Proton pump inhibitors may increase the risk of cisplatin-induced acute kidney injury in patients with nasopharyngeal carcinoma: a prospective cohort study

Cisplatin is the most commonly used platinum-based treatment for nasopharyngeal carcinoma (NPC). However, its clinical application is limited owing to its nephrotoxicity and gastrointestinal reactions. Proton pump inhibitors (PPIs) have been reported to increase nephrotoxicity risk in previous studies. We aimed to evaluate whether PPIs increase cisplatin-induced nephrotoxicity in patients with NPC. In total, 295 patients were included in this prospective cohort study: 145 in the PPIs group and 150 in the non-PPIs group. All patients underwent cisplatin-based induction chemotherapy, followed by cisplatin-based concurrent chemoradiotherapy. The PPIs group received 40 mg of intravenous esomeprazole sodium for 7 days in each chemotherapy cycle. Chi-squared test and logistic regression analyses with odds ratios and 95% confidence intervals were applied to assess the association between PPIs and the risk of acute kidney injury (AKI). AKI incidence in the PPIs group was significantly higher than that in the non-PPIs group (P = 0.005). After adjusting for various confounders including demographic features, clinical features, and renal function indices, PPIs use was significantly associated with a higher AKI risk (odds ratio: 2.775; 95% confidence interval 1.280–6.020; P = 0.010). The incidences of acute and chronic kidney diseases were similar between both groups (P > 0.05), whereas the incidence of nausea was lower in the PPIs group than in the non-PPIs group (P = 0.029). This study has shown that PPIs use may increase the risk of cisplatin-induced acute nephrotoxicity in patients with NPC.


Treatments
Eligible patients received three cycles of induction chemotherapy (ICT) followed by three cycles of cisplatinbased CCRT.The choice of ICT regimen was based on the clinical judgment of the attending physician.The ICT regimen included gemcitabine plus cisplatin (GP) regimen (gemcitabine 1000 mg/m 2 , cisplatin 80 mg/m 2 ) and docetaxel plus cisplatin (TP) regimen (docetaxel 75 mg/m 2 , cisplatin 75 mg/m 2 ) once every 3 weeks for three cycles.Radiotherapy was initiated 3 weeks after the last ICT cycle.During CCRT, cisplatin was administered concurrently with radiotherapy at 100 mg/m 2 every 3 weeks for three cycles.According to the NCCN guidelines, PPIs should be used when receiving cisplatin-based chemotherapy in patients with pre-existing gastric diseases or those who experience a gastrointestinal reaction of more than two degrees during chemotherapy 6 .Patients were divided into PPIs and non-PPIs groups based on whether they used PPIs.The PPIs group received an intravenous drip of esomeprazole sodium (40 mg/time, once a day) starting 1 day before each cisplatin chemotherapy cycle for 7 days, for a total of six cisplatin chemotherapy cycles, including 3 ICT cycles and 3 CCRT cycles based on cisplatin.The total dose of esomeprazole sodium was 1680 mg.The non-PPIs group received chemotherapy without PPIs.

Data collection
The following information was collected from each patient: age, sex, weight, height, body surface area (BSA), tumor stage, history of diabetes and hypertension, ICT regimen, potassium, and infusion volume.The values of SCr, eGFR, BUN, and cystatin C (CysC) before and after chemotherapy were also recorded.All patients received an antiemetic premedication with a 5-hydroxytryptamine (5-HT) 3 receptor antagonist and a neurokinin-1 receptor antagonist.Adverse effects were defined according to the Common Terminology Criteria for Adverse

Assessment of outcome
AKI was set as the primary outcome and was diagnosed and staged according to the kidney disease improving global outcome criteria 12 .AKI is defined as renal insufficiency caused by injury leading to changes in renal structure or function as well as meeting one of the following three conditions: (1) an increase in SCr within 48 h with the absolute value increasing by ≥ 26.5 μmol/l (0.3 mg/dl); (2) an increase in SCr by ≥ 50% (reaching 1.5 times the baseline value) within 7 days; (3) a decrease in urine volume by < 0.5 ml/ (kg • h) for more than 6 h.Most patients did not have a catheter; thus, urine volume was not used to diagnose AKI.Therefore, the standard SCr was used in this study.AKI stage I was defined as an increase in SCr by ≥ 26.5 μmol/l (0.3 mg/dl) within 48 h, or SCr increase by ≥ 50% within 7 days.AKI stage II was defined as an increase in SCr level to 2.0-2.9 times the baseline value, and AKI stage III was defined as an increase in SCr levels to ≥ 3 times the baseline value, or increase of ≥ 354 μmol/l, or the initiation of renal replacement therapy.Patients who met AKI criteria for ≥ 7 days and less than 3 months after enrollment were considered to have acute kidney disease (AKD).CKD was defined as previous evidence indicating persistence of the markers of renal injury for ≥ 3 months (microalbuminuria, proteinuria > 500 mg/24 h or imaging abnormalities) or eGFR < 60 ml/min per 1.73 m 2 for ≥ 3 months.Patients in both groups were tested for renal function indicators before and 48 h after cisplatin chemotherapy in each cycle to observe the occurrence of AKI.Patients with NPC with AKI were followed up every 3 months for 1 year to evaluate the long-term effects of PPIs on renal function in patients receiving cisplatin chemotherapy.

