Background
Everolimus is a major active metabolite of sirolimus, which acts as a selective inhibitor of the mammalian target of rapamycin (mTOR) [
1]. Everolimus has been developed as an immunosuppressant that is administered after solid organ transplantation based on its antiproliferative properties [
1,
2]. In particular, an mTOR-inhibitor-based regimen in which calcineurin inhibitors are withdrawn or reduced has been evaluated as a maintenance immunosuppressant therapy to minimize calcineurin-inhibitor toxicity [
2,
3]. Although mTOR inhibitors have been considered to lack nephrotoxicity when used alone, the combination of mTOR inhibitors and full-dose calcineurin inhibitors has been shown to exacerbate nephrotoxicity. Moreover, the nephrotoxicity of mTOR inhibitors has been demonstrated in patients with glomerulonephritis and in experimental animal models of glomerular injury [
4,
5]. Recently, everolimus received approval for use in the treatment of advanced renal cell carcinoma (RCC) and several other cancers at a dose of 10 mg once daily, which is a higher dose than that used for immunosuppression [
6‐
8]. Increased serum creatinine level was one of the frequently reported laboratory abnormalities during observed in a phase 3 trial of everolimus for metastatic renal cell cancer [
6]. However, the information regarding the nephrotoxicity associated with everolimus, especially in cancer patients with clinical settings, is sparse. Therefore, we conducted this research to evaluate the incidence, severity, risk factors, and prognosis of acute kidney injury (AKI) in patients receiving everolimus as an anticancer therapy. We were particularly interested in patients with RCC who already had a decreased mass of functioning nephrons because of nephrectomy, invasion of cancer, or previous treatment with vascular endothelial growth factor receptor/tyrosine kinase inhibitors (VEGFR-TKIs).
Discussion
This retrospective analysis examined the incidence, risk factors, and clinical implications of the development of AKI during everolimus treatment in real-world cancer patients. Twenty-three percent of patients who received everolimus to treat RCC experienced AKI, and 67% of AKI events were considered everolimus-associated AKI without other nephrotoxic insults. In contrast to RCC patients, AKI events were not observed in any of the patients with other cancers, for whom baseline eGFR was much higher than the levels detected in patients with RCC. Baseline eGFR was the only independent risk factor of everolimus-associated AKI among patients with RCC. Differences in treatment duration and in the reason for drug discontinuation were not observed between the AKI group and non-AKI groups, which indicates that the occurrence of AKI did not have a high impact on therapeutic decision making by clinicians.
As many new chemotherapeutic agents have emerged in recent decades, nephrologists should be alerted to the potential nephrotoxicity of new drugs [
11‐
14]. VEGFR-TKI is a representative target agent with well-established nephrotoxicity [
11,
15]. Everolimus is familiar to nephrologists as an alternative immunosuppressant to calcineurin inhibitors after kidney transplantation, with the advantage of lack of nephrotoxicity [
1‐
3]. However, everolimus has been examined as a treatment for various cancers and renal adverse effects have been reported [
6,
16]. In fact, the incidence and severity were divergent in clinical studies and target cancers, which confused clinicians regarding the recognition of drug nephrotoxicity [
17‐
19]. This research clearly showed that AKI was not uncommon in subjects with impaired kidney function, but was rare in subjects with normal kidney function. Impaired kidney function at the baseline is a general feature in subjects with RCC who have started to take everolimus. Therefore, clinicians should be cautious about potential nephrotoxicity when prescribing everolimus to RCC patients.
It is not surprising that most RCC patients have decreased kidney function when they initiate everolimus treatment. Currently, everolimus is indicated in metastatic RCC after progression on VEGFR-TKI therapy [
20,
21]. Thus, patients have a high probability of reduced functioning in nephrons because of previous radical nephrectomy, the presence of a neoplastic mass replacing renal parenchyma, or previous exposure to VEGFR-TKI therapy. We assumed that nephrons with reduced function render RCC patients vulnerable to the adverse renal effects of everolimus. Several studies have demonstrated that mTOR inhibitors have nephrotoxicity in injured kidneys [
5,
22]. The combination of mTOR inhibitors with full-dose calcineurin inhibitors exacerbates the nephrotoxicity of the drug [
1]. In addition, everolimus treatment converts the reversible glomerulonephritis into chronic progressive disease in
Thy1 models via the inhibition of glomerular repair [
5]. Moreover, everolimus treatment induces renal deterioration and proteinuria in the remnant kidney model [
22]. Consistently, baseline eGFR was an independent risk factor of everolimus-associated AKI in this analysis.
The observation that the nephrotoxicity of everolimus was evident in patients with RCC compared with kidney transplant recipients who also had reduced nephron functioning was not an unexpected finding. The dosage of everolimus as an anticancer treatment is 10 mg per day, which is about three times higher than that used for immunosuppression in transplantation patients [
1,
2,
6,
7]. An experimental study showed that everolimus-induced glomerular injury developed in a dose-dependent manner [
5].
It is noteworthy that everolimus treatment was continued or resumed in most patients with AKI without renal deterioration, unless there was progressive disease or other significant adverse events. Most of the AKI events (13 of 14) were mild and nonprogressive (categorized into AKI-risk or AKI-injury according to ADQI criteria) during everolimus treatment for 20 weeks. This finding has important clinical significance when considering that the drug is indicated for patients with few therapeutic options. In addition, decreased renal function was recovered after the cessation of treatment, including one patient who was in the AKI-failure category.
There were some limitations to this research. First, as a retrospective analysis, selection and misclassification biases were inevitable. However, everolimus treatment in cancer patients is standardized at our center, and serum creatinine is monitored regularly, which might minimize those biases. Second, the effects of everolimus-associated AKI on patient mortality were not elucidated in this research. Third, we did not evaluate the incidence of proteinuria and increment of preexisting proteinuria, which are other renal adverse effects of anti-angiogenic drugs. In addition, this research did not provide any information on the histological features of everolimus-associated AKI, because none of subjects who experienced AKI underwent kidney biopsy, probably because the AKI was mostly mild and reversible.
Conclusions
In conclusion, we demonstrated that AKI associated with everolimus, which is used as an anticancer therapy, is not uncommon in subjects with impaired kidney function, whereas it is rare in subjects with normal kidney function. Therefore, clinicians should be cautious about potential nephrotoxicity when prescribing everolimus to patients with decreased kidney function, in whom serial measurements of serum creatinine are needed. In addition, everolimus treatment could be continued at a reduced dose or after a short-term off period even in patients with AKI without renal deterioration. Therefore, the treatment decision should be made using a multidisciplinary approach that includes the assessment of the oncological benefit of everolimus and other therapeutic options for cancer in each individual. A large-scale, prospective study is needed to clarify the incidence of everolimus-associated AKI and its impact on patients’ survival.
Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made.
The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.
Competing interests
The authors declare that they have no competing interests.
Authors’ contributions
LJE, OHY, and LH made substantial contributions to the study conception and design. HSH, PJH, JHR, and LJE made substantial contributions to the acquisition, analysis, and interpretation of the data; KDJ, KY, and HW were involved in the drafting and revision of the manuscript; LJE and OHY gave final approval of the version to be published; and KDJ and KY agreed to be accountable for all aspects of the work, and to ensure that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All authors read and approved the final manuscript.