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Chemotherapy nephrotoxicity and dose modification in patients with kidney impairment: Molecularly targeted agents and immunotherapies

Chemotherapy nephrotoxicity and dose modification in patients with kidney impairment: Molecularly targeted agents and immunotherapies
Authors:
Jaime R Merchan, MD, MMSc
Kenar D Jhaveri, MD
Section Editors:
Reed E Drews, MD
Jeffrey S Berns, MD
Deputy Editors:
Diane MF Savarese, MD
Albert Q Lam, MD
Literature review current through: Aug 2022. | This topic last updated: May 04, 2022.

INTRODUCTION — The development of novel anticancer therapies over the past two decades has improved patient survival rates compared with conventional chemotherapy. Several of these agents take advantage of molecular abnormalities that have been detected in certain types of cancer and are collectively referred to as molecularly targeted agents. Many of these drugs, however, have been associated with significant kidney complications, ranging from electrolyte disorders to acute kidney injury requiring dialysis [1-3].

This topic review will cover renal toxicities seen with several classes of molecularly targeted and biologic agents, preventive strategies, and recommended dose modifications in patients with kidney impairment. Nephrotoxicity and renal dose modification for conventional chemotherapeutic drugs, immune-mediated kidney toxicity associated with checkpoint inhibitor immunotherapy (ie, ipilimumab, pembrolizumab, nivolumab), and kidney toxicity associated with drugs that target the vascular endothelial growth factor (VEGF) pathway are discussed elsewhere. 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 also discussed separately. (See "Chemotherapy nephrotoxicity and dose modification in patients with kidney impairment: Conventional cytotoxic agents" and "Toxicities associated with checkpoint inhibitor immunotherapy", section on 'Kidney' and "Toxicity of molecularly targeted antiangiogenic agents: Non-cardiovascular effects", section on 'Proteinuria/nephrotic syndrome' and "Overview of kidney disease in the cancer patient" and "Tumor lysis syndrome: Pathogenesis, clinical manifestations, definition, etiology and risk factors" and "Kidney disease following hematopoietic cell transplantation".)

QUANTIFYING KIDNEY FUNCTION FOR POSSIBLE DOSE ADJUSTMENT — 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. 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).

Quantifying the number of functioning nephrons for the purpose of dose modification can be achieved through measuring the creatinine clearance (CrCl), which is cumbersome and subject to error, or, more commonly by using methods to estimate either CrCl (by formulae such as the Cockcroft-Gault (calculator 1 and calculator 2)) or glomerular filtration rate (GFR) using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) calculator (calculator 3). These three methods are now the most common methods used in routine clinical practice to estimate kidney function, due primarily to convenience. There is no consensus on the optimal formula to use; many prefer estimates of GFR. This subject is discussed in more detail elsewhere. (See "Chemotherapy nephrotoxicity and dose modification in patients with kidney impairment: Conventional cytotoxic agents", section on 'Estimation of GFR for possible dose adjustment'.)

Proposed guidelines for dose adjustment of antineoplastic drugs in patients with kidney disease are available from several groups that are still, unfortunately, based on CrCl [4-6]. 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 [7].

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 (CKD-EPI).

ALK INHIBITORS

Crizotinib — Crizotinib is a kinase inhibitor that is approved for treatment of advanced anaplastic lymphoma kinase (ALK) fusion gene-positive non-small cell lung cancer. (See "Anaplastic lymphoma kinase (ALK) fusion oncogene positive non-small cell lung cancer", section on 'Crizotinib'.)

Drug-induced reductions in glomerular filtration rate (GFR) are reported in patients treated with crizotinib, mostly during the first two weeks of therapy [8]. However, the early onset, small size of the change (24 percent), minimal cumulative effect, and rapid reversibility after treatment discontinuation all suggest that this is not a direct nephrotoxic effect of the drug. Nevertheless, increased vigilance with regard to concomitant use of renally cleared or nephrotoxic agents is warranted in patients receiving crizotinib. Some have suggested that the acute effects on creatinine clearance (CrCl) reflect an effect of the drug on creatinine excretion rather than a true reduction in GFR [9]. If crizotinib-associated changes in creatinine-based assessments of kidney function suggest the need for dose modification of either crizotinib or concomitant medications that are renally excreted, direct measurement of GFR using external filtration markers (eg, iothalamate or iohexol clearance) may be needed. This test is available in some clinical centers, and it requires an intramuscular or intravenous injection of the marker followed by serial sampling of blood and urine. (See "Assessment of kidney function", section on 'Measurement of GFR (selected settings)'.)

In addition, the development of complex renal cysts (3 percent) has been described in patients treated with crizotinib [10-12]. Both the formation of new cysts and progression of preexisting renal cysts can occur. Cyst development appears to be reversible upon discontinuation of the drug, and spontaneous cyst regression with continuous crizotinib treatment has also been reported [11]. The mechanism by which crizotinib induces cyst formation and/or growth is unknown.

Hyponatremia and hypokalemia have also been reported with crizotinib [3,13].

Crizotinib is 22 percent excreted in urine [14], and drug exposure is increased in individuals with severe (but not mild to moderate) kidney impairment [15]. The United States Prescribing Information for crizotinib and guidelines from Cancer Care Ontario recommend a reduction in the starting dose to 250 mg once (rather than twice) daily in patients with CrCl <30 mL/min not requiring dialysis. There are no data in patients undergoing dialysis.

Other ALK inhibitors — Four other anaplastic lymphoma kinase (ALK) inhibitors are available: ceritinib, alectinib, brigatinib, and lorlatinib. Increases in creatinine have been seen in 11 to 28 percent of patients treated with alectinib [16,17], and proteinuria has been reported with lorlatinib [18].

Ceritinib, alectinib, and brigatinib have minimal renal clearance, while the kidneys account for approximately one-half of drug clearance for lorlatinib. Dose adjustment for preexisting kidney disease is not recommended for any of these drugs in patients with mild to moderate kidney impairment [16]. However, a reduced dose of lorlatinib is recommended in the United States prescribing information for severe kidney impairment (CrCl <30 mL/min). The safety of these drugs in patients with end-stage kidney disease has not been specifically studied.

BCL-2 INHIBITORS — Although many targeted treatments used for treatment of hematologic malignancies are associated with tumor lysis syndrome (TLS; eg, obinutuzumab, ofatumumab), the B cell lymphoma-2 (BCL-2) inhibitor venetoclax, which is used in the treatment of refractory chronic lymphocytic leukemia, is associated with a particularly high incidence of TLS, which can cause acute kidney injury and severe electrolyte abnormalities. A gradual, stepwise dose-escalation strategy has been introduced in an effort to reduce this risk. (See "Tumor lysis syndrome: Pathogenesis, clinical manifestations, definition, etiology and risk factors", section on 'Hematologic malignancies' and "Treatment of relapsed or refractory chronic lymphocytic leukemia", section on 'BCL2 inhibitors: Venetoclax'.)

BCR-ABL1 AND KIT INHIBITORS — There are several small molecule inhibitors of BCR-ABL1, a tyrosine kinase that is the constitutively activated gene product of the Philadelphia chromosome in chronic myelogenous leukemia (CML); some also inhibit the tyrosine kinase receptor KIT (CD117) and platelet-derived growth factor receptor (PDGFR), which are constitutively activated in gastrointestinal stromal tumors (GIST).

Bosutinib — Bosutinib is a dual tyrosine kinase inhibitor (TKI) that targets both the ABL and SRC pathways; it does not target KIT or PDGFR. It is approved for treatment of refractory CML. (See "Treatment of chronic myeloid leukemia in chronic phase after failure of initial therapy", section on 'Bosutinib'.)

Although there are no published cases of acute kidney injury (AKI), hypophosphatemia and an apparently reversible decline in glomerular filtration rate (GFR) have been reported during long-term therapy with bosutinib [19]. The United States Prescribing Information for bosutinib recommends monitoring patients for kidney impairment at baseline and during therapy.