Statistical analysis
The significance level (α) was defined as 0.05, and power calculations (1-β) were defined as 0.9.Based on our previous clinical results for the primary outcome, the sample size was calculated using the AKI incidence rate, and the minimum sample size was 270.
The distribution of the variables was evaluated using the Shapiro-Wilk test.Normally distributed variables were expressed as means and standard deviations and compared using the independent-samples t-test, whereas non-normally distributed variables were reported as medians with interquartile ranges and compared using the Wilcoxon rank-sum test.Categorical variables were expressed as numbers and percentages and compared using the chi-square test or Fisher's exact test.Pre-and post-treatment comparisons in different groups were performed using the paired-samples t-test or Mann-Whitney U test.Logistic regression models with odds ratios (ORs) and 95% confidence intervals (CIs) were used to evaluate the effect of PPIs use on AKI risk.The crude model only included whether PPIs were used, without adjustment for confounders.In model 1, we adjusted for demographic features, including age, sex, height, weight, and BSA.In model 2, we further adjusted for clinical features, including clinical stage, ICT regimens, hypertension, diabetes, and chemotherapy hydration.In model 3, covariates were additionally adjusted for baseline renal function indices, including SCr, eGFR, BUN, and CysC.All statistical analyses were performed using R software version 4.3.1 (R Foundation for Statistical Computing, Viena, Austria).A two-sided P value of less than 0.05 was considered statistically significant.

Patient characteristics
The study flow chart is illustrated in Fig. 1.We included 295 patients with NPC in this study: 145 patients in the PPIs group and 150 patients in the non-PPIs group.Overall, the patients had a mean age of 50.75 years, and 229 (78%) were men.One-hundred twenty (41%) patients had stage III disease, and 175 (59%) had stage IVA disease.A total of 105 (36%) patients received GP regimen for three cycles followed by CCRT, and 190 (64%) patients received TP regimen for three cycles followed by CCRT.Regarding comorbidities, a few patients in both groups were diagnosed with diabetes (9%) and hypertension (11%).In this study, patients in both groups received approximately 3,000 ml of hydration daily during chemotherapy.The baseline features of the two groups are presented in Table 1.

Primary outcome
The incidence of AKI was 19.3% (28/145) in the PPIs group and 8.0% (12/150) in the non-PPIs group, with a significant difference (P = 0.005; Table 2).In addition, most patients with AKI in both groups were at stage 1, with 27 patients in the PPIs group and 11 patients in the non-PPIs group, respectively.Only one patient in each groups had stage II AKI, and no stage III AKI was present in either group.A significant difference was observed in the severity of AKI between the two groups (P = 0.005; Table 2).Most patients had increased values of SCr, BUN, and CysC and decreased values of eGFR after cycle 1 of chemotherapy compared with those before chemotherapy.A comparison of renal function before and after chemotherapy is illustrated in Fig. 2.After chemotherapy, the average SCr level in the PPIs group was significantly higher than that in the non-PPIs group (P = 0.016; Fig. 2A), and the average eGFR in the PPIs group was significantly lower than that in the non-PPIs group after chemotherapy (P = 0.004; Fig. 2B).While no significant differences were observed in the average values of BUN and CysC between the two groups after chemotherapy (P > 0.05), the values in the PPIs group tended to be lower than those in the non-PPIs group (Fig. 2C,D).

Secondary outcomes
The difference in the incidences of AKD and CKD between the two groups was not significant (P > 0.05; www.nature.com/scientificreports/(P = 0.029).However, no significant difference was observed in the incidence of vomiting between the two groups (Table 2).
We analyzed the relationship between the use of PPIs and the occurrence of AKI using a logistic regression model after adjusting for various confounding factors (Table 4).A crude univariate logistic regression analysis model revealed that the combined use of PPIs during cisplatin chemotherapy was significantly associated with the incidence of AKI, with an OR of 2.752 (95% CI 1.340-5.652,P = 0.006).After adjusting for a series of confounders, multivariate analyses indicated a significant effect of PPIs administration on AKI incidence (OR 2.775, 95% CI 1.280-6.020,P = 0.010) in the fully adjusted model.

