Version October 2024
INTRODUCTION — Some anticancer therapies take advantage of molecular alterations that have been detected in certain types of cancer. These therapies are collectively referred to as molecularly targeted agents. However, many of these drugs have been associated with significant kidney complications, ranging from electrolyte disorders to acute kidney injury requiring dialysis [1-3].
Therapeutic approaches that harness the immune system to control and treat cancer are known as "immunotherapy." Some immunotherapy regimens can also cause significant kidney complications. (See "Principles of cancer immunotherapy".)
This topic review will cover kidney toxicities seen with several classes of molecularly targeted agents and immunotherapy used for cancer treatment. Nephrotoxicity of chemotherapy and other cytotoxic agents is discussed separately. (See "Nephrotoxicity of chemotherapy and other cytotoxic agents".)
DOSING CONSIDERATIONS FOR NEPHROTOXICITY — Some agents may require dose adjustments in patients with baseline kidney disease and those who develop kidney toxicity while on cancer treatment. When known, individual drug dosing guidelines and adjustments for kidney toxicity are available through the drug monographs included with UpToDate.
ALK INHIBITORS
Crizotinib — Crizotinib is a kinase inhibitor that is used to treat advanced anaplastic lymphoma kinase (ALK) fusion gene-positive non-small cell lung cancer. (See "Anaplastic lymphoma kinase (ALK)-positive advanced non-small cell lung cancer", section on 'Crizotinib'.)
Drug-induced reductions in glomerular filtration rate (GFR) have been reported in patients treated with crizotinib, mostly during the first two weeks of therapy [4]. 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. 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 [5].
However, rare cases of acute kidney injury (AKI) have been reported following treatment with crizotinib [6-8]. In two such cases, kidney biopsy revealed evidence of acute tubular injury.
In addition, the development of complex kidney cysts (3 percent) has been described in patients treated with crizotinib [9-11]. Both the formation of new cysts and progression of preexisting kidney 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 [10]. The mechanism by which crizotinib induces cyst formation and/or growth is unknown. The diagnosis and management of kidney cysts in adults are discussed separately. (See "Simple and complex kidney cysts in adults".)
Hyponatremia and hypokalemia have also been reported with crizotinib [3,12]. Management of these electrolyte disorders is presented separately. (See "Overview of the treatment of hyponatremia in adults" and "Clinical manifestations and treatment of hypokalemia in adults".)
Other ALK inhibitors — Other available anaplastic lymphoma kinase (ALK) inhibitors include ceritinib, alectinib, brigatinib, and lorlatinib. Increases in creatinine have been seen in 11 to 28 percent of patients treated with alectinib [13,14], and proteinuria has been reported with lorlatinib [15].
ANTIANGIOGENIC AGENTS — Angiogenesis inhibitors are used to treat a variety of cancers, such as renal cell carcinoma and colorectal cancer, among others. (See "Systemic therapy for advanced and metastatic clear cell renal carcinoma" and "Initial systemic therapy for metastatic colorectal cancer".)
These agents, which block the vascular endothelial growth factor (VEGF) pathway, include the following:
●Ligand inhibitors, which bind to and inhibit ligand binding to the VEGF receptor (VEGFR), thereby preventing activation of the receptor. Examples include bevacizumab (or other biosimilars), ramucirumab, and aflibercept.
●Receptor tyrosine kinase inhibitors (TKIs), which block the intracellular domain of the VEGFR. Examples include sunitinib, sorafenib, pazopanib, ponatinib, axitinib, cabozantinib, lenvatinib, regorafenib, vandetanib, cabozantinib, tivozanib, and fruquintinib, among others.
Class effects of antiangiogenic agents
Proteinuria/nephrotic syndrome — 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 [16-18]. Hypertension frequently accompanies proteinuria. (See "Cardiovascular toxicities of molecularly targeted antiangiogenic agents", section on 'Hypertension'.)
