Erlotinib is the first-line treatment for patients with locally advanced or metastatic EGFR mutations with NSCLC, primarily as maintenance therapy for these patients (30). Erlotinib can be used in combination with VEGF antibodies, such as bevacizumab (31). The usual dose of erlotinib is 150 mg orally per day, and the drug binds to plasma proteins up to 95%. Its metabolites are excreted mainly in feces, while the proportion of renal elimination is less than 9% (32). FDA Adverse Event Reporting System (FAERS) review revealed that 63 patients with acute kidney injury and 8 patients developed hypomagnesemia (33). Recently, Crosnier et al. (27) indicated that 139/303(45.9%) patients present with acute kidney injury among the patients with lung cancer (271/303) by reviewing the VigiBase^® the WHO Global Database, and diarrhea-related acute kidney injury was the leading cause.

In a small clinical trial of 17 patients with solid tumors treated with erlotinib and sorafenib, the incidence of hypophosphatemia was 76%. In comparison, another clinical trial that enrolled 25 patients diagnosed with glioma showed a 30% incidence of hypophosphatemia (34, 35). Erlotinib can affect magnesium hemostasis, but its effect on systemic magnesium concentrations does not appear to be as good as that observed in antibody-based EGFR inhibitors, and the erlotinib-induced hypomagnesemia may be corrected by magnesia supplementation (13). There are several proteins in the distal convoluted tubules that have been implicated in the transport of magnesium, including magnesium-permeable transient receptor potential cation channel, subfamily M, member 6 (TRPM6) and transient receptor potential cation channel, subfamily M, member 7 (TRPM7) (36). EGF is a magnesiotropic hormone that regulates magnesium levels by regulating the TRPM6 type channel. Mutation of EGF gene resulted in impaired basolateral sorting of pro-EGF, thereby the renal EGFR is inadequately stimulated, inducing insufficient activation of TRPM6 type channel and thus hypomagnesemia occurred, as described in Figure 1 (37).

Therefore, it is recommended that all patients have their magnesium levels checked before starting treatment and then every 2 to 4 weeks, especially those with heart disease history. The severity of hypomagnesemia is closely related to treatment. Generally, EGFR TKIs induced hypomagnesemia may be corrected by extra magnesium supplementation. Hypomagnesemia can be divided into 5 grades according to the magnesium level (Grade 1 is 0.73-0.50 mmol/L, Grade 2 is 0.50-0.40 mmol/L, Grade 3 is 0.40-0.30 mmol/L, Grade 4 is <0.30 mmol/L, Grade 5 is death) (38). Grade 1 hypomagnesemia requires close monitoring of magnesium levels without medication. In grade 2 hypomagnesemia, magnesium supplementation, usually given intravenously with a dose of 4 grams of magnesium sulfate weekly, is highly recommended to avoid fatal arrhythmias, especially for those ineffective and poorly tolerated to oral magnesium supplementation (32, 39). Patients with grade 3/4 hypomagnesemia are advised to take 6-10 grams of magnesium sulfate twice a day twice a week, and monitor serum magnesium every other day until a stable state is reached. Another strategy may be to consider 2-month discontinuation of magnesium sulfate therapy in patients requiring frequent magnesium sulfate infusions (39).

In addition, hypophosphatemia has been reported in patients treated with EGFR inhibitors. Possible mechanism related to hypophosphatemia might involve sodium phosphate co-transporters in the proximal tubule (39). In general, hypophosphatemia should not be considered as a reason to discontinue aggressive cancer treatment unless it is recurrent and life-threatening, especially given that the use of these drugs may significantly improve life expectancy in many cancer patients. Intravenous rehydration should be considered in any symptomatic or severely exhausted patient (phosphate <1.0 mg/dL). Oral replacement therapy can be resumed after the patient has resolved symptoms or serum phosphate > 1.5 mg/dL (40). Therefore, it is advisable to check electrolyte levels before initiation of therapy, and then routinely monitor to prevent the development of severe complications caused by electrolyte disorders.

