Vascular endothelial growth factor inhibitors

Angiogenesis, the process by which new blood vessels form, plays an integral role in tumorigenesis and is mediated by vascular endothelial growth factors (VEGF). Accordingly, drugs that inhibit this pathway have emerged as an effective anticancer therapy in various malignancies, such as lung, breast, colon, renal cell carcinoma, and ovarian cancer. VEGF inhibition works by several proposed mechanisms, including monoclonal antibodies against the VEGF molecule, small molecule tyrosine kinase inhibitors (TKIs) of the VEGF receptors, soluble decoy receptors, and ribozymes that target VEGF messenger ribonucleic acid. Bevacizumab, ramucirumab, and aflibercept (a soluble decoy receptor of VEGF) are monoclonal antibodies that bind to the VEGF molecule, preventing it from binding to the receptor, thus inhibiting endothelial cell proliferation and vessel formation, whereas the small molecule TKIs (sunitinib, sorafenib, pazoponib, axinitib, cabozatinib, lenvatinib, regorafanib, and vendatinib) block the intracellular domain of VEGF. ^,

Proteinuria is a class effect of all VEGF inhibitors; however, the exact mechanism is unclear. VEGF plays an important role in the regulation of renal vascular endothelium and maintenance of normal kidney function. VEGF is found on both endothelial cells and podocytes (renal epithelial cells) among other cells, and the interaction between the glomerular endothelial cells and podocytes via the VEGF pathway is necessary to maintain glomerular filtration by preserving the integrity of the glomerular slit diaphragm. It has been theorized that VEGF inhibition can lead to podocyte injury and can therefore lead to proteinuria. Histologic findings in these patients can show renal limited thrombotic microangiopathy (TMA) ( Fig. 17.2 ) and in some cases minimal change disease (MCD) or focal segmental glomerulosclerosis (FSGS) ( Fig. 17.3 ). Preexisting kidney disease and renal cell carcinoma may be predisposing factors. Treatment can be continued in those cases where proteinuria is not in the nephrotic range, and HTN and proteinuria can be aggressively managed with angiotensin-converting enzyme inhibitor (ACEI) or angiotensin receptor blocker (ARB) inhibition. AKI, especially when caused by TMA, is an indication for drug discontinuation.

A 56-year-old male with history of renal cell cancer receives bevacizumab presents with acute rise in creatinine, hypertension, and proteinuria. The kidney biopsy depicted shows acute thrombotic microangiopathy (light microscopy view).

A 78-year-old male with history of renal cell cancer receives sunitinib and presents with sudden onset nephrotic syndrome. The kidney biopsy depicted reveals minimal change nephropathy (electron microscopy view). RBC , Red blood cell.

HTN frequently accompanies proteinuria. Several mechanisms have been proposed in the pathogenesis of HTN, including decreased nitrous oxide and microvasculature rarefaction leading to nitrous oxide dysregulation ( Fig. 17.4 ). The adverse effects of both proteinuria and HTN were initially described with bevacizumab, the first anti-VEGF drug introduced to clinical practice. The HTN appears to be dose dependent, as observed in several studies, with one study reporting the relative risk of HTN of 3.0 in low-dose bevacizumab (3, 5 or 7.5 mg/kg) as compared with high-dose (10 or 15 mg/kg). Another study by Yang et al. demonstrated that the rate of HTN was 3% in the low-dose bevacizumab group (3 mg/kg), compared with 36% in the high-dose cohort (10 mg/kg). Similarly, the HTN reported with small molecule TKIs appears to be dose dependent as well. Interestingly, the development of HTN may portend a better response to therapy, and therefore should encourage physicians to continue treatment while managing the blood pressure. The choice of antihypertensive agents should be individualized with ACEIs or ARBs as first-line options and calcium channel blockers as a reasonable second line.

Multiple mechanisms by which vascular endothelial growth factor (VEGF) blockade induces hypertension. VEGF signaling blockade inhibits nitrous oxide (NO) production, enhances endothelin-1 secretion, and causes capillary rarefaction. All of these effects cause increased afterload and consequent increased blood pressure. In addition, VEGF blockade shifts the pressure-natriuresis curve and decreases lymphangiogenesis, and both of these effects contribute to volume overload and hypertension. ECF , Extracellular fluid.