●Incidence and mechanism – The overall incidence of mild proteinuria in patients treated with bevacizumab ranges from 21 to up to 63 percent. However, grade 3 or 4 proteinuria (table 1) (defined as 3+ on dipstick, >3.5 g of protein/24 hours, or the nephrotic syndrome) affects approximately 2 percent of treated patients [19]. The incidence of proteinuria is not higher in patients who receive shorter bevacizumab infusions (ie, 10 versus 90 minutes) [20].
Less data are available for aflibercept. In a phase III trial, proteinuria developed in 62 percent of patients treated with aflibercept plus chemotherapy (versus 41 percent of those treated with chemotherapy alone), and it was severe (grade 3 or 4) in 7.8 versus 1.2 percent [21].
Among patients treated with ramucirumab, the risk of proteinuria may be lower. In a meta-analysis of six placebo-controlled randomized trials, the incidence of all-grade proteinuria for ramucirumab versus placebo was 9.4 versus 3.1 percent, while the risk of severe (grade 3 or 4) proteinuria was 1.1 versus 0.04 percent [22].
Among patients treated with antiangiogenic TKIs, the incidence of mild and asymptomatic proteinuria also ranges from 21 to 63 percent, but heavy proteinuria is reported in up to 6.5 percent of patients [17]. In a meta-analysis, the incidence of all-grade and high-grade proteinuria with VEGFR TKIs was 18.7 and 2.4 percent, respectively, with a corresponding increased risk of all-grade (odds ratio [OR] 2.92, 95% CI 1.09-7.82) and high-grade (OR 1.97, 95% CI 1.01-3.84) proteinuria when compared with controls [23]. The incidence of proteinuria with regorafenib may be lower than with other agents (7 percent all grade in one trial, 1 percent grade 3 or 4) [24].
The exact mechanism underlying proteinuria is not known. Reports of kidney biopsies among patients with proteinuria receiving VEGF-targeted agents are sparse. In an observational study that included 100 patients who underwent kidney biopsies due to anti-VEGF treatment-related hypertension and proteinuria, the most common histologic findings were thrombotic microangiopathy (TMA) and minimal change disease and/or collapsing-like focal segmental glomerulosclerosis (MCN/cFSGS) in 73 and 27 patients, respectively [25]. While TMA was associated predominantly with VEGF ligand inhibitor therapy, MCN/cFSGS was associated with VEGF TKI therapy. The factors associated with the occurrence and severity of proteinuria are unknown. Preexisting kidney disease (including higher baseline urine protein levels and hypertension) and renal cell carcinoma, as compared with other malignant diseases, may be predisposing factors. (See "Systemic therapy for advanced and metastatic clear cell renal carcinoma", section on 'Patients with chronic kidney disease'.)
●Management – The implications of asymptomatic proteinuria from VEGF inhibitors are unknown, and it is possible that most 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. 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'.)
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 [26]. However, this complication is uncommon, and many institutions do not routinely dipstick urine prior to each dose of bevacizumab.
Baseline and periodic urinalyses are recommended during treatment with pazopanib, lenvatinib, axitinib, and tivozanib, 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 and tivozanib but undefined for axitinib). There are no guidelines for other VEGF TKIs; however, good clinical practice dictates baseline and periodic assessment of proteinuria for these agents as well.
Although discontinuation of the antiangiogenic agent results in significant reduction in proteinuria, persistence is common [27]. For patients with persistent proteinuria, in the absence of specific therapy directed against the underlying disease, lowering of intraglomerular pressure, which may reduce protein excretion, may be achieved by the administration of an angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB). However, there are no randomized controlled trials evaluating the benefit of these agents in patients with proteinuria due to antiangiogenic agents. (See "Overview of the management of chronic kidney disease in adults", section on 'Patients with proteinuria'.)
Thrombotic microangiopathy — Rarely, cases of systemic drug-induced TMA have been reported with specific antiangiogenic agents (eg, bevacizumab, sorafenib, sunitinib). Patients may present with microangiopathic hemolysis; kidney-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'.)
Management of drug-induced TMA is presented separately. (See "Drug-induced thrombotic microangiopathy (DITMA)".)
Other kidney toxicities — Other kidney toxicities reported with specific antiangiogenic agents are discussed below.