Discussion
Chemotherapy is important in treating NPC, and platinum-based chemotherapy is recognized as the first-line treatment.Cisplatin, one of the most common chemotherapeutic drugs, is widely used to treat NPC 13,14 .While cisplatin provides a substantial survival benefit for patients with NPC, patient adherence to treatment is reduced because of its adverse side effects, including nephrotoxicity, gastrointestinal toxicity, and bone marrow toxicity 15 .The use of cisplatin is often limited owing to the development of nephrotoxicity, with studies indicating an incidence between 20 and 30% 16 .Due to its nephrotoxic side effects, hydration and diuretics are often required during and before cisplatin administration in chemotherapy to prevent renal dysfunction 17 .However, AKI still occurs in some patients receiving hydration therapy, which affects the efficacy and prognosis of chemotherapy.The pathophysiology of cisplatin-induced AKI is highly complex and is associated with cellular uptake and efflux, oxidative stress, endoplasmic reticulum stress, inflammatory responses, apoptosis, necrosis, and autophagy 5 .AKI is a well-defined risk factor for CKD, and patients who develop AKI have a several-fold increased risk of developing CKD 18 .Renal tubulointerstitial fibrosis can occur during repeated episodes of AKI induced by cisplatin 19 , and cisplatin-induced AKI can lead to CKD. www.nature.com/scientificreports/ In addition, gastrointestinal toxicity is a common complication of cisplatin chemotherapy.Chemotherapy drugs can stimulate the gastrointestinal mucosa and cause the significant release of 5-HT from intestinal enterochromaffin cells of the gastrointestinal mucosa to act on 5-HT3 receptors at the end of the gastrointestinal vagus fibers, resulting in an increased afferent impulse of the vagus nerve fibers and abnormal excitation of the vomiting center, leading to gastrointestinal reactions.Additionally, chemotherapeutic drugs and their metabolites can act directly on chemoreceptors, which send excitatory nerve impulses to the vomiting centers.Various    22 .In addition, some studies have also revealed that PPIs have antitumor effects on other tumors 23,24 .PPIs are widely prescribed to reduce gastric acidity; however, over 50% of PPIs prescriptions are inappropriate or unnecessary.Additionally, several studies have demonstrated that PPIs use increases the risk of AKI, CKD, and ESRD [25][26][27] .Hart et al. studied the relationship between the use of PPIs and the risk of developing AKI and CKD 25 .In the AKI cohort, the incidence of AKI was significantly higher than that in non-exposed individuals.In the CKD cohort, the incidence of CKD was significantly higher than in patients who did not use PPIs.Xie et al. established a cohort study, in which enrolled patients were treated with acid inhibitors, and revealed that PPIs use was associated with an increased risk of chronic renal outcomes 26 .Klatte et al. found that people using PPIs had an increased risk of doubling creatinine levels and a 30% or more decrease in eGFR, which were associated with AKI and ESRD 27 .PPIs-acute interstitial nephritis (AIN) is the pathological manifestation of AKI caused by PPIs.Several studies have demonstrated that PPIs can cause AIN; however, the pathogenic mechanism of PPIs-AIN remains unclear.Most researchers believe that this is a specific immune-mediated response 28,29 .PPIs and/or their metabolites may be deposited in the renal tubular interstitium and bind to the normal components of the renal tubular basement membrane, acting as haptens or directly stimulating T cells to mediate AIN.In addition, PPIs can induce antibody production and deposition in the renal interstitium in the form of circulating immune complexes.Acute inflammation and injury of the renal tubulointerstitial tissue caused by PPIs-AIN can lead to chronic tubulointerstitial fibrosis, scar formation, and tubular atrophy, ultimately leading to CKD if PPIs are not stopped and treated promptly 30 .
There are currently few studies on the effects of cisplatin-based chemotherapy combined with PPIs on renal toxicity in patients with NPC.Further, the effects of AKI on long-term renal function in patients with NPC are poorly understood.We explored the association between PPIs use and AKI occurrence during cisplatin-based chemotherapy in patients with NPC.The incidence of AKI was significantly higher in the PPIs group than in the non-PPIs group (19.3% vs. 8.0%, P = 0.005), suggesting that PPIs may increase the incidence of AKI in patients with NPC.PPIs have been confirmed to synergistically aggravate cisplatin-induced AKI in vitro.Ye et al. discovered that lansoprazole up-regulated necroptotic biomarkers, including receptor-interacting protein kinase (RIPK) 1, phosphorylated receptor-interacting protein kinase (p-RIPK) 3, and phosphorylated mixed lineage kinase domain-like (p-MLKL) to induce tubular cell death via the tumor necrosis factor (TNF)-α-mediated RIPK1/ RIPK3/MLKL pathway, indicating that necroptosis and inflammation aggravate cisplatin-induced AKI 11 .Some studies have shown that necroptosis promotes inflammation, the inflammatory cytokine TNF similarly induces necroptosis, indicating a potential positive feedback loop between inflammation and necroptosis 31,32 .These negative effects can lead to irreversible kidney damage.Similarly, an in vitro study demonstrated that omeprazole increased the expression of the tubular cell injury marker neutrophil gelatinase associated lipocalin (NGAL) and the oxidative stress marker Heme-Oxygenase-1 to promote cell death, supporting its nephrotoxic potential 33 .
