human kidneys
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Tyrosine kinase inhibitors (TKIs) have been employed in recent years for the treatment of several forms of thyroid cancer. For example, the US Food and Drug Administration (FDA) has approved the TKIs vandetanib and cabozantinib for use in treating medullary thyroid carcinoma (MTC). Their effectiveness has prompted the introduction of a second generation of TKIs, also approved by the FDA, that target specific altered oncogenes. 

TKIs work by inhibiting the vascular endothelial growth factor receptor (VEGF-R). This action gives TKIs anti-cancer properties; however, they likely also contribute to multiple toxicities. One such toxicity is renal. 

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In this article, we will be examining the pathogenesis and risk factors for nephrotoxicity in advanced thyroid cancer that is being treated with TKIs. We will be referencing the work of Nervo and colleagues from Italy, who have written a study that explores the renal adverse events seen with commonly used TKIs. 

A Common Cause of Kidney Problems 

First of all, it is worth mentioning that drug-induced nephrotoxicity is a problem that is common across different medical conditions. In fact, drug-induced nephrotoxicity is one of the most common causes of acute kidney injury (AKI) and chronic kidney disease (CKD). 

“Kidney injury may occur in various renal compartments such as the renal vascular supply, the glomerulus, the tubule interstitium and the collecting ducts,” Wu and Hang wrote in their study on drug-induced nephrotoxicity. “The injury in these kidney compartments are generally caused by one or multiple mechanisms including alteration in glomerular hemodynamics, tubular cell toxicity, inflammation, crystal nephropathy, rhabdomyolysis, and thrombotic microangiopathy.” 

Aside from TKIs, Wu and Hang provided a list of other drugs that commonly cause kidney damage: 

  • Aminoglycosides, cisplatin, radio contrast agents, and amphotericin B can cause tubular cell necrosis. 
  • Nonsteroidal anti-inflammatory drugs (NSAIDs) can cause inflammation. 
  • Cidofovir/adefovir/tenofovir can cause tubular cell apoptosis. 

So how do TKIs cause kidney injury? “The mechanisms underlying proteinuria induced by thyroid cancer TKIs (TC-TKIs) are still not thoroughly understood,” Nervo et al wrote.

However, one theory is that by inhibiting the VEGF pathway, vascular production of nitric oxide is reduced, leading to systemic and intraglomerular hypertension that causes proteinuria. When patients stop taking anti-VEGF drugs, a decrease in blood pressure and proteinuria can usually be observed. 

In addition, there are other possible ways in which the anti-VEGF properties of TKIs result in renal injury.

“Pharmacological inhibition of the VEGF axis can cause a perturbation of endothelial-podocyte signaling and lead to kidney damage,” Nervo and colleagues wrote.

Studies have shown that the renal biopsies of the majority of patients taking TKIs exhibit podocytopathies, including minimal change disease (MCD) and collapsing focal segmental glomerulosclerosis (FSGS). It is also thought that TKIs used in thyroid cancer inhibit other pathways, such as the fibroblast growth factor (FGF) axis, with the end result being the worsening of kidney injury.

Monitoring and Management Approaches 

Before we talk about the management of TKI-induced nephrotoxicity, it behooves us to remind ourselves of the importance of the close monitoring of kidney function so that immediate action can be taken should kidney injury be detected.

“Intensive clinical monitoring of drug-induced nephrotoxicity is crucial in clinical practice,” Wu and Hang wrote. “Firstly, [patients aged more than 60 years], infants and other high risk patients must be identified and extensive monitoring of kidney function should be conducted. Secondly, the drug dosage and drug combinational treatment should be carefully considered for different individuals.”

In addition, physicians should weigh the possibility of nephrotoxicity before prescribing TKIs.

“Before the start of TKI therapy, a detailed record of the patient’s clinical data and medical history is essential to detect specific risk factors for [renal adverse effects], including the presence of uncontrolled hypertension and [diabetes mellitus],” Nervo et al wrote. ”Optimization of blood pressure levels and a good glycemic control are recommended before starting therapy.” 

Once drug-induced nephrotoxicity is diagnosed, appropriate medical intervention can begin. The problem, however, is that there are no standard guidelines on how this should be carried out: “Regarding TC-TKIs-related RAEs management, no evidence-based guidelines or interventional studies are available,” Nervo and colleagues wrote. 

However, there are some medical interventions that can be introduced. For example, new onset of hypertension can be controlled using antihypertensive medications, such as angiotensin-converting enzyme (ACE) inhibitors and angiotensin 2 receptor blockers (ARBs). They work by lowering intraglomerular pressure and decreasing protein excretion. In CKD, patients are advised to have a low protein intake (less than 0.8 g/kg/day). 

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“Proteinuria generally improves when the TKI is interrupted, or its dosage is reduced, suggesting a dose-dependent relationship,” Nervo et al wrote. This means that TKIs can be temporarily stopped until edema or an elevated creatinine is resolved, as well as when urinary protein levels fall to less than 2 g/24 hours. 

Weighing Drug Toxicity 

There are no drugs in the world that do not come with some adverse effects for some people. However, when the adverse effects outweigh any benefit that the drug may confer, then it bears close examination on whether the drug should be prescribed at all. In the case of TKI-induced nephrotoxicity, physicians need to make a decision on whether they are confident of treating TKI-induced nephrotoxicity if they choose to continue prescribing TKIs for patients with thyroid cancers.

References

Nervo A, Retta F, Ragni A, et al. Nephrotoxicity in advanced thyroid cancer treated with tyrosine kinase inhibitors: an update. Crit Rev Oncol Hematol. 2021;168:103533. doi:10.1016/j.critrevonc.2021.103533

Wu H, Huang J. Drug-induced nephrotoxicity: pathogenic mechanisms, biomarkers and prevention strategies. Curr Drug Metab. 2018;19(7):559-567. doi:10.2174/1389200218666171108154419