Erlotinib-related acute and chronic kidney dysfunction, though uncommon, still occur in clinical practice. Even for the same type of drug, patients may respond differently due to the different chemical structure of the drug. Maruyama et al (41) described that a 57-year-old patient with advanced lung adenocarcinoma developed nephrotic syndrome after taking gefitinib, which improved after discontinuation and switched to erlotinib without any kidney damage, and possible explanation is related to drug hypersensitivity reactions. Besides, another case reported that patient had only mild proteinuria on erlotinib, but developed nephrotic range proteinuria on gefitinib (42). While all EGFR TKIs have the potential to cause direct damage to glomerular podocytes, these drugs may also produce podocyte damage through indirect pathways. Different pathways of injury may explain the severity of podocyte injury in these EGFR TKIs (42). However, more researches are needed to explore the precise mechanism. Therefore, it is highly recommended to check the renal function before erlotinib therapy, and then check routinely for early recognition and treatment to prevent the development of severe complications.

Gefitinib is another TKI that blocks the activity of the EGFR tyrosine kinase. Gefitinib is used across all lines of therapy for patients with locally advanced or metastatic NSCLC with activating mutations of EGFR (20, 28). The usual dose of gefitinib is 250 mg orally per day, and the drug binds to plasma proteins up to 90%. Its metabolites are excreted mainly in feces, while the proportion of renal elimination is less than 4% (32). The most common adverse effect caused by gefitinib included diarrhea, vomiting and skin rash. Also, renal dysfunction of gefitinib were observed in clinical studies, with literature reviewed that 6.6% patients with gefitinib therapy developed fluid retention (43, 44). According to the FAERS, 7 patients after gefitinib initiation developed acute kidney injury, with hypokalemia and hyponatremia as the second and third adverse renal effects (33).

Pathological manifestations, including minimal change and mild IgA deposition, crescent formation, and tubular injury under microscopy have been reported in patients treated with EGFR inhibitors. A possible mechanism was proposed as an allergic or immune reaction as mild interstitial infiltration of lymphocytes was noted under the renal biopsy (44, 45). Kumasaka et al (44) reported a 76-year-old male presented with nephrotic syndrome after gefitinib therapy. Renal biopsy confirmed minimal change disease under electron microscopy, and her renal function discovered after discontinuation of gefitinib. Another case of acute renal failure due to thrombotic thrombocytopenic purpura/hemolytic uremic syndrome caused by gefitinib has been also reported. A 73-year-old male without potential precipitating factors for renal insufficiency has become uremic and acidosis after 16-day therapy of gefitinib. His renal function improved rapidly after gefitinib discontinuation (45). Kaneko et al (46) described the first case of gefitinib-related membranous nephropathy. Possible mechanisms include that gefitinib can act as a hapten attached to some native proteins, triggering an antibody response. Through long-term use, gefitinib may produce autoimmune reactions. In addition, gefitinib can locally bind to the increased phosphorylation of EGFR on podocytes, change its structure and induce antibodies, and thereby lead to subepithelial immune complexes (44, 46). During the first few weeks of gefitinib treatment, close monitoring of kidney function is required. When renal insufficiency is found, gefitinib should be discontinued immediately, and efforts should be made to find other secondary factors, and the next treatment should be determined until the cause is identified.

Afatinib, an orally administered irreversible EGFR TKI, is the first-line treatment for patients with EGFR mutation-positive advanced squamous NSCLC and patients harboring uncommon EGFR mutation, including G719X, S768I, and L861Q mutation (18, 47). Studies have shown that compared to first-generation EGFR TKIs, afatinib has a more favorable outcome, with significantly prolonged progression-free survival and time to treatment failure (47, 48). The recommended dose of afatinib is 40 mg orally per day. The drug binds mainly to plasma proteins and is excreted in feces, the proportion of which is excreted in the urine does not exceed 5% (32). Pharmacokinetic data indicate that in patients with mild or moderate renal impairment, the dosage of afatinib does not need to be adjusted, but 30 mg orally is prescribed to patients with severe renal impairment, even those patients under hemodialysis (49). In preliminary trials of afatinib, the incidence of hypokalemia was 34% (50). 26 patients under afatinib therapy developed acute kidney injury was noted in the FEARS report, which was followed by hypokalemia and hyponatremia (33). Koch et al (51) reported a case of hyponatremia in a 58-year-old female patient with EGFR-positive lung adenocarcinoma treated with afatinib. Serum electrolytes should be monitored closely in patients treated with EGFR TKIs and drugs should not be discontinued unless the symptoms are very severe.