A small number of patients develop more severe kidney disease, manifested by nephrotic range proteinuria and AKI. Unfortunately, few undergo diagnostic kidney biopsy. Review of reported cases highlights that the most common histopathologic lesion, acute TMA, has been reported in patients with advanced cancers treated with bevacizumab and VEGF trap (aflibercept). Other anti-VEGF therapy induced kidney lesions included FSGS, mesangioproliferative glomerulonephritis, cryoglobulinemic glomerulonephritis, immune complex glomerulonephritis, glomerular endotheliosis, and acute interstitial nephritis (AIN). All patients developed proteinuria, whereas half developed HTN or AKI. In most of the cases, kidney function normalized or stabilized, proteinuria resolved, and blood pressure control improved after discontinuation of the agent. ^, Fig. 17.5 summarizes the VEGF effects on blood pressure and proteinuria.

Summary of the antivascular endothelial growth factor (anti-VEGF) therapy on blood pressure and podocytes.

Tyrosine kinase inhibitors

Protein kinases are important mediators of the signal transduction process and regulate cell proliferation, differentiation, migration, metabolism, and antiapoptotic signaling. The most important protein kinases are the serine/threonine and tyrosine kinases, which are characterized by their ability to catalyze the phosphorylation of serine/threonine or tyrosine residues in proteins, respectively. There are two types of tyrosine kinases: receptor and cellular tyrosine kinases. Receptor tyrosine kinases consist of an extracellular ligand binding domain, a transmembrane domain, and an intracellular catalytic domain. They are activated by ligand binding to the extracellular domain. Cellular tyrosine kinases play a role in the downstream signal transduction pathway, in the cytoplasm or nucleus. Tyrosine kinases are involved in several steps of neoplastic development and progression; the signaling pathways normally prevent unregulated proliferation; however, these pathways are usually genetically altered in cancer cells, thus allowing for constitutive activity of the tyrosine kinases and unregulated cell growth and proliferation. Thus TKIs are effective anticancer agents, because they interfere with this unregulated process. Receptor TKIs target the epidermal growth factor receptor (EGFR), platelet derived growth factor receptor (PDGFR), and vascular endothelial growth factor receptor (VEGFR), whereas cellular TKIs can target breakpoint cluster region–abelson (BCR-ABL) (imatinib) and Bruton’s kinase (ibrutinib). These agents could target single receptors, such as EGFR (geftinib), or could be multitargeted, such as sunitinib, which targets VEGFR, PDGFR, kit, Flt3, and RET. Some of the renal side effects of common TKIs, such as sunitinib and sorafenib, were discussed earlier with anti-VEGF therapy, as their effects are similar on the kidney.

Like anti-VEGF drugs, the small molecule TKIs of the VEGFR family (sunitinib, sorafenib, pazopanib, axitinib, cabozantinib, lenvatinib, and vandetanib) are also potent inhibitors of angiogenesis, and thus have a similar adverse effect profile. Sunitinib and sorafenib target multiple receptor kinases including VEGFR, PDGFR, c-kit among others. Sunitinib, sorafenib, pazopanib, and axitinib have known effects of HTN, proteinuria, TMA, and chronic and acute interstitial nephritis. Sorafenib is also known to cause hypophosphatemia and hypocalcemia, thought to be related to pancreatic dysfunction from the drug leading to vitamin D malabsorption and secondary hyperparathyroidism. Table 17.2 summarizes reported renal toxicities specific to VEGF inhibitors.