The United States Prescribing Information also describes a dedicated kidney impairment trial of single-dose bosutinib in 26 patients, in whom there was a 35 and 60 percent increase in drug exposure for patients with moderate and severe preexisting kidney impairment, respectively. As a result, a lower starting dose for patients with severe (creatinine clearance [CrCl] <30 mL/min) or moderate (CrCl 30 to 50 mL/min) preexisting kidney impairment is recommended. Dose reduction is also recommended for treatment-emergent kidney impairment. Similar guidelines are available from Cancer Care Ontario.

Dasatinib — Dasatinib is a second-generation TKI used mainly in patients with imatinib-resistant CML. It has effects on BCR-ABL1 as well as PDGFR and KIT. (See "Treatment of chronic myeloid leukemia in chronic phase after failure of initial therapy", section on 'Dasatinib'.)

Rare cases of AKI have been reported with the use of this agent [20-26], including one patient who developed rhabdomyolysis [24] and others with thrombotic microangiopathy [23,27]. In addition, there have been reports of proteinuria and nephrotic syndrome occurring in patients treated with dasatinib [25,26]; in all cases, proteinuria resolved upon discontinuation of the drug or switching to imatinib. Of the TKIs that target the BCR-ABL pathway, dasatinib is the only agent associated with the development of proteinuria. Some have suggested that dasatinib nephrotoxicity is primarily through its effect on glomerular podocytes and is independent of systemic or glomerular inhibition of vascular endothelial growth factor (VEGF) [28,29].

Less than 4 percent of dasatinib and its metabolites are renally excreted, and neither the United States Prescribing Information for dasatinib nor guidelines from Cancer Care Ontario indicate a need for dose adjustment in patients with preexisting kidney impairment.

Imatinib — Imatinib is a small molecule first-generation TKI that targets BCR-ABL1 and KIT; the drug is commonly used for treatment of both CML and GIST. (See "Tyrosine kinase inhibitor therapy for advanced gastrointestinal stromal tumors".)

Acute and chronic kidney injury have been described in patients treated with extended-duration imatinib for CML [19,30-33]; in one report, the mean decrease in estimated GFR was 2.77 mL/min/1.73 m2 per year [30]. Leukemic infiltration into the kidney should always be considered in the differential diagnosis when a patient with CML presents with kidney impairment, regardless of the clinical stage, as the kidney failure may respond to chemotherapy [34]. In one study of patients with CML, AKI and chronic kidney disease occurred in 7 and 12 percent of patients, respectively [30]. Potential mechanisms of injury include tumor lysis syndrome, acute tubular injury, and rhabdomyolysis; inhibition of tubular secretion of creatinine may also be a contributing factor to an observed rise in serum creatinine [31,32,35-39]. Kidney impairment appears to be dose dependent, as higher doses have been associated with a higher incidence of tubular damage [38].

Hypophosphatemia can occur in patients treated with imatinib [40,41]. In one case series, hypophosphatemia was associated with low serum total calcium and 25-hydroxyvitamin D levels, with an incidence close to 10 percent [40]. The mechanism underlying hypophosphatemia is unclear, but it may be related to the inhibition of renal tubular reabsorption of phosphorus.

There is a single case report of the syndrome of inappropriate antidiuretic hormone secretion (SIADH) from high-dose imatinib in the literature. (See "Pathophysiology and etiology of the syndrome of inappropriate antidiuretic hormone secretion (SIADH)".)

The United States Prescribing Information for imatinib recommends modification of the initial dose for patients with mild to moderate kidney impairment (CrCl <39 mL/min) because of reduced drug clearance. Owing to the lack of data, patients with severe dysfunction (CrCl <20 mL/min) should be approached cautiously; limited data suggest a dose of 100 mg daily is tolerated in such patients [42]. Cancer Care Ontario guidelines recommend caution in patients with mild to moderate preexisting renal insufficiency and that the drug be discontinued for CrCl <20 mL/min. Imatinib can be safely administered to patients on hemodialysis, although experience is limited [43-45].

Another alternative to dose reduction for patients who develop chronic kidney disease during treatment with a first-generation TKI such as imatinib is substitution of a second-generation agent (dasatinib, nilotinib), which has a lower risk of kidney injury during therapy [46].

Other agents — Kidney impairment has not been reported with nilotinib, and there are no recommendations for dose reduction for preexisting kidney impairment. On the other hand, the molecular targets of ponatinib, a multitargeted TKI, include the VEGF receptor, and proteinuria is a class effect of VEGF inhibitors. (See 'VEGF pathway inhibitors' below.)

BRAF AND MEK INHIBITORS

Vemurafenib and dabrafenib — Vemurafenib and dabrafenib are potent inhibitors of the kinase domain in the mutant BRAF gene; they are both approved for the treatment of patients with advanced melanoma whose tumors contain a BRAF V600E mutation. A decrease in creatinine clearance (CrCl) has been reported in patients treated with vemurafenib, generally occurring in the first two months of therapy, which appears to be caused, at least in part, by inhibition of tubular creatinine secretion [47]. This effect is generally reversible when vemurafenib is discontinued. (See "Systemic treatment of metastatic melanoma with BRAF and other molecular alterations", section on 'Toxicities of BRAF and MEK inhibitors'.)

Acute kidney injury (AKI) [48-52] and one case of Fanconi syndrome have also been reported with vemurafenib [48-50,53]. The precise mechanism of kidney injury is unclear, but kidney biopsies, when performed, have shown evidence of acute tubular damage and interstitial fibrosis [51,52]. Kidney failure reported in association with vemurafenib is more common in men [51,52]. AKI can also occur with dabrafenib, although the incidence appears to be less than that with vemurafenib [51].

The United States Prescribing Information for vemurafenib and the United States Prescribing Information for dabrafenib do not provide any dose adjustments for patients with mild to moderate kidney impairment based upon the results of population pharmacokinetic testing [54,55]. There are insufficient data to inform dosing of either drug in patients with severe kidney impairment or on dialysis. Guidelines from Cancer Care Ontario also state that the appropriate dose has not been established in severe kidney impairment, including dialysis. However, limited clinical experience suggests that it is feasible to administer vemurafenib, as well as dabrafenib in combination with trametinib, to patients with end-stage kidney disease (ESKD) undergoing hemodialysis [56,57].

Trametinib and cobimetinib — Trametinib and cobimetinib are potent and highly specific inhibitors of the mitogen-activated extracellular kinases 1 and 2 (MEK1/MEK2). They are both used for the treatment of advanced melanoma. (See "Systemic treatment of metastatic melanoma with BRAF and other molecular alterations", section on 'Toxicities of BRAF and MEK inhibitors'.)

There have been no published reports of nephrotoxicity associated with trametinib monotherapy, although monotherapy with MEK inhibitors can lead to hypertension [58,59].

Renal excretion of both drugs is low and unlikely to affect drug exposure [60,61]. The United States Prescribing Information for trametinib does not recommend dose adjustment for patients with mild to moderate kidney impairment; a recommended dose has not been established for patients with severe kidney impairment or those on dialysis. United States Prescribing Information for cobimetinib is similarly worded. Similar guidelines are also available for trametinib from Cancer Care Ontario. However, as noted above, limited clinical experience suggests that it is feasible to administer trametinib in combination with dabrafenib to patients with ESKD undergoing hemodialysis [56].

Combination regimens — BRAF and MEK inhibitors are frequently combined for the treatment of several tumors, including advanced melanoma. Kidney impairment, hyponatremia, and rare cases of glomerulonephritis have been described in patients treated with the combination of BRAF and MEK inhibitors [58,62-65]. As an example, in the phase III Columbus trial of combined encorafenib plus binimetinib versus either drug alone for metastatic BRAF-mutated advanced melanoma, the incidence of any increase in creatinine (grade 1 through 4) was 93 percent in the combined therapy arm, but only 3.6 percent had a grade 3 to 4 creatinine increase (table 1).