Lenvatinib — Lenvatinib is an orally active inhibitor of several tyrosine kinases, including VEGFR, fibroblast growth factor receptor (FGFR), platelet-derived growth factor receptor (PDGFR), RET, and KIT. In addition to proteinuria, a class effect of VEGF inhibitors, serious, including fatal, kidney failure or impairment can occur in patients treated with lenvatinib [28-30]:
●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) [29]. 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 [30].
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 [24,31,32]. These abnormalities are usually mild to moderate and do not require dose reductions or treatment interruptions.
Sorafenib and sunitinib — Sorafenib and sunitinib have been associated with acute and chronic interstitial nephritis in case reports [33-35]. Sorafenib is also known to cause hypophosphatemia and hypocalcemia [36]. This effect has been attributed to vitamin D malabsorption and secondary hyperparathyroidism, although the precise mechanism for this is unclear [37]. Thus, in patients taking sorafenib, vitamin D, phosphorus, and calcium levels should be routinely monitored.
Vandetanib — Vandetanib is an orally active inhibitor of several tyrosine kinases, including RET, VEGFR, and epidermal 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 [38,39]. Hypertension has been reported in approximately 10 to 34 percent of patients [38,40,41].
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 kidney clearance and increased nephrotoxicity of other coadministered agents, such as cisplatin [42].
BCL-2 INHIBITORS — 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 tumor lysis syndrome (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. These issues are discussed in more detail separately. (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::ABL AND KIT INHIBITORS — There are several small molecule inhibitors of BCR::ABL, a tyrosine kinase that is the constitutively activated protein 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).
Imatinib — Imatinib is a small molecule first-generation tyrosine kinase inhibitor (TKI) that targets BCR::ABL 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 [43-47]. In one study, acute kidney injury (AKI) and chronic kidney disease occurred in 7 and 12 percent of patients, respectively; with long-term treatment, the mean decrease in estimated glomerular filtration rate (eGFR) was 2.77 mL/min/1.73 m2 per year [43]. Potential mechanisms of injury include tumor lysis syndrome (TLS), acute tubular injury, and rhabdomyolysis; inhibition of tubular secretion of creatinine may also be a contributing factor to an observed rise in serum creatinine [44,45,48-52]. Kidney function impairment appears to be dose dependent, as higher doses have been associated with a higher incidence of tubular damage [51].
Hypophosphatemia can occur in patients treated with imatinib [53,54], with one case series reporting an incidence of 51 percent [53]. 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)".)
Dasatinib — Dasatinib is a second-generation TKI used mainly in patients with imatinib-resistant CML. It has effects on BCR::ABL 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 dasatinib [55-61], including one patient who developed rhabdomyolysis [59] and others with thrombotic microangiopathy [58,62]. In addition, there have been reports of proteinuria and nephrotic syndrome [60,61,63]; 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) [64,65].
Bosutinib — Bosutinib is a dual 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 AKI, hypophosphatemia and an apparently reversible decline in GFR have been reported during long-term therapy with bosutinib [46].
Other agents
●Nilotinib – Nilotinib has not been reported to cause nephrotoxicity.
●Ponatinib – Ponatinib, a multitargeted TKI with activity against the VEGF receptor, has been associated with the development of nephrotic syndrome and secondary focal segmental glomerulosclerosis in one case report [66].
BRAF INHIBITORS — Vemurafenib and dabrafenib are potent inhibitors of the kinase domain in the mutant BRAF gene. These agents are used to treat BRAF V600E mutant melanoma. (See "Systemic treatment of metastatic melanoma with BRAF and other molecular alterations".)
●Vemurafenib – An increase in serum creatinine concentration has been reported with vemurafenib, which generally occurs in the first two months of therapy. This appears to be caused, at least in part, by inhibition of tubular creatinine secretion [67]. 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) [68-72] and one case of Fanconi syndrome have also been reported with vemurafenib [68-70,73]. The precise mechanism of kidney injury is unclear, but kidney biopsies, when performed, have shown evidence of acute tubular damage and interstitial fibrosis [71,72]. Vemurafenib-associated kidney injury appears to be more common in males [71,72].