Lenvatinib also targets several tyrosine kinases including RET, KIT, VEGFR, and PDGFRA. No significant renal toxicities have been reported with this drug. Regorafenib is associated with several electrolyte abnormalities, including hypophosphatemia, hypocalcemia, hyponatremia, and hypokalemia. However, these abnormalities are usually mild to moderate and do not require dose adjustments or interruptions in treatment. As with other VEGF inhibitors, there is a significant incidence of HTN. In the initial trial evaluating regorafenib as monotherapy for previously untreated metastatic colorectal cancer, the incidence of HTN was 28%, with 7% reported as grade 3. The incidence of proteinuria was lower at 7%, with 1% reported as grade 3. Unlike bevacizumab, the HTN associated with regorafenib does not appear to be dose dependent. A systematic review by Wang et al. evaluated 1069 patients from five clinical trials. The incidence of all grade and high-grade HTN were 44.4% and 12.5%, respectively. An analysis of the U.S. Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) database confirmed HTN as the most common adverse event (57 cases of 125 total cases of regorafenib-related toxicity), followed by AKI (40 cases) and hypophosphatemia (8 cases).

Vandetanib targets VEGFR2, EGFR, and RET. This agent has also been associated with several electrolyte disturbances, such as hypocalcemia, hypokalemia, hyponatremia, and hypercalcemia. Similar to other VEGF inhibitors, there is also a significant incidence of HTN. In a phase 2 trial of vandetanib, in locally advanced or metastatic differentiated thyroid cancer, HTN was seen as frequently as 34% of cases. ^, Analysis of the FAERS database identified a total of 57 adverse renal events for vandetanib between 2011 and 2015, with the majority identified as renal impairment (defined as proteinuria, AKI, elevated serum creatinine +/- nephritis, 30 cases) and HTN (21 cases), with the remainder being electrolyte disturbances. Vandetanib has also been shown to have an inhibitory effect on several human renal transporters, such as multidrug and toxin exclusion (MATE)-1 and MATE-2, which are responsible for drug clearance. Inhibition of these transporters at the apical membrane of the tubular cells may lead to increased concentrations of the drug within renal tubular epithelial cells, resulting in increased nephrotoxicity of other coadministered agents, such as cisplatin. ^,

B cell lymphoma 2 inhibitors

B cell lymphoma (BCL)-2 is a key regulator of apoptosis. Inhibitors of this pathway are emerging as effective therapies for various hematologic malignancies. Venetoclax is a potent selective inhibitor of BCL-2, and has been approved for the treatment of refractory chronic lymphoid leukemia (CLL), both as monotherapy and in combination with cytotoxic chemotherapy. There is a particularly high incidence of tumor lysis syndrome, which can lead to AKI and subsequent electrolyte abnormalities. In a phase 1 dose escalation study to assess safety and pharmacokinetic profile, 56 patients received active treatment in one of eight dose groups per day; in an expansion cohort, the dose escalation was adjusted to a stepwise ramp up. Clinical tumor lysis syndrome occurred in three of 56 patients in the dose escalation cohort but was not present after adjustments to the dose escalation schedule were made in the expansion cohort. Thus a stepwise dose escalation strategy ( Fig. 17.6 ), with close monitoring of renal function and electrolytes, is advised to reduce the risk of tumor lysis syndrome.

Recommended once daily dosing schedule for venetoclax 5-week dose ramp up used in clinical trials for patients with chronic lymphocytic leukemia. There is high risk for tumor lysis syndrome with this agent, with any measurable lymph nodes with largest diameter greater than 10 cm OR absolute lymphocyte count greater than 25 × 10 ⁹ /L AND any measurable lymph node with largest diameter greater than 5 cm, then the first doses of 20 mg and 50 mg should be inpatient dosing and laboratory monitoring done at 0, 4, 8, 12, and 24 hours. Hydration with 1 to 2 L/day of fluids with rasburicase recommended. Early nephrology consultation in certain very high-risk situations.

BCR-ABL and kit inhibitors

The bcr-abl oncogene, present in 95% of patients with chronic myelogenous leukemia (CML), codes for the constitutively activated tyrosine kinase that is implicated in the pathogenesis of this disease. The introduction of BCR-ABL inhibitors have changed the landscape of CML, improving overall survival and inducing higher rates of complete cytogenetic response and major molecular response. Several small molecule inhibitors of BCR-ABL exist, including imatinib, dasatinib, nilotinib, bosutinib, and ponatinib.

