Evaluation of urinary vanin-1 for the early prediction of cisplatin-induced acute kidney injury during neoadjuvant chemotherapy for esophageal cancer

Evaluation of urinary vanin-1 for the early prediction of cisplatin-induced acute kidney injury during neoadjuvant chemotherapy for esophageal cancer | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Evaluation of urinary vanin-1 for the early prediction of cisplatin-induced acute kidney injury during neoadjuvant chemotherapy for esophageal cancer Tomonobu Uchino, Yuna Iwano, Yasunori Miyazaki, Michiaki Nakajo, and 7 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-5164399/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 23 Dec, 2024 Read the published version in Cancer Chemotherapy and Pharmacology → Version 1 posted 8 You are reading this latest preprint version Abstract Purpose Cisplatin (CDDP) induces acute kidney injury (AKI) as a side effect during neoadjuvant chemotherapy (NAC). Urinary vanin-1 excretion might increase during CDDP treatment. We investigated whether urinary vanin-1 may be an early biomarker of CDDP-induced AKI. Methods Thirty patients were administrated 80 mg/m 2 CDDP on day 1 as NAC for esophageal cancer. Blood and urine samples were collected on days 1, 2, 3, 4 and 6 after CDDP administration. Serum creatinine (sCr) and urinary vanin-1 were measured. Creatinine clearance (cCr) and estimated glomerular filtration rate (eGFR) were calculated from sCr. Based on the change of sCr after CDDP administration, AKI and non-AKI groups were defined using the Kidney Disease Improving Global Outcomes classification. Changes in sCr, cCr, eGFR, and urinary vanin-1 were compared between the two groups. Results A gradual increase in sCr and decrease in eGFR were observed over time post-CDDP administration, with differences between the two groups becoming significant by day 4. However, urinary vanin-1 levels increased on day 3 after CDDP administration, and the difference between the two groups was already significant on day 3. Receiver operating characteristic curves of urinary vanin-1 on day 3 revealed that a cut-off value of 3.17 ng urinary vanin-1/mg urinary creatinine yielded an area under the curve, sensitivity, and specificity of 0.83 (P < 0.05), 75.0%, and 22.7%, respectively. The non-AKI incidence below the cut-off value of urinary vanin-1 of 3.17 ng/mg uCr was 89.5%. Conclusion Urinary vanin-1 is a superior minimally invasive biomarker for early prediction of CDDP-induced AKI. acute kidney injury cisplatin creatinine clearance estimated glomerular filtration rate serum creatinine vanin-1 Figures Figure 1 Figure 2 Figure 3 Introduction Esophageal cancer (EC) is the eighth most common cancer and sixth leading cause of cancer-related deaths worldwide. Many chemotherapy regimens for treating locally advanced tumors have been reported [1, 2]. Fluorouracil (5-FU) and cisplatin (CDDP) combination therapy (FP) is used as the standard treatment. Recently, triplet chemotherapy with docetaxel, CDDP, and 5-FU has been used as neoadjuvant chemotherapy (NAC) for the treatment of stage II or III EC [3]. CDDP binds to the N7 reactive center on purine residues and as such can cause DNA damage in cancer cells, blocking cell division, and resulting in apoptotic cell death [4]. Along with its strong anticancer effect, CDDP induces several toxicities, causing nausea, neuropathy, myelosuppression, and kidney injury [5–7]. Acute kidney injury (AKI) is a serious problem associated with CDDP-based chemotherapy [5], which may lead to the cessation or change of CDDP treatment. Therefore, detecting cisplatin-induced AKI at an early stage is crucial for therapeutic intervention. In clinical settings, serum creatinine (sCr), creatinine clearance (cCr), and estimated glomerular filtration rate (eGFR) are used as biomarkers in monitoring aimed at preventing AKI. cCr [8] and eGFR [9] are calculated using sCr levels and parameters such as age, sex, weight, and body surface area. Creatinine is the final metabolic product of creatine, which serves as an energy source during muscle contraction, and the amount of creatinine produced is determined by muscle mass. Creatinine is filtered through the renal glomerulus and is excreted in the urine. Therefore, sCr levels increase when the glomerular filtration rate is decreased. sCr levels reportedly do not change unless the glomerular filtration rate decreases by about 50% [10, 11], and thus may not be suitable for sensitively determining AKI. In Japan, the guidelines for the treatment of renal injury during cancer chemotherapy were published in 2016 and have since been updated [12]. In these guidelines, several novel biomarkers for the early prediction of CDDP-induced AKI are only weakly recommended. An increase in the