Cisplatin-related gastric damage is usually limited to superficial erosions, mostly in the antral region 34 .Cisplatin blocks acetylcholine release in smooth muscle cells and induces pyloric spasms and accumulation of hydrochloric acid and enzymes in the stomach, causing mucosal injury 35 .PPIs are the most effective agents for treating gastric acid-related disorders and preventing mucosal damage.Sartori et al. conducted two sequential randomized trials to assess the use of PPIs as prophylactic agents in chemotherapy 36,37 .The first trial demonstrated that only 19% of patients receiving omeprazole had erosion or gastritis, compared with 47% of patients in the placebo group 36 .The second trial reported that omeprazole was significantly superior to placebo regarding endoscopic results and symptom control 37 .The results of the two trials were similar, demonstrating the overall benefits of omeprazole for mucosal protection and symptom relief.However, PPIs have no significant pharmacological gastroprotective effect in patients with cancer treated with cisplatin 38,39 , and further research is needed.Our results revealed that the incidence of nausea in the PPIs group was significantly lower than that in ) were significantly more susceptible to cisplatin-induced AKI.Patients with AKI were older (87.5% > 45 years) than those without AKI (67.5% > 45 years).Additionally, in older patients, the renal interstice is more vulnerable to damage owing to compromised peritubular blood flow, which permits a longer exposure time between the medication and the interstice 40 .This finding is consistent with the results of previous trials and clinical studies 41,42 .The baseline SCr level, the main diagnostic test for AKI, was strongly related to the development of cisplatin-induced nephrotoxicity.Liu et al. constructed a predictive model that included baseline SCr risk factors to identify patients susceptible to cisplatin-induced nephrotoxicity 43 .Moreover, comorbid diabetes was an independent risk factor for cisplatininduced AKI in our study.Mathe et al. reported that diabetes mellitus could result in severe microangiopathy and interstitial inflammation, increasing tissue susceptibility and further enhancing the risk of cisplatin-induced AKI in patients with lung cancer 44 .However, the underlying pathophysiological mechanism by which comorbid diabetes aggravates cisplatin-induced AKI in patients with NPC requires further exploration.
Our results suggest that combining cisplatin chemotherapy and PPIs in patients with NPC may further increase the incidence of AKI.In this study, after adjusting for confounding factors, there was a significant correlation between the combined use of PPIs during cisplatin chemotherapy and the occurrence of AKI.This aligns with previous in vivo experimental mice study, which revealed that lansoprazole increasing tubular necroptosis via TNF-α-mediated RIPK1/RIPK3/MLKL pathway further aggravates cisplatin-induced AKI 11 .Lansoprazole aggravated the renal tubular injury in mice caused by cisplatin, resulting in increased SCr and BUN.Compared with previous mouse models, the degree of renal injury in our clinical trial was lower because only SCr was high and BUN was not, which may also be related to the high doses of cisplatin and PPIs used in the animal experiments.
However, our results are different from those reported by others earlier [45][46][47] .The study by Ikemura et al., investigated co-administration of clinical doses of PPIs protected kidney function in patients receiving cisplatin and fluorouraci 45,46 .This discrepancy may be explained by the retrospective nature and the unbalanced sample size of the above study, which cannot adjust for all confounding variables and inevitably leads to bias.In addition, due to the different renal function evaluation time points compared to our study, the incidence of acute kidney injury and chronic kidney disease in the above study had not been reported.Ghonaim et al. reported that Pantoprazole, as promising cisplatin-nephrotoxic protective agents for treating patients with head and neck cancer, effectively ameliorated nephrotoxicity 47 .However, a clinical intervention trial reported that pantoprazole did not protect children with osteosarcoma who had received cisplatin, methotrexate, or doxorubicin against cisplatin nephrotoxicity 48 .The study did not meet the planned endpoints and revealed that PPIs combined with cisplatin did not ameliorate nephrotoxicity, which supports our findings.The differences in these results may be due to regional and ethnic differences, differences in the age of the participants, a lack of a separate non-PPIs group, different doses and administration patterns of PPIs, and different types of cancer and chemotherapy regimens used.
Despite the significant contributions of our study, several limitations warrant consideration.First, all participants in this study were Asian, which could introduce bias due to the homogeneity of the population sample.Second, the sample size is small and patients might be highly selected.Third, this study had a relatively short follow-up period of 12 months.Thus, we could not observe the long-term effect of PPIs on renal function among the NPC patients.Finally, these results stem from a single-center prospective cohort study, and since observational studies were unable to establish causal relationships, their generalizability requires further evaluation.Acknowledging these limitations, a multi-center, large-scale randomized controlled trial is needed to further validate our findings.