Imatinib is a first generation TKI that targets BCR-ABL, KIT, and PDGFR. Both AKI and chronic kidney injury have been reported in patients treated with imatinib. In one study of 105 CML patients, 7% of patients developed AKI and 12% patients developed chronic kidney disease (CKD). The mean decrease in estimated glomerular filtration rate (GFR) was 2.77 mL/min/1.73 m ² per year. Potential mechanisms of renal injury include tumor lysis syndrome and acute tubular injury; sometimes an isolated Fanconi syndrome develops. Rhabdomyolysis has also been reported. The kidney injury does appear to be dose dependent, as seen with renal cell cancer treatment, with higher doses associated with a higher incidence of renal tubular damage. Two common electrolyte abnormalities reported are hypocalcemia and hypophosphatemia. In one case series, the incidence of hypophosphatemia was close to 10% and associated with low calcium and 25-OH vitamin D levels. The underlying mechanism for hypophosphatemia is unclear, but may be related to the inhibition of tubular reabsorption of phosphorus.

Dasatinib is a second generation TKI used in imatinib-resistant CML. It also has effects on PDGFR and KIT. There have been several cases of AKI reported with the use of this drug, including one patient who developed rhabomyolysis, and another patient who developed thrombotic thrombocytopenic purpura. In addition, there is a 5% incidence of proteinuria with this agent. Nephrotic syndrome has also been described. ^, Of the BCR-ABL TKIs, dasatinib is the only one associated with proteinuria. In all cases the proteinuria resolved upon discontinuation of the drug or switching to imatinib.

Nilotinib is also an inhibitor of BCR-ABL, c-KIT, and PDGFR. It has been associated with HTN. The effect of nilotinib on CKD was evaluated in animal models, where it has been shown to be nephroprotective. Interestingly, treatment with nilotinib significantly decreased renal cortical expression of profibrogenic genes (such as IL-1B and monocyte chemotactic protein-1 ), which correlated with tubulointerstitial damage; in addition, nilotinib significantly prolonged survival. These results suggest that nilotinib may limit the progression of CKD.

Bosutinib is a dual TKI that targets the ABL and SRC pathways that is approved for the treatment of refractory CML. The only renal toxicities reported with this agent are hypophosphatemia and an apparently reversible decline in GFR. Ponatinib is a multitargeted TKI, with VEGF being one of the molecular targets. As such, the renal toxicities that are a class effect of VEGF can be seen with this agent.

V-RAF murine sarcoma viral oncogene homolog B inhibitors

Mutations that drive signaling pathways critical to tumor growth are attractive molecular targets for cancer therapy. The mitogen-activating protein kinase (MAPK) pathway is one such pathway, estimated to be dysregulated in about 50% of malignancies. RAF is a kinase along this pathway that, once activated, phosphorylates mitogen-activated protein kinases (MEK) and activates MAPK, which in turn stimulates cell growth. Mutations in v-RAF murine sarcoma viral oncogene homolog B (BRAF), most commonly a valine-to-glutamic acid substitution at codon 600 (V600E), have been demonstrated in approximately 50% of patients with melanoma. Vemurafenib, an inhibitor of mutated BRAF, has shown significant improvements in survival when compared with standard therapy. The initial phase III study did not report significant renal toxicity. In 2016 Wanchoo et al. did a comprehensive review of AKI with BRAF inhibitors; the most common findings were acute tubulointerstitial damage and decreased GFR in 1 month and some nonnephrotic range proteinuria. The mechanism of AKI is not clear; however, kidney biopsies, when done, showed acute tubulointerstitial damage and interstitial fibrosis ( Fig. 17.7 ). Multiple other publications have reported various renal toxicities. One series of eight cases from France demonstrated decrease in GFR, whereas another case reported Fanconi syndrome with severe hypokalemia, which improved after interruption of therapy. Another study showed that vemurafenib induces a dual mechanism of increase in plasma creatinine with both an inhibition of creatinine tubular secretion and slight impairment in kidney function. However, this adverse effect is mostly reversible when vemurafenib is discontinued and should not dissuade physicians from continuing treatment if effective. Finally, an analysis of the FAERS database reported 132 cases of AKI, more commonly identified in older men. There were 13 reported cases of AKI with dabrafenib in the same review period. Eight cases of electrolyte disorders were reported (hypokalemia and hyponatremia); however, no cases of hypophosphatemia were found, contrary to prior reports.