CAR-T CELL THERAPY — Chimeric antigen receptor modified (CAR)-T cells are a form of genetically modified autologous immunotherapy that can be used to treat certain forms of non-Hodgkin lymphoma and leukemia. The patient's T cells are collected from blood and modified to express a CAR that is specific for a tumor antigen, followed by ex vivo expansion and then re-infusion back to the patient. Tisagenlecleucel, axicabtagene ciloleucel, idecabtagene vicleucel, lisocabtagene maraleucel, loncastuximab tesirine, brexucabtagene autoleucel, and ciltacabtagene autoleucel are CD19-directed CAR-T cell immunotherapies approved by the US Food and Drug Administration to treat certain types of relapsed or refractory B-cell hematologic malignancies, including multiple myeloma. (See "Treatment of relapsed or refractory acute lymphoblastic leukemia in adults", section on 'CAR-T' and "Principles of cancer immunotherapy", section on 'Chimeric antigen receptors' and "Diffuse large B cell lymphoma (DLBCL): Second or later relapse or patients who are medically-unfit", section on 'CAR-T cell therapy' and "Multiple myeloma: Treatment of third or later relapse", section on 'Chimeric antigen receptor T cells'.)

In published trials of CD19-directed CAR-T cell therapy, a cytokine release syndrome (CRS) has been reported in over 40 percent of patients, regardless of the disease studied or the construct of the CAR-T cells [66-68]. CRS can result in multiorgan dysfunction, including acute kidney injury (AKI) [69,70]. The release of high concentrations of cytokines can lead to vasodilation, decreased cardiac output, and intravascular volume depletion due to increased vascular permeability and third spacing of fluids, all of which cause reduced perfusion to the kidneys and AKI. The rise in serum creatinine is observed approximately 7 to 10 days postinfusion [71,72]. Prerenal AKI and/or acute tubular injury may develop in this setting depending upon the severity of hypotension and its duration. (See "Cytokine release syndrome (CRS)".)

In a systematic review of 22 studies including 3376 patients, the overall estimated incidence of AKI among patients treated with CAR-T cell therapy was 19 percent, and the estimated incidence of AKI requiring kidney replacement therapy was 4 percent [73]. A subgroup analysis found that the incidence of AKI was higher among children and young adults compared with adults (22 versus 17 percent). The incidence of CRS among patients receiving CAR-T cell therapies was 75 percent.

In this analysis, the majority of patients had received axicabtagene ciloleucel, a CD-19-targeting CAR-T that has a CD28 costimulatory domain, and is characterized by rapid T-cell expansion, and robust inflammatory cytokine secretion. Use of a different agent, tisagenlecleucel, that targets the same epitope of CD-19 but has a different costimulatory domain and a reduced inflammatory profile, may be associated with lower toxicity rates, including AKI [69,74].

The reversibility of AKI was addressed in a single-institution retrospective review of 46 adult patients with non-Hodgkin lymphoma treated with CAR-T cell therapy over a one-year period, in which the cumulative incidence of any grade AKI by day 100 was 30 percent, mostly grade 1 (21.7 percent) [69]. No patient developed severe AKI necessitating kidney replacement therapy. Most patients recovered, with kidney function returning to baseline within 30 days.

Electrolyte disorders have also been reported in patients undergoing CAR-T cell therapy. They may include hyperphosphatemia and hyperkalemia, attributable to tumor lysis syndrome (TLS), but also hypokalemia and hypophosphatemia, which appear unrelated to TLS, although the mechanism is not clearly defined. (See "Tumor lysis syndrome: Pathogenesis, clinical manifestations, definition, etiology and risk factors", section on 'Clinical manifestations'.)

As examples:

Adverse reactions reported in the United States Prescribing Information for tisagenlecleucel, from a trial of 68 children and young adults undergoing treatment for B-cell acute lymphocytic leukemia, noted grade 3 or 4 hypokalemia in 27 percent and grade 3 or 4 hypophosphatemia in 19 percent.

In the United States Prescribing Information for axicabtagene ciloleucel toxicity data from 108 patients with relapsed/refractory B-cell non-Hodgkin lymphoma noted grade 3 or 4 hypokalemia was seen in 10 percent, grade 3 or 4 hypophosphatemia was seen in 50 percent, and grade 3 or 4 hyponatremia in 19 percent.

CHECKPOINT INHIBITOR IMMUNOTHERAPY — Checkpoint inhibitors, immunomodulatory antibodies that are used to enhance the immune system, have substantially improved the prognosis for patients with advanced melanoma and are likely to significantly improve the treatment of advanced disease in a number of other malignancies. The primary targets for checkpoint inhibition include (see "Principles of cancer immunotherapy"):

Programmed cell death 1 receptor (PD-1) and its ligand, programmed cell death 1 ligand (PD-L1)

Cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4)

Despite important clinical benefits, checkpoint inhibition is associated with a unique spectrum of side effects termed immune-related adverse events. Acute kidney injury is a rare complication of checkpoint inhibitor immunotherapy. The most common reported underlying pathology is acute tubulointerstitial nephritis, but immune complex glomerulonephritis and thrombotic microangiopathy have also been observed. This subject is discussed in detail elsewhere. (See "Toxicities associated with checkpoint inhibitor immunotherapy", section on 'Kidney'.)

EGFR PATHWAY INHIBITORS — Inhibitors of the epidermal growth factor receptor (EGFR) pathway include small molecule tyrosine kinase inhibitors (afatinib, erlotinib, and gefitinib) and monoclonal antibodies targeting the EGFR (cetuximab and panitumumab).

Anti-EGFR monoclonal antibodies — Monoclonal antibodies targeting the epidermal growth factor receptor (EGFR; cetuximab and panitumumab), which are typically used for treatment of advanced colorectal cancer, are all associated with the progressive development of hypomagnesemia due to renal magnesium wasting [75-80]. (See "Systemic therapy for nonoperable metastatic colorectal cancer: Selecting the initial therapeutic approach", section on 'Benefit of cetuximab and panitumumab'.)

The mechanism for this has been attributed to inhibition of EGFR signaling at the distal convoluted tubule, which under normal physiologic conditions, plays an important role in regulating transepithelial magnesium transport. (See "Regulation of magnesium balance", section on 'Distal reabsorption'.)

The frequency of this complication with cetuximab was illustrated in a meta-analysis of 19 clinical reports totaling 3081 patients assigned to cetuximab-based treatment [81]. Thirty-seven percent of patients developed hypomagnesemia of any grade during therapy; the incidence of grade 3 or 4 hypomagnesemia (<0.9 mg/dL) was 5.6 percent. Whether the severity of hypomagnesemia represents a surrogate marker of oncologic outcomes in patients treated with cetuximab for advanced colorectal cancer (as is the development of an acneiform rash) is unclear; the data are conflicting [82-84].

Hypomagnesemia resolves after treatment is discontinued. Hypomagnesemia may lead to secondary hypocalcemia, and periodic monitoring of serum magnesium and calcium levels is warranted during therapy and for at least eight weeks after treatment discontinuation. (See "Hypomagnesemia: Clinical manifestations of magnesium depletion" and "Regulation of magnesium balance".)

Cetuximab also causes hypokalemia in approximately 8 percent of patients [85]. The exact mechanism underlying this complication is not established; magnesium deficiency may contribute. Thus, periodic monitoring of serum potassium is warranted during therapy with cetuximab. (See "Causes of hypokalemia in adults".)

In addition, other renal toxicities have been reported with cetuximab, including acute kidney injury (AKI) [3,86], one case report of diffuse proliferative glomerulonephritis [87], and another case report of nephrotic syndrome [88]. The cause of AKI is not clear. EGFR, which is mainly expressed in the distal and collecting tubules, is involved in maintaining tubular integrity, and activation of EGFR leads to growth and generation of tubular epithelial cells after acute tubular injury. In patients prone to experiencing kidney injury, treatment with anti-EGFR agents might be a "second hit" for the development of AKI.

