Cisplatin is a platinum-based anticancer drug widely used to treat various types of cancer and contributes to the improvement in outcomes like 5-year survival. However, side effects of cisplatin including ototoxicity, neurotoxicity, nausea, and myelosuppression frequently occur, and the main dose-limiting side effect is nephrotoxicity [
]. Previous reports showed that cisplatin nephrotoxicity occurred in approximately 7–29% of patients and several risk factors were reported [
]. For example, de Jongh et al. reported that age, female gender, smoking, paclitaxel co-administration, hypoalbuminemia were the risk factors of cisplatin nephrotoxicity in 400 patients with advanced solid tumors [
]. It was also reported that higher plasma platinum concentrations, hyperuricemia, and hypoalbuminemia were associated with renal dysfunction due to cisplatin [
Though hydration, monitoring of renal function, and adjustment of cisplatin doses depending on renal function [
] are commonly performed in usual clinical practice, specific therapeutic approaches for the prevention and treatment of cisplatin nephrotoxicity has not been established yet. To ameliorate cisplatin nephrotoxicity, numerous approaches such as blocking inflammation, injury signaling, and cell death pathway have been reported in animal models or cultured cells [
]. However, whether these approaches are applicable to human patients is still unknown [
The pathophysiological mechanisms of cisplatin nephrotoxicity include its direct tubular epithelial cell toxicity as well as the reduction of renal blood flow as a consequence of endothelial dysfunction and vasoconstriction [
]. However, there are few reports in literature that have assessed the influence of hemodynamic conditions such as lower blood pressure and decreased food intake on cisplatin nephrotoxicity [
]. Thus, we hypothesized that risk factors such as lower blood pressure and decreased food intake deteriorate cisplatin nephrotoxicity by reducing renal blood flow despite routine administration of hydration.
In this study, we retrospectively reviewed a cohort of patients treated with cisplatin-based chemotherapy for head and neck cancer, esophageal cancer, or gastric cancer. The subject selection criteria were determined according to the following two reasons: patients with these types of cancer tend to decrease their food intake from trismus, dysphagia, or gastrointestinal symptoms and these cancers are similar in cisplatin dosage and administration interval. The objective of this study was to investigate the influence of lower blood pressure and decreased food intake on the incidence of cisplatin nephrotoxicity.
Study design and participants
We conducted a retrospective cohort study at University Hospital, Kyoto Prefectural University of Medicine, Kyoto, Japan. By searching electronic medical records, we identified hospitalized patients aged 18 years or older with head and neck cancer, esophageal cancer, or gastric cancer, who received intravenous cisplatin administration between January 2011 and December 2012. The following patients were excluded from the study: patients who received cisplatin before the observation period, those with a history of previous cisplatin administration at other hospitals, those with an interval of cisplatin administration of less than 2 weeks, and those receiving maintenance dialysis.
We analyzed the incidence of cisplatin nephrotoxicity in the first cycle of cisplatin chemotherapy and the relationship of potential risk factors to the incidence of cisplatin nephrotoxicity. Then, we evaluated all cycles of cisplatin chemotherapy during the observation period to investigate the relationship of lower blood pressure and decreased food intake to the incidence of cisplatin nephrotoxicity, because these factors can vary among cycles of chemotherapy even in the same patient. The study was approved by the Ethics Committee on Human Research of Kyoto Prefectural University of Medicine and was carried out in accordance with the Declaration of Helsinki. Patient records/information was anonymized and de-identified prior to analysis.
Outcomes and follow-up
The primary outcome was the incidence of cisplatin nephrotoxicity defined as the increase in serum creatinine after cisplatin administration more than 1.5 times baseline according to the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 [
]. We used serum creatinine, measured prior to each cycle of cisplatin administration as the baseline value, and collected the highest serum creatinine in the first 4 weeks of the cycle.