A 78-year-old male with melanoma on vemurafenib presents with acute rise in serum creatinine, and the kidney biopsy depicted shows acute interstitial nephritis (light microscopy view).

Mitogen-activated protein kinases inhibitors

MEK inhibitors have clinical activity in melanoma patients who harbor that V600 mutation and are mostly used in combination with BRAF inhibitors. Trametinib and cobimetinib are potent, highly specific inhibitors of MEK1/MEK2. There have been no published cases of nephrotoxicity with trametinib. Monotherapy with this agent can lead to HTN. Renal insufficiency, hyponatremia, and rare cases of glomerulonephritis have been described in patients treated with the combination of a BRAF and MEK inhibitor; however, this may reflect the additive effect of the BRAF inhibitor rather than a sole effect of the MEK inhibitor. In the unique case of glomerulonephritis and granulomatous vasculitis of the kidney, kidney function recovered completely after withdrawal of the therapy.

Anaplastic lymphoma kinase target inhibitors

Anaplastic lymphoma kinase (ALK) is a member of the insulin receptor tyrosine kinase family. ALK gene mutations are linked with many cancers, including non-small cell lung cancer (NSCLC), anaplastic large cell lymphoma, Hodgkin lymphoma, rhabdomyosarcoma, and neuroblastoma.

Among the patients with NSCLC (most common lung cancer type), a small subgroup with mutation of echinoderm microtubule-associated protein-like 4 (EML4)-ALK are highly sensitive to ALK TKIs. Crizotinib is the first FDA-approved ALK target inhibitor medication. It has been associated with several adverse renal effects. In a retrospective review done by Brosnan et al. at the University of Colorado, crizotinib therapy was associated with a mean reduction in GFR by 23.9% within first 12 weeks. However, the mechanism for decline in GFR was unclear. Most patients recovered their estimated GFR (eGFR) after cessation of crizotinib therapy. Hence the authors hypothesized that the drop in GFR could be attributable to interference of tubular secretion of creatinine by crizotinib, given that it occurred rapidly and was largely reversible on stopping the drug. As a result, they postulate that crizotinib is not directly nephrotoxic. However, there has been a single case report of biopsy proven acute tubular necrosis (ATN) after crizotinib use by Gastaud et al. There is an increased risk of new renal cysts (primarily complex cysts) formation and progression of preexisting cysts associated with the use of crizotinib. Renal cyst changes were observed in 22% of patients in Taiwan, after crizotinib treatment, and spontaneously regressed after stopping the drug. A single case of spontaneous regression of crizotinib associated complex renal cysts despite continuous crizotinib therapy has been reported. ^, Electrolyte disorders, such as hypokalemia and hyponatremia, have also been observed with crizotinib use in FDA Adverse Event Reporting System (FAERS) analysis. A recent review on adverse renal effects of crizotinib have reported additional adverse effects, including peripheral edema.

Epidermal growth factor receptor 1 target inhibitors

EGFR inhibitors are divided into two major classes. The first class includes monoclonal antibodies, namely cetuximab and panitumumab. The second class comprises three small molecule TKIs: erlotinib, geftinib, and afatinib. Major adverse renal effects of EGFR target inhibitors are electrolyte abnormalities.