Hyponatremia has also been described in patients treated with cetuximab. In a systematic review and meta-analysis of 13 phase III studies including 6670 patients treated with eight targeted agents, all-grade hyponatremia occurred most commonly in patients treated with the combination of brivanib and cetuximab (63.4 percent) [89]. Patients treated with cetuximab had the highest incidence of high-grade hyponatremia (34.8 percent).

Kidney function has no influence on the exposure to cetuximab or panitumumab [90-94]. Neither the United States Prescribing Information nor guidelines from Cancer Care Ontario provide dose modification guidelines for cetuximab or panitumumab in patients with preexisting kidney impairment (including those on dialysis).

EGFR tyrosine kinase inhibitors — Afatinib, erlotinib, gefitinib, dacomitinib, osimertinib, and mobocertinib are all used in the treatment of non-small cell lung cancer. (See "Systemic therapy for advanced non-small cell lung cancer with an activating mutation in the epidermal growth factor receptor".)

Electrolyte disorders, such as hypomagnesemia, hypokalemia, and hypophosphatemia, have been reported with all six agents, although the incidence overall seems less than that with the EGFR monoclonal antibodies [3]. In addition, there are case reports of nephrotic syndrome with kidney biopsy findings consistent with minimal-change disease and membranous nephropathy occurring in patients treated with gefitinib [95-97].

Less than 8 percent of these drugs and their metabolites are excreted in the urine. Although data are limited, dose modification for erlotinib and gefitinib is not required in patients with impaired kidney function, including those on dialysis [16,98-100]. No dosage adjustments for mobocertinib or dacomitinib are required for mild to moderate kidney impairment; the recommended dose for these agents is not established in those with more severe kidney disease, including those on dialysis [101,102]. Osimertinib dose adjustment is not needed for patients with moderate to severe kidney impairment, but there is no recommended dose for patients with end stage kidney disease (creatinine clearance [CrCl] <15 mL/min) [103].

Moderate to severe kidney impairment has a minor influence on the pharmacokinetics of afatinib [104]. Nevertheless, the United States Prescribing Information for afatinib recommends dose modification for patients with severe kidney impairment (estimated glomerular filtration rate [GFR] 15 to 29 mL/min/1.73 m2). Guidelines from Cancer Care Ontario also support a reduced dose for CrCl 15 to 29 mL/min and that the drug be avoided with more severe kidney failure or in patients undergoing dialysis. However, at least two case series support the safety of a reduced dose of afatinib (30 mg daily) in patients undergoing hemodialysis [105,106].

Lapatinib is discussed below. (See 'Lapatinib' below.)

FGFR INHIBITORS — As a class effect, all inhibitors of fibroblast growth factor receptor (FGFR) such as erdafitinib, infigratinib, and pemigatinib cause hyperphosphatemia because the FGFR pathway is important for phosphate homeostasis via feedback mechanisms that involve fibroblast growth factor (FGF) 23, 1,25-dihydroxyvitamin D, and parathyroid hormone [107-112]. As such, hyperphosphatemia represents a pharmacodynamic effect of this class of drugs. (See "Overview of the causes and treatment of hyperphosphatemia", section on 'Increased tubular reabsorption of phosphate'.)

Hyperphosphatemia can lead to soft tissue mineralization, cutaneous calcifications, calcinosis, and non-uremic calciphylaxis [113]. Although hyperphosphatemia occurs in over 60 percent of treated patients, it is generally mild (grade 1 or 2 (table 2)). In general, hyperphosphatemia occurs early after treatment initiation (average 15 to 20 days) and can be managed with a low phosphate diet, concomitant phosphate binders, dose reduction, and/or dose interruption. Although hypophosphatemia has also been reported [109], this might have resulted from the continued use of a low phosphate diet or phosphate binders for hyperphosphatemia during off-treatment times or from negative-feedback effects on phosphate homeostasis.

Acute kidney injury (AKI) has also been reported in patients treated with FGFR inhibitors [114-117]. In one study, 6 percent of patients treated with erdafitinib experienced AKI, with 2 percent having grade 3 or higher AKI [115]. In a case report describing AKI in a patient receiving rogaratinib, a selective pan-FGFR tyrosine kinase inhibitor that is not available in the United States, kidney biopsy showed acute tubular necrosis [114]. AKI improved with treatment discontinuation, and reintroduction of therapy at a lower dose level did not prompt recurrence of kidney injury.

Erdafitinib, infigratinib, and pemigatinib are approved anticancer agents in the United States. The United States Prescribing Information for all three drugs suggests close monitoring of phosphate levels, and in the case of erdafitinib, restriction of phosphate intake during therapy; there are also dose modification guidelines and recommendations for initiation of phosphate lowering therapy for hyperphosphatemia, when required [118-120]. (See "Overview of the causes and treatment of hyperphosphatemia", section on 'Treatment of hyperphosphatemia'.)

The United States Prescribing Information for pemigatinib also suggests a reduced initial dose of the drug for individuals with severe kidney impairment (estimated GFR 15 to 29 mL/min/1.73 m2).

HER2 INHIBITORS

Trastuzumab, ado-trastuzumab emtansine, and pertuzumab — Trastuzumab is a recombinant humanized monoclonal antibody that binds to the extracellular domain of human epidermal growth factor receptor 2 (HER2) and inhibits proliferation of cells that overexpress the HER2 protein. Ado-trastuzumab emtansine (T-DM1) is an antibody-drug conjugate consisting of trastuzumab linked to the microtubule inhibitor emtansine (DM1), a derivative of maytansine. Pertuzumab is a humanized monoclonal antibody that binds the extracellular dimerization domain of HER2 and prevents it from binding to itself or to other members of the epidermal growth factor receptor (EGFR) family. Pertuzumab is typically administered in combination with trastuzumab rather than as a single agent; all three drugs are used for the treatment of HER2-positive breast cancer. (See "Systemic treatment for HER2-positive metastatic breast cancer".)

There are no published case reports of nephrotoxicity with either trastuzumab or pertuzumab. An analysis of the US Food and Drug Administration (FDA) Adverse Event Reporting System identified a total of 360 and 100 renal adverse events for trastuzumab and pertuzumab, respectively, reported between 2011 and 2015 [3]. Among the most commonly reported events were renal impairment (defined as proteinuria, acute kidney injury [AKI], elevated serum creatinine, and/or nephritis), hypokalemia, hypertension, hypomagnesemia, and hyponatremia. However, it is not clear that these events were directly caused by the drugs as opposed to the underlying disease, concomitant medications, or prior chemotherapy given to these patients.

Rare cases of fetal nephrotoxicity associated with anhydramnios have been described with trastuzumab administered during pregnancy; in three cases, there was spontaneous improvement after discontinuation of trastuzumab [121-123]. (See "Gestational breast cancer: Treatment", section on 'Trastuzumab'.)

Patients treated with ado-trastuzumab emtansine can develop hypokalemia during therapy (overall incidence approximately 10 percent of any grade, 2 to 3 percent grade 3 or 4 (table 2)) [93,124].

Renal excretion of trastuzumab is very low [125]. However, among patients treated with trastuzumab, the presence of preexisting kidney impairment has been associated with a higher risk of cardiotoxicity. One study found that an estimated glomerular filtration rate (GFR) of <78 mL/min/1.73 m2 was an independent predictor for cardiotoxicity at 12 months post-treatment [126]. (See "Cardiotoxicity of trastuzumab and other HER2-targeted agents".)