Conclusions
Our study revealed that combining cisplatin chemotherapy and PPIs in patients with NPC may further increase the incidence of AKI.Additionally, PPIs can be appropriately used in cisplatin chemotherapy to prevent and treat gastrointestinal reactions caused by chemotherapeutic drugs.Our study provides strong evidence supporting the regulation of the rational use of PPIs and scientific chemotherapy drug dispensing strategies for NPC specialists.

Table 1 .
Patient characteristics of PPIs group and Non-PPIs group.PPIs proton pump inhibitors, BSA body surface area, ICT induction chemotherapy, CCRT concurrent chemoradiotherapy, SCr serum creatinine, eGFR estimated glomerular filtration rate, BUN blood urea nitrogen, CysC cystatin C. a Cisplatin dose of 80 mg/m 2 , b Cisplatin dose of 75 mg/m 2 .

Table 2 .
Primary and secondary outcomes of the study: incidence and severity of AKI, incidence of AKD and CKD, and incidence of nausea and vomiting.AKI acute kidney injury, AKD acute kidney disease, CKD chronic kidney disease, PPIs proton pump inhibitors.

Table 3 .
21ivariateneurotransmitters and receptors are involved in the vomiting reactions, such as 5-HT 3, dopamine receptors, acetylcholine, and NK-1 receptors20.Therefore, 5-HT 3 receptor antagonists, NK-1 receptor antagonists, glucocorticoids, general antiemetic drugs, PPIs, and H 2 receptor antagonists are conventionally used to prevent nausea and vomiting.PPIs are commonly used to inhibit gastric acid secretion and protect the gastric mucosa and are commonly used clinically to reduce gastrointestinal reactions in patients during chemotherapy.Uwagawa et al. discovered that patients receiving chemotherapy had a high incidence of gastroesophageal reflux disease and that rabeprazole significantly improved the symptoms of gastroesophageal reflux disease caused by chemotherapy21.Wang et al. revealed that intermittent high-dose PPIs enhanced the antitumor effect of chemotherapy in patients with metastatic breast cancer without additional evidence of toxicity by reducing tumor acidity and overcoming acid-related chemoresistance and multivariate logistic regression for AKI.AKI acute kidney injury, CI confidence interval, PPIs proton pump inhibitors, ICT induction chemotherapy, CCRT concurrent chemoradiotherapy, SCr serum creatinine, eGFR estimated glomerular filtration rate, BUN blood urea nitrogen, CysC cystatin C. Variables Univariate Multivariate Odds ratio (95% CI) P Odds ratio (95% CI) P Vol.:(0123456789) Scientific Reports | (2024) 14:18839 | https://doi.org/10.1038/s41598-024-69821-6www.nature.com/scientificreports/

Table 4 .
Associations between PPIs uses and the risk of AKI by Logistic regression models.a Model 1 was adjusted for demographic features, including age, sex, height, weight, and BSA.b Model 2 was additionally adjusted for clinical features, including clinical stage, induction chemotherapy regimens, hypertension, diabetes, and chemotherapy hydration.c Model 3 was additionally adjusted for renal function indices, including SCr, eGFR, BUN, and CysC. the non-PPIs group (P = 0.029), suggesting that PPIs may reduce gastrointestinal reactions in patients receiving cisplatin chemotherapy.In our study, patients aged ≥ 45 years (OR 4.258, 95% CI 1.218-14.888),high baseline SCr level (OR 1.067, 95% CI 1.015-1.121),and comorbid diabetes (OR 3.724, 95% CI 1.386-10.006