●Dabrafenib – AKI can also occur with dabrafenib, although the incidence appears to be less than that with vemurafenib [71].
BRAF inhibitors (dabrafenib, vemurafenib, encorafenib) are frequently used in combination with mitogen-activated extracellular kinase (MEK) inhibitors (eg, trametinib, cobimetinib, binimetinib) for the treatment of various BRAF V600E mutated tumors. While nephrotoxicity has not been reported with MEK inhibitor monotherapy, the combination of BRAF and MEK inhibitors have been reported to cause kidney function impairment, hyponatremia, and rare cases of glomerulonephritis [74-78]. As an example, in one study of encorafenib plus binimetinib in metastatic BRAF-mutant melanoma, the incidence of increased creatinine as a laboratory abnormality was 93 percent [26], but severe (grade 3 to 4) increases were uncommon (4 percent) (table 2 and table 1) [78-80].
BTK INHIBITORS
Ibrutinib — Ibrutinib is an orally active, covalent (irreversible) inhibitor of Bruton tyrosine kinase (BTK), a mediator of the B cell receptor signaling pathway that inhibits malignant B cell survival. The use of this agent to treat chronic lymphocytic leukemia is discussed separately. (See "Selection of initial therapy for symptomatic or advanced chronic lymphocytic leukemia/small lymphocytic lymphoma".)
Serious and potentially fatal cases of acute kidney injury (AKI) have occurred with ibrutinib therapy [81-83]. In one report of 111 patients receiving ibrutinib for mantle cell lymphoma, AKI developed in three (2.7 percent) [81]. 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 [82]. The mechanism of this injury is unclear at this point, but tumor lysis syndrome (TLS) might be contributory. (See "Tumor lysis syndrome: Pathogenesis, clinical manifestations, definition, etiology and risk factors".)
Pirtobrutinib — Pirtobrutinib is an orally active, non-covalent (reversible) inhibitor of BTK, a mediator of the B cell receptor signaling pathway that inhibits malignant B cell survival. The use of this agent to treat mantle cell lymphoma is discussed separately. (See "Treatment of relapsed or refractory mantle cell lymphoma", section on 'Bruton tyrosine kinase inhibitors'.)
Pirtobrutinib has been reported to cause increased creatinine levels. In one study, the incidence of increased creatinine of any grade was 30 percent, but severe (grade 3 to 4) increases were uncommon (less than 2 percent) [84].
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. (See "Treatment for hormone receptor-positive, HER2-negative 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 [85-91]. 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 estimated glomerular filtration rate (eGFR) based on cystatin C [92,93]. 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 [91]. Dose adjustments of abemaciclib should not be based upon creatinine levels because they may not reflect true kidney function. If deterioration in kidney function is suspected, alternative measurements of kidney function (ie, levels of cystatin C and cystatin-based eGFR) can be obtained to distinguish true acute kidney injury (AKI) from impaired tubular creatinine secretion. (See "Assessment of kidney function", section on 'eGFR from cystatin C'.)
EGFR INHIBITORS — Inhibitors of the epidermal growth factor receptor (EGFR) pathway include small molecule tyrosine kinase inhibitors (TKIs) (afatinib, erlotinib, and gefitinib) and monoclonal antibodies targeting the EGFR (cetuximab and panitumumab). These agents are used in the treatment of advanced colorectal cancer and head and neck cancer. (See "Initial systemic therapy for metastatic colorectal cancer", section on 'Benefit of cetuximab and panitumumab' and "Treatment of metastatic and recurrent head and neck cancer".)
Anti-EGFR monoclonal antibodies — Monoclonal antibodies targeting the EGFR (cetuximab and panitumumab) are all associated with the progressive development of hypomagnesemia due to renal magnesium wasting [94-99].
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 [100]. 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 [101-103].