Despite this finding, drug disposition does not appear to be altered in patients with renal insufficiency. Pertuzumab dose adjustments are not needed for mild to moderate kidney impairment; elimination has not been studied in patients with severe renal impairment (<30 mL/min) [16]. There are no dose adjustments for patients with kidney impairment, including those on dialysis, for either trastuzumab in the United States Prescribing Information or for pertuzumab in the United States Prescribing Information. There are scant data in the literature about use of either drug in patients undergoing dialysis. One report noted good clinical outcomes in two patients treated with standard-dose trastuzumab while receiving dialysis; pharmacokinetic data were not available [127].

There are no dose adjustments for patients with renal impairment, including those on dialysis, in the United States Prescribing Information for ado-trastuzumab emtansine.

Lapatinib — Lapatinib is a dual tyrosine kinase inhibitor that interrupts both the EGFR (erbB1) and HER2 (erbB2) pathways. In a phase II trial with this agent, seven patients experienced treatment-related grade 3 toxicity, two of whom developed hyponatremia [128]. An analysis of the FDA Adverse Event Reporting System identified a total of 171 kidney adverse events reported between 2011 and 2015, most of which were cases of hypokalemia (61 cases) and AKI (48 cases); a few cases of hypertension, hypomagnesemia, and hyponatremia were also reported [3].

The United States Prescribing Information for lapatinib provides no dose adjustments for patients with renal impairment; however, due to the minimal renal elimination (<2 percent), dose adjustments may not be necessary.

MET INHIBITORS — Capmatinib and tepotinib are mesenchymal-epithelial transition (MET) tyrosine kinase inhibitors that are both approved for treatment of advanced non-small cell lung cancer with specific MET mutations that lead to MET exon 14 skipping. (See "Personalized, genotype-directed therapy for advanced non-small cell lung cancer", section on 'MET abnormalities'.)

Treatment with either agent may result in an asymptomatic rise in serum creatinine, which spontaneously returns to baseline upon discontinuation of the agent [129,130]. Inhibition of tubular creatinine secretion may explain this phenomenon.

MTOR INHIBITORS — The extensive experience with mechanistic (previously called mammalian) target of rapamycin (mTOR) inhibitors in solid organ transplantation as well as advances in our understanding of the role of the Akt/mTOR pathway in the maintenance of podocyte viability have led to concerns about short- and long-term nephrotoxicity with these agents [131,132]. (See "Biology of glomerular podocytes", section on 'Direct podocyte injury'.)

Proteinuria and, more rarely, kidney dysfunction have been reported in patients taking mTOR inhibitors. The phenomena appear to be dose dependent and reversible with cessation of the medication. These issues are discussed in more detail elsewhere. (See "Pharmacology of mammalian (mechanistic) target of rapamycin (mTOR) inhibitors", section on 'Kidney function'.)

Temsirolimus — Temsirolimus is a parenterally administered rapamycin analog that functions as a competitive mTOR inhibitor. (See "Antiangiogenic and molecularly targeted therapy for advanced or metastatic clear cell renal carcinoma".)

There are rare case reports of temsirolimus-associated glomerulopathy and acute tubular necrosis [133,134].

Temsirolimus is cleared mainly by the liver, with some excretion in the feces. Due to the small amount of renal excretion (less than 5 percent), dose adjustment is not needed in the setting of kidney insufficiency or end-stage kidney disease on hemodialysis [16,135]. However, one study did note a higher rate of treatment-related rash (45 versus 15 percent) and infection (27 versus 8 percent) in patients receiving mTOR inhibitors for renal cell cancer who had preexisting kidney impairment (creatinine clearance [CrCl] ≤60 mL/min) compared with those with normal kidney function [136].

PEPTIDE RECEPTOR RADIOLIGAND THERAPY — Lutetium Lu-177 dotatate (177Lu-Dotatate) is a radiolabeled somatostatin analog that is approved for treatment of somatostatin-receptor-positive progressive gastrointestinal and pancreatic neuroendocrine tumors (NETs). (See "Metastatic well-differentiated gastrointestinal neuroendocrine (carcinoid) tumors: Systemic therapy options to control tumor growth", section on 'Lutetium Lu-177 dotatate' and "Metastatic well-differentiated pancreatic neuroendocrine tumors: Systemic therapy options to control tumor growth and symptoms of hormone hypersecretion", section on 'Lutetium-177 dotatate'.)

Kidney irradiation may result in glomerular damage. During each peptide receptor radioligand therapy (PRRT) treatment (which is administered every eight weeks for four doses), a four-hour intravenous infusion with an amino acid solution is needed (two hours prior to and two hours following each dose) to protect the kidneys from the radiation effects of the therapeutic radionuclide. The available data suggest that this protocol results in low rates of nephrotoxicity during therapy (1 percent with grade 2 increases in creatinine in one Dutch report [137]). Following treatment, the average annual decrease in creatinine clearance (CrCl) was 3.4 percent, but no patient had an annual decrease in renal function of >20 percent. No risk factors for kidney toxicity could be identified.

However, rates of nephrotoxicity may be higher depending on the means of assessment. An analysis of kidney function over time using technetium-99m (99mTc) diethylenetriaminepentaacetic acid (DTPA) clearance to accurately assess glomerular filtration rate (GFR) in 74 consecutive patients with gastroenteropancreatic NETs undergoing PRRT with 177Lu-Dotatate noted slight kidney impairment (GFR loss >2 mL/min/m2 per year) in 43 percent [138]. By contrast, there was only one case of grade 3 or worse nephrotoxicity (table 1) as assessed by serum creatinine (1.3 percent).

VEGF PATHWAY INHIBITORS — Two different approaches have been used to block the vascular endothelial growth factor (VEGF) pathway: VEGF ligand inhibitors (bevacizumab, ramucirumab, and aflibercept), which bind to and inhibit ligand binding to the VEGF receptor (VEGFR), thus preventing activation of the receptor, and small molecule tyrosine kinase inhibitors (TKIs; sunitinib, sorafenib, pazopanib, ponatinib, axitinib, cabozantinib, lenvatinib, regorafenib, vandetanib), which block the intracellular domain of the VEGFR.

Proteinuria and thrombotic microangiopathy – Proteinuria is a class effect of all VEGF inhibitors. Bevacizumab, ramucirumab, aflibercept, and the small molecule antiangiogenic TKIs all produce asymptomatic proteinuria, occasionally causing nephrotic syndrome. Hypertension frequently accompanies proteinuria. (See "Toxicity of molecularly targeted antiangiogenic agents: Cardiovascular effects", section on 'Hypertension' and "Toxicity of molecularly targeted antiangiogenic agents: Non-cardiovascular effects", section on 'Proteinuria/nephrotic syndrome'.)

The exact mechanism underlying proteinuria is not known. Reports of kidney biopsies among patients with proteinuria receiving VEGF-targeted agents are sparse; when reported, the most common causative agent was bevacizumab. Histologic findings have included thrombotic microangiography (especially with lenvatinib), collapsing glomerulopathy, and isolated reports of cryoglobulinemic and immune complex glomerulonephritis. The factors associated with the occurrence and severity of proteinuria are unknown. Preexisting renal disease (including higher baseline urine protein levels and hypertension) and renal cell carcinoma, as compared with other malignant diseases, may be predisposing factors. (See "Toxicity of molecularly targeted antiangiogenic agents: Non-cardiovascular effects", section on 'Incidence and mechanism'.)

The implications of asymptomatic proteinuria from VEGF inhibitors are unknown, and it is possible that the vast majority of cases have no clinical consequences. However, proteinuria has been linked to adverse cardiovascular outcomes and progression to end-stage kidney disease (ESKD) in patients with chronic kidney disease, and as such, proteinuria is identified as a target for treatment in kidney diseases in general. (See "Secondary factors and progression of chronic kidney disease", section on 'Albuminuria'.)