urinary excretion of kidney injury molecule-1 (KIM-1F) and neutrophil gelatinase-associated lipocalin (NGAL) has been observed after CDDP administration. These molecules enable the prediction of CDDP-induced AKI at an early stage [13–15]. Moreover, Hosohata et al. reported that urinary excretion of vanin-1, an epithelial glycosylphosphatidylinositol (GPI)-anchored pantetheinase, increases before the increase in urinary levels of KIM-1, NGAL, and N-acetyl-b-D-glucosaminidase (NAG) in rats with nephrotoxicant- and drug-induced renal tubular injury [16, 17]. Furthermore, they evaluated the increase in urinary vanin-l on day 3 after CDDP administration in combination therapy with gemcitabine (GC regimen) for urothelial carcinoma (UC) and found that the increase in vanin-1 occurred earlier and more clearly than other biomarkers (sCr, cCr, blood urea nitrogen [BUN], KIM-1, NGAL, and NAG) [18]. In EC, combination therapy using 80 mg/m 2 CDDP and 5-FU (FP regimen) has been used as NAC. Considering that CDDP-induced AKI is dose-dependent and that the CDDP dose in the GC regimen is 70 mg/m 2 , the risk of CDDP-induced AKI might be higher for patients with EC receiving the FP regimen than for patients receiving the GC regimen. Therefore, an effective biomarker for early prediction of CDDP-induced AKI is required in clinical practice. This study investigated the efficacy of vanin-1 as an early biomarker of CDDP-induced AKI in the FP regimen in esophageal carcinoma by comparing clinically common biomarkers, such as sCr, cCr, and eGFR. In this study, urinary vanin-1 was measured in the urine samples of patients with EC, who were administered CDDP (80 mg/m 2 ) in the FP regimen, on days1, 2, 3, 4 and 6 after CDDP administration. The vanin-1 transition from day 1 to day 6 was compared with changes in sCr, cCr, and eGFR. Materials and methods Patients and study design Thirty patients with EC who visited the Department of Gastroenterological Surgery at Shizuoka General Hospital and received CDDP as NAC, between August 2018 and August 2021, were enrolled in this study. The Institutional Review Boards of Shizuoka General Hospital (approval number: SGH#2017049) and the University of Shizuoka (approval number: 29–46) approved the protocols. All participants signed an informed consent form before enrolling in the study. All patients received the FP regimen (800 mg/m 2 5-FU on days 2–5 and 80 mg/m 2 CDDP on day 1), for two courses of NAC. Blood (for detection of sCR) and morning urine samples (for detection of vanin-1) were collected on days 1, 2, 3, 4 and 6. An urine sample on day 1 was collected before start of CDDP adminisitarion. Collected urine samples were stored at -80°C until analysis. Diagnostic criteria for cisplatin-induced acute kidney injury According to the guidelines for the treatment of renal injury during cancer chemotherapy in Japan [12], AKI was diagnosed based on the Kidney Disease Improving Global Outcomes (KDIGO) classification[19]. According to KDIGO classification, AKI is defined as any of the following (Not Graded): An increase in sCr by ≧ 0.3 mg/dl ( ≧ 26.5 µmol/l) within 48 hours; or an increase in sCr to ≧ 1.5 times the baseline value within the previous 7 days, or a urine volume ≦ 0.5 ml/kg/h for 6 hours. Therefore, AKI diagnoses and non-AKI status after CDDP administration were classified using the KDIGO classification in this study. Urinary vanin-1 analysis Urinary vanin-1 levels were measured using a commercially available human vanin-1 enzyme-linked immunosorbent assay kit (ABclonal, Inc., Woburn, MA, USA), according to the manufacturer’s instructions. Urinary creatinine (uCR) was measured using a commercially available kit (LabAssay Creatinine [Jaffé method], FUJIFILM Wako Pure Chemical Corporation, Osaka, Japan). The obtained urinary vanin-1 concentrations for each patient were calibrated by dividing these values by the uCR concentrations. Statistical analysis The Mann–Whitney U test was performed to evaluate the differences between the AKI and non-AKI groups. The ability of biomarkers to discriminate between patients experiencing the primary outcome within 6 days after cisplatin administration was determined using receiver-operating characteristic (ROC) curves, which were used to assess sensitivity and specificity for detecting CDDP-induced nephrotoxicity along with 95% confidence intervals (CI). Probability analysis was performed according to the Kaplan–Meier method, and outcomes were compared between subgroups using a log-rank test. Statistical significance was set at P < 0.05. Statistical analyses were performed using Origin Pro 2024b (64-bit) SR1 10.0.5.157 (academic) (Lightstone Corp., Tokyo, Japan). Results Summary of patient characteristics Table 1 presents the patient characteristics. We