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 [104]. 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 kidney toxicities have been reported with cetuximab, including acute kidney injury (AKI) [3,105], one case report of diffuse proliferative glomerulonephritis [106], and another case report of nephrotic syndrome [107]. 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) [108]. Patients treated with cetuximab had the highest incidence of high-grade hyponatremia (34.8 percent).
EGFR tyrosine kinase inhibitors — Afatinib, erlotinib, gefitinib, dacomitinib, osimertinib, and mobocertinib (withdrawn by manufacturer) 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 hyponatremia, hypocalcemia, hypomagnesemia, hypokalemia, and hypophosphatemia) have been reported with all EGFR TKIs, although the incidence overall seems less than that with the EGFR monoclonal antibodies [3]. Such electrolyte abnormalities should be corrected prior to initiating therapy to reduce the risk of cardiotoxicity seen with some of these agents (eg, mobocertinib). Further details are discussed separately. (See "Cardiotoxicity of cancer chemotherapy agents other than anthracyclines, HER2-targeted agents, and fluoropyrimidines", section on 'Osimertinib and mobocertinib'.)
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 [109-111].
FGFR INHIBITORS — Fibroblast growth factor receptor (FGFR) inhibitors, such as erdafitinib, are used in the treatment of metastatic bladder cancer. (See "Treatment of metastatic urothelial carcinoma of the bladder and urinary tract".)
All inhibitors of FGFR (eg, erdafitinib and pemigatinib) cause hyperphosphatemia as a class effect. This is 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 [112-117]. (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 [118]. Although hyperphosphatemia occurs in over 60 percent of treated patients, it is generally mild (grade 1 or 2 (table 3)). 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 [114], 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 [119-122]. In one study, 6 percent of patients treated with erdafitinib experienced AKI, with 2 percent having grade 3 or higher AKI [120]. In a case report describing AKI with rogaratinib, a selective pan-FGFR tyrosine kinase inhibitor (TKI), kidney biopsy showed acute tubular necrosis [119]. AKI improved with treatment discontinuation, and reintroduction of therapy at a lower dose level did not prompt recurrence of kidney injury.
HER2 INHIBITORS — Systemic agents that inhibit human epidermal growth factor receptor 2 (HER2) are used to treat a variety of malignancies that express HER2, such as breast cancer, gastric cancer, colorectal cancer, and salivary gland tumors. (See "Systemic treatment for HER2-positive metastatic breast cancer" and "Second- and later-line systemic therapy for metastatic colorectal cancer", section on 'RAS wild-type, HER2 overexpressors' and "Second- and later-line systemic therapy for metastatic gastric and esophageal cancer", section on 'HER2-positive adenocarcinoma' and "Malignant salivary gland tumors: Treatment of recurrent and metastatic disease", section on 'HER2 overexpression'.)
●Trastuzumab is a recombinant humanized monoclonal antibody that binds to the extracellular domain of HER2 and inhibits proliferation of cells that overexpress the HER2 protein.
●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.
●Ado-trastuzumab emtansine (T-DM1) is an antibody-drug conjugate consisting of trastuzumab linked to the microtubule inhibitor emtansine (DM1), a derivative of maytansine.
●Lapatinib is a dual tyrosine kinase inhibitor (TKI) that interrupts both the EGFR (erbB1) and HER2 (erbB2) pathways.
●Tucatinib is an oral TKI that is selective for the kinase domain of HER2, with minimal inhibition of EGFR.
●Fam-trastuzumab deruxtecan is an antibody-drug conjugate composed of an anti-HER2 antibody, a cleavable tetrapeptide-based linker, and a cytotoxic topoisomerase I inhibitor.
There are no published case reports of nephrotoxicity with either trastuzumab or pertuzumab.
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 [123-125]. (See "Gestational breast cancer: Treatment", section on 'Anti-HER2 therapies'.)
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 3)) [126,127].
In a phase II trial of lapatinib, seven patients experienced treatment-related grade 3 toxicity, two of whom developed hyponatremia [128]. An analysis of the US Food and Drug Administration (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 acute kidney injury (AKI) (48 cases); a few cases of hypertension, hypomagnesemia, and hyponatremia were also reported [3].