Rarely, cases of systemic drug-induced thrombotic microangiopathy (TMA) have been reported with specific antiangiogenic agents (eg, bevacizumab, sorafenib). Patients may present with microangiopathic hemolysis; renal-only manifestations including acute kidney injury and/or hypertension, or proteinuria alone; or a more systemic TMA syndrome. Withdrawal of the offending agent is critical because drug-induced TMA can be fatal. (See "Drug-induced thrombotic microangiopathy (DITMA)", section on 'Clinical manifestations' and "Drug-induced thrombotic microangiopathy (DITMA)", section on 'Drugs associated with DITMA'.)

Other kidney toxicities – Less commonly, nephritic syndrome, acute kidney injury (AKI), and proliferative glomerulonephritis have been reported with bevacizumab; AKI and diabetes insipidus have been reported in clinical trials of vandetanib in medullary thyroid and lung cancer, although causality has not been proven. Increases in creatinine during therapy have also been reported with axitinib, sunitinib, and sorafenib, although kidney failure is rare. (See "Toxicity of molecularly targeted antiangiogenic agents: Non-cardiovascular effects", section on 'Incidence and mechanism'.)

Bevacizumab and other anti-VEGF monoclonal antibodies — The United States Prescribing Information for bevacizumab recommends intermittent monitoring for the development of proteinuria but does not provide specific recommendations, except temporary withholding of the drug if protein excretion is >2 g per 24 hours, and permanent discontinuation for nephrotic syndrome. However, this complication is uncommon, and many institutions do not routinely dipstick urine prior to each dose of bevacizumab. Baseline and periodic urinalyses are also recommended during treatment with pazopanib, lenvatinib, and axitinib, with treatment interruption or discontinuation for patients who develop moderate to severe proteinuria (defined as ≥3 g per 24 hours for pazopanib and ≥2 g per 24 hours for lenvatinib, but undefined for axitinib). There are no guidelines for sorafenib, sunitinib, vandetanib, ponatinib, regorafenib, or cabozantinib; however, good clinical practice dictates baseline and periodic assessment of proteinuria for these agents as well. (See "Toxicity of molecularly targeted antiangiogenic agents: Non-cardiovascular effects", section on 'Management'.)

Monoclonal antibodies are generally cleared by catabolism; for bevacizumab, aflibercept, and ramucirumab, no dosing adjustment is recommended for patients with kidney function impairment, including those undergoing dialysis [139,140].

Small molecule tyrosine kinase inhibitors — Small molecule TKIs are partly excreted by the kidneys. In general, these drugs can be safely given to patients with mild to moderate kidney function impairment, with adequate monitoring and dose adjustment as needed [136,141]. Most of these drugs have not been studied in patients with severe kidney function impairment or ESKD. However, at least one report suggests that more than one-half of patients who have chronic kidney disease at the start of therapy will experience a further rise in creatinine during treatment with sunitinib or sorafenib [141]. Agent-specific nephrotoxicity and dose modification are discussed below.

Lenvatinib — Lenvatinib is an orally active inhibitor of several tyrosine kinases, including RET, KIT, VEGFR, and platelet-derived growth factor receptor alpha (PDGFRA). In addition to proteinuria, a class effect of VEGF inhibitors, serious, including fatal, kidney failure or impairment can occur in patients treated with lenvatinib [142-144]:

Kidney function impairment occurred in 14 percent of patients receiving lenvatinib (initial dose 24 mg daily) in the SELECT trial (disseminated thyroid cancer) and in 7 percent of patients receiving lenvatinib (initial dose 8 or 12 mg daily, depending on body weight) in the REFLECT trial (hepatocellular carcinoma) [143]. Grade 3 to 5 kidney failure or impairment occurred in 3 percent (disseminated thyroid cancer) and 2 percent (hepatocellular carcinoma) of patients, including one fatality in each study.

In Study 205 (renal cell cancer), kidney function impairment or failure occurred in 18 percent of patients receiving lenvatinib (18 mg daily) with everolimus, including grade 3 in 10 percent of patients.

Others report three cases of biopsy-proven renal TMA in patients treated with lenvatinib, presenting as proteinuria with a stable serum creatinine [144].

The United States Prescribing Information for lenvatinib recommends adjustment of the initial dose of this agent for patients receiving the drug for disseminated thyroid cancer or renal cell cancer if they have severe preexisting kidney impairment (creatinine clearance [CrCl] <30 mL/min). A similar recommendation is made by Cancer Care Ontario. No studies have been conducted in patients with ESKD, and guidance is not available from either source. Dose reduction guidelines do not apply to patients receiving the drug for hepatocellular carcinoma. (See "Differentiated thyroid cancer refractory to standard treatment: Systemic therapy", section on 'Mutation not identified' and "Systemic treatment for advanced hepatocellular carcinoma", section on 'Lenvatinib' and "Antiangiogenic and molecularly targeted therapy for advanced or metastatic clear cell renal carcinoma", section on 'Lenvatinib plus everolimus'.)

Regorafenib — Regorafenib is an orally administered inhibitor of angiogenic (including VEGFR 1 to 3), stromal, and oncogenic receptor tyrosine kinases.

In addition to hypertension and the proteinuria that is seen with other antiangiogenic TKIs, regorafenib has been associated with several electrolyte abnormalities, including hypophosphatemia, hypocalcemia, hyponatremia, and hypokalemia [145-147]. These abnormalities are usually mild to moderate and do not require dose reductions or treatment interruptions. An analysis of the US Food and Drug Administration (FDA) Adverse Event Reporting System identified a total of 125 cases of regorafenib-associated kidney adverse events between 2011 and 2015; hypertension was the most common event (57 cases), followed by kidney impairment (40 cases) and hypophosphatemia (eight cases) [3].

The United States Prescribing Information for regorafenib does not recommend adjustment of the initial dose for patients with CrCl >15 mL/min. There are no data to guide treatment in patients undergoing dialysis. Similarly, guidelines from Cancer Care Ontario suggest no dose adjustment for CrCl 60 to 90 mL/min and close monitoring without initial dose adjustment for moderate kidney impairment; no data are available in severe kidney impairment or ESKD.

Sorafenib and sunitinib — Sorafenib and sunitinib have been associated with acute and chronic interstitial nephritis in case reports [148-150]. Sorafenib is also known to cause hypophosphatemia and hypocalcemia [151]. This effect has been attributed to vitamin D malabsorption and secondary hyperparathyroidism, although the precise mechanism for this is unclear [152]. Thus, in patients taking sorafenib, vitamin D, phosphorus, and calcium levels should be routinely monitored.

The United States Prescribing Information for sorafenib suggests no dose adjustment for patients with mild, moderate, or severe renal impairment not undergoing dialysis. However, a phase I study indicated that the initial dose of sorafenib should be reduced to 200 mg twice daily for patients with a CrCl between 20 and 30 mL/min and to 200 mg once daily for those on hemodialysis [153]. Conclusions regarding initial dose could not be reached in patients with a CrCl less than 20 mL/min who were not undergoing hemodialysis. Guidelines from others, including Cancer Care Ontario, suggest reducing the dose by one-half for CrCl 20 to 40 mL/min and avoiding the drug with worse kidney function [45].

Some patients undergoing dialysis may tolerate higher doses. Doses of 200 mg twice daily have been associated with a higher incidence of adverse effects in patients undergoing hemodialysis in some [154], but not all [155], studies. Some patients may even tolerate dose escalation to 400 mg twice daily [156,157].

The pharmacokinetics and safety of sunitinib have been evaluated in a small number of patients with renal insufficiency [141,155,157-161]:

In a study of 24 patients, a single dose of 50 mg of sunitinib appeared to be well tolerated in those with severe kidney impairment (CrCl <30 mL/min) or ESKD on hemodialysis [155]. The pharmacokinetics of sunitinib and its major metabolite (SU12662) in patients with severe kidney impairment appeared similar to that in patients with normal kidney function, while in patients with ESKD, plasma exposure to both sunitinib and SU12662 was actually 47 percent lower compared with patients with normal or severely impaired kidney function not on dialysis.

