INTRODUCTION — A variety of kidney diseases and electrolyte disorders can result from the drugs that are used to treat malignant disease, including conventional cytotoxic agents; molecularly targeted agents, which take advantage of molecular abnormalities that drive cancer progression; and immunotherapeutic agents. All of these drugs can affect the glomerulus, tubules, interstitium, or renal microvasculature via different mechanisms, with clinical manifestations that range from an asymptomatic elevation of serum creatinine and electrolyte disorders to acute kidney injury requiring dialysis. One study estimated that potentially nephrotoxic drugs were used in 80 percent of chemotherapy sessions [1].
The kidneys are also a major elimination pathway for many antineoplastic drugs and their metabolites, and kidney impairment can result in delayed drug excretion and metabolism of chemotherapeutic agents, and increased systemic toxicity. Many drugs require dose adjustment when administered in the setting of kidney insufficiency (table 1). Minimizing nonrenal systemic toxicity may be a particular problem in patients on chronic hemodialysis, especially when the details of drug elimination and metabolism are not fully known.
The nephrotoxicity of conventional cytotoxic chemotherapy agents, preventive strategies, and recommended dose modifications in patients with kidney impairment will be reviewed here. Kidney toxicities seen with several classes of molecularly targeted and biologic agents, kidney toxicity associated with drugs that target the vascular endothelial growth factor pathway, immune-mediated kidney toxicity associated with checkpoint inhibitor immunotherapy (ie, ipilimumab, pembrolizumab, nivolumab), an overview of kidney diseases associated with various cancers (including paraneoplastic syndromes), and the kidney complications of tumor lysis syndrome and hematopoietic cell transplantation are discussed elsewhere.
●(See "Toxicities associated with checkpoint inhibitor immunotherapy", section on 'Kidney'.)
●(See "Overview of kidney disease in the cancer patient".)
●(See "Tumor lysis syndrome: Pathogenesis, clinical manifestations, definition, etiology and risk factors".)
●(See "Kidney disease following hematopoietic cell transplantation".)
ESTIMATION OF GFR FOR POSSIBLE DOSE ADJUSTMENT — There are two principal pathways for drug excretion by the kidney: glomerular filtration and tubular secretion. Glomerular filtration plays a major role with non-protein-bound small molecules (ie, of a size that can pass through the glomerular capillary wall). Such molecules cannot be filtered if they are protein bound in the circulation; these drugs, if they are renally excreted, enter the urine by secretion in the proximal tubule.
For those drugs in which renal excretion is an important determinant of elimination of the intact drug or an active metabolite, dose adjustment is often required if kidney function is impaired. Although the prevalence of an elevated serum creatinine is low in cancer patients (<10 percent), the prevalence of a reduced glomerular filtration rate (GFR) is relatively high (50 to 53 percent in two cohort studies [1,2]).
For most chemotherapeutic drugs (with the exception of high-dose methotrexate), measurement of serum drug concentrations is not usually performed. (See "Therapeutic use and toxicity of high-dose methotrexate", section on 'Laboratory monitoring during treatment'.)
Dose adjustment in this setting is typically based upon two factors: an estimation of GFR, which serves as an index of the number of functioning nephrons, and evaluation of clinical signs of drug toxicity (eg, neutropenia, thrombocytopenia). Clinicians should use the method to estimate GFR that provides the most accurate assessment of GFR [3-5]. A creatinine clearance (CrCl) calculation based upon a 24-hour collection of urine is cumbersome and subject to error due to incomplete urine collection. Estimation equations for CrCl (eg, Cockcroft-Gault (calculator 1 and calculator 2)) and estimates of GFR using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI; (calculator 3)) equations based upon a stable serum creatinine concentration also correlate with the measured GFR. These three methods are now the most common methods used in routine clinical practice to estimate kidney function, due primarily to convenience.
There is currently no consensus on the optimal formula to estimate GFR in cancer patients. While some suggest that all bedside formulae provide similar levels of concordance in estimation of GFR for the purpose of dosing renally excreted cancer drugs [6], others consider the Cockcroft-Gault formula to be the least precise and body surface area (BSA)-adjusted CKD-EPI to be the most accurate [5,7]. These issues are discussed in detail elsewhere. (See "Assessment of kidney function".)
Of note, a point-of-care device for measuring serum creatinine (the i-STAT system, used for routine testing in some clinical laboratories) can give a falsely elevated creatinine measurement in patients receiving hydroxyurea [8]. In such cases, a method of creatinine measurement other than i-STAT should be used. (See 'Hydroxyurea' below.)
Determining the appropriate dosing of a drug that is eliminated even partially by the kidneys according to estimates of kidney function requires reference to evidence-based recommendations. Proposed guidelines for dose adjustment of antineoplastic drugs in patients with kidney disease that are still unfortunately based on CrCl are available from several groups [1,9,10]. When known, dosing guidelines for individual drugs in patients with chronic kidney disease (and those undergoing dialysis) are available through the Lexicomp drug database within UpToDate and are summarized in the sections below [5].
However, in our view, estimates of GFR are preferred. If a clinician uses estimates of GFR using one of the formulas above, then dosing should be based on that value, although most guidelines do not use these formulas to estimate GFR. Throughout this topic, the term CrCl will be used for renal dose adjustment since this is how renal dosing is reported in the United States Prescribing Information and Cancer Care Ontario guidelines. However, CrCl in this topic will generally refer to any measurement or estimation of CrCl (eg, Cockcroft-Gault) or GFR (MDRD or CKD-EPI).
RISK FACTORS FOR NEPHROTOXICITY — Several factors can potentiate kidney dysfunction and contribute to the nephrotoxic potential of antineoplastic drugs. These include:
●Intravascular volume depletion, either due to external losses or fluid sequestration (as in ascites or edema). This is one of the most common factors contributing to the nephrotoxic potential of antineoplastic drugs.
●The concomitant use of nonchemotherapeutic nephrotoxic drugs (eg, certain antibiotics [including aminoglycoside antibiotics], nonsteroidal anti-inflammatory agents, and proton pump inhibitors) or radiographic ionic contrast media in patients with or without preexisting kidney dysfunction. (See "Contrast-associated and contrast-induced acute kidney injury: Clinical features, diagnosis, and management".)
●Urinary tract obstruction secondary to the underlying tumor.
●Intrinsic kidney disease that is idiopathic, related to other comorbidities, age related, or related to the cancer itself. (See "The aging kidney" and "Overview of kidney disease in the cancer patient".)
DRUG HANDLING IN DIALYSIS PATIENTS — Minimizing nonrenal systemic toxicity in patients receiving chemotherapy may be a particular problem in patients on chronic hemodialysis, especially when the details of drug elimination and metabolism are not fully known [11]. For patients undergoing dialysis, two issues must be considered:
●Since the kidneys are no longer functioning, dose reduction may be needed to avoid overexposure and drug toxicity.
●Drug clearance by dialysis must be taken into account for appropriate timing of chemotherapy in patients treated with hemodialysis.
For those drugs in which a substantial fraction is removed by hemodialysis, chemotherapy should be administered after dialysis to avoid drug removal and loss of efficacy. On the other hand, for drugs that are not significantly removed by dialysis, administration is not related to the timing of dialysis.
Partial dialysis removal may be used to improve drug tolerance. As an example, dialysis sessions may be started at a certain time following administration of a drug such as cisplatin to remove the drug that has not been distributed to its site of action but may still contribute to side effects.
Data on management of cytotoxic chemotherapy drugs and combination regimens in patients undergoing dialysis are scant and consist mainly of single case reports. Proposed guidelines for dose adjustment and timing of cytotoxic drug administration in patients undergoing hemodialysis are available from several groups [1,9,12]. When known, dosing guidelines for individual drugs in patients undergoing dialysis are available through the Lexicomp drug database in UpToDate.
ALKYLATING AGENTS
Bendamustine — Bendamustine is an alkylating agent that is used for treatment of chronic lymphocytic leukemia and indolent B cell non-Hodgkin lymphoma. Moderate kidney impairment (creatinine clearance [CrCl] 40 to 80 mL/min) does not appear to alter the pharmacokinetics [13]. For patients with CrCl <40 mL/min, limited data suggest that grade 3 or 4 treatment-related toxicity is more frequent [14]. The United States Prescribing Information for one bendamustine product (Treanda) recommends that bendamustine not be used in patients with CrCl <30 mL/min. Similar guidance is available from Cancer Care Ontario. The United States Prescribing Information for a second marketed bendamustine product (Bendeka) recommends that the drug not be administered for CrCl <40 mL/min.
Cyclophosphamide — The main urologic toxicity of cyclophosphamide is hemorrhagic cystitis. The primary renal effect of cyclophosphamide is hyponatremia, which is due to an increased effect of antidiuretic hormone (syndrome of inappropriate antidiuretic hormone secretion [SIADH]) impairing the kidney's ability to excrete water [15-17]. Chemotherapy-induced nausea may also play a contributory role since nausea is a potent stimulus to antidiuretic hormone release. (See "Chemotherapy and radiation-related hemorrhagic cystitis in cancer patients" and "Pathophysiology and etiology of the syndrome of inappropriate antidiuretic hormone secretion (SIADH)".)