Cetuximab is used in the treatment of metastatic colorectal cancer and was approved by the FDA in February 2004. ^, Shortly after its approval for colorectal cancer, Schrang et al., at Memorial Sloan-Kettering Cancer Center, observed profound hypomagnesemia in a patient with metastatic colon cancer treated with cetuximab. This prompted the investigators to review the laboratory profiles for 154 colorectal cancer patients treated with cetuximab over the first 6 months of its commercial availability at the institution. However, only 22% of patients had magnesium level checked as none of the practice guidelines required serum magnesium surveillance after its approval. Among these patients, 24% had severe hypomagnesemia. Subsequently, several studies reported hypomagnesemia associated with cetuximab use. In 2006, Fakih et al. observed an incidence of grade 3 (< 0.9–0.7 mg/dL) and grade 4 (< 0.7 mg/dL) hypomagnesemia as 27%. Although these earlier studies reported a high incidence of grade 3 to 4 hypomagnesemia, recent studies have reported an incidence of grade 3 to 4 hypomagnesemia as 5.6%, 2.9%, and 3.7% of patients, respectively. Similarly, discrepancies are also seen in the incidence of overall hypomagnesemia, with two largest metaanalyses reporting between 25.8% to 36.7%. ^, Risk factors for development of hypomagnesemia are duration of treatment, age, and baseline magnesium level. The mechanism of action for hypomagnesemia, is a reduction of transport of transient receptor potential melastatin (TRPM) 6/7 ion channels. Both EGFR and TRMP 6 are expressed in the distal convoluted tubule, which is the main active site of renal magnesium handling. EGFR activation is required for activity and movement of TRPM 6 ion channels into the apical membrane. Therefore blockage of EGFR by cetuximab impairs TRPM 6 ion channels activity, causing magnesium wasting in the distal convoluted tubule ( Fig. 17.8 ).

Cetuximab (C) is an epidermal growth factor receptor (EGFR) antibody that causes kidney magnesium wasting by competing with EGF for its receptor. Normally, EGF binds its receptor (EGFR) and stimulates magnesium reabsorption in the distal convoluted cell. EGFR activation is associated with magnesium absorption through transient receptor potential M6 (TRPM6) in the apical membrane. ATPase , adenosine triphosphatase; NCC , sodium chloride cotransporter. Reproduced from Perazella MA. Onconephrology: renal toxicities of chemotherapeutic agents. Clin J Am Soc Nephrol. 2012;7:1713-1721.

A review by Faikh et al. provides a detailed description about management of hypomagnesemia. No magnesium replacement is necessary for grade 1 hypomagnesemia, because these patients are typically asymptomatic. Oral magnesium supplementation can be given for grade 2 (0.9–1 mg/dL) hypomagnesemia. An alternative therapy is weekly intravenous replacement of magnesium sulfate (4 g) in patients who are unable to tolerate oral magnesium. Patients with severe grade 3 and 4 hypomagnesemia are at increased risk of developing cardiac arrhythmias and require much higher doses of intravenous magnesium sulfate, ranging from 6 to 10 g daily. Hypokalemia and hypocalcemia may also develop from hypomagnesemia. Potassium wasting by the kidney occurs from loss of magnesium inhibitory effect on renal outer medullary potassium channels, whereas release and effect of parathyroid hormone is impaired with hypomagnesemia, promoting hypocalcemia. Monitoring of serum magnesium levels every other day is helpful to guide the frequency of replacement in these patients. An alternative approach for these patients is to stop cetuximab for 2 months and then restart. In addition, medications associated with development of hypomagnesemia, such as thiazide diuretics and proton pump inhibitors, should be stopped. As per FAERS review, cetuximab has the second highest number of events for any of the targeted therapies. About 467 individuals had adverse renal events. Interestingly, out of these, 172 had AKI, although the most commonly reported side effect is hypomagnesemia on literature search.

So far, only one clinical trial has reported kidney failure in about 2% of the patients. Two cases of glomerular diseases have also been described with cetuximab use. ^, Given the very high number of cases associated with AKI in FAERS data, it certainly needs to be studied in the future. Other electrolyte abnormalities associated with its usage are hyponatremia and hypokalemia. ^,

Panitumumab is another monoclonal antibody EGF target inhibitor. The most commonly reported adverse renal effect with panitumumab therapy is hypomagnesemia. The incidence of hypomagnesemia was about 36% in a clinical trial where panitumumab was used for colorectal cancer. In a recent randomized trial on patients with head and neck cancer performed in 26 countries, panitumumab therapy caused hypomagnesemia in approximately 12% and hypokalemia in 10% of the study population. Therefore frequent monitoring and repletion of magnesium levels should be done for patients on monoclonal antibody EGFR target inhibitor chemotherapy.