In a published case report of two patients with ESKD receiving repeated doses of sunitinib (daily for four weeks on, two weeks off) for renal cell cancer, the pharmacokinetics of sunitinib were similar to those in patients with normal kidney function [159].

Another report included 19 patients with an estimated glomerular filtration rate (GFR) <30 mL/min at the start of sunitinib therapy for advanced renal cell cancer, 10 of whom were undergoing dialysis [160]. Starting doses were 25 to 50 mg daily for four of every six weeks. Treatment efficacy was comparable with that reported in patients with normal kidney function. Dose reduction for toxicity was required in eight patients, but only one patient required treatment discontinuation. Similar results have been reported by others in patients with renal cell cancer undergoing hemodialysis [155].

Thus, these data suggest that sunitinib doses of 25 to 50 mg daily are well tolerated in patients with severe kidney dysfunction or ESKD on hemodialysis. The United States Prescribing Information for sunitinib concludes that no adjustment to the starting dose is required in patients with mild, moderate, and severe kidney impairment. They also note that for patients with ESKD on hemodialysis, the sunitinib exposure is actually lower and that subsequent doses may be increased gradually up to twofold based upon safety and tolerability. Similar guidance is available from others, including Cancer Care Ontario [45].

Vandetanib — Vandetanib is an orally active inhibitor of several tyrosine kinases, including RET, VEGFR, and endothelial growth factor receptor (EGFR). As noted in the United States Prescribing Information for vandetanib, increases in creatinine during therapy occur in approximately 16 percent of patients and may be severe.

Vandetanib has been associated with a number of electrolyte disturbances, such as hypocalcemia, hypomagnesemia, hypokalemia, hyponatremia, and hypercalcemia [162,163]. Hypertension has been reported in approximately 10 to 34 percent of patients [162,164,165]. An analysis of the FDA Adverse Event Reporting System identified a total of 57 kidney adverse events for vandetanib reported between 2011 and 2015; the majority were kidney impairment (defined as proteinuria, AKI, elevated serum creatinine, and/or nephritis; 30 cases) and hypertension (21 cases), with the remainder being electrolyte disorders. However, it is not clear that these kidney events were directly caused by the drug as opposed to the underlying disease, concomitant medications, or prior chemotherapy given to these patients.

Vandetanib has also been shown to have inhibitory activity on several human renal transporters, such as multidrug and toxin extrusion 1 and 2 (MATE-1 and MATE-2K), which are responsible for the clearance of multiple drugs and toxins. Inhibition of MATE-1 and MATE-2K at the apical membrane of the tubular cells might lead to decreased renal clearance and increased nephrotoxicity of other coadministered agents, such as cisplatin [166].

Vandetanib is partially excreted in urine, and exposure is increased in subjects with mild, moderate, and severe kidney impairment [167].

The United States Prescribing Information for vandetanib recommends a dose reduction from 300 to 200 mg daily for patients with moderate to severe kidney impairment (CrCl ≤50 mL/min). Similar recommendations are available from others, including Cancer Care Ontario [45].

OTHER TARGETED AGENTS

Brentuximab — Brentuximab vedotin is an antibody-drug conjugate with a CD30-directed antibody linked to the antitubulin agent monomethyl auristatin E (MMAE). It is approved for the treatment of refractory Hodgkin lymphoma and anaplastic large cell lymphoma. (See "Treatment of relapsed or refractory peripheral T cell lymphoma", section on 'Brentuximab'.)

No kidney toxicities have been reported with this agent; however, severe renal impairment increases the likelihood of severe adverse reactions and death in patients receiving brentuximab. The United States Prescribing Information for brentuximab and Cancer Care Ontario guidelines recommend avoidance of the drug in patients with creatinine clearance (CrCl) <30 mL/min.

Ibrutinib — Ibrutinib is an orally active inhibitor of Bruton tyrosine kinase, a mediator of the B cell receptor signaling pathway that inhibits malignant B cell survival; it is approved as a single agent for treatment of mantle cell lymphoma. (See "Treatment of relapsed or refractory mantle cell lymphoma", section on 'Ibrutinib'.)

Serious and potentially fatal cases of acute kidney injury (AKI) have occurred with ibrutinib therapy [168-170]. In one report of 111 patients receiving ibrutinib for mantle cell lymphoma, AKI developed in three (2.7 percent) [168]. Overall, increases in serum creatinine levels of up to 1.5 times the upper limit of normal (ULN) and 1.5 to 3 times ULN have been reported in 67 and 9 percent of patients treated with ibrutinib, respectively [169]. The mechanism of this injury is unclear at this point, but tumor lysis syndrome might be contributory. (See "Tumor lysis syndrome: Pathogenesis, clinical manifestations, definition, etiology and risk factors".)

Less than 1 percent of ibrutinib is excreted renally, and exposure is not altered in patients with mild to moderate kidney dysfunction (CrCl >25 mL/min). Data are not available for patients with worse kidney function or those on dialysis.

Moxetumomab — Moxetumomab pasudotox is a CD22-directed cytotoxin that is approved for treatment of refractory hairy cell leukemia (HCL). (See "Treatment of hairy cell leukemia", section on 'Moxetumomab pasudotox'.)

Renal toxicity has been reported with this agent:

In a phase II trial of 80 patients, AKI of any grade was reported during therapy in three patients (4 percent), and grade 3 or 4 AKI occurred in two [171].

In a combined safety database of 129 HCL patients treated with moxetumomab pasudotox, 34 (26 percent) reported an adverse kidney event of any grade, including AKI, renal failure and kidney impairment (approximately 2 percent each), increase in serum creatinine (17 percent), and proteinuria (8 percent) [172]. Most were mild to moderate in severity; only two patients had grade 3 AKI (table 1). At the end of treatment, serum creatinine remained elevated in 5 percent of patients.

The United States Prescribing Information recommends monitoring renal function prior to each dose, and delaying a new cycle of treatment in patients with grade 3 or worse elevations in creatinine or upon worsening from baseline by two or more grades. There is no guidance concerning initial dose reduction in patients with preexisting kidney impairment.

PARP inhibitors — Inhibitors of poly-adenosine diphosphate ribose polymerase (PARP) are approved for treatment of BRCA-mutated breast cancer, for platinum-sensitive relapsed epithelial ovarian cancer (regardless of BRCA mutation status), and as maintenance therapy for pancreatic cancer in patients with BRCA1 or BRCA2 mutations who have not progressed after platinum-based chemotherapy. (See "Medical treatment for relapsed epithelial ovarian, fallopian tube, or peritoneal cancer: Platinum-sensitive disease", section on 'PARP inhibition' and "ER/PR negative, HER2-negative (triple-negative) breast cancer", section on 'Patients with previous exposure to chemotherapy' and "Initial systemic chemotherapy for metastatic exocrine pancreatic cancer", section on 'PARP inhibitor maintenance therapy'.)

Olaparib is extensively metabolized in the liver, and 44 percent of the drug is excreted in the urine. Increases in creatinine have been reported in 25 to 30 percent of patients treated with olaparib, but most are mild (only 2 percent are grade 3 (table 1)) [173]. The United States Prescribing Information recommends a dose reduction for patients with moderate kidney impairment (CrCl 31 to 50 mL/min). Cancer Care Ontario also recommends a dose reduction for CrCl 31 to 50 mL/min and suggests not using the drug with worse chronic kidney disease or end-stage kidney disease.

Deterioration in kidney function during therapy is also reported with niraparib [174].

Urine excretion is a major route of elimination for another of these agents: talazoparib. The United States Prescribing Information for talazoparib suggests a reduced initial dose in patients with moderate (CrCl 30 to 59 mL/min) and severe (CrCl 15 to 29 mL/min) kidney impairment. The drug has not been studied in those requiring hemodialysis.