Hyponatremia is usually seen in patients receiving high doses of intravenous (IV) cyclophosphamide (eg, 30 to 50 mg/kg or 6 g/m2 in the setting of hematopoietic stem cell transplantation). Although less common, hyponatremia can also occur with oral therapy or with lower IV doses (eg, 10 to 15 mg/kg) given as pulse therapy in autoimmune diseases such as lupus nephritis. (See "Kidney disease following hematopoietic cell transplantation".)
Hyponatremia typically occurs acutely and resolves within approximately 24 hours after discontinuation of the drug. Hyponatremia poses a particular problem for patients undergoing high-dose IV cyclophosphamide, who are often fluid loaded to prevent hemorrhagic cystitis [17]. The combination of increased antidiuretic hormone effect and enhanced water intake can lead to severe, occasionally fatal hyponatremia within 24 hours. This complication can be minimized by using isotonic saline rather than hypotonic solutions to maintain a high urine output. However, hyponatremia can worsen even with isotonic saline administration. (See "Treatment of hyponatremia: Syndrome of inappropriate antidiuretic hormone secretion (SIADH) and reset osmostat", section on 'Therapies to raise the serum sodium'.)
The need for cyclophosphamide dose reduction in patients with pre-existing kidney insufficiency is controversial.
Dose adjustment is not recommended by several authors citing the lack of association between kidney function and either cyclophosphamide clearance or hematologic toxicity [18,19]. On the other hand, others suggest the need for dose adjustment based upon the altered pharmacokinetics in kidney insufficiency [20]. Not surprisingly, the recommendations from expert groups are variable:
●The United States Prescribing Information for cyclophosphamide states that patients with severe kidney impairment (CrCl = 10 mL/min to 24 mL/min) are at risk for decreased kidney excretion and higher plasma levels of cyclophosphamide and its metabolites, which may result in increased toxicity. They do not recommend a specific dose reduction, but do recommend that such patients be closely monitored for signs and symptoms of toxicity.
●Some authors advocate a 25 percent dose reduction in patients with CrCl <10 mL/min [10], while others have suggested only a 10 and 20 percent dose reduction for patients with CrCl values less than 55 and 20 mL/min, respectively [21].
●Guidelines from Cancer Care Ontario for management of patients receiving cyclophosphamide suggest a 25 percent reduction in dose in patients with CrCl <50 mL/min and use of extreme caution or drug discontinuation for CrCl <10 mL/min.
In patients with end-stage kidney disease (ESKD), cyclophosphamide is moderately hemodialyzable; it should be administered after hemodialysis [10,12,22]. In patients on peritoneal dialysis, some authors suggest a 25 percent dose reduction [10]. (See "Drug removal in continuous kidney replacement therapy".)
Ifosfamide — Similar to cyclophosphamide, the predominant toxicity of ifosfamide on the urinary tract is hemorrhagic cystitis. Ifosfamide can also cause SIADH. (See "Chemotherapy and radiation-related hemorrhagic cystitis in cancer patients" and "Pathophysiology and etiology of the syndrome of inappropriate antidiuretic hormone secretion (SIADH)".)
However, nephrotoxicity is more likely with ifosfamide than with cyclophosphamide. Ifosfamide nephrotoxicity affects the proximal tubule and is characterized by one or more of the following signs of acute tubular dysfunction:
●Metabolic acidosis with a normal anion gap (hyperchloremic acidosis) due to type 1 (distal) or type 2 (proximal) renal tubular acidosis
●Hypophosphatemia induced by decreased proximal phosphate reabsorption, which can lead to rickets in children
●Renal glucosuria, aminoaciduria, and a marked increase in beta-2-microglobulin excretion, all from generalized proximal dysfunction
●Polyuria due to nephrogenic diabetes insipidus
●Hypokalemia, which may be severe, resulting from increased urinary potassium losses
These data on tubular dysfunction come predominantly from pediatric patients treated with ifosfamide. There are few data on long-term kidney function in adults who have received ifosfamide. However, a persistent decline in glomerular filtration rate (GFR) over time has been described after as little as one course of ifosfamide in adults [23]. Nephrotoxicity due to ifosfamide is discussed in detail elsewhere. (See "Ifosfamide nephrotoxicity".)
Pre-existing kidney disease is a risk factor for ifosfamide nephrotoxicity. Guidelines for dose reduction based upon kidney function are available from expert groups, although they differ markedly:
●The United States Prescribing Information for ifosfamide does not contain specific dose adjustment guidelines, citing the lack of formal studies conducted in patients with kidney impairment. However, patients with kidney impairment should be closely monitored for toxicity, with consideration of dose reduction.
●Kintzel suggests the following [18]:
•CrCl 46 to 60 mL/min – 20 percent dose reduction
•CrCl 31 to 45 mL/min – 25 percent dose reduction
•CrCl <30 mL/min – 30 percent dose reduction
●By contrast, Aronoff suggests reducing the dose by 25 percent only in patients with CrCl <10 mL/min [10].
●Others suggest a 25 percent dose reduction for CrCl 10 to 50 mL/min and a 50 percent dose reduction for CrCl <10 mL/min [24].
●Guidelines from Cancer Care Ontario recommend a 25 percent dose reduction for CrCl 40 to 60 mL/min, a 50 percent dose reduction for CrCl 20 to 40 mL/min, and that the drug be discontinued for CrCl <10 mL/min.
Ifosfamide is dialyzable, and it should be administered after hemodialysis with a 50 percent dose reduction [24,25]. A 50 percent dose reduction is also suggested for patients on peritoneal dialysis [24].
Melphalan — Melphalan is an alkylating agent that is used mainly for the treatment of multiple myeloma. Melphalan has been associated with the development of SIADH [26,27]. (See "Pathophysiology and etiology of the syndrome of inappropriate antidiuretic hormone secretion (SIADH)".)
Although the drug is mostly metabolized by the liver, 10 to 30 percent is excreted unchanged in the urine.
Recommendations from expert groups for dose reduction in the setting of kidney insufficiency differ:
●The United States Prescribing Information for IV melphalan suggests a 50 percent dose reduction in patients with kidney insufficiency (defined only as a blood urea nitrogen [BUN] ≥30 mg/dL).
●Others recommend that the dose of IV melphalan used as a conditioning regimen for hematopoietic cell transplantation be reduced from 200 to 140 mg/m2 in patients with serum creatinine >2 mg/dL (177 micromol/L) [28].
●Another guideline recommends a 25 percent dose reduction in IV melphalan for CrCl 10 to 50 mL/min and a 50 percent dose reduction for CrCl <10 mL/min [24].
●Aronoff recommends the following dose modification for oral melphalan [10]:
•CrCl 10 to 50 mL/min – 25 percent dose reduction.
•CrCl <10 mL/min – 50 percent dose reduction.
●Other clinicians recommend a 25 percent dose reduction for oral melphalan in patients with multiple myeloma and a serum creatinine concentration above 2 mg/dL (177 micromol/L) to prevent severe myelotoxicity [29].
●Another guideline recommends a decrease in the initial oral melphalan dose from 6 mg once daily to 4 mg once daily in patients with CrCl 10 to 50 mL/min and a decrease in dose from 6 mg daily to 3 mg daily in those with CrCl <10 mL/min [24].
●Guidelines from Cancer Care Ontario recommend dose reduction for both oral and IV melphalan as follows:
•CrCl 10 to 50 mL/min – 25 percent dose reduction
•CrCl <10 mL/min – 50 percent dose reduction
Melphalan is dialyzable. Some recommend administering one-half of the usual dose after dialysis in patients undergoing hemodialysis and in those undergoing peritoneal dialysis [24]. Experience with high-dose IV melphalan in patients on dialysis is limited [30].
Nitrosoureas — A slowly progressive, chronic interstitial nephritis that is generally irreversible can be induced by prolonged therapy with the nitrosoureas carmustine (BiCNU), lomustine (CCNU), and streptozocin [31,32]. Although the exact mechanism of nephrotoxicity is not completely elucidated, these agents may produce nephrotoxicity through alkylation of tubular cell proteins. Their metabolites, which are thought to be responsible for nephrotoxicity, persist in the urine for up to 72 hours following administration [33].
Although the primary dose-limiting toxicity of carmustine is pulmonary injury, it has been associated with kidney insufficiency in several reports [34]. Histologic changes include mild interstitial infiltrates and tubular changes. (See "Nitrosourea-induced pulmonary injury".)
Streptozocin, a non-myelosuppressive nitrosourea, has been associated with nephrotoxicity in up to 75 percent of patients treated for prolonged periods of time. Although nephrotoxicity is not necessarily dose related, it is rare in patients treated with <1 to 1.5 g/m2 per week [35]. Streptozocin damages the kidney tubules, causing atrophy and tubulointerstitial nephritis [36]; other case reports describe uric acid nephrolithiasis and acute kidney injury [37], and diabetes insipidus [38] following streptozocin.