included 30 patients, with a median age of 60 years (range 59.5–74.0 years). Grades 1, 2, 3, and 4 tumors accounted for 1, 15, 12, and 2 patients, respectively. No significant differences in baseline variables, including body weight, renal function, or cisplatin dose, were found between the AKI and non-AKI groups. Change in the biomarkers after cisplatin administration Figure 1 Comparison of changes in the (a) serum creatinine (sCr), (b) creatinine clearance (cCr), (c) estimated glomerular filtration rate (eGFR), and (d) urinary vanin-1 levels after cisplatin (CDDP) administration in the AKI and non-AKI groups Data are mean ± SE *, P < 0.05 vs. non-AKI group, †, P < 0.05 vs. Day 0 in the AKI group, † †, P < 0.05 vs. Day 0 in non-AKI group. sCr levels increased with time after CDDP administration in the AKI group, but not in the non-AKI group. Significant differences between the AKI and non-AKI groups were observed on days 4 and 6. Figure 1 b shows that no significant differences were observed in cCr between the AKI and non-AKI groups, although cCr had a tendency to decrease gradually in the AKI group. The eGFR value was decreased with time after CDDP administration in the AKI group and a significant difference was observed on days 4 and 6 relative to day 0. In the comparison of AKI and non-AKI groups, a significant difference was observed between the groups on days 4 and 6. Urinary vanin-1 levels were increased on days 3, 4, and day 6 relative to day 1 before CDDP administration in both groups. The urinary vanin-1 level was higher in the AKI than in the non-AKI group. Moreover, a significant difference in urinary vanin-1 was observed between the AKI and non-AKI groups on days 3 and 4. Predictive abilities of biomarkers The ability of each biomarker to predict AKI was evaluated. Figure 2 shows the ROC curves for sCr, cCr, eGFR, and urinary vanin-1 levels on day 3 after cisplatin administration. The AUC values obtained with the sCr, cCr, eGFR, and urinary vanin-1 were 0.70 (P = 0.10), 0.61 (P = 0.32), 0.69 (P = 0.12) and 0.83 (P < 0.05), respectively. Urinary vanin-1 represented the highest AUC value. From the results of ROC curve of vanin-1 (Fig. 1 (d)), the cut off value was calculated and the value was 3.17 ng/mg uCr. And Sensitivity and specificity in a cut off point were urinary vanin-1were 75.0 and 22.7%, respectively. Figure 3 shows bees warm plots of urinary vanin-1 in non-AKI and AKI groups, with a dashed line at the cutoff value (3.17 ng vanin-1/mg uCr). The number of non-AKI and AKI participants under the cut-off value was 17 and 2, respectively. Thus, the non-AKI incidence below the 3.17 ng vanin-1/mg uCr cut-off value was 89.5%. Discussion In this study, the change in urinary vanin-1 from day 1 to 6 after administration of CDDP at a dose of 80 mg/m 2 was compared with those of sCr, cCr, and eGFR in patients with EC. For urinary vanin-1, significant differences were observed on day 3, although significant differences in sCr level and eGFR were observed after day 4. Furthermore, urinary vanin-1 showed the highest AUC on day 3 and the non-AKI incidence below the cut-off value of urinary vanin-1 (3.17 ng/mg uCr) was 89.5%. Therefore, these results strongly suggested that urinary vanin-1 could also predict high-dose CDDP-induced AKI in patients receiving NAC for EC. AKI is classified as acute tubular necrosis (ATN) or acute interstitial nephritis. Oxidative stress is one of the mechanisms underlying the development of ATN. Proximal tubular toxicity develops due to direct nephrotoxic effects, such as mitochondrial dysfunction, lysosomal hydrolase inhibition, phospholipid damage, and increased intracellular calcium concentration, leading to the formation of reactive oxygen species with injurious oxidative stress. Several drugs, such as CDDP, aminoglycosides (gentamycin, kanamycin, streptomycin, and tobramycin), amphotericin B, antiviral agents (adefovir, cidofovir, and tenofovir), radiocontrast agents, and bisphosphonates, have been reported to induce damage of renal proximal tubules. Vanin-1 is a GPI-anchored protein consisting of basic and nitrilase domains [20, 21]. Vanin-1 catalyzes the hydrolysis of pantetheine to pantothenic acid (vitamin B5) and cysteamine and is involved in the regulation of oxidative stress and inflammation [22, 23]. Yoshida et al. showed that renal vanin-1 levels increased by approximately 2.7-fold after renal ischemia–reperfusion in rats, a renal injury model that involves oxidative stress [24]. Moreover, Hosohata et al. reported that the urinary excretion of vanin-1 increased before the urinary increase in KIM-1, NGAL, and NAG in rats with nephrotoxicant- and drug-induced renal tubular injury [18]. Significant differences in urinary vanin-1 levels on day 3 after CDDP