Selinexor — Selinexor is a selective inhibitor of the nuclear export protein exportin 1 (XPO1); it is approved in combination with dexamethasone for the treatment of multiply relapsed or refractory multiple myeloma and for relapsed/refractory diffuse large B cell lymphoma. (See "Diffuse large B cell lymphoma (DLBCL): Second or later relapse or patients who are medically-unfit", section on 'Selinexor' and "Multiple myeloma: Treatment of third or later relapse", section on 'Selinexor'.)

Selinexor can cause hyponatremia, which may be severe [175-177]. In an integrated safety analysis of 437 patients enrolled in clinical trials of selinexor in multiple myeloma, hyponatremia (defined as serum sodium <135 mmol/L) was observed in 138 (32 percent), and 83 (19 percent) had grade ≥3 hyponatremia (table 2) [177].

The mechanism of hyponatremia is not yet elucidated.

The United States Prescribing Information for selinexor recommends close monitoring of serum sodium levels, particularly in the first two months of treatment, and provides dose modification guidelines for serum sodium levels ≤130 mEq/L during therapy.

CDK4/6 inhibitors — The cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors palbociclib, ribociclib, and abemaciclib are used in the care of patients with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative (HR+/HER2-) advanced breast cancer.

Between 10 and 25 percent of patients treated with abemaciclib have increased serum creatinine levels during therapy, whereas to date none of the clinical trials on palbociclib have reported increased serum creatinine levels [178-184]. In a post hoc analysis of the MONARCH I study, the rise in serum creatinine seen with abemaciclib was not accompanied by changes in other markers of kidney function such as blood urea nitrogen, cystatin C, or eGFR based on cystatin C [185,186]. The underlying mechanism and the extent of kidney damage related to this agent remain unclear. Another study found that patients receiving abemaciclib experienced a mild (approximately 10 to 40 percent) reversible increase in serum creatinine due to inhibition of tubular creatinine secretion. Data on other CDK4/6 inhibitors are limited but a similar pathophysiology for elevated serum creatinine levels is likely. (See "Drugs that elevate the serum creatinine concentration", section on 'Decreased secretion'.)

Although creatinine levels typically remain elevated during abemaciclib treatment, they return to normal upon treatment discontinuation [184]. Dose adjustments of abemaciclib should not be based upon creatinine levels, because they may not reflect true kidney function. If a clinician suspects deterioration in kidney function, alternative measurements of kidney function (ie, levels of cystatin C and cystatin-based eGFR) can be assessed in order to recognize true AKI as opposed to impaired tubular creatinine secretion. (See "Assessment of kidney function", section on 'eGFR from cystatin C'.)

No dose adjustments are necessary for palbociclib for reduced kidney function, but this has not been evaluated in patients with advanced chronic kidney disease or those on dialysis. For ribociclib, a dose reduction of the initial dose to 200 mg once daily is needed for patients with eGFR 15 to 30 mL/min/1.73 m2 (based on a pharmacokinetic study in subjects without cancer; ribociclib has not been studied in patients with breast cancer and severe kidney function impairment) [187].

No data are available for dosing of abemaciclib from the manufacturer.

OTHER BIOLOGIC AGENTS

Interferons — Recombinant interferon alfa (IFNa) can cause proteinuria, which can be massive; the histology is consistent with minimal-change nephropathy or focal segmental glomerulosclerosis [188,189]. Thrombotic microangiopathy is a rare complication seen mostly in patients with chronic myeloid leukemia treated with high doses of IFNa over long periods of time [190]. (See "Focal segmental glomerulosclerosis: Pathogenesis", section on 'Interferon' and "Overview of kidney disease in the cancer patient", section on 'Chemotherapy-associated glomerular disorders'.)

Interferon gamma has been associated with acute tubular necrosis when used for the treatment of acute lymphoblastic leukemia [191]. However, this agent is not currently used clinically for treatment of any neoplastic condition.

Interleukin-2 — Recombinant human interleukin-2 (IL-2) can induce a relatively severe capillary leak syndrome, leading to edema, plasma volume depletion, and a reversible fall in glomerular filtration rate (GFR) [192-194]. For example, in one study of 199 consecutive patients, most patients experienced oliguria, hypotension, and weight gain, and 13 percent of cycles were discontinued because of a substantial rise in the plasma creatinine concentration (from 1.2 to 2.7 mg/dL [106 to 238 micromol/L]) [194]. Poor renal function promptly reversed after cessation of therapy.

It has been proposed that plasma volume depletion is responsible for the development of acute kidney failure. Although the clinical course and improvement in creatinine clearance (CrCl) and urine output following low-dose dopamine [195] are compatible with this hypothesis, the observations that renal plasma flow is normal in affected patients [192] and that the urinalysis may reveal red cells, white cells, granular casts, and modest proteinuria [193] suggest that there may also be some direct kidney injury.

Patients with normal kidney function before treatment usually recover within the first week after discontinuing therapy. Patients with underlying kidney impairment may take longer periods of time to recover from the kidney failure.

Therapy for kidney failure secondary to IL-2 treatment is supportive. It is directed at maintaining intravascular volume and stabilizing hemodynamic parameters, as well as avoiding other potential nephrotoxic agents. Preventive measures include a strict selection of patients who are candidates for IL-2 therapy. Older patients, patients with underlying kidney failure, and patients taking nephrotoxic agents are at higher risk for complications such as capillary leak syndrome and prerenal azotemia.

SUMMARY

Molecularly targeted anticancer agents can cause kidney toxicity by a number of mechanisms. Several factors can potentiate kidney dysfunction and contribute to nephrotoxicity, including intravascular volume depletion, the concomitant use of non-chemotherapeutic nephrotoxic drugs (eg, aminoglycoside antibiotics, nonsteroidal anti-inflammatory drugs [NSAIDs]) or radiographic ionic contrast media in patients with or without preexisting renal 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. (See "Chemotherapy nephrotoxicity and dose modification in patients with kidney impairment: Conventional cytotoxic agents", section on 'Risk factors for nephrotoxicity'.)

For those drugs in which renal excretion is an important determinant of elimination of the intact drug or an active metabolite, renal impairment can alter excretion and increase systemic toxicity. Dose adjustment is often required. The most commonly used molecularly targeted agents for which dose modification may be needed in the setting of kidney insufficiency are listed in the table (table 3).

Dose adjustment in this setting is typically based upon two factors: an estimation of glomerular filtration rate (GFR), which 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 all bedside formula for estimating GFR provide similar levels of concordance when used for the purpose of dosing renally excreted cancer drugs. (See "Chemotherapy nephrotoxicity and dose modification in patients with kidney impairment: Conventional cytotoxic agents", section on 'Estimation of GFR for possible dose adjustment'.)

Minimizing nonrenal systemic toxicity in patients receiving molecularly targeted agents may be a particular problem in patients on chronic dialysis, especially when the details of drug elimination and metabolism are not fully known. For patients undergoing dialysis, two issues must be considered (see "Chemotherapy nephrotoxicity and dose modification in patients with kidney impairment: Conventional cytotoxic agents", section on 'Drug handling in dialysis patients'):

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.

Chimeric antigen receptor modified T (CAR-T) cells are a form of genetically modified autologous immunotherapy that can be used to treat certain forms of non-Hodgkin lymphoma and leukemia. Over 40 percent of patients undergoing CAR-T cell therapy develop cytokine release syndrome, which can result in multiorgan dysfunction, including acute kidney injury (AKI). Electrolyte abnormalities are also observed, which can be attributable to tumor lysis syndrome in some cases. (See 'CAR-T cell therapy' above.)

AKI is a rare complication of checkpoint inhibitor immunotherapy. The most common reported underlying pathology is acute tubulointerstitial nephritis, but immune complex glomerulonephritis and thrombotic microangiopathy have also been observed. (See 'Checkpoint inhibitor immunotherapy' above.)

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Topic 114914 Version 30.0

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