Erlotinib, gefitinib, and afatinib are TKIs that act on EGFR. A phase I trial including sorafenib and erlotinib combination in patients with advanced solid tumors reported hypophosphatemia in about 76% of the patients. In this trial, it is unclear how much sorafenib contributed to hypophosphatemia, which is a known complication of this drug. Broniscer et al. conducted a trial in which erlotinib was administered concurrently with radiotherapy, and noted a 30% incidence of hypophosphatemia. A phase II trial with erlotinib for advanced NSCLC reported hypokalemia, elevation in serum creatinine, and hypomagnesemia in 5%, 4%, and 1% of the patients, respectively. In 2009, a single case of crescentic glomerulonephritis with erlotinib use was described by Kurita et al. In FAERS analysis, 63 cases of AKI and eight cases of hypomagnesemia have been reported.

Gefitinib is used in the treatment of NSCLC. Its use has been associated with the development of nephrotic syndrome. Kidney biopsy in a patient from Japan who developed nephrotic syndrome with gefitinib therapy demonstrated MCD. A recent case of MCD had remission of proteinuria after discontinuation of gefitinib therapy. In addition to MCD, immunoglobulin A nephropathy, tubulointerstitial nephritis, and AKI have also been reported with gefitinib therapy. ^, On review of the FAERS database, 15 cases of adverse renal effects were seen and about a half of them were AKI.

In a randomized control trial, afatinib therapy was associated with hypokalemia in approximately 34% of patients. No other published data on nephrotoxicity with this agent are available. Twenty-six cases of AKI, six cases of hypokalemia, and five cases of hyponatremia were noted in FAERS review.

Human epidermal growth factor receptor 2 target inhibitors

Human epidermal growth factor receptor (HER) 2 is a member of transmembrane EGFR with tyrosine kinase activity. Overexpression of this receptor is observed in approximately 20% of breast cancers. Trastuzumab is a humanized monoclonal antibody that acts on HER 2 receptor. Trastuzumab has a major role in the treatment of HER 2-positive metastatic breast cancer. It is also used as an adjuvant therapy in HER 2-positive metastatic gastric cancer. It has been associated with anhydramnios and fetal nephrotoxicity in three separate case reports. One of the major complications seen after its use is cardiac dysfunction, which requires regular cardiac screening with MUGA scan or echocardiography. ^, Russo et al. analyzed echocardiograms of 499 patients who underwent treatment with trastuzumab therapy for 12 months and found that GFR less than 78 mL/min/1.73 m ² was the strongest predictor of cardiotoxicity. Cardiac toxicity leading to congestive heart failure can cause AKI from cardiorenal physiology. Therefore routine monitoring of renal function should be considered in patients receiving this medication. In a randomized control trial, trastuzumab in combination with other chemotherapy caused more nephrotoxicity when used in gastric cancer, as compared with standard chemotherapy. Approximately 124 cases of AKI associated with trastuzumab have been reported in the FAERS database. Electrolyte disorders, such as hypokalemia, hyponatremia, and hypomagnesemia have also been reported. Tumor lysis syndrome from trastuzumab use was recently described. Ado-trastuzumab emtansine is a conjugate of trastuzumab linked to cytotoxic agent emtansine (DM1). Hypokalemia is observed in about 10% of patients treated with this agent. ^,

Pertuzumab binds to the extracellular dimerization domain of HER 2 and is used primarily in combination with trastuzumab for treatment of HER 2-positive breast cancer. Analysis of FAERS data revealed approximately 100 cases of nephrotoxicity. Out of these, 46 cases had AKI. However, there are no published data on nephrotoxicity with this agent in clinical trials or case reports.

Lapatinib is a dual TKI and blocks both EGFR (erbB1) and HER 2 (erbB2) pathways. The only published data available on adverse renal effects with this agent is hyponatremia. There are 171 cases documented in the FAERS database. Most cases had hypokalemia and AKI, whereas a small number had HTN, hypomagnesemia, and hyponatremia.