administration were also observed between the AKI- and non-AKI groups in patients with UC treated with the GC regimen [18]. Since urinary vanin-1 increased with oxidative stress following CDDP administration, urinary vanin-1 increased on day 3, even in the non-AKI group in our results. Therefore, these results indicate that oxidative stress associated with CDDP administration affects urinary vanin-1 excretion in both groups and that the sensitivity is greater in the AKI group than in the non-AKI group. Hosohata et al. reported that initial vanin-1 levels tended to be high in patients with AKI [18]. However, no significant difference in initial vanin-1 levels was observed between the AKI- and non-AKI groups in our study. UC is subject to a certain amount of oxidative stress due to the presence of cancerous lesions in the urinary tract, which may lead to the excretion of vanin-1. Hydronephrosis is a complication of UC, and it has been reported in animal experiments that urinary vanin-1 levels increase when hydronephrosis occurs [25]. Unlike UC, EC does not have cancerous lesions in the urinary tract; therefore, baseline vanin-1 levels may have been low, even in the AKI group. Risk factors of CDDP-induced AKI include male sex, cardiac disease, and hypertension [26, 27]. Table 1 shows that all patients with CDDP-induced AKI were male, and the relative percentages of cardiac disease and hypertension in the AKI group were 37.5% and 62.5%, respectively. Some clinical studies have found sex-associated renal toxicity with CDDP administration. Their studies showed that sex differences were not a predictor of CDDP-induced nephrotoxicity [28–33]. Moreover, CDDP pharmacokinetics were not associated with age, sex, or measures of kidney dysfunction in patients undergoing chemotherapy [34]. However, in our study, all patients who developed AKI were male. According to a nationwide survey by the Japan Esophageal Society (8,019 cases treated in 2013 and analyzed in 2019), the male-to-female ratio in patients with EC is approximately 5.4:1, with more men than women. CDDP-induced AKI has been associated with comorbidities, such as cardiac disease, hypertension, and diabetes [35, 36]. In patients with cardiac diseases, a reduction in renal perfusion caused by decreased cardiac output may affect the clearance of CDDP by renal excretion [37, 38]. The renal clearance of teicoplanin and vancomycin is reduced in patients with heart disorders. Therefore, decreased renal perfusion, associated with cardiac disease, has been suggested to influence CDDP clearance. A decrease in renal blood flow due to heart disorders reduces renal clearance, causing renal dysfunction, whereas chronic systemic hypertension accelerates kidney aging [39]. Atherosclerosis of the kidney is more common in patients with hypertension, and hypertensive nephrosclerosis is related to chronic ischemic damage to the tubulointerstitum, a major site of CDDP nephrotoxicity[40, 41]. The data suggested that the nephrotoxicity of high-dose CDDP is aggravated in patients with hypertension and that antihypertensive drugs may also affect nephrotoxicity in patients with a history of hypertension. Nevertheless, sex differences in the development of AKI after CDDP administration and the sensitivity of vanin-1 cannot be discussed in the small number of patients in the current study, which is a limitation of the study. In conclusion, urinary vanin-1 is a better biomarker than sCr, cCr, and eGFR, which are the biomarkers commonly used in clinical practice, for detecting early CDDP-induced AKI in patients with EC who are treated with the FP regimen. In future studies, the number of cases should be increased and the usefulness of vanin-1 in predicting AKI in patients receiving CDDP-containing regimens for EC should be examined. Since many high-dose CDDP regimens are used in cancer chemotherapy, the measurement of urinary vanin-1 levels for predicting CDDP-induced AKI may also be applicable to other high-dose CDDP regimens. Declarations Funding This study was partially supported by The Research Foundation for Pharmaceutical Sciences. Conflict of interest The authors declare no conflicts of interest associated with this manuscript. Ethics approval and consent for participation The study protocol was approved by the Institutional Review Board of Shizuoka General Hospital (approval number: SGH#2017049) and the University of Shizuoka (approval number: 29-46). Informed consent was obtained from all individual participants included in the study. Consent for publication Not applicable Availability of data and material The datasets generated and/or analyzed in the current study are available from the corresponding author upon reasonable request. Code availability Not applicable. Authors’ contributions Tomonobu Uchino and MasakazuTakagi designed and directed the project. Yasunori Miyazaki, Michiaki Nakajo, Misa Osawa, Erina Nagai, Yusuke Taki, Shinsuke Sato, and Masaya Watanabe developed the trial design. Yuna Iwano performed the experiments and analyzed the data. Michiaki Nakajo and Yasunori Miyazaki developed the analytical method for measuring urinary vanin-1. Tomonobu Uchino, Yuna Iwano, and Yasunori Miyazaki drafted the manuscript and designed the figures. All authors contributed to the writing of the final manuscript and read and approved the final manuscript for submission for publication. References Kitagawa Y, Ishihara R, Ishikawa H, et al (2023) Esophageal cancer practice guidelines 2022 edited by the Japan esophageal society: part 1. Esophagus 20:343–372. https://doi.org/10.1007/s10388-023-00993-2 Tanaka Y, Yoshida K, Suetsugu T, et al (2018) Recent advancements in esophageal cancer treatment in Japan. 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Uchino","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABEklEQVRIie3RPUsDMRjA8acE2iW2aw7h+hWeI6CDil/lCYW7Ra1jx07XRXG9IvgZbnSMBOwScXUzUycX6aJwgqngImnlNpH8IRkSfpAXgFjsT8ZB+zn1owvkZwHAvvdoC0HZjvhQTdcEfpBguHi4M+eTpqh1b+lcY9Jkphm+3sJwMIWlCxF7RqayeFprvo/EjdzlxNTcQlZpKDBEnjiandKT55euIGHUDYxXfgU6NUAutpAC/cEEoScDx8xHCce/EUINe4LIqGtBbNQpQW0iiT1Bw63M5pp7oguZVI5ll6UYVSZ8l/7CyhWfpMO+P1jy1hyk4pGYeC8Pj65mF3noxTa2/h6etxFf9e5bk1gsFvuPfQL+b1/6j/eQogAAAABJRU5ErkJggg==","orcid":"","institution":"University of Shizuoka","correspondingAuthor":true,"prefix":"","firstName":"Tomonobu","middleName":"","lastName":"Uchino","suffix":""},{"id":382277109,"identity":"4cd76acd-f839-44c3-b5ed-b49d0378aa14","order_by":1,"name":"Yuna Iwano","email":"","orcid":"","institution":"University of Shizuoka","correspondingAuthor":false,"prefix":"","firstName":"Yuna","middleName":"","lastName":"Iwano","suffix":""},{"id":382277110,"identity":"2432eac7-0189-4c50-b498-d269d48ac396","order_by":2,"name":"Yasunori Miyazaki","email":"","orcid":"","institution":"University of Shizuoka","correspondingAuthor":false,"prefix":"","firstName":"Yasunori","middleName":"","lastName":"Miyazaki","suffix":""},{"id":382277111,"identity":"8b40d564-f35a-4e06-ba82-4e15ea4a7790","order_by":3,"name":"Michiaki Nakajo","email":"","orcid":"","institution":"University of Shizuoka","correspondingAuthor":false,"prefix":"","firstName":"Michiaki","middleName":"","lastName":"Nakajo","suffix":""},{"id":382277112,"identity":"26cbd5ba-1999-4f8f-97fa-f3335b0689a3","order_by":4,"name":"Misa Osawa","email":"","orcid":"","institution":"Shizuoka General Hospital","correspondingAuthor":false,"prefix":"","firstName":"Misa","middleName":"","lastName":"Osawa","suffix":""},{"id":382277113,"identity":"5d9a6ec1-a4d1-4c8a-bf94-ed62d1a730af","order_by":5,"name":"Erina Nagai","email":"","orcid":"","institution":"Shizuoka General Hospital","correspondingAuthor":false,"prefix":"","firstName":"Erina","middleName":"","lastName":"Nagai","suffix":""},{"id":382277114,"identity":"52142f43-48fd-4080-8ede-f1239d2afe25","order_by":6,"name":"Yusuke Taki","email":"","orcid":"","institution":"Shizuoka General Hospital","correspondingAuthor":false,"prefix":"","firstName":"Yusuke","middleName":"","lastName":"Taki","suffix":""},{"id":382277115,"identity":"43cec928-cdb1-4af0-9993-cb02cb162473","order_by":7,"name":"Shinsuke Sato","email":"","orcid":"","institution":"Shizuoka General Hospital","correspondingAuthor":false,"prefix":"","firstName":"Shinsuke","middleName":"","lastName":"Sato","suffix":""},{"id":382277116,"identity":"d46baf5e-5c36-4ebb-afce-dad41d60adff","order_by":8,"name":"Masaya Watanabe","email":"","orcid":"","institution":"Shizuoka General Hospital","correspondingAuthor":false,"prefix":"","firstName":"Masaya","middleName":"","lastName":"Watanabe","suffix":""},{"id":382277117,"identity":"63be3229-5df8-487e-b36c-bbf2c721592b","order_by":9,"name":"Masakazu Takagi","email":"","orcid":"","institution":"Seisei Rehabilitation Hospital","correspondingAuthor":false,"prefix":"","firstName":"Masakazu","middleName":"","lastName":"Takagi","suffix":""},{"id":382277118,"identity":"15180ccb-5cd7-4ea4-885f-bb33d5bb103c","order_by":10,"name":"Yoshiyuki Kagawa","email":"","orcid":"","institution":"University of Shizuoka","correspondingAuthor":false,"prefix":"","firstName":"Yoshiyuki","middleName":"","lastName":"Kagawa","suffix":""}],"badges":[],"createdAt":"2024-09-27 11:29:59","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-5164399/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-5164399/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1007/s00280-024-04737-6","type":"published","date":"2024-12-23T15:57:13+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":70917306,"identity":"0e535482-d98e-47d7-8569-f1dd3a74dfc1","added_by":"auto","created_at":"2024-12-09 08:19:10","extension":"jpeg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":369285,"visible":true,"origin":"","legend":"\u003cp\u003eComparison of changes in the (a) serum creatinine (sCr), (b) creatinine clearance (cCr), (c) estimated glomerular filtration rate (eGFR), and (d) urinary vanin-1 levels after cisplatin (CDDP) administration in the AKI and non-AKI groups\u003c/p\u003e\n\u003cp\u003eData are mean ± SE *, P \u0026lt; 0.05 vs. non-AKI group, †, P \u0026lt; 0.05 vs. Day 0 in the AKI group, † †, P \u0026lt; 0.05 vs. Day 0 in non-AKI group.