Mild proteinuria or an asymptomatic elevation in the plasma creatinine concentration is usually the first sign of kidney involvement, followed by signs of proximal tubular damage (eg, phosphaturia, glycosuria, aminoaciduria, uricosuria, and bicarbonaturia). In one study of 52 patients treated for advanced islet cell carcinoma, the most common sign of nephrotoxicity was proteinuria (51 percent), followed by renal tubular acidosis (17 percent), Fanconi syndrome (13 percent), and azotemia (26 percent) [39]. Nephrotoxicity contributed to death in 11 percent of treated patients.
The onset of clinical nephrotoxicity may be delayed from several months to as long as several years after nitrosoureas have been discontinued. As a result, careful long-term follow-up is essential. If it develops, nephrotoxicity typically persists for approximately two to three weeks after the drug is stopped. There is no known therapy for this disorder once it has begun. It has been suggested, however, that the nephrotoxicity can be diminished by the use of forced diuresis (2 liters of isotonic saline per hour for two hours) when the drug is being given [40].
Little published information is available to guide dosing of nitrosoureas in patients with kidney impairment. The United States Prescribing Information does not contain dosing adjustments for any of these drugs in the setting of pre-existing kidney insufficiency.
Guidelines are available from several groups, although they differ:
●Aronoff recommends the following modification scheme for streptozocin and lomustine [10]:
•CrCl 10 to 50 mL/min – 25 percent dose reduction
•CrCl <10 mL/min – 50 to 75 percent dose reduction
●Guidelines from Cancer Care Ontario recommend:
For streptozocin:
•Pre-existing kidney impairment:
-Drug is contraindicated
•Kidney impairment during therapy:
-CrCl 10 to 50 mL/min – 25 percent dose reduction
-CrCl <10 mL/min – Avoid or treat with caution at a reduced dose
For lomustine:
•CrCl 10 to 50 mL/min – 25 percent dose reduction
•CrCl <10 mL/min – 50 percent dose reduction
In patients with ESKD, there are no guidelines for the dosing of streptozocin. For lomustine, some clinicians recommend a 50 to 75 percent dose reduction in patients undergoing hemodialysis or peritoneal dialysis [24].
Temozolomide — Temozolomide is an orally active alkylating agent with efficacy in brain tumors. Patients with mild to moderate kidney dysfunction have similar pharmacokinetics compared with those who have normal function, although patients with severe kidney dysfunction have not been studied [41]. The United States Prescribing Information for temozolomide does not provide guidance for dose reduction in the setting of pre-existing kidney insufficiency or for patients undergoing dialysis. Guidelines from Cancer Care Ontario suggest close monitoring of patients with severe kidney impairment, with consideration given to dose modification.
Experience with temozolomide in patients undergoing hemodialysis is very limited [42].
Trabectedin — Trabectedin is a marine-derived alkylating agent that is approved for treatment of advanced soft tissue sarcoma. Cases of kidney failure (occasionally fatal) have been reported, some of which are attributable to rhabdomyolysis [43-47].
According to the United States Prescribing Information, dose adjustment is not needed for CrCl ≥30 mL/min; there is no dose adjustment provided for more severe kidney insufficiency as dosing has not been specifically studied in this population. Guidelines from Cancer Care Ontario recommend that the drug not be used in patients with CrCl <30 mL/min. Neither hemodialysis nor peritoneal dialysis enhances elimination of trabectedin [48,49].
ANTIMETABOLITES — The elimination of many antimetabolites, including capecitabine, methotrexate, fludarabine, and pentostatin, is at least partially dependent upon kidney function. Of the clinically useful antimetabolites, only methotrexate is associated with significant kidney toxicity.
Capecitabine — In contrast to fluorouracil, which is cleared through nonrenal mechanisms and therefore does not require dose adjustment in patients with kidney dysfunction, systemic exposure to the oral fluoropyrimidine capecitabine is higher in patients with moderate (creatinine clearance [CrCl] 30 to 50 mL/min) and severe (CrCl <30 mL/min) kidney impairment. The United States Prescribing Information for capecitabine suggests a 25 percent dose reduction in patients with CrCl 30 to 50 mL/min and that the drug is contraindicated in those with more severe kidney impairment. The same recommendation is made in guidelines from Cancer Care Ontario.
However, these recommendations were based upon a single phase II trial that included a total of four patients with severe kidney impairment (glomerular filtration rate [GFR] <30 mL/min) [50]; among these patients, there was a high rate of grade 3 or 4 adverse events, which led to a shorter than expected duration of treatment. Some suggest that with close monitoring and dose modification based upon the incidence and severity of adverse events, capecitabine can be safely administered to patients with severe renal impairment, including those on hemodialysis, if there is no safe alternative to its use. One study retrospectively evaluated the use of capecitabine in 12 patients with CrCl <30 mL/min or end-stage kidney disease (ESKD) on dialysis [51]; with reductions of up to 50 percent of the starting dose in patients who developed adverse effects, the drug was well tolerated. Support for the safety of an initial 50 percent dose reduction for individuals on hemodialysis is also provided by a second case series [52]. For patients undergoing dialysis, the drug should be given afterward.
Clofarabine — Clofarabine is a purine nucleoside analog that exerts its antineoplastic effect by inhibiting DNA synthesis and the enzyme ribonucleotide reductase. It is approved for acute lymphoblastic leukemia in children, and it is also being used for relapsed or refractory acute myeloid leukemia and acute lymphoblastic leukemia in adults. (See "Treatment of relapsed or refractory acute lymphoblastic leukemia in adults", section on 'Clofarabine' and "Treatment of relapsed or refractory acute myeloid leukemia", section on 'Remission re-induction'.)
Two case reports describe severe kidney injury shortly after drug administration; one patient was found to have 4 g of proteinuria, and the other developed anuria and required dialysis [53,54]. No biopsy data exist to help propose a mechanism of injury in these patients, but ribonucleoside reductase may be contributing to podocyte injury and the development of proteinuria [53].
The magnitude of nephrotoxicity risk is unclear. In one study, the risk of acute kidney injury (AKI) was as high as 55 percent following use of clofarabine in patients undergoing hematopoietic cell transplantation [55]. Age was the strongest predictor of AKI. The area under the curve of concentration X time (AUC, mg/mL x min) was higher in patients who developed AKI; those with the highest dose-normalized AUCs experienced the most severe grades of AKI. One of those patients had a kidney biopsy that showed acute toxic tubular necrosis as the likely mechanism of injury.
Kidney insufficiency increases drug exposure, which might worsen treatment-related toxicity [56,57]. The United States Prescribing Information for clofarabine suggests a 50 percent dose reduction for patients with a baseline CrCl of 30 to 60 mL/min. There is insufficient information for dose recommendations in patients with CrCl <30 mL/min or on hemodialysis. Clofarabine has not been well studied in patients undergoing dialysis; there is one case report suggesting that the drug is not dialyzable [58].
For patients who develop grade 3 or higher increases in creatinine during treatment (table 2), the United States Prescribing Information recommends discontinuing the drug and reinitiating it with a 25 percent dose reduction after kidney function has stabilized. Guidelines are not available from Cancer Care Ontario.
Cytarabine — Cytarabine is used for the treatment of acute leukemia and intrathecally for treatment and prophylaxis of meningeal leukemia. The drug is predominantly excreted in the urine as an inactive metabolite. The United States Prescribing Information for cytarabine does not contain renal dose adjustment guidelines. However, guidelines are available from others suggesting dose reduction in the setting of kidney impairment for patients receiving high-dose cytarabine (eg, from 3 to 2 g/m2 or schedule modification from every 12 to every 24 hours) [18,59]. Guidelines from Cancer Care Ontario suggest the need for dose reduction if CrCl is <60 mL/min. Cytarabine has not been well studied in patients undergoing dialysis.
Fludarabine and cladribine — Fludarabine and cladribine have not been associated with kidney dysfunction except in the context of tumor lysis syndrome. (See "Tumor lysis syndrome: Pathogenesis, clinical manifestations, definition, etiology and risk factors", section on 'Hematologic malignancies'.)
Approximately one-half of each administered dose of fludarabine is excreted in the urine [60]. Specific dose adjustment guidelines are available from a number of groups, all of which differ substantially:
●The United States Prescribing Information for fludarabine recommends a 20 percent dose reduction for CrCl 30 to 70 mL/min and that the drug not be administered for more severe kidney insufficiency.
●Cancer Care Ontario recommends a 50 percent dose reduction for CrCl 30 to 70 mL/min and that the drug not be used for CrCl <30 mL/min.
●Aronoff suggests a 25 percent dose reduction for CrCl 10 to 50 mL/min and a 50 percent dose reduction for CrCl <10 mL/min [10].
●Others suggest a 20 percent dose reduction for CrCl 50 to 79 mL/min, a 40 percent dose reduction for CrCl 30 to 49 mL/min, and that the drug be avoided for CrCl <30 mL/min [24].