Increased creatinine of any grade has been reported with tucatinib (14 to 58 percent) and fam-trastuzumab deruxtecan (16 percent), but severe (grade 3 to 4) toxicity is extremely rare for both agents (not reported for tucatinib and 1 percent for fam-trastuzumab deruxtecan) [26].
MTOR INHIBITORS — The extensive experience with mechanistic (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 [129,130]. (See "Biology of glomerular podocytes", section on 'Direct podocyte injury'.)
Proteinuria and, more rarely, kidney function impairment 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 is a parenterally administered rapamycin analog that functions as a competitive mTOR inhibitor. There are rare case reports of temsirolimus-associated glomerulopathy and acute tubular necrosis [131,132]. (See "Antiangiogenic and molecularly targeted therapy for advanced or metastatic clear cell renal carcinoma".)
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 "Systemic therapy of metastatic well-differentiated pancreatic neuroendocrine tumors", section on 'Lutetium Lu-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 [133]). Following treatment, the average annual decrease in creatinine clearance (CrCl) was 3.4 percent, but no patient had an annual decrease in kidney 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 function impairment (GFR loss >2 mL/min/m2 per year) in 43 percent [134]. By contrast, there was only one case of grade 3 or worse nephrotoxicity (table 2) as assessed by serum creatinine (1.3 percent).
OTHER TARGETED AGENTS
MET inhibitors — Capmatinib and tepotinib are mesenchymal-epithelial transition (MET) tyrosine kinase inhibitors (TKIs) 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 [135,136]. Inhibition of tubular creatinine secretion may explain this phenomenon.
PARP inhibitors — Inhibitors of poly(ADP-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 inhibitors no longer used' and "ER/PR negative, HER2-negative (triple-negative) breast cancer", section on 'Patients with previous exposure to chemotherapy' and "Initial systemic therapy for metastatic exocrine pancreatic cancer", section on 'Maintenance therapy'.)
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 2)) [137]. Deterioration in kidney function during therapy has also been reported with niraparib [138].
Oral gamma secretase inhibitors — Nirogacestat is an oral gamma secretase inhibitor that targets the NOTCH pathway. This agent is used to treat desmoid tumors. (See "Desmoid tumors: Systemic therapy".)
Hyperphosphatemia is a class effect of oral gamma secretase inhibitors [139]. In a phase III trial of patients with desmoid tumors, hyperphosphatemia of any grade was observed in 42 percent of patients treated with nirogacestat, although severe (grade ≥3) hyperphosphatemia was uncommon (3 percent) [140].
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 "Multiple myeloma: Treatment of second or later relapse", section on 'Selinexor' and "Diffuse large B cell lymphoma (DLBCL): Second or later relapse or patients who are medically unfit", section on 'Selinexor'.)
Selinexor can cause hyponatremia, which may be severe [141-143]. 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 3) [143].
The mechanism of hyponatremia is not yet elucidated.
IMMUNOTHERAPIES — Therapeutic approaches that harness the immune system to control and treat cancer are known as "immunotherapy." Some immunotherapy regimens can also cause significant kidney complications. (See "Principles of cancer immunotherapy".)
Bispecific T-cell engagers — Bispecific T-cell engagers (BiTEs) are antibodies that function as linkers between T cells and specific target antigens. (See "Principles of cancer immunotherapy", section on 'Bispecific T cell engagers'.)
Examples of BiTEs used in clinical practice include teclistamab, elranatamab, talquetamab, and blinatumomab. (See "Multiple myeloma: Administration considerations for common therapies", section on 'Bispecific antibodies' and "Treatment of relapsed or refractory acute lymphoblastic leukemia in adults", section on 'Blinatumomab'.)
BiTes are commonly associated with cytokine release syndrome (CRS), which can result in multiorgan dysfunction, including acute kidney injury (AKI). As an example, in a phase I trial of patients with treatment-refractory multiple myeloma treated with teclistamab, CRS was observed in a majority (72 percent) of patients [144]. The evaluation and management of BiTE-associated CRS is discussed separately. (See "Cytokine release syndrome (CRS)", section on 'Bispecific T cell engager-associated CRS'.)