\u003c/p\u003e","description":"","filename":"floatimage1.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-5164399/v1/8a3ec0541154bf111356fca1.jpeg"},{"id":70917304,"identity":"ba80e02d-d8ef-4934-9258-d8d2dfb3b8cb","added_by":"auto","created_at":"2024-12-09 08:19:10","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":141236,"visible":true,"origin":"","legend":"\u003cp\u003eReceiver operating characteristic (ROC) curves of (a) serum creatinine (sCR), (b) creatinine clearance (cCr), (c) estimated glomerular filtration rate (eGFR), and (d) urinary vanin-1 at day 3 after cisplatin administration\u003c/p\u003e","description":"","filename":"floatimage264.png","url":"https://assets-eu.researchsquare.com/files/rs-5164399/v1/0da89b1abffd34652f80a3a1.png"},{"id":70919181,"identity":"970f4194-f8dc-4729-b1f7-72aa474cbce1","added_by":"auto","created_at":"2024-12-09 08:27:10","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":43736,"visible":true,"origin":"","legend":"\u003cp\u003eBee-swarm plot of urinary vanin-1 on day 3 in non-AKI and AKI groups\u003c/p\u003e","description":"","filename":"floatimage358.png","url":"https://assets-eu.researchsquare.com/files/rs-5164399/v1/a70c26d970d42bdab677e5c4.png"},{"id":72640759,"identity":"740d6deb-6196-4ad3-80b9-cbc99fd9830f","added_by":"auto","created_at":"2024-12-30 16:09:30","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":934198,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5164399/v1/79a5f1d2-80f6-4a0e-a768-77162c321c63.pdf"},{"id":70917307,"identity":"9a686e59-1418-4c2f-93d0-7b0a054f2b25","added_by":"auto","created_at":"2024-12-09 08:19:10","extension":"tif","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":1823852,"visible":true,"origin":"","legend":"","description":"","filename":"Table1.tif","url":"https://assets-eu.researchsquare.com/files/rs-5164399/v1/7b4f2d1fa95d982575fff56f.tif"}],"financialInterests":"No competing interests reported.","formattedTitle":"Evaluation of urinary vanin-1 for the early prediction of cisplatin-induced acute kidney injury during neoadjuvant chemotherapy for esophageal cancer","fulltext":[{"header":"Introduction","content":"\u003cp\u003eEsophageal cancer (EC) is the eighth most common cancer and sixth leading cause of cancer-related deaths worldwide. Many chemotherapy regimens for treating locally advanced tumors have been reported [1, 2]. Fluorouracil (5-FU) and cisplatin (CDDP) combination therapy (FP) is used as the standard treatment. Recently, triplet chemotherapy with docetaxel, CDDP, and 5-FU has been used as neoadjuvant chemotherapy (NAC) for the treatment of stage II or III EC [3].\u003c/p\u003e \u003cp\u003eCDDP binds to the N7 reactive center on purine residues and as such can cause DNA damage in cancer cells, blocking cell division, and resulting in apoptotic cell death [4]. Along with its strong anticancer effect, CDDP induces several toxicities, causing nausea, neuropathy, myelosuppression, and kidney injury [5\u0026ndash;7]. Acute kidney injury (AKI) is a serious problem associated with CDDP-based chemotherapy [5], which may lead to the cessation or change of CDDP treatment. Therefore, detecting cisplatin-induced AKI at an early stage is crucial for therapeutic intervention.\u003c/p\u003e \u003cp\u003eIn clinical settings, serum creatinine (sCr), creatinine clearance (cCr), and estimated glomerular filtration rate (eGFR) are used as biomarkers in monitoring aimed at preventing AKI. cCr [8] and eGFR [9] are calculated using sCr levels and parameters such as age, sex, weight, and body surface area. Creatinine is the final metabolic product of creatine, which serves as an energy source during muscle contraction, and the amount of creatinine produced is determined by muscle mass. Creatinine is filtered through the renal glomerulus and is excreted in the urine. Therefore, sCr levels increase when the glomerular filtration rate is decreased. sCr levels reportedly do not change unless the glomerular filtration rate decreases by about 50% [10, 11], and thus may not be suitable for sensitively determining AKI.