Burton kinase inhibitor

Ibrutinib is a burton kinase inhibitor used for treatment of CLL and mantle cell lymphoma. It is largely excreted in the feces (90%) and less than 10% is excreted in urine. As a result, there is no dose adjustment recommendation for patients with CKD. A multicenter study undertaken in patients with relapsed or refractory CLL, treated with ibrutinib, reported a 13% incidence of HTN and 21% incidence of peripheral edema. In another study involving patients with mantle cell lymphoma, serum creatinine elevation was seen in approximately 35% of patients. Out of these, approximately 5% had grade 3 kidney failure; however, preexisting HTN and dehydration were confounding factors in these cases. As per medication package insert, 9% of patients had an increase in serum creatinine that was 1.5 to 3 times normal.

Mammalian target of rapamycin inhibitors

Mammalian target of rapamycin (mTOR) is a member of phosphatidylinositol-3-kinase-related kinases (PIKKs) family. It is made up of two protein complexes, mTORC1 and mTORC2, both of which are important in cellular regulation. Sirolimus was approved by the FDA in 1997. It has been used in organ transplant population for prevention of allograft rejection and is not currently used as an anticancer medication. It has been associated with proteinuria and podocytopathies. Four cases of biopsy proven ATN with mTOR inhibitors have been described in the literature. Temsirolimus is a parenterally administered mTOR inhibitor, which has been associated with ATN and podocytopathies, such as MCD and FSGS. Everolimus is used for the treatment of advanced HER2/hormone receptor breast cancer and progressive neuroendocrine tumors of pancreatic, gastrointestinal, and lung origin. It is also used as a second-line agent for renal cell carcinoma. In a retrospective analysis, there was a high incidence of everolimus-associated AKI (16.2%) in patients with renal cell carcinoma. An increased incidence of AKI with decreasing eGFR was also observed with this drug. Recently, a case report of AKI from everolimus use in a breast cancer patient was reported.

Proteasome inhibitors

The proteasome pathway is important for cell cycle, cell function, and survival, and it plays a crucial role in targeted destruction of cellular proteins, making proteasome inhibition an important target in cancer therapy. Bortezomib, a boronate peptide, is a reversible inhibitor of chymotrypsin-like activity of the 26S proteasome. It is the first-generation proteasome inhibitor approved in 2003 for the treatment of multiple myeloma. There have been five case reports of AKI and TMA associated with the use of bortezomib. A possible mechanism for development of TMA includes inhibition of the ubiquitination of inhibitor of κB, thereby preventing nuclear factor κB from entering the nucleus, leading to decreased VEGF production. ^, There has also been one reported case of bortezomib associated AIN.

Carfilzomib, a tetra peptide epoxyketone, is an irreversible inhibitor of chymotrypsin-like activity of 20S proteasome. It is approved for the treatment of relapsed or refractory multiple myeloma. AKI was initially reported in 25% of 266 patients in the phase 2 study of this drug. Multiple cases of AKI have been reported with this drug; likely mechanisms include prerenal causes, tumor lysis syndrome, and biopsy-proven TMA. There are 12 reported cases of TMA associated with carfilzomib. ^, Yui et al. published the largest case series of 11 patients who developed proteasome inhibitor-induced TMA, eight from carfilzomib and three from bortezomib. In the carFilzOmib for advanCed refractory mUltiple myeloma European Study (FOCUS) trial that compared carfilzomib to low-dose steroids in relapsed multiple myeloma, the investigators found that the incidence of grade 3 AKI was 8% in the carfilzomib group compared with 3% in the control group. In this cohort, up to 24% of patients developed adverse renal events.

Drug dosing in chronic kidney disease and dialysis patients

Because the majority of the targeted therapies are associated with potential systemic toxicity and nephrotoxicity, accurate dosing in CKD and patients on dialysis is of great importance. As noted in prior chemotherapy trials, most trials excluded patients on dialysis or with severe CKD (GFR < 30 ml/min). This limits our understanding of dosing in CKD and dialysis patients. In Table 17.3 , we summarize the existing published literature on dosing of these agents in CKD and dialysis (wherever data are available).

Table 17.3

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