Osimertinib, a third-generation EGFR TKI, has been developed due to the acquired T790M mutation caused by resistance for advanced NSCLC EGFR mutant patients progressed after first-line EGFR TKI therapy (52). The T790M mutation is the most common mechanism of acquired resistance in NSCLC treatment, accounting for 50-60% of secondary resistance after first-line therapy (53). Usually, administration with osimertinib 20 mg once per day is chosen as the initiating dose, which is sufficient to inhibit EGFR T790M, while doses equivalent to 80 mg or more are expected to lead to profound inhibition of tumor growth (52). A clinical trial for patients with EGFR inhibitor-resistant NSCLC at doses of 20 to 240 mg once daily revealed that diarrhea is the most common toxicity, followed by rash, nausea, and decreased appetite (24). Research has found that adverse effect is more common in patients with impaired renal function, however, under close monitor, osimertinib can be safely administered to cancer patients undergoing regular hemodialysis (54). In another clinical trial with locally advanced or metastatic, MET-amplified, EGFR mutation-positive NSCLC, a case of acute renal failure was found in patients treated with osimertinib plus savolitinib (55). Recently, more cases related to renal toxicities were reported. Niitsu et al (56) reported a patient with NSCLC developed acute kidney injury associated with biopsy-proven mild IgA deposition, crescent formation, and tubular injury after initiation of osimertinib and his renal function recovered after reducing the dose of osimertinib (from 80 mg/day to 40 mg/day). Another case reported that a patient with advanced lung adenocarcinoma presented with myalgia, muscular weakness after 5-month treatment with osimertinib and bevacizumab. He was diagnosed with osimertinib-associated rhabdomyolysis and developed acute renal insufficiency, hyperuricemia, metabolic acidosis and electrolyte disorders. However, all symptoms recovered after discontinuation of osimertinib (57). Few cases of osimertinib-related kidney dysfunction were reported and more attention and follow-up are required.

Crizotinib, the first-generation oral small molecule targeted therapy, inhibits multiple tyrosine kinase inhibitors, especially ALK, MET and ROS1. It has been shown to significantly improve outcomes compared with chemotherapy in both first-line and subsequent treatment in patients with ALK-positive advanced NSCLC. The recommended dose of crizotinib is 250 mg twice orally per day (63, 64).

According to the FDA, about 4% of patients develop complex renal cysts after initiation of crizotinib. Lin et al (65) revealed significant changes in renal cysts in 7 patients (22%) among 32 patients treated with crizotinib for ALK-positive advanced NSCLC, however, these may reverse after crizotinib discontinuation. An analysis of 255 patients treated with crizotinib for at least 6 months showed that 9% of patients acquired new cysts, and 2% of patients with pre-existing cysts developed new cysts and acquired enlargements in existing cysts (66). A retrospective study of 60 patients treated with crizotinib identified that female (p=0.008) and the presence of renal cysts on baseline scan (p=0.044) significantly related with renal cyst development or growth during initiation of crizotinib therapy (67). Also, Asians, especially Koreans tend to have higher odd ratios of developing de no renal cysts during crizotinib treatment (66).

Another adverse renal effect related to crizotinib is acute kidney injury. Camidge et al (68) have demonstrated that elevated serum creatinine with crizotinib occurs mainly in the first 12 weeks after initiation of crizotinib. There is little evidence of cumulative effects with long-term treatment, and renal function is largely restored after discontinuation within one week, suggesting that this may be primarily an effect on creatinine secretion rather than true nephrotoxicity, which is named pseudo acute kidney injury.

However, there were still case reports related to actual kidney injury. Gastaud et al (69) reported a case that a 49-year-old patient with previously normal renal function developed AKI after 3 weeks of crizotinib treatment, and renal function returned to normal on day 8 after discontinuation and renal biopsy showed diffuse acute tubular injury and tubular necrosis. Another case described by Izzedine et al (70) showed a patient diagnosed with NSCLC along with chronic kidney disease presented with progressive renal function worsening after 11-month crizotinib therapy, with kidney biopsy revealing features of acute tubular injury without interstitial cell infiltration and renal arteriolar myocyte vacuolization.

Electrolyte disorders have also occurred during clinical practice, including hypophosphatemia, hyponatremia, hypokalemia and hypocalcemia. Among them, hypophosphatemia has come to the first as a serious adverse event with up to 15% of all participants reporting during the treatment of crizotinib (71). Researches have revealed that hypophosphatemia is a sensitive prognostic factor related to the in-hospital day, severe complications or all-cause mortality. Still, the exact mechanism for these adverse events remains unclear, and there are no formal recommendations for guidance. Possible explanation for hypophosphatemia is associated with inhibiting the insulin-like growth factor-1 (IGF-1) located in the proximal tubules blocking the phosphate reabsorption, thus resulting in phosphaturia (40).