\u003c/p\u003e \u003cp\u003e In Japan, the guidelines for the treatment of renal injury during cancer chemotherapy were published in 2016 and have since been updated [12]. In these guidelines, several novel biomarkers for the early prediction of CDDP-induced AKI are only weakly recommended. An increase in the urinary excretion of kidney injury molecule-1 (KIM-1F) and neutrophil gelatinase-associated lipocalin (NGAL) has been observed after CDDP administration. These molecules enable the prediction of CDDP-induced AKI at an early stage [13\u0026ndash;15]. Moreover, Hosohata \u003cem\u003eet al.\u003c/em\u003e reported that urinary excretion of vanin-1, an epithelial glycosylphosphatidylinositol (GPI)-anchored pantetheinase, increases before the increase in urinary levels of KIM-1, NGAL, and N-acetyl-b-D-glucosaminidase (NAG) in rats with nephrotoxicant- and drug-induced renal tubular injury [16, 17]. Furthermore, they evaluated the increase in urinary vanin-l on day 3 after CDDP administration in combination therapy with gemcitabine (GC regimen) for urothelial carcinoma (UC) and found that the increase in vanin-1 occurred earlier and more clearly than other biomarkers (sCr, cCr, blood urea nitrogen [BUN], KIM-1, NGAL, and NAG) [18]. In EC, combination therapy using 80 mg/m\u003csup\u003e2\u003c/sup\u003e CDDP and 5-FU (FP regimen) has been used as NAC. Considering that CDDP-induced AKI is dose-dependent and that the CDDP dose in the GC regimen is 70 mg/m\u003csup\u003e2\u003c/sup\u003e, the risk of CDDP-induced AKI might be higher for patients with EC receiving the FP regimen than for patients receiving the GC regimen. Therefore, an effective biomarker for early prediction of CDDP-induced AKI is required in clinical practice.\u003c/p\u003e \u003cp\u003eThis study investigated the efficacy of vanin-1 as an early biomarker of CDDP-induced AKI in the FP regimen in esophageal carcinoma by comparing clinically common biomarkers, such as sCr, cCr, and eGFR. In this study, urinary vanin-1 was measured in the urine samples of patients with EC, who were administered CDDP (80 mg/m\u003csup\u003e2\u003c/sup\u003e) in the FP regimen, on days1, 2, 3, 4 and 6 after CDDP administration. The vanin-1 transition from day 1 to day 6 was compared with changes in sCr, cCr, and eGFR.\u003c/p\u003e"},{"header":"Materials and methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003ePatients and study design\u003c/h2\u003e \u003cp\u003eThirty patients with EC who visited the Department of Gastroenterological Surgery at Shizuoka General Hospital and received CDDP as NAC, between August 2018 and August 2021, were enrolled in this study. The Institutional Review Boards of Shizuoka General Hospital (approval number: SGH#2017049) and the University of Shizuoka (approval number: 29\u0026ndash;46) approved the protocols. All participants signed an informed consent form before enrolling in the study.\u003c/p\u003e \u003cp\u003eAll patients received the FP regimen (800 mg/m\u003csup\u003e2\u003c/sup\u003e 5-FU on days 2\u0026ndash;5 and 80 mg/m\u003csup\u003e2\u003c/sup\u003e CDDP on day 1), for two courses of NAC. Blood (for detection of sCR) and morning urine samples (for detection of vanin-1) were collected on days 1, 2, 3, 4 and 6. An urine sample on day 1 was collected before start of CDDP adminisitarion. Collected urine samples were stored at -80\u0026deg;C until analysis.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eDiagnostic criteria for cisplatin-induced acute kidney injury\u003c/h3\u003e\n\u003cp\u003e According to the guidelines for the treatment of renal injury during cancer chemotherapy in Japan [12], AKI was diagnosed based on the Kidney Disease Improving Global Outcomes (KDIGO) classification[19]. According to KDIGO classification, AKI is defined as any of the following (Not Graded): An increase in sCr by ≧\u0026thinsp;0.3 mg/dl (\u0026thinsp;≧\u0026thinsp;26.5 \u0026micro;mol/l) within 48 hours; or an increase in sCr to ≧\u0026thinsp;1.5 times the baseline value within the previous 7 days, or a urine volume\u0026thinsp;≦\u0026thinsp;0.5 ml/kg/h for 6 hours. Therefore, AKI diagnoses and non-AKI status after CDDP administration were classified using the KDIGO classification in this study.\u003c/p\u003e\n\u003ch3\u003eUrinary vanin-1 analysis\u003c/h3\u003e\n\u003cp\u003eUrinary vanin-1 levels were measured using a commercially available human vanin-1 enzyme-linked immunosorbent assay kit (ABclonal, Inc., Woburn, MA, USA), according to the manufacturer\u0026rsquo;s instructions. Urinary creatinine (uCR) was measured using a commercially available kit (LabAssay Creatinine [Jaff\u0026eacute; method], FUJIFILM Wako Pure Chemical Corporation, Osaka, Japan). The obtained urinary vanin-1 concentrations for each patient were calibrated by dividing these values by the uCR concentrations.