Baseline characteristics of patients were extracted from electronic medical records as follows: age, sex, smoking status (current and former, never), history of hypertension, history of diabetes, history of cardiovascular disease, cancer types, and combined anticancer drugs. Cardiovascular disease was defined as angina or myocardial infarction, referring to a previous report [
]. The clinical parameters below were collected at each cycle of chemotherapy: height, weight, body mass index (BMI), body surface area (BSA), cisplatin dose, cumulative cisplatin dose, cycle number, combination of anticancer drugs, amount of hydration, diuretics, food form (solid, non-solid), amount of food intake, and antihypertensive medications including calcium channel blockers and renin-angiotensin system (RAS) inhibitors. We served food containing 1600–1800 kcal, 6–9 g of NaCl daily and less than 30% of food intake was arbitrarily defined as “low food intake”. Non-solid food was defined as liquid food or food which was minced or pasted. Non-solid food was served when the patients could not eat solid food because of nausea or gastro-intestinal obstruction due to the cancer. All patients received the drug within the manufacturer’s recommended dose and the hydration protocol that is routine in our institute. We collected systolic and diastolic blood pressure and baseline laboratory data such as serum creatinine, C-reactive protein (CRP), serum albumin, and hemoglobin measured prior to cisplatin administration.
Data are shown as number (percentage) for categorical variables and mean ± standard deviation (SD) for continuous variables. Categorical variables were compared using chi-square tests or Fisher’s exact tests for small sample sizes. Chi-square test with Bonferroni correction was used for multiple comparisons. Continuous variables were compared using a Welch’s
Multivariate logistic regression analysis was performed to evaluate the influence of clinical variables on cisplatin nephrotoxicity in the first cycle of chemotherapy. The variables included age, sex, cisplatin dose per BSA, food form (solid, non-solid), systolic blood pressure, and the use of RAS inhibitors. Data of logistic regression analysis are given as adjusted odds ratio (OR) with a 95% confidence interval (CI) and
To examine the relationship between blood pressure and nephrotoxicity, all cycles were grouped into quartiles based on systolic blood pressure. The incidence of nephrotoxicity and the prevalence of antihypertensive medication use in each group were calculated. Then, the relationship between cisplatin nephrotoxicity, quartiles of systolic blood pressure, and food form (solid or non-solid food) were analyzed.
Differences were determined to be significant when the two-sided
P value was less than 0.05. Statistical analyses were performed using JMP software, Version 10 (SAS Institute Inc., Cary, NC).
This retrospective cohort study addresses the risk of cisplatin nephrotoxicity and especially focuses on the impact of lower blood pressure and decreased food intake. In this study, we verified that lower blood pressure prior to cisplatin administration, and the use of RAS inhibitors were associated with the incidence of cisplatin nephrotoxicity. We also showed that non-solid food intake is a risk of cisplatin nephrotoxicity in case of coincidence with lower blood pressure.
Our study showed that lower blood pressure, especially lower than 107 mmHg, prior to cisplatin administration was a significant risk for the incidence of cisplatin nephrotoxicity. In terms of cisplatin metabolism, the unbound cisplatin in the plasma is freely filtered by the glomerulus and is not reabsorbed [
]. On the other hand, circulating cisplatin is transported into proximal tubular epithelial cells by the organic cation transporter 2 (OCT2) which is highly expressed in the basolateral membrane of proximal tubules, which depends on the serum cisplatin concentration [
]. The renal accumulation of cisplatin causes direct tubular epithelial cytotoxicity [
]. In patients with lower blood pressure, it is expected that urinary excretion of cisplatin is delayed by a decreased glomerular filtration rate (GFR). As a result, it takes a longer time for the serum cisplatin concentration to drop off and for cisplatin uptake into tubular epithelial cells through OCT2 to increase, which eventually accelerates cisplatin nephrotoxicity. The pathophysiology of cisplatin nephrotoxicity also involves vascular injury such as microangiopathy and vasoconstriction, which causes a reduction of renal blood flow and GFR [
]. Moreover, it is reported that an increase of sodium excretion in urine and polyuria occur after cisplatin administration [
], which induce further reduction of blood volume and a subsequent decrease in renal blood flow.