Twenty to 35 percent of each dose of cladribine is excreted in the urine [61], but there are no available data upon which to base a recommendation for dose modification in patients with kidney insufficiency. Recommendations from expert groups are variable:
●Guidelines are not provided in the United States Prescribing Information for cladribine.
●Aronoff recommends a 25 percent dose reduction for patients with CrCl 10 to 50 mL/min and a 50 percent dose reduction for CrCl <10 mL/min [10].
●Cancer Care Ontario recommends a 25 percent dose reduction for CrCl 10 to 50 mL/min and a 50 percent reduction for CrCl ≤10 mL/min.
●Others suggest a 30 percent dose reduction for CrCl 10 to 50 mL/min and a 50 percent dose reduction for CrCl <10 mL/min [24].
There are no recommendations for either drug in patients undergoing hemodialysis. In patients undergoing peritoneal dialysis, some clinicians recommend a 50 percent dose reduction for fludarabine and cladribine [10,24].
Gemcitabine — Gemcitabine is a cell cycle-specific pyrimidine antagonist; the most common form of kidney toxicity is AKI with microangiopathic hemolytic anemia (thrombotic microangiopathy [TMA], previously referred to as thrombotic thrombocytopenic purpura/hemolytic uremic syndrome [TTP-HUS]) [62-64]. The incidence ranges from 0.015 to 1.4 percent, and in some reports (but not others [65]), risk is highest in those who have received cumulative gemcitabine doses over 20,000 mg/m2 [64]. Prior therapy with mitomycin C may be a risk factor for the development of TMA [63].
This diagnosis should be considered in a patient who develops Coombs-negative hemolytic anemia, thrombocytopenia, AKI, and/or neurologic findings while receiving gemcitabine. Drug discontinuation is recommended if this occurs. (See "Drug-induced thrombotic microangiopathy (DITMA)", section on 'Cancer therapies'.)
Although patients with elevated creatinine levels may have greater than expected toxicity from gemcitabine, even at reduced doses [66], a dose modification scheme based upon preexisting kidney dysfunction has not been developed. The United States Prescribing Information for gemcitabine does not provide guidance for dose reduction in the setting of pre-existing significant kidney dysfunction. Cancer Care Ontario guidelines state only that gemcitabine should be used with caution in patients with kidney insufficiency.
Retrospective reports suggest that administration of gemcitabine is feasible in patients with ESKD on hemodialysis. While gemcitabine removal by hemodialysis has never been studied, its inactive metabolite difluorodeoxycytidine is removed by hemodialysis [67]. Guidelines suggest that hemodialysis be initiated 6 to 24 hours after each dose of gemcitabine [12,68]. Patients receiving long-term hemodialysis may be at a higher risk of developing significant gemcitabine-related hematological toxicity. There are no available data or dosing guidelines for patients undergoing peritoneal dialysis.
Hydroxyurea — Hydroxyurea is used for treatment of non-chronic myelogenous leukemia (CML) myeloproliferative disorders and in patients with sickle cell anemia to reduce the frequency of painful crises and the need for blood transfusions. (See "Hydroxyurea use in sickle cell disease" and "Prognosis and treatment of polycythemia vera and secondary polycythemia", section on 'Hydroxyurea' and "Prognosis and treatment of essential thrombocythemia", section on 'Hydroxyurea' and "Management of primary myelofibrosis", section on 'Hydroxyurea'.)
Approximately 40 to 50 percent of the drug is excreted renally [69,70], and dose reductions are needed in patients with kidney dysfunction. Recommendations from expert groups are variable:
●The United States Prescribing Information for hydroxyurea suggests a 50 percent dose reduction for individuals with CrCl <60 mL/min or for those with ESKD who are undergoing hemodialysis, regardless of the intent of therapy. On dialysis days, administer hydroxyurea after dialysis.
●Cancer Care Ontario guidelines for use of hydroxyurea in malignant disease suggest a 50 percent reduction in the initial dose for patients with CrCl 10 to 60 mL/min and that the drug be discontinued for CrCl <10 mL/min.
●Others suggest an alternative dose reduction schema for patients with malignant disease, with a 50 percent dose reduction for CrCl 10 to 50 mL/min and an 80 percent dose reduction for CrCl <10 mL/min or those with ESKD who are on hemodialysis (with administration after dialysis) or peritoneal dialysis [10,24].
For patients receiving hydroxyurea, serum creatinine should be periodically reassessed during treatment. A point-of-care device for measuring serum creatinine (the i-STAT system) that is used for routine testing in some clinical laboratories can give a falsely elevated creatinine measurement [8]. Thus, individuals treated with hydroxyurea who have high serum creatinine should be retested using a different method to distinguish this artifact from true kidney disease. (See "Hydroxyurea use in sickle cell disease", section on 'Falsely elevated serum creatinine and other laboratory tests'.)
Methotrexate — Methotrexate at doses less than 0.5 to 1 g/m2 is usually not associated with kidney toxicity unless underlying kidney dysfunction is present. By contrast, high-dose intravenous methotrexate (1 to 15 g/m2) can precipitate in the tubules and induce tubular injury; at particular risk are patients who are volume depleted and those who excrete acidic urine. Maintenance of adequate urinary output and alkalinization will lessen the probability of methotrexate precipitation. This topic is discussed in detail elsewhere. (See "Therapeutic use and toxicity of high-dose methotrexate", section on 'Renal toxicity' and "Crystal-induced acute kidney injury", section on 'Methotrexate'.)
Methotrexate can also produce a transient decrease in GFR, with complete recovery within six to eight hours of discontinuing the drug. The mechanism responsible for this functional kidney impairment involves afferent arteriolar constriction or mesangial cell constriction that produces reduced glomerular capillary surface area and diminished glomerular capillary perfusion and pressure [71]. Methotrexate has also been associated with the syndrome of inappropriate antidiuretic hormone secretion (SIADH). (See "Pathophysiology and etiology of the syndrome of inappropriate antidiuretic hormone secretion (SIADH)".)
Methotrexate excretion is decreased in patients who have kidney insufficiency, and higher levels of bone marrow and gastrointestinal toxicity may result [72]. Patients with ileal conduits and those with third-space fluid collections (eg, ascites, pleural effusion) may also experience greater methotrexate toxicity, particularly if their CrCl is low [73]. For patients with an ileal conduit, the mechanism is thought to be increased reabsorption of excreted drug through the mucosa of the conduit [74,75].
Guidelines from expert groups for dose modification of methotrexate in the setting of kidney insufficiency differ:
●The United States Prescribing Information for methotrexate does not contain recommended dose adjustments for kidney insufficiency, stating only that serum creatinine must be normal and CrCl must be >60 mL/min prior to initiation of treatment. However, dose modification guidelines have been proposed by several clinical groups [10,18]. As examples:
•For adults, Aronoff recommends a 50 percent dose decrease in patients with CrCl 10 to 50 mL/min and that the drug be avoided in patients with worse kidney function [10].
•Cancer Care Ontario guidelines suggest a 25 percent dose reduction for CrCl 80 mL/min, a 40 percent dose reduction for CrCl 60 mL/min, a 50 percent dose reduction for CrCl 50 mL/min, and that the drug be discontinued for CrCl <50 mL/min. They also state that less conservative dose modification could be considered for low-dose regimens (<50 mg/m2) and that high-dose methotrexate should only be administered if the CrCl is >60 mL/min.
Drug removal by hemodialysis is incomplete since methotrexate is protein bound and therefore not readily dialyzable [76-78]. However, methotrexate can be removed by hemodialysis, especially when using high-flux hemodialysis membranes. (See "Crystal-induced acute kidney injury", section on 'Methotrexate'.)
For patients who are receiving low-dose oral methotrexate and are undergoing hemodialysis or peritoneal dialysis, some suggest a 50 to 75 percent dose reduction [10,24] and that the drug be administered after dialysis. Most guidelines suggest avoidance of methotrexate in the setting of dialysis [12].
Pemetrexed — Pemetrexed is a derivative of methotrexate that is approved for treatment of advanced non-small cell lung cancer and pleural mesothelioma. (See "Systemic treatment for unresectable malignant pleural mesothelioma" and "Systemic chemotherapy for advanced non-small cell lung cancer", section on 'Initial chemotherapy regimen'.)
Pemetrexed has been associated with kidney damage (including acute tubular necrosis, interstitial edema, renal tubular acidosis, and diabetes insipidus) [79-81]. The risk of AKI is thought to be low (1 to 5 percent in some clinical studies according to the United States Prescribing Information), but higher risks have been reported by others (21 to 54 percent), mainly in patients with non-small cell lung cancer treated with combination chemotherapy that includes pemetrexed [81,82]. Baseline kidney impairment appears to be a risk factor for AKI [81,82]. Some cases may not be reversible [81-83].