CAR-T cell therapy — Chimeric antigen receptor modified (CAR)-T cells are a form of genetically modified autologous immunotherapy. 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. (See "Principles of cancer immunotherapy", section on 'CAR-T cells'.)
CAR-T cell therapy is used to treat certain hematologic malignancies including leukemia, lymphoma, and multiple myeloma. Examples that are used in clinical practice include CAR-T cells directed against CD19 (axicabtagene ciloleucel, brexucabtagene autoleucel, lisocabtagene maraleucel, loncastuximab tesirine, tisagenlecleucel) and BCMA (ciltacabtagene autoleucel, idelcabtagene vicleucel). (See "Treatment of relapsed or refractory acute lymphoblastic leukemia in adults", section on 'CAR-T' and "Diffuse large B cell lymphoma (DLBCL): Second or later relapse or patients who are medically unfit", section on 'Chimeric antigen receptor T cell therapy' and "Multiple myeloma: Treatment of second or later relapse", section on 'Chimeric antigen receptor T cells'.)
In published trials of CD19-directed CAR-T cell therapy, a CRS has been reported in over 40 percent of patients, regardless of the disease studied or the construct of the CAR-T cells [145-147]. CRS can result in multiorgan dysfunction, including AKI [148,149]. 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 [150,151]. 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 incidence of CRS among patients receiving CAR-T cell therapies was 75 percent, the overall estimated incidence of AKI was 19 percent, and the estimated incidence of AKI requiring kidney replacement therapy was 4 percent [152]. A subgroup analysis found that the incidence of AKI was higher among children and young adults compared with adults (22 versus 17 percent).
In this analysis, most patients had received axicabtagene ciloleucel, a CD19-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 CD19 but has a different costimulatory domain and a reduced inflammatory profile, may be associated with lower toxicity rates, including AKI [148,153].
Besides age, other potential risk factors for AKI after CAR T-cell therapy are lower baseline kidney function at CAR-T cell initiation, exposure to intravenous contrast material, and a progressive increase in markers of tumor lysis or use of higher total doses of glucocorticoids or tocilizumab after CAR-T cell infusion [154].
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) [148]. 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. The mechanism is not clearly defined. The diagnosis and management of TLS is discussed separately. (See "Tumor lysis syndrome: Pathogenesis, clinical manifestations, definition, etiology and risk factors", section on 'Clinical manifestations' and "Tumor lysis syndrome: Prevention and treatment".)
Immune checkpoint inhibitors — Immune checkpoint inhibitors (ICIs) are used to treat a variety of malignancies. These antibodies inhibit the following targets to enhance the immune system as part of cancer therapy (table 4). (See "Principles of cancer immunotherapy", section on 'Immune checkpoint inhibitors'.).
ICIs have a unique spectrum of side effects termed immune-related adverse events. Further details on these and other kidney toxicities seen with ICIs are discussed separately. (See "Toxicities associated with immune checkpoint inhibitors", section on 'Kidney'.)
Interleukin-2 — Recombinant human interleukin-2 (IL-2) was initially used to treat advanced melanoma and kidney cancer, but its use has been effectively replaced by other effective, less toxic ICIs. (See "Interleukin 2 and experimental immunotherapy approaches for advanced melanoma", section on '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) [155-157]. Older patients, patients with underlying kidney failure, and patients taking nephrotoxic agents are at higher risk for capillary leak syndrome and prerenal azotemia. 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]) [157]. Poor kidney function promptly reversed after cessation of therapy.
It has been proposed that plasma volume depletion is responsible for the development of AKI. Although the clinical course and improvement in creatinine clearance (CrCl) and urine output following low-dose dopamine [158] are compatible with this hypothesis, the observations that renal plasma flow is normal in affected patients [155] and that the urinalysis may reveal red cells, white cells, granular casts, and modest proteinuria [156] 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 function impairment may take longer periods of time to recover from the kidney injury.
Therapy for kidney injury 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. The management of capillary leak syndrome is discussed separately. (See "Idiopathic systemic capillary leak syndrome", section on 'Treatment'.)