Renal cyst formation has been reported in patients treated with ALK inhibitors, especially those treated with the first-generation crizotinib. Yet, the potential causal relationship between crizotinib treatment and renal cyst formation has not been fully established. Hepatocyte growth factor receptor (HGF) is the only known ligand for MET and plays a vital role in embryonic development, tissue regeneration, and tumor progression. In the kidney, HGF is found in mesenchymal cells, while MET is expressed in non-mesenchymal cells. Activation of the HGF/MET signaling axis is associated with the development of renal cysts (66, 72). Another possible explanation is attributed to the imbalance of testosterone hormone levels, whose secretion decreased under crizotinib treatment but recovered after discontinuation of crizotinib (73). Routine ultrasound and renal function examination are needed when initiating ALK inhibitors.

ALK inhibitors have been associated with the occurrence of acute kidney injury and chronic kidney disease in clinical practice. Acute elevation of serum creatinine when initiating first-generation crizotinib may not be a reflection of true kidney injury, but rather a pseudo-kidney injury due to creatinine transporter inhibition, thereby interfering with creatinine secretion in the proximal tubule (58).

Still, cases of real acute kidney dysfunction are reported in the patients treated with ALK inhibitors. It is thought that MET is mainly expressed in the proximal convoluted tubule, proximal loop of Henle loop and distal convoluted tubule. Crizotinib competitively inhibits creatinine and water secretion by inhibiting the c-Met pathway, which may be the mechanism that predisposes to acute kidney injury (58, 70).

Recently, an analysis revealed that the calculated glomerular filtration rate in cancer patients undergoing TKIs was higher in almost all cases when using cystatin C (74). Therefore, it is important to recalculate with both serum creatinine and cystatin C to identify the actual situation when using crizotinib. Patients undergoing treatment with crizotinib should maintain proper hydration, regularly monitor kidney function, and promptly report any symptoms indicating potential kidney injury to healthcare professionals. Also, physicians should carefully assess the risk-benefit ratio before prescribing crizotinib to patients with known risk factors for kidney disease.

Ceritinib, an oral small molecule, ATP-competitive tyrosine kinase inhibitor of ALK, is 20 times as potent as crizotinib in enzymatic assays. It is always used in patients harboring ALK mutation involving L1196M, G1296A, I1171T, and S1206Y mutations. The recommended dose of ceritinib is 750 mg orally per day (75, 76). The most common adverse events caused by ceritinib include gastrointestinal disorder (grade 1 or 2 diarrhea, nausea) or hepatic disorders among up to 5% of patients, which generally required essential approach and is reversible after drug modifications or discontinuation. Serum creatinine levels were elevated in 11% of patients, and hypomagnesemia occurred in 8% of patients undergo ceritinib therapy. Patients treated with ceritinib often present with hypophosphatemia and this is dose-dependent (75, 77). Hyponatremia is another common electrolyte disorder in patients treated with ceritinib therapy. More than 5% of patients developed hyponatremia during ceritinib therapy. A postulated explanation attributed hyponatremia in patients treated with ALK inhibitors to inadequate secretion of antidiuretic hormone in the collecting ducts and thus producing hyponatremia (78). Hypocalcemia and hypokalemia are also reported though in patients treated with ceritinib (59).

In conclusion, it is necessary to regularly monitor electrolyte levels and kidney function, recognize symptoms and signs early, and take relevant measures to intervene. Dose reductions have not usually been required (77).

Alectinib, a second-generation oral ALK TKIs, is highly selective and more potent against ALK. It has been used in patients with ALK mutations that cause resistance to crizotinib, such as L1196M and C1156Y (79). The recommended dose of alectinib is 600 mg twice orally per day. Alectinib has good brain barrier penetration, resulting in high concentrations in the cerebral blood fluid. The brain is the most common site of metastasis in patients with ALK-positive NSCLC treated with crizotinib, and many patients suffer recurrence of central nervous system involvement (80, 81). Common adverse effect caused by alectinib are constipation (35.6%), edema (33.6%) and myalgia (30.8%). The gastrointestinal and hepatobiliary disorders are the two most common vital adverse effects that calls for emergent attention and treatment (82).