Pemetrexed is primarily excreted unchanged by renal excretion. Dose adjustment is not necessary in patients with CrCl ≥45 mL/min [84]. Data in patients with more severe kidney impairment are limited; however, a pharmacokinetic/pharmacodynamics modeling analysis concluded that severe kidney impairment was associated with a high rate of neutropenia, despite dose individualization based on kidney function [85]. The United States Prescribing Information for pemetrexed recommends that the drug not be used in patients with CrCl <45 mL/min. Furthermore, there are recommendations for avoidance of nonsteroidal anti-inflammatory drugs in the days prior to and immediately following each dose of pemetrexed in patients with mild to moderate kidney impairment (CrCl 45 to 79 mL/min) because of the potential for decreased clearance of pemetrexed. Similar guidelines are available from others [24,86], including Cancer Care Ontario.
There are no data on the use of pemetrexed in patients undergoing hemodialysis or peritoneal dialysis, and specific recommendations are not available from any group.
Pentostatin — Pentostatin is used for treatment of hairy cell and other leukemias, and for treatment of acute graft-versus-host disease. (See "Treatment of hairy cell leukemia", section on 'Pentostatin' and "Treatment of T cell prolymphocytic leukemia" and "Treatment of acute graft-versus-host disease", section on 'Pentostatin'.)
Approximately 90 percent of each dose is excreted in the urine [87]. The United States Prescribing Information for pentostatin does not contain dose adjustment guidelines for patients with kidney insufficiency, stating only that there are insufficient data to recommend a starting or subsequent dose for patients with CrCl <60 mL/min. However, others suggest a 50 percent dose reduction for patients with CrCl <60 mL/min [18,24,88,89].
Pralatrexate — Pralatrexate is an antifolate used for the treatment of relapsed or refractory peripheral T cell lymphoma. (See "Treatment of relapsed or refractory peripheral T cell lymphoma", section on 'Pralatrexate'.)
Pralatrexate is partially excreted in the urine [90]. The available evidence suggests that drug exposure in patients with mild to moderate kidney impairment is similar to that in patients with normal kidney function [91]. The United States Prescribing Information suggests a reduced dose for patients with severe kidney impairment (CrCl <30 mL/min/1.73 m2). There are no data on the use of pralatrexate in patients undergoing hemodialysis or peritoneal dialysis, and specific recommendations are not available from any group.
ANTIMICROTUBULE AGENTS
Taxanes — The taxanes paclitaxel and docetaxel undergo minimal renal excretion. The limited data indicate that both can be safely administered to patients with kidney insufficiency and that dose modification is not required [10]. Both paclitaxel [92-95] and docetaxel [96] have been administered safely at standard doses to patients on chronic peritoneal or hemodialysis, although some guidelines suggest a dose reduction for docetaxel in patients undergoing hemodialysis [12].
Cabazitaxel is a new semisynthetic taxane. Cases of kidney failure were reported in a randomized trial conducted in men with metastatic prostate cancer, including four with a fatal outcome. Most occurred in association with sepsis, dehydration, or obstructive uropathy. Hemorrhagic cystitis has also been reported. (See "Chemotherapy in advanced castration-resistant prostate cancer", section on 'Men who have received prior docetaxel' and "Chemotherapy and radiation-related hemorrhagic cystitis in cancer patients", section on 'Chemotherapy'.)
There are no guidelines for cabazitaxel dose reduction in patients with mild to moderate kidney insufficiency. In population-based pharmacokinetic trials, there was no difference in clearance in patients with mild or moderate kidney insufficiency (creatinine clearance [CrCl] <80 but >30 mL/min) [97]. The United States Prescribing Information recommends no dose adjustment for patients not requiring hemodialysis, and careful monitoring during treatment in patients with end-stage kidney disease (ESKD; CrCl <15 mL/min/1.73m2). Guidelines from Cancer Care Ontario suggest discontinuation of therapy for CrCl <15 mL/min.
Vinca alkaloids — Vincristine, vinblastine, and vinorelbine have all been associated with the syndrome of inappropriate antidiuretic hormone secretion (SIADH) in a small number of treated patients [98,99]. (See "Pathophysiology and etiology of the syndrome of inappropriate antidiuretic hormone secretion (SIADH)".)
All three drugs are mainly eliminated through hepatic metabolism, with a minority of the dose (8 to 20 percent) recovered in the urine. Both the United States Prescribing Information and guidelines from Cancer Care Ontario indicate that dose reduction is not needed for patients with kidney insufficiency who are not undergoing dialysis. However, a lower starting dose of vinorelbine has been suggested by some authors in patients with ESKD who are undergoing hemodialysis [12].
Eribulin — Eribulin mesylate, a synthetic analogue of halichondrin B (a substance derived from a marine sponge), inhibits the polymerization of tubulin and microtubules. It is used for the treatment of advanced breast cancer and soft tissue sarcoma.
Less than 10 percent of the drug is excreted in the urine. Formal pharmacokinetic trials have not been conducted in patients with kidney impairment. However, the United States Prescribing Information for eribulin recommends a lower starting dose in patients with moderate or severe kidney insufficiency (CrCl 15 to 49 mL/min). Cancer Care Ontario guidelines recommend a lower starting dose in patients with CrCl 15 to 50 mL/min and that the drug be avoided in patients with ESKD (CrCl <15 mL/min). Others suggest that the drug be avoided in individuals with CrCl <30 mL/min [24].
ANTITUMOR ANTIBIOTICS
Anthracyclines and related agents — Anthracyclines such as daunorubicin and doxorubicin have been known to cause nephrotic syndrome with kidney lesions consistent with minimal change disease, focal segmental glomerular sclerosis not otherwise specified (NOS), or collapsing glomerulopathy [100]. In addition, pegylated liposomal doxorubicin has been associated with renal thrombotic microangiopathy, nephrotic syndrome, and acute kidney injury [101-103]. (See "Drug-induced thrombotic microangiopathy (DITMA)", section on 'Cancer therapies'.)
Doxorubicin, epirubicin, mitoxantrone, and daunorubicin, as well as their major metabolites, are excreted mainly through the bile and, to a lesser extent, by urinary excretion. Although Aronoff recommends no dose reduction for epirubicin or any other anthracycline in patients with kidney failure [10], others disagree:
●The United States Prescribing Information recommends that lower doses of epirubicin be considered in patients with severe kidney impairment (serum creatinine >5 mg/dL). A 50 percent dose reduction is also recommended for daunorubicin in patients with serum creatinine >3 mg/dL.
●Guidelines from Cancer Care Ontario recommend a 50 percent dose reduction for both epirubicin and daunorubicin if the creatinine is greater than two times the upper limit of normal (ULN).
Although experience is limited, some suggest that dose adjustment is not needed for doxorubicin or epirubicin in patients undergoing hemodialysis or peritoneal dialysis, and that administration should follow hemodialysis [10,12].
Bleomycin — Kidney toxicity is not described as a complication of bleomycin therapy. However, kidney insufficiency is known to alter bleomycin elimination, particularly in patients with creatinine clearance [CrCl] <25 to 35 mL/min, increasing the likelihood of treatment-related toxicity, particularly pulmonary toxicity [104-106]. (See "Bleomycin-induced lung injury", section on 'Dose and renal insufficiency'.)
Few patients with kidney impairment receiving bleomycin have been studied [21,107]; however, dose reduction guidelines are available from several groups:
●The United States Prescribing Information specifies a dose reduction schema for patients with CrCl <50 mL/min.
●Aronoff suggests a 25 percent dose reduction for patients with CrCl 10 to 50 mL/min and a 50 percent reduction for CrCl <10 mL/min [10]. These guidelines are endorsed by Cancer Care Ontario.
Specific guidelines are not available for patients undergoing hemodialysis or peritoneal dialysis.
Mitomycin — There is a possible association of mitomycin with drug-induced thrombotic microangiopathy that has not been definitively established. This subject is discussed in detail elsewhere. (See "Drug-induced thrombotic microangiopathy (DITMA)", section on 'Cancer therapies'.)
Less than 20 percent of mitomycin is excreted in the urine [18]. Mitomycin can be administered to patients with kidney insufficiency, with close monitoring for signs and symptoms of acute kidney injury. Guidelines differ for dose reduction in the setting of pre-existing kidney impairment:
●The United States Prescribing Information states to avoid use in patients with serum creatinine >1.7 mg/dL, but it offers no other dose adjustment guidelines.
●Aronoff recommends a dose reduction of 25 percent only for patients with CrCl <10 mL/min [10].
●Cancer Care Ontario recommends that the drug be withheld for serum creatinine >150 micromol/L (1.7 mg/dL) or in patients with moderate to severe kidney impairment.
There are no specific dosing guidelines in patients undergoing hemodialysis. Some clinicians recommend a 25 percent dose reduction in patients undergoing peritoneal dialysis [10].
PLATINUM AGENTS
Cisplatin — Cisplatin is one of the most commonly used antineoplastic drugs, and it is also one of the most nephrotoxic. Cisplatin is associated with acute kidney injury (AKI), thrombotic microangiopathy (TMA), hypomagnesemia, proximal tubular dysfunction (ie, Fanconi-like syndrome), and anemia that is out of proportion to the drug's myelosuppressive effects. Hydration is essential for all patients to prevent cisplatin-induced nephrotoxicity [108]. Cisplatin-induced kidney insufficiency is discussed in detail elsewhere. (See "Cisplatin nephrotoxicity".)
