Background
Cisplatin is one of the most commonly administered agents in the treatment of cancer. Cisplatin-based chemotherapy has demonstrated survival benefits for patients with resected early-stage non-small cell lung cancer (NSCLC), advanced-stage NSCLC, small-cell lung cancer (SCLC) and malignant pleural mesothelioma [
1‐
4]. However, cisplatin can have severe side effects—in particular, cisplatin-induced nephrotoxicity, which is dose dependent and is the major side effect that limits the acceptable dose of cisplatin [
5]. Impairment of renal function has been shown to be a clinical problem in 25–35 % of patients treated with cisplatin [
5]. Therefore, it is important to identify the predictors of cisplatin-induced nephrotoxicity and to avoid administrating cisplatin to patients with these risk factors.
Recent studies have reported several risk factors for chronic kidney disease (CKD), including lifestyle-related diseases, smoking, use of non-steroidal anti-inflammatory drugs (NSAIDs), cardiac disease and cerebrovascular disease [
6]. Patients with risk factors for CKD may have a higher incidence of cisplatin-induced nephrotoxicity. Indeed, acute kidney injury (AKI) is more frequently observed in patients with CKD [
7,
8]. Furthermore, recent studies have reported that patients with lung cancer have a higher incidence of comorbidities than do patients with other cancers [
9]. The aims of this study were to evaluate the prevalence of CKD risk factors in thoracic malignancy patients who received cisplatin and to elucidate the correlation between nephrotoxicity due to cisplatin-based chemotherapy in patients with CKD risk factors.
Discussion
Cisplatin is one of the most active cytotoxic agents in treatment of thoracic malignancies. Cisplatin or carboplatin combination chemotherapy is recommended as the first-line chemotherapy for patients with lung cancer [
17,
18]. Because cisplatin has more severe non-hematological toxicity than carboplatin does, particularly in terms of nephrotoxicity and gastrointestinal toxicity, cisplatin is more poorly tolerated than carboplatin. Although cisplatin-based chemotherapy has been reported to be superior to carboplatin-based chemotherapy in non-squamous NSCLC patients, the number of patients administered cisplatin-based chemotherapy was limited in clinical practice [
2]. Recent progress in antiemetic therapies has greatly reduced cisplatin-induced gastrointestinal toxicity. We and other investigators have reported that triple antiemetic therapy with a 5-HT
3 receptor antagonist, dexamethasone and aprepitant ameliorates cisplatin-induced nausea and vomiting [
19,
20]. However, cisplatin-induced nephrotoxicity remains an unsolved problem. Although previous studies have reported less toxic methods for administrating cisplatin, such as hydration with the supplementation of magnesium and mannitol, cisplatin-induced nephrotoxicity still occurs in 6–14 % of patients [
21,
22]. Compatible with these studies, the current study showed that the incidence of AKI was 21.4 % (18/84), despite the administration of hydration, magnesium supplementation and mannitol. We need to develop more effective strategies to prevent cisplatin-induced nephrotoxicity.
