Differentiated thyroid cancer (DTC) is the most common histologic type of thyroid cancer and surgery is the first choice of treatment, with postoperative radioiodine (RAI) therapy if necessary (1–3).. Lenvatinib is a multi-kinase inhibitor that blocks a variety of receptors, including vascular endothelial growth factor receptor (VEGFR) 1-3 (4–6). In the SELECT study, a global Phase III trial in RAI-refractory DTC, lenvatinib significantly improved progression-free survival to 18.3 months, compared to 3.6 months with a placebo (7). As a result, lenvatinib is recommended for use in patients with RAI-refractory DTC (8).

Proteinuria associated with anti-cancer drug use is mainly caused by damage to the glomerulus of the kidney by targeting VEGF (9, 10); for instance, bevacizumab, an anti-VEGF drug causes the event in a dose-dependent manner in 41%–63% of patients (11, 12). Lenvatinib-induced proteinuria is one of the most frequent adverse events, represented by 31% for all grades and 10% for grade ≥3 in the SELECT trial, and notably, occurs more frequently in Japanese patients than in others (7, 13).. However, protocols and strategies for monitoring and managing proteinuria induced by lenvatinib remain unestablished. According to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) v4.0, which were used to evaluate adverse effects in the SELECT study, a proteinuria ≤2+ or less is defined as grade 2 proteinuria, but if a proteinuria ≤3+ develops, a 24-hour urine sample should be performed when proteinuria ≥3+ develops; a urine sample with >3.5 g/gCre is defined as a grade ≥3 proteinuria. Because this 24-hour urine sample test relies on the patient collecting overnight urine samples, which is difficult to test during outpatient therapy, lenvatinib was often withdrawn when proteinuria ≥3+ developed (14). Thus, the details of renal dysfunction with continued lenvatinib after the onset of proteinuria ≥3+ are unclear. Since lenvatinib was continued regardless of the degree of proteinuria in the absence of a rapid decrease in either eGFR or edema, and to not decrease the intensity of treatment at our hospital, we investigated the effect of the degree of proteinuria on renal function in this study.

In this study, we examined the impact of the development of proteinuria ≥3+ on renal function during lenvatinib treatment. There was a significant decrease in eGFR in all patients from 2 years after the start of treatment, but it was clear that eGFR improved after the end of treatment. Furthermore, in the latest values of eGFR during treatment, the development of severe renal dysfunction or renal failure corresponding to a chronic kidney disease stage ≥G4 or higher was not significantly different between the two groups, and there was no permanent discontinuation of treatment due to renal dysfunction in both groups (18). Proteinuria induced by VEGF inhibitors, such as bevacizumab, increases in a dose-dependent manner, but is not associated with any renal dysfunction, such as decreased renal clearance and azotemia (19, 20). However, lenvatinib use causes proteinuria more frequently than use of other VEGF inhibitors because of the stronger VEGF inhibitory action of lenvatinib; furthermore, renal dysfunction occurred in 4.2% of patients in the SELECT study (7, 21). Patients with thyroid cancer treated with lenvatinib long-term have a significant decrease in eGFR after 2 years of treatment, which was also seen in this study (22). However, the change in ΔeGFR showed no significant difference between the high proteinuria and low proteinuria group at each time point, indicating that eGFR decreased regardless of the degree of proteinuria. In contrast, patients who ended treatment in both the high and low proteinuria groups showed a significant improvement in eGFR after the end of treatment, indicating that the decrease in eGFR during treatment was not due to irreversible renal dysfunction. In summary, although lenvatinib produces proteinuria more frequently than other VEGF inhibitors, eGFR declines after 2 years of treatment, regardless of the degree of proteinuria, and this decline in eGFR with lenvatinib is reversible. This suggests that lenvatinib-induced proteinuria may be only one of the phenotypes of renal dysfunction caused by VEGF inhibitors, and it is important to be aware of changes in renal function, regardless of the degree of proteinuria.

In general, risk factors for impaired renal function include age >65 years, diabetes mellitus, and hypertension (23). In addition, hypertension is a frequent side effect of lenvatinib use; and calcium channel blockers, angiotensin-converting enzyme inhibitors, and angiotensin II receptor blockers are often used to treat this side effect. However, these antihypertensive drugs can cause renal dysfunction (24–27). In this study, the multivariate analysis revealed that patients with a history of diabetes mellitus and patients who developed proteinuria ≥3+ were significantly associated with the risk of decrease in ΔeGFR. Unlike for other malignancies, the available treatment options for thyroid cancer are limited. Therefore, patients who respond to lenvatinib are more likely to use it long-term, and background factors such as medical history and age at the time of treatment initiation should also be considered. Diabetes mellitus can cause diabetic nephropathy, which manifests as a decrease in renal function over a long period (28), and increased proteinuria, which is strongly associated, along with decreased eGFR, with the risk of future end stage kidney disease in patients with diabetes mellitus (28, 29). In this study, renal failure was observed in one patient with a history of diabetes who developed proteinuria ≥3+. In addition, patients in the study with a history of diabetes showed a decrease in eGFR after 4 years of treatment compared to both the overall population and the population with no history of diabetes. These results suggest that eGFR and proteinuria should be carefully monitored in patients with a history of diabetes at the time of lenvatinib initiation. In addition, factors that were not identified in the multivariate analysis are reportedly associated with decreased renal function, suggesting that it is important to continue treatment with attention to the decrease in eGFR.

Two important limitations to this study must be considered. The first is that eGFR is a Japanese-specific value, which is affected by muscle mass. Therefore, eGFR may be overestimated in patients with reduced muscle mass, such as those with sarcopenia. Second, the protocol did not provide for temporary interruption or dose reduction of lenvatinib administration as a result of worsening proteinuria or renal function. Therefore, interruption or dose reduction was done at the discretion of the physician, and judgments based on the physician’s experience and knowledge may have affected renal function. However, there was no significant difference in ΔeGFR trends over time depending on the degree of proteinuria or in the development of severe renal dysfunction in the two groups. Thus, the results suggest that renal function should be monitored, and treatment continued cautiously regardless of the degree of urinary protein, but larger study are needed to confirm these findings.

Regardless of the degree of proteinuria, eGFR decreased after 2 years of lenvatinib treatment; however, the incidence of end stage renal dysfunction or renal failure was not significantly different between the two groups. In addition, patients with a history of diabetes mellitus should continue treatment with careful attention because it is a risk factor for a decrease in eGFR. Therefore, it is recommended to continue lenvatinib cautiously until more prospective data are published, paying attention to patient background and renal function.

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

The studies involving human participants were reviewed and approved by Shinya Suzuki, National Cancer Center Hospital East. Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.

YS, SS, and AS designed this concept, performed the statistical analyses, and wrote the manuscript. TE, SO, TF, FS, TY, MS, TK, and MT interpreted and discussed the data. All authors contributed to the article and approved the submitted version.