The optimal approach to cisplatin therapy in patients with pre-existing kidney impairment or persistent kidney impairment during therapy is unknown. Clinical trial protocols often require a serum creatinine of less than 2 mg/dL (177 micromol/L) or a creatinine clearance (CrCl) of ≥60 mL/min for administration of the full dose of cisplatin, and they exclude patients with more significant kidney impairment [109]. This restriction is probably related more to concerns regarding increased nonrenal toxicity (ototoxicity, neuropathy) than to an increased risk of AKI.
The United States Prescribing Information for cisplatin recommends that repeat courses of cisplatin not be given unless or until serum creatinine is <1.5 mg/dL and/or blood urea nitrogen (BUN) is <25 mg/dL; there are no suggested renal dose adjustment guidelines.
Empiric guidelines have suggested that cisplatin can be administered at a reduced dose to patients with kidney impairment, although extensive data supporting such recommendations are lacking and specific recommendations differ [10,18]:
●Kintzel suggests a 25 percent dose reduction for CrCl 46 to 60 mL/min and a 50 percent dose reduction for CrCl 30 to 45 mL/min [18]. These guidelines are endorsed by Cancer Care Ontario.
●Aronoff suggests that cisplatin can be administered to patients with even more severe kidney impairment, recommending a 25 percent dose reduction for CrCl 10 to 50 mL/min and a 50 percent dose reduction in those with CrCl <10 mL/min [10].
Although the available data are scant and predominantly comprised of single case reports, cisplatin-containing chemotherapy combinations have been successfully administered to patients undergoing hemodialysis [12,110-112]. One guideline suggests that such patients have a 50 to 75 percent reduction in dose and that the drug be administered after hemodialysis [12]. A 50 percent dose reduction is also recommended for patients undergoing peritoneal dialysis [10,24].
Carboplatin — In both experimental and clinical studies, carboplatin is significantly less nephrotoxic than cisplatin [113,114]. This increase in safety may reflect the enhanced stability of carboplatin, which has carboxylate and cyclobutane moieties in the cis position rather than chloride [114]. Hypomagnesemia appears to be the most common manifestation of nephrotoxicity, although it occurs less often than with cisplatin [115,116]. (See "Cisplatin nephrotoxicity".)
AKI has been reported, particularly in patients previously treated with several courses of cisplatin [114]. Direct tubular injury leading to acute tubular necrosis is the primary mechanism. A less common renal side effect is renal magnesium wasting [117,118].
AUC dose calculation — The importance of renal clearance to the metabolism and excretion of carboplatin is emphasized by its usual dosing schema, which is based upon an estimate of the glomerular filtration rate (GFR) and the desired level of drug exposure according to the area under the curve of concentration X time (AUC, mg/mL x min), rather than the more common dosing calculation based upon body surface area (mg/m2).
Using the desired target AUC (which typically varies between 5 and 7 mg/mL x min) and the estimated GFR, the dose of carboplatin is then calculated using the Calvert formula: total carboplatin dose (mg) = target AUC x (estimated CrCl + 25). Because of potential changes in weight or kidney function, this calculation should be repeated prior to each administered course of carboplatin.
The following issues are relevant to the carboplatin dose calculation:
●Total carboplatin dose is calculated in mg, not mg/m2.
●Maximum GFR – When using an estimate instead of a direct measurement of GFR to calculate the carboplatin dose using the Calvert formula, calibration of the creatinine assay may impact dosing. In the United States, as of the end of 2010, all laboratories must use a creatinine method that has calibration that is traceable to an Isotope Dilution Mass Spectrometry (IDMS) reference measurement procedure [119]. However, this gives lower creatinine results than the older measurements, and hence, higher estimates of GFR. This could result in higher calculated carboplatin doses and may potentially result in increased toxicities. The US Food and Drug Administration (FDA) recommends limiting the maximal GFR for the calculation to 125 mL/min [120], thereby capping the carboplatin dose for a desired AUC.
●Obese patients – Another point of unresolved controversy is the appropriate weight to use when calculating estimated GFR. The original Cockcroft-Gault formula to estimate GFR used actual body weight, but none of the patients was obese. Most clinicians use actual body weight in the Cockcroft-Gault formula for nonobese patients, although institutional practice varies. However, the use of actual body weight in the Cockcroft-Gault calculation can result in an overestimate of GFR and a higher than needed carboplatin dose in obese individuals [121]. The United States Gynecologic Oncology Group (GOG) recommends that actual weight be used for estimation of GFR when using the Cockcroft-Gault equation as long as patients have a body mass index (BMI) of <25 (calculator 4). For other patients, use of an adjusted weight is suggested (adjusted weight [kg] = [(actual weight - ideal weight) x 0.40] + ideal weight). A calculator for ideal body weight is available (calculator 5).
These issues are all discussed in greater detail elsewhere. (See "Dosing of anticancer agents in adults", section on 'AUC-based dosing'.)
Not all carboplatin-containing regimens use AUC-based dosing. For carboplatin dosed on an mg/m2 basis, the United States Prescribing Information for carboplatin suggests the following dose reduction schema based upon kidney function:
●CrCl 41 to 59 mg/dL – Reduce initial dose from 300 to 360 mg/m2 to 250 mg/m2
●CrCl 16 to 40 mg/dL – Reduce initial dose to 200 mg/m2
●CrCl ≤15 mg/dL – Not recommended
Use in dialysis — Chemotherapy regimens incorporating carboplatin have been successfully used in patients undergoing hemodialysis [122-127]. Some authors recommend a total dose (in mg) of 25 x AUC and that the dose be administered after hemodialysis [12]. In patients on peritoneal dialysis, guidelines suggest a 75 percent dose reduction [10,24].
Oxaliplatin — In contrast to cisplatin and carboplatin, clinically significant kidney toxicity, such as acute tubular necrosis, is rare, although it does occur with the third-generation platinum compound oxaliplatin, sometimes in the setting of immune-mediated intravascular hemolysis [128-131]. Limited data with oxaliplatin suggest no exacerbation of pre-existing mild kidney impairment during treatment [132]. Oxaliplatin has been associated with TMA in rare single case reports. (See "Drug-induced thrombotic microangiopathy (DITMA)", section on 'Oxaliplatin'.)
Oxaliplatin is predominantly cleared by the kidneys [133]. Oxaliplatin doses up to 130 mg/m2 every three weeks have been well tolerated in patients with mild to moderate kidney dysfunction (CrCl >20 mL/min), and dose reduction appears not to be necessary in these patients [134]. The United States Prescribing Information for oxaliplatin suggests a reduced starting dose in patients with severe kidney impairment (CrCl <30 mL/min), while Cancer Care Ontario guidelines recommend avoiding the drug in such patients.
Some experts recommend a 30 percent dose reduction in patients undergoing hemodialysis [12], although others suggest that this is not necessary if hemodialysis is performed shortly after drug administration and the dosing interval is extended to three weeks [135]. There are no specific guidelines for dose modification in patients undergoing peritoneal dialysis.
MISCELLANEOUS CYTOTOXIC AGENTS
Arsenic trioxide — Arsenic trioxide is used for treatment of acute promyelocytic leukemia. (See "Initial treatment of acute promyelocytic leukemia in adults", section on 'ATO plus ATRA'.)
While toxic exposure to arsenic can lead to tubulointerstitial disease of the kidney and rhabdomyolysis [136], these are only rarely associated with the lower doses of arsenic trioxide used for cancer treatment [137]. (See "Arsenic exposure and poisoning".)
The metabolites of arsenic trioxide are primarily excreted in the urine. Drug exposure may be higher in patients with severe kidney impairment (creatinine clearance [CrCl] <30 mL/min) [138]. While the United States Prescribing Information for arsenic trioxide and Cancer Care Ontario guidelines provide no specific recommendations, both suggest that patients with CrCl <30 mL/min should be closely monitored for toxicity during treatment and that a dose reduction may be warranted. The use of this drug in patients on dialysis has not been studied.
Etoposide — Urinary excretion accounts for approximately 20 to 40 percent of each administered dose of etoposide [139]. Kidney insufficiency has been associated with increased exposure and higher levels of hematologic toxicity [140,141].
The United States Prescribing Information for etoposide recommends a 25 percent reduction if the CrCl is 15 to 50 mL/min, and that further dose reduction may be needed for more severe kidney dysfunction. Cancer Care Ontario guidelines are similar, although they recommend a 50 percent dose reduction or drug discontinuation if the CrCl is <15 mL/min.
Different guidelines are available from others:
●For adults, Aronoff recommends a 25 percent dose reduction with CrCl 10 to 50 mL/min and a 50 percent reduction for CrCl <10 mL/min [10].