Previous studies demonstrated that old age, female sex, current smoking, hyperuricemia, hypoalbuminemia, diabetes mellitus, cardiovascular disease and NSAID use are risk factors for cisplatin-induced nephrotoxicity [
15,
21,
23]. Because recent evidence has demonstrated that CKD is a risk factor for AKI, we hypothesized that patients with risk factors for CKD would also be at risk for cisplatin-induced nephrotoxicity [
7]. The present study showed that comorbidities, including CKD risk factors, were frequent in patients with thoracic malignancies (Additional file
2: Table S1). Univariate analysis demonstrated that cardiac disease and NSAID use were statistically significant predictors of cisplatin-induced nephrotoxicity (Table
2). Although multivariate analysis revealed that no single factor was significantly associated with cisplatin-induced AKI, AKI did occur significantly more frequently in patients who had both cardiac disease and NSAID use (Table
3). The risk factors for cardiac disease, such as hypertension, diabetes mellitus, dyslipidemia and smoking, are also risk factors for CKD. These factors cause atherosclerosis in the renal arteries and induce chronic ischemic injury to the tubulointerstitium [
24]. Because tubular cells are the major target of cisplatin-induced nephrotoxicity, it is not surprising that cardiac disease is associated with this complication [
25]. Nonselective cyclooxygenase (COX) inhibition by NSAIDs decreases prostaglandin synthesis and induces vasoconstriction and renal ischemia. Cisplatin has been suggested to induce injury in the renal vasculature and ischemic injury of the kidneys; thus these effects of NSAIDs may exacerbate cisplatin-induced nephrotoxicity [
25]. In this study, the non-selective COX inhibitor loxoprofen was prescribed to 13 of the 17 patients who had received NSAIDs (76.8 %). Use of selective COX 2 inhibitors may reduce the risk of cisplatin-induced nephrotoxicity. Furthermore, our study showed that an increased number of CKD risk factors may be related to a higher incidence of cisplatin-induced AKI (Tables
2 and
3). Patients without CKD risk factors did not develop cisplatin-induced AKI. By contrast, patients with 5 or more CKD risk factors had relatively higher odds ratio (OR 4.55, 95 % CI 0.73–28.65; Table
3). We also investigated whether CCI score, which is a method of classifying prognostic comorbidity, correlated with the incidence of cisplatin-induced AKI, but no association was found [
16].
In previous studies, cisplatin-induced nephrotoxicity has been assessed on the basis of the elevated sCre levels [
21,
26]. However, Launay-Vacher et al. analyzed data for 4684 cancer patients and found that elevated sCre levels were less sensitive than was decreased Cre clearance for detecting renal impairment [
27]. In that study, renal impairment was commonly found in cancer patients (57.4 %), and 53.4 % required dose reduction due to nephrotoxicity. The authors concluded that the use of nephrotoxic drugs should be avoided in cancer patients at high risk for AKI. Thus, we included decreased eGFR (estimated using the equation developed by the Japanese Society of Nephrology) in our AKI criteria [
10]. The current study demonstrated that a decrease in the eGFR ≥ 25 % from the baseline level was detected in 22.4 % (18/84) of the patients, although only 9.5 % (8/84) exhibited elevated sCre levels of > 0.3 mg/dl or ≥ 1.5 times baseline. These data suggest that GFR should be included in assessment of cisplatin-induced nephrotoxicity. Cisplatin causes cell injury and death in the proximal and distal tubules. Although the long-term effects of cisplatin on renal function have not been fully elucidated, previous studies indicated that cisplatin treatment may lead to subclinical but permanent reductions in GFR [
28]. By contrast, Moon et al. reported that the elevated sCre levels recovered in 80.5 % of patients after cisplatin-induced AKI [
29]. In the present study, of the 18 patients who had cisplatin-induced AKI, the eGFR in 16 (88.9 %) recovered to more than 75 % of the baseline level during the follow-up period. Cisplatin combination chemotherapy has been recommended as the first-line chemotherapy for lung cancer patients [
17,
18]. Patients who develop cisplatin-induced AKI may have a higher risk of nephrotoxicity with subsequent chemotherapies. Indeed, AKI is a well-defined risk factor for CKD, and patients who develop AKI have a several-fold increased risk of developing CKD [
30]. Further investigation should be carried out to evaluate whether subsequent chemotherapies can be safely administered to patients who had experienced cisplatin AKI.
Competing interests
The authors declare that they have no competing interests.
Authors’ contributions
KS collected the clinical data and drafted the manuscript. SW conducted the study. AO, SS, DI, TT, KN, RK, MO and SM participated in patient care and collected the data. JT, TS, TK and HK analyzed and interpreted the data. HY and IN provided the administrative support. All the authors have read and approved the final version of the manuscript.