SUMMARY
●General principles – Some molecularly targeted agents and immunotherapies that are used to treat cancer have been associated with significant kidney complications. The kidney toxicities of different drug classes are described in detail above. Selected agents are highlighted below.
●Dosing considerations – Some agents may require dose adjustments in patients with baseline kidney disease and those who develop kidney toxicity while on cancer treatment. When known, individual drug dosing guidelines and adjustments for kidney toxicity are available through the drug monographs included within UpToDate. (See 'Dosing considerations for nephrotoxicity' above.)
●Molecularly targeted agents
•Antiangiogenic agents – Antiangiogenic agents block the vascular endothelial growth factor (VEGF) pathway. These agents include ligand inhibitors, which bind to and inhibit ligand binding to the VEGF receptor (VEGFR), thereby preventing activation of the receptor, and receptor tyrosine kinase inhibitors (TKIs), which block the intracellular domain of the VEGFR. Specific nephrotoxic class effects of antiangiogenic agents include:
-Proteinuria/nephrotic syndrome – The overall incidence of proteinuria ranges from 21 to 63 percent, but severe (grade 3 or 4) proteinuria (table 1) is uncommon. Patients treated with these agents should be intermittently monitored for proteinuria; treatment interruption or discontinuation may be indicated for moderate to severe proteinuria. (See 'Proteinuria/nephrotic syndrome' above.)
-Thrombotic microangiopathy (TMA) – TMA is rare but has been reported with specific antiangiogenic agents (eg, bevacizumab, sorafenib). Patients may present with microangiopathic hemolysis; kidney-only manifestations including acute kidney injury (AKI) 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 'Thrombotic microangiopathy' above and "Drug-induced thrombotic microangiopathy (DITMA)".)
•CDK4/6 inhibitors – The cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor abemaciclib results in increased serum creatinine levels in 10 to 25 percent of patients, which is likely related to inhibition of tubular creatinine secretion. These creatinine levels typically remain elevated during therapy and return to normal upon treatment discontinuation. If deterioration in kidney function is suspected, alternative measurements of kidney function (ie, levels of cystatin C and cystatin-based estimated glomerular filtration rate [eGFR]) can be obtained to distinguish true AKI from impaired tubular creatinine secretion. (See 'CDK4/6 inhibitors' above.)
•EGFR inhibitors – Hypomagnesemia is common with anti-epidermal growth factor receptor (EGFR) monoclonal antibodies (cetuximab and panitumumab). Other electrolyte disorders (such as hyponatremia, hypocalcemia, hypomagnesemia, hypokalemia, and hypophosphatemia) have been reported with all EGFR TKIs. (See 'EGFR inhibitors' above.)
•FGFR inhibitors – Hyperphosphatemia is a class effect of fibroblast growth factor receptor (FGFR) inhibitors (eg, erdafitinib, infigratinib, and pemigatinib). (See 'FGFR inhibitors' above.)
•Ibrutinib – Ibrutinib has been associated with serious and potentially fatal cases of AKI. The mechanism of injury is unclear, but tumor lysis syndrome (TLS) may be contributory. (See 'Ibrutinib' above.)
•Imatinib – Imatinib is associated with acute and chronic kidney injury when administered for extended durations and hyperphosphatemia. (See 'Imatinib' above.)
●Immunotherapies
•CAR-T cell therapy – Chimeric antigen receptor modified (CAR)-T cells can cause cytokine release syndrome (CRS) and AKI. Electrolyte disorders have also been reported, including hyperphosphatemia and hyperkalemia related to TLS but also hypokalemia and hypophosphatemia unrelated to TLS. (See 'CAR-T cell therapy' above and "Cytokine release syndrome (CRS)", section on 'CAR-T cell-associated CRS'.)
•Immune checkpoint inhibitors – Immune checkpoint inhibitors have a unique spectrum of side effects termed immune-related adverse events. Further details are discussed separately. (See "Toxicities associated with immune checkpoint inhibitors", section on 'Kidney'.)
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