●Kintzel recommends a 15 percent dose reduction for CrCl 46 to 60 mL/min, a 20 percent dose reduction for CrCl 31 to 45 mL/min, and a 25 percent dose reduction for CrCl ≤30 mL/min [18].
Several case reports note the safe use of etoposide in patients undergoing hemodialysis [111,126,142]. Available guidelines suggest a 50 percent dose reduction, with administration either before or after dialysis [10,12]. In patients undergoing peritoneal dialysis, some clinicians recommend a 50 percent dose reduction [24].
Irinotecan — After administration, irinotecan is enzymatically converted to an active metabolite, SN-38. Urinary excretion of irinotecan and SN-38 accounts for <20 percent of drug elimination [143].
There are conflicting data on whether irinotecan doses require modification in patients with kidney insufficiency. Whereas the kidneys are responsible for only a small fraction of drug clearance and only small amounts of irinotecan have been recovered in urine [144], several reports note excess toxicity in patients with end-stage kidney disease (ESKD), even with reduced doses [145-149]. Excess toxicity has been attributed to higher exposure to SN-38 [148].
There are no formal guidelines for dose reduction in the setting of kidney disease. Neither the United States Prescribing Information nor Cancer Care Ontario contains dose adjustment guidelines for patients with kidney insufficiency. The United States Prescribing Information states that irinotecan is not recommended for use in patients on dialysis. However, in such patients, a review of published cases suggests that weekly doses of 50 to 80 mg/m2 are generally tolerated, whereas even single doses of >125 mg/m2 have been associated with severe adverse events [148]. Largely based on this experience, some authors suggest that patients undergoing hemodialysis receive initial doses of 50 mg/m2 weekly, preferably after hemodialysis sessions or on nondialysis days [12]. There are no specific guidelines in patients undergoing peritoneal dialysis.
Topotecan — Topotecan is predominantly cleared by the kidneys, and increased toxicity may be seen in patients with moderate kidney insufficiency [10,150]. Specific guidelines for dose reduction from expert groups differ:
●The United States Prescribing Information for intravenous topotecan recommends a 50 percent reduction in the initial dose for CrCl 20 to 39 mL/min; there are insufficient data to provide a dose recommendation for those with more severe impairment. For oral topotecan, the United States Prescribing Information suggests a reduction in the initial dose from 2.3 mg/m2 per day to 1.5 mg/m2 per day for CrCl 30 to 49 mL/min and a reduction to 0.6 mg/m2 per day for CrCl <30 mL/min.
●Cancer Care Ontario guidelines suggest a 50 percent dose reduction for CrCl 20 to 39 mL/min and that the drug be avoided with more severe kidney impairment.
●For adults, Aronoff suggests a 50 percent dose reduction for patients with CrCl 10 to 50 mL/min and a 75 percent dose reduction for CrCl <10 mL/min [10]. Avoid use in hemodialysis patients and in those receiving continuous ambulatory peritoneal dialysis; give a reduced dose (0.75 mg/m2) for continuous renal replacement therapy. For children, a 25 percent dose reduction is recommended for CrCl 30 to 50 mL/min, a 50 percent dose reduction for CrCl 10 to 29 mL/min, and a 75 percent dose reduction for CrCl <10 mL/min. For continuous renal replacement therapy, give a 50 percent reduced dose.
●Kintzel recommends a 20 percent dose reduction for CrCl 46 to 60 mL/min, a 25 percent dose reduction for CrCl 31 to 45 mL/min, and a 30 percent dose reduction for CrCl ≤30 mL/min [18].
IMMUNOMODULATORY DRUGS — Immunomodulatory imide drugs (IMiDs), which include thalidomide, lenalidomide, and pomalidomide, are used for the treatment of relapsed or recurrent multiple myeloma, a disease that frequently is associated with kidney impairment. (See "Kidney disease in multiple myeloma and other monoclonal gammopathies: Etiology and evaluation" and "Multiple myeloma: Administration considerations for common therapies", section on 'Immunomodulatory drugs' and "Multiple myeloma: Treatment of first or second relapse", section on 'Lenalidomide sensitive'.)
Thalidomide — Thalidomide, a first-generation IMiD, is metabolized via nonenzymatic hydrolysis, and <1 percent of the unchanged drug is excreted in the urine [151]. In the initial report showing thalidomide activity against multiple myeloma, 8 out of 84 patients had a >50 percent increase in serum creatinine; however, the kidney injury was attributed to underlying disease progression and not drug-related toxicity [152]. In clinical practice, the use of thalidomide has not been associated with clinically significant acute kidney injury. However, there are reports of otherwise unexplained hyperkalemia in patients with myeloma treated with thalidomide [153,154].
Dose adjustment is not necessary for patients with kidney impairment, including those on dialysis. However, close monitoring of potassium levels is prudent for such individuals.
Lenalidomide — Lenalidomide is an analog of thalidomide that, in contrast to thalidomide, is predominantly excreted in the urine as unchanged drug. The half-life and area under the curve of concentration X time (AUC) for lenalidomide increase as creatinine clearance (CrCl) decreases [155]. As a result, patients with pre-existing kidney insufficiency are at risk for increased drug toxicity [156,157]. In one analysis of 72 patients with multiple myeloma who were treated with lenalidomide plus dexamethasone, individuals with CrCl <40 mL/min had an 8.4-fold higher likelihood of requiring a lenalidomide dose reduction for grade 3 or worse myelosuppression [156].
Cases of lenalidomide-induced acute kidney injury have been reported, including a case of biopsy-proven acute interstitial nephritis [158,159]. In a series of 41 patients with immunoglobulin light chain amyloidosis who were treated with lenalidomide, 27 (66 percent) developed kidney dysfunction (defined as a ≥50 percent increase in serum creatinine) during treatment, including four of the eight patients without underlying renal amyloidosis [160]. Severe kidney dysfunction occurred in 13 patients (32 percent), four of whom required dialysis. The median time to kidney dysfunction after starting lenalidomide was 44 days (interquartile range 15 to 108 days).
Other types of kidney injury have been reported, but they seem to be rare overall:
●At least one patient has developed Fanconi syndrome (generalized proximal tubular dysfunction characterized by phosphaturia, renal glucosuria, aminoaciduria, tubular proteinuria, and proximal renal tubular acidosis) while receiving lenalidomide [161].
●One patient has been described with acute interstitial nephritis and a drug reaction with eosinophilia, rash, and systemic symptoms (DRESS syndrome) [162]. (See "Drug reaction with eosinophilia and systemic symptoms (DRESS)".)
●A case of minimal change disease was reported in a patient with Waldenström macroglobulinemia being treated with lenalidomide [163].
●Lenalidomide has multiple immunomodulatory effects, and activation of the immune system may result in immune-mediated complications. As examples, there have been several case reports of acute allograft rejection after treatment with this drug [164-166]. (See "Kidney disease in multiple myeloma and other monoclonal gammopathies: Treatment and prognosis".)
The United States Prescribing Information for lenalidomide recommends the following dose reduction strategy for individuals treated for multiple myeloma or mantle cell lymphoma who have preexisting kidney disease, which have been externally validated [167]:
●CrCl 30 to 60 mL/min – Reduce the initial dose from 25 mg once daily to 10 mg once daily
●CrCl 15 to 30 mL/min – Reduce the initial dose to 15 mg once every other day
●CrCl <15 mL/min or end-stage kidney disease (ESKD) on dialysis – Reduce the initial dose to 5 mg once daily (on dialysis days, the dose should be administered after dialysis)
Separate guidelines are provided for patients receiving lenalidomide for treatment of myelodysplastic syndrome and for maintenance treatment of myeloma following autologous stem cell transplantation:
●CrCl 30 to 60 mL/min – 5 mg once daily
●CrCl 15 to 30 mL/min (nondialysis dependent) – 2.5 mg once daily
●CrCl <15 mL/min or dialysis dependent – 2.5 mg once daily (on dialysis days, the drug should be administered after dialysis)
These recommendations for lenalidomide dose reduction during treatment with lenalidomide plus dexamethasone for multiple myeloma are also endorsed by the International Myeloma Working Group (IMWG) [168] and Cancer Care Ontario.
Slightly different dose reduction guidelines are available from Cancer Care Ontario for patients receiving lenalidomide for myelodysplastic syndrome:
●CrCl 30 to 59 mL/min – 5 mg once daily
●CrCl <30 mL/min not requiring dialysis – 5 mg every other day
●CrCl <30 mL/min requiring dialysis – 5 mg three times a week following dialysis
There are no specific dosing guidelines for lenalidomide in patients on peritoneal dialysis.
Pomalidomide — Pomalidomide is a second-generation IMiD that is used for treatment of multiple myeloma and Kaposi sarcoma. (See "Classic Kaposi sarcoma: Clinical features, staging, diagnosis, and treatment", section on 'Pomalidomide' and "Multiple myeloma: Treatment of first or second relapse", section on 'Bortezomib, pomalidomide, dexamethasone (VPd)'.)