Still, renal adverse events have been reported in patients treated with alectinib, commonly grade 1 or 2 nephrotoxicity. Grade 3 renal adverse events including elevated serum creatinine and neutropenia were reported in 26% of patients, and hypophosphatemia was reported in 2~4% of patients (81, 83). Ramachandran et al (84) reported that a 72-year-old patient with ALK-positive metastatic NSCLC developed acute kidney injury which necessitated emergency hemodialysis within 6-week treatment of alectinib. He recovered completely within 7-10 days on alectinib withdrawal. Recently, one case of biopsy-proven a mixed pattern of acute interstitial nephritis and acute tubular necrosis was reported with this agent for a 68-year-old patient with ALK-positive NSCLC stage IV. After initiation of corticotherapy, renal function in this patient returned to baseline. The patient was finally discharged from the hospital, the and treatment with alectinib was changed to lorlatinib, and renal function remained stable after 10 months of lorlatinib (85).

Brigatinib, another highly selective ALK TKIs with a 12-fold stronger potent against ALK than crizotinib, has been widely applied in patients with regressive ALK-positive metastatic NSCLC or resistant to crizotinib. The recommended dose of brigatinib is 90 mg orally per day (86). Gastrointestinal disorder (nausea, diarrhea), fatigue and headache are the most common adverse effects and needed emergent attention and treatment (58).

Brigatinib-induced renal adverse events have been rarely reported in clinical practice. Wang et al (87) reported that a 39-year-old patient with advanced ALK-rearranged NSCLC developed tumor lysis syndrome after 22-day therapy of brigatinib, whose serum creatinine rose from 73 μmol/L to 320.2 μmol/L over 22 days of brigatinib treatment. Emergent hemodialysis is required; however, the patient and his family refused any other further interventions due to the worse prognosis, and finally he passed away within 24h.

Lorlatinib, a selective third-generation tyrosine kinase inhibitor, has been used to treat crizotinib-resistant ROS1-positive NSCLC and glioblastoma. Lorlatinib has shown high potency in crizotinib-resistant NSCLC with ROS1 G2032R mutation and the recommended dose of lorlatinib is 100 mg orally per day (88–90). Common adverse events of lorlatinib involve neurocognitive impairments, such as slowed speech and thinking and word-finding difficulty, which are dose-limited (91). Up to 50% of patients develop peripheral edema when treated with lorlatinib (10). Also, lorlatinib-related glomerular-toxicity may happen. Betton et al (92) reported that a 64-year-old female diagnosed with lung adenocarcinoma presented with diffuse edema and proteinuria after 1-month treatment with lorlatinib. She was diagnosed with lorlatinib-related nephrotic syndrome with a kidney-biopsy revealing diffuse podocytes foot process disappearance under electron microscopy and her symptoms relived after discontinuation of this drug. However, due to disease progression, the patient was restarted with lorlatinib and subsequently increased to 3.6 g/g proteinuria within 3 days of initiation (92). In addition, McGee et al (93) described a case of 63-year-old female with lung adenocarcinoma developed extinct hyperlipidemia, which may be caused by minimal change disease under renal biopsy. Another case reported by Lee et al (94) revealed a 68-year-old with ROS1 rearranged stage IV lung adenocarcinoma presented proteinuria after receiving lorlatinib, and her symptoms improved when reducing dose from 100 mg to 50 mg daily. However, the related mechanism remained unknown.

Peripheral edema seems to be the most common adverse event after ALK inhibitor therapy, occurring in nearly 50% of participants under the first-generation crizotinib and the third-generation lorlatinib, generally grade 1-2 adverse events (10). However, the exact mechanism remained unknown, but a postulated mechanism referred to the inhibition of the c-MET pathway. In the kidney, MET is expressed in the tubules, including proximal tubules, proximal loop of Henle and the distal tubules. Inhibition of this pathway may lead to electrolyte disorders (73). Peripheral edema generally appears late in the therapy of ALK inhibitors, which appears to be a late-onset cumulative effect. In patients with low-grade edema, compression stockings, leg elevation, and lifestyle changes should be advised first before starting dose adjustment (58). Also, it is important to monitor renal function regularly and take management with dose modification. Diuretics drugs may be a proper choice for cases with more resistant.