MTX. Weak organic acids, such as salicylates or sulfisoxazole, increase MTX levels by displacing the drug from binding sites on plasma proteins. In addition, renal tubular transport is diminished by probenecid and by salicylates. Specific avoidance of these agents reduces the risk of inducing nephrotoxicity or increasing other side effects.

Nitrosoureas

Each of the nitrosoureas (lomustine [CCNU], methyl-CCNU, BCNU) was predicted to have significant nephrotoxicity.^45,46 Initial small Phase I and Phase II trials failed to reveal evidence of renal compromise, but with their use in large Phase III trials, drug-induced nephrotoxicity was encountered.^47–49 Unlike the nephrotoxicity associated with MTX and cisplatin, these agents cause interstitial nephritis. The specific mechanism by which this occurs is unclear. At present, limiting the total cumulative dose of the agents is the only way of preventing this; hydration does not appear to alter it. Monitoring such patients with serial urinalysis and serum creatinine concentrations appears to be the most reliable way to screen for nephrotoxicity.

Mitomycin C

Mitomycin C is an antibiotic isolated from Streptomyces caespitosus. Although this agent has significant activity against a variety of tumors, it has received rather limited use because of prolonged thrombocytopenia and unpredictable side effects, which are dose limiting.

The unique clinical nephrotoxicity of mitomycin C is a striking hemolytic uremic syndrome (HUS). This is sometimes manifested by early elevation of serum creatinine or anemia, with a rise in serum lactate acid dehydrogenase (LDH), indicating hemolysis. Patients receiving mitomycin C should be carefully monitored for HUS. Total cumulative doses of less than 30 mg/m² of body surface area are rarely, if ever, associated with HUS. The most difficult problem in managing the HUS of patients treated with mitomycin C is that it is sometimes difficult to anticipate because the onset can be delayed after the time of delivery of the agent.

Mitomycin C-induced nephrotoxicity can be prevented by limiting the cumulative dose to less than 30 mg/m² of body surface area. The use of steroids, which are believed to reduce the pulmonary toxicity of this agent, has not clearly demonstrated a role in reducing nephrotoxicity. Plasmapheresis appears to provide therapeutic benefit in selected patients, although only limited studies have been performed.^50,51 Small numbers of studies have been performed, but they seem to indicate that therapeutic benefit can be achieved in selected patients.

Immunologic Agents

Interleukin-2 (IL-2) causes renal insufficiency by direct toxic effect on the kidneys and by prerenal azotemia from capillary leak syndrome. This renal toxicity is commonly reversible after discontinuation of the drug, intravenous saline, albumin, pressors, and renal dose dopamine.³³

Cyclosporine produces renal vasoconstriction primarily at the afferent arteriole, causing arterial hypertension, fluid retention, and ultimately renal dysfunction.⁵² The acute nephrotoxicity is reversible with dose modification. In contrast, chronic administration may cause a slowly irreversible renal failure secondary to renal tubular fibrosis and afferent arteriopathy with proteinaceous material.⁵³

Tacrolimus causes renal injury in a fashion similar to cyclosporine. In contrast to cyclosporine, however, it is less likely to cause arterial hypertension. Tacrolimus stimulates transforming growth factor (TGF)-β1 expression and inhibits matrix protein degradation.⁵⁴

Other Agents

On the basis of preclinical studies, the anthracyclines daunorubicin and doxorubicin were predicted to cause renal toxicity.^55–57 Anthracycline-induced nephrotoxicity has not, however, been convincingly reported in clinical trials. Ifosfamide can cause proximal tubular dysfunction, distal renal tubular acidosis, nephrogenic diabetes insipidus, and a syndrome of inappropriate antidiuretic hormone release. Multiple new agents are associated with kidney toxicity, but data are limited. Fludarabine has been reported to cause urologic complications related to urinary tract infections in 12% to 22% of patients.^10,58,59 Abnormal renal function is observed in less than 5% of patients treated with fludarabine,^10,59–61 and it is related to tumor lysis syndrome. Paclitaxel has been associated with elevation of serum creatinine in about 18% of human immunodeficiency virus (HIV) patients treated for Kaposi sarcoma.^10,62,63 Gemcitabine is linked to sporadic renal failure associated with thrombotic microangiopathy.⁶⁴