Pomalidomide is predominantly metabolized by the liver. In one of the three trials that evaluated its efficacy in multiple myeloma, the incidence of grade 3 to 4 kidney toxicity (table 2) was 5.9 percent [169]. In addition, a single case of acute kidney injury with crystal nephropathy was attributed to pomalidomide; however, the confounding factors included concurrent use of levofloxacin, which may have contributed to both the acute kidney injury and the crystal formation [170].
The United States Prescribing Information for pomalidomide provides no dose adjustments for patients with pre-existing kidney impairment, except for those on hemodialysis, who require initial dose reduction; on dialysis days, the drug should be administered after hemodialysis because exposure of pomalidomide could be significantly decreased during dialysis. The same recommendation is endorsed by Cancer Care Ontario. The IMWG recommends no dose adjustments for individuals with multiple myeloma and CrCl ≥45 mL/min but states that there are insufficient data for individuals with CrCl <45 mL/min [168].
PROTEASOME INHIBITORS — Proteasome inhibitors block the action of proteasomes, which are enzyme complexes responsible for the degradation of intracellular proteins. These agents have been approved for use in the treatment of multiple myeloma. (See "Multiple myeloma: Initial treatment" and "Treatment protocols for multiple myeloma" and "Multiple myeloma: Administration considerations for common therapies", section on 'Proteasome inhibitors'.)
Bortezomib — In general, nephrotoxicity is uncommon with bortezomib, although several cases of thrombotic microangiopathy (TMA) have been reported. (See "Drug-induced thrombotic microangiopathy (DITMA)", section on 'Cancer therapies'.)
In addition, a case of biopsy-proven acute interstitial nephritis with granuloma formation has been described [171].
The United States Prescribing Information as well as guidelines from Cancer Care Ontario and the International Myeloma Working Group (IMWG) [168] all state that no dose adjustment is necessary for patients with kidney impairment, including those on dialysis. For hemodialysis patients, bortezomib should be administered after dialysis since dialysis may reduce bortezomib concentrations [172]. There are no specific guidelines for patients undergoing peritoneal dialysis.
Carfilzomib — There have been reports of creatinine elevations in up to 25 percent of patients treated with carfilzomib:
●In a phase II study of 266 patients with relapsed and refractory myeloma treated with single-agent carfilzomib, acute kidney injury was reported in 25 percent [173]. Although the majority of renal adverse effects were mild, progressive kidney disease occurred in 3.8 percent of patients, leading to discontinuation of the drug in two patients.
●In another phase III trial of patients with relapsed or refractory multiple myeloma who received carfilzomib or a control regimen of low-dose glucocorticoids with optional cyclophosphamide, the incidence of grade 3 acute kidney injury (table 2) was higher in the carfilzomib arm (8 versus 3 percent) [174]. Renal adverse events of any type also occurred more frequently in the carfilzomib group (24 versus 9 percent); in both groups, these events were more likely to occur among patients with lower creatinine clearance (CrCl; <30 mL/min) and in those with evidence of a urine monoclonal protein.
Potential mechanisms for acute kidney injury in patients treated with carfilzomib include prerenal causes (eg, hypovolemia), tumor lysis-like syndrome, or acute tubular necrosis [175-180]. (See "Drug-induced thrombotic microangiopathy (DITMA)", section on 'Cancer therapies' and "Kidney disease in multiple myeloma and other monoclonal gammopathies: Etiology and evaluation", section on 'Less common causes of albuminuria'.)
TMA has also been described in patients treated with carfilzomib. In one case series, the median time between drug initiation and diagnosis was 21 days (range 5 days to 17 months), and the majority had complete resolution of TMA after discontinuation of the proteasome inhibitor [181]. (See "Drug-induced thrombotic microangiopathy (DITMA)", section on 'Cancer therapies'.)
The pharmacokinetics and safety of carfilzomib are not altered by pre-existing kidney impairment, including in patients on hemodialysis [182,183]. Both the United States Prescribing Information and guidelines from Cancer Care Ontario state that dose adjustments are not required for patients with pre-existing mild, moderate, or severe kidney impairment, including those on dialysis. The IMWG suggests that carfilzomib can be safely administered to patients with CrCl ≥15 mL/min; although there are fewer data, carfilzomib may also be administered to patients with CrCl <15 mL/min [168]. In hemodialysis patients, carfilzomib should be administered after dialysis.
For patients who develop kidney toxicity during treatment with carfilzomib, the United States Prescribing Information provides specific guidelines for management of the dose. If serum creatinine is ≥2 times baseline, CrCl is <15 mL/min or decreases to ≤50 percent of baseline, or the patient requires dialysis, one should withhold the dose and monitor kidney function. If kidney toxicity is attributable to carfilzomib, resume dosing when kidney function has improved to within 25 percent of baseline; resume with a one-dose-level reduction. If toxicity is not due to carfilzomib, dosing may be resumed at the discretion of the prescriber. These guidelines are also endorsed by Cancer Care Ontario.
Ixazomib — Ixazomib is an orally active proteasome inhibitor; as with other proteasome inhibitors, TMA has been reported rarely [184]. (See "Drug-induced thrombotic microangiopathy (DITMA)", section on 'Cancer therapies'.)
Ixazomib is predominantly excreted in the urine, and initial dose adjustment is needed in patients with severe kidney impairment. Both the United States Prescribing Information for ixazomib and guidelines from Cancer Care Ontario recommend reducing the starting dose from 4 mg once weekly to 3 mg once weekly in patients with CrCl <30 mL/min or end-stage kidney disease (ESKD) requiring dialysis (CrCl <30 mL/min). IMWG guidelines state only that ixazomib can be safely administered in combination with lenalidomide and dexamethasone in patients with CrCl ≥30 mL/min [168].
For patients with ESKD, ixazomib is not dialyzable and can be administered without regard for the timing of dialysis.
SUMMARY AND RECOMMENDATIONS
●Cytotoxic chemotherapy can cause kidney toxicity through a number of mechanisms. Several factors can potentiate kidney dysfunction and contribute to the nephrotoxic potential of antineoplastic drugs. These include intravascular volume depletion, the concomitant use of nonchemotherapeutic nephrotoxic drugs (eg, aminoglycoside antibiotics, nonsteroidal anti-inflammatory drugs) or radiographic ionic contrast media in patients with or without pre-existing kidney dysfunction, tumor-related urinary tract obstruction, and intrinsic kidney disease that is idiopathic, related to other comorbidities, or related to the cancer itself.
These factors should be considered by the treating oncologist before initiating treatment in order to minimize the risk of excessive toxicity.
●For those drugs in which renal excretion is an important determinant of elimination of the intact drug or an active metabolite, kidney impairment can alter excretion and increase systemic toxicity. Dose adjustment is often required.
●The most commonly used chemotherapeutic agents for which dose modification may be needed in the setting of kidney insufficiency are listed in the table (table 1).
Dose adjustment in this setting is typically based upon two factors: an estimation of glomerular filtration rate (GFR) or creatinine clearance (CrCl) that serves as an index of the number of functioning nephrons, and evaluation of clinical signs of drug toxicity (eg, neutropenia, thrombocytopenia). The available data in cancer patients suggest that most bedside formulae for estimating GFR or CrCl provide similar levels of concordance when used for the purpose of dosing renally excreted cancer drugs. In our view, estimates of GFR are preferred. (See 'Estimation of GFR for possible dose adjustment' above.)
●Minimizing nonrenal systemic toxicity in patients receiving chemotherapy may be a particular problem in patients on chronic hemodialysis, especially when the details of drug elimination and metabolism are not fully known [11]. For patients undergoing dialysis, two issues must be considered (see 'Drug handling in dialysis patients' above):
•Since the kidneys are no longer functioning, dose reduction may be needed to avoid overexposure and drug toxicity.
•Drug clearance by dialysis must be taken into account for appropriate timing of chemotherapy in patients treated with hemodialysis.
●The following issues are pertinent to the dosing of carboplatin, which is uniquely based upon estimated GFR:
•For most patients, carboplatin dosing uses the Calvert formula, which is based upon desired exposure (area under the curve of concentration X time [AUC]) and GFR. When GFR is estimated based upon measured serum creatinine, we suggest limiting the maximal GFR to 125 mL/min for this calculation (Grade 2C). This suggestion does not apply if the GFR is directly measured. (See 'AUC dose calculation' above.)
•When calculating carboplatin doses, actual weight should be used for estimation of GFR by the Cockcroft-Gault equation as long as patients have a body mass index (BMI) of <25 (calculator 4). For other patients, use of an adjusted weight is suggested (adjusted weight [kg] = [(actual weight - ideal weight) x 0.40] + ideal weight). A calculator for ideal body weight is available (calculator 5).
71 : Changes in glomerular filtration rate associated with high-dose methotrexate therapy in adults.
72 : Changes in glomerular filtration rate associated with high-dose methotrexate therapy in adults.
79 : Interstitial nephritis and nephrogenic diabetes insipidus in a patient treated with pemetrexed.
88 : Pentostatin pharmacokinetics and dosing recommendations in patients with mild renal impairment.