Regarding antihypertensive drugs, this study also suggests that the use of RAS inhibitors was associated with cisplatin nephrotoxicity independent of systolic blood pressure. RAS is activated when the renal perfusion pressure is decreased by hypotension or volume depletion [
]. Angiotensin II increases systemic blood pressure by contracting arterioles, promotes sodium reabsorption in renal tubules, and increases extracellular fluid [
]. Consequently, angiotensin II maintains glomerular filtration pressure and GFR [
]. An experimental study using dogs showed a dissociation of autoregulation in renal blood flow and GFR was introduced by RAS inhibitors; GFR dramatically dropped off according to the decrease in renal perfusion pressure while renal blood flow was preserved in the same condition [
]. In fact, patients taking RAS inhibitors are at high risk of developing acute kidney injury during intercurrent illnesses such as volume depletion, because the contraction of efferent arterioles is inhibited by RAS inhibitors [
]. In addition, RAS can be activated by volume depletion from sodium wasting or polyuria and vascular contraction after cisplatin administration. It was reported that plasma renin activity and plasma aldosterone concentrations were elevated after cisplatin administration [
]. RAS inhibitors may suppress this humoral response, resulting in exacerbating renal ischemia and delaying cisplatin excretion by inhibiting RAS activation to maintain GFR.
On the other hand, Saleh et al. reported that the angiotensin receptor blocker losartan has protective effects against cisplatin-induced nephrotoxicity in a rat model [
]. In that study, losartan did not affect cisplatin uptake by the kidney, but significantly counteracted cisplatin-induced lipid peroxidation and glutathione depletion. They concluded that the renoprotective effect is due to antioxidant properties [
]. In our study, in subjects who tend to present with volume depletion from decreased food intake, the harmful effect on glomerular filtration pressure might exceed the antioxidative effect of RAS inhibitors. Further investigation is needed to address this issue.
Concerning food intake, the prevalence of appetite loss is high among cancer patients and various causes are involved. For example, emotional distress by the diagnosis or treatment [
], active inflammatory reaction caused by cancer, chemotherapy or irradiation may decrease the appetite [
]. Of note, patients of head and neck cancer frequently developed taste and smell disturbance because of cancer involvement in taste nerves or local taste bud injury caused by irradiation or surgery, which remarkably decrease the patient’s quality of life. Unless essential minerals are appropriately supplied, lower food intake reflects the reduction of sodium intake, resulting in a notable decrease in blood pressure and subsequent increase in the risk of cisplatin nephrotoxicity. In fact, our study demonstrated that non-solid food intake was a risk of cisplatin nephrotoxicity only in case of lower blood pressure. From these findings, we have to pay much attention to food intake and subsequent lower blood pressure in order to avoid cisplatin nephrotoxicity.
This study showed no significant association between cisplatin dose and nephrotoxicity in multivariate analysis. Reece et al. reported that the peak plasma level of ultrafilterable platinum correlated with a decline in creatinine clearance after cisplatin therapy in 22 cancer patients who received cisplatin [
]. Lagrange et al. also reported that platinum concentration was only related to the incident rate of nephrotoxicity and that platinum concentration was related to pretreatment renal function, BSA, cisplatin dose, number of administration in 121 cycles of 62 cancer patients who received cisplatin every 3 weeks [
]. In our institute, cisplatin dose is empirically reduced in the presence of pre-existing renal dysfunction [
]. It is suggested that cisplatin dose adjustment for renal impairment hides possible associations between cisplatin dose and nephrotoxicity in this study.
Our study has several limitations. First, our analysis is lacking an appropriate control group such as patients who maintained adequate food intake or those with higher blood pressure. Therefore, we classified patients according to food form and blood pressure, and evaluated their association with the outcome within a cohort. Second, the study also has the inherent limitations of a retrospective study. To quantify feeding status, we used two parameters: food form (solid, non-solid) and amount of food intake. The medical records of these data were partially semi-quantitative. The quantitative indicators of food intake or other parameters for nutritional status are needed for further investigation. Third, serum creatinine, used for primary outcome in this study, can overestimate basal renal function and underestimate renal prognosis in patients with weight loss due to cancer. To avoid the latter problem, we evaluated short-term creatinine changes within 4 weeks. Finally, there was the lack of longitudinal data including blood pressure and body weight. These data can elucidate the change in distribution of blood pressure and relevant factors in cancer patients.