\u003c/p\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eThe Mann\u0026ndash;Whitney U test was performed to evaluate the differences between the AKI and non-AKI groups. The ability of biomarkers to discriminate between patients experiencing the primary outcome within 6 days after cisplatin administration was determined using receiver-operating characteristic (ROC) curves, which were used to assess sensitivity and specificity for detecting CDDP-induced nephrotoxicity along with 95% confidence intervals (CI). Probability analysis was performed according to the Kaplan\u0026ndash;Meier method, and outcomes were compared between subgroups using a log-rank test. Statistical significance was set at P\u0026thinsp;\u0026lt;\u0026thinsp;0.05. Statistical analyses were performed using Origin Pro 2024b (64-bit) SR1 10.0.5.157 (academic) (Lightstone Corp., Tokyo, Japan).\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eSummary of patient characteristics\u003c/h2\u003e \u003cp\u003eTable\u0026nbsp;1 presents the patient characteristics. We included 30 patients, with a median age of 60 years (range 59.5\u0026ndash;74.0 years). Grades 1, 2, 3, and 4 tumors accounted for 1, 15, 12, and 2 patients, respectively. No significant differences in baseline variables, including body weight, renal function, or cisplatin dose, were found between the AKI and non-AKI groups.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eChange in the biomarkers after cisplatin administration\u003c/h3\u003e\n\u003cp\u003e \u003c/p\u003e \u003cp\u003eFigure\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e Comparison of changes in the (a) serum creatinine (sCr), (b) creatinine clearance (cCr), (c) estimated glomerular filtration rate (eGFR), and (d) urinary vanin-1 levels after cisplatin (CDDP) administration in the AKI and non-AKI groups\u003c/p\u003e \u003cp\u003eData are mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SE *, P\u0026thinsp;\u0026lt;\u0026thinsp;0.05 vs. non-AKI group, \u0026dagger;, P\u0026thinsp;\u0026lt;\u0026thinsp;0.05 vs. Day 0 in the AKI group, \u0026dagger; \u0026dagger;, P\u0026thinsp;\u0026lt;\u0026thinsp;0.05 vs. Day 0 in non-AKI group.\u003c/p\u003e \u003cp\u003esCr levels increased with time after CDDP administration in the AKI group, but not in the non-AKI group. Significant differences between the AKI and non-AKI groups were observed on days 4 and 6. Figure\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eb shows that no significant differences were observed in cCr between the AKI and non-AKI groups, although cCr had a tendency to decrease gradually in the AKI group. The eGFR value was decreased with time after CDDP administration in the AKI group and a significant difference was observed on days 4 and 6 relative to day 0. In the comparison of AKI and non-AKI groups, a significant difference was observed between the groups on days 4 and 6. Urinary vanin-1 levels were increased on days 3, 4, and day 6 relative to day 1 before CDDP administration in both groups. The urinary vanin-1 level was higher in the AKI than in the non-AKI group. Moreover, a significant difference in urinary vanin-1 was observed between the AKI and non-AKI groups on days 3 and 4.\u003c/p\u003e\n\u003ch3\u003ePredictive abilities of biomarkers\u003c/h3\u003e\n\u003cp\u003eThe ability of each biomarker to predict AKI was evaluated. Figure\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e shows the ROC curves for sCr, cCr, eGFR, and urinary vanin-1 levels on day 3 after cisplatin administration.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eThe AUC values obtained with the sCr, cCr, eGFR, and urinary vanin-1 were 0.70 (P\u0026thinsp;=\u0026thinsp;0.10), 0.61 (P\u0026thinsp;=\u0026thinsp;0.32), 0.69 (P\u0026thinsp;=\u0026thinsp;0.12) and 0.83 (P\u0026thinsp;\u0026lt;\u0026thinsp;0.05), respectively. Urinary vanin-1 represented the highest AUC value. From the results of ROC curve of vanin-1 (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e(d)), the cut off value was calculated and the value was 3.17 ng/mg uCr. And Sensitivity and specificity in a cut off point were urinary vanin-1were 75.0 and 22.7%, respectively.\u003c/p\u003e \u003cp\u003eFigure \u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e shows bees warm plots of urinary vanin-1 in non-AKI and AKI groups, with a dashed line at the cutoff value (3.17 ng vanin-1/mg uCr).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eThe number of non-AKI and AKI participants under the cut-off value was 17 and 2, respectively. Thus, the non-AKI incidence below the 3.17 ng vanin-1/mg uCr cut-off value was 89.5%.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eIn this study, the change in urinary vanin-1 from day 1 to 6 after administration of CDDP at a dose of 80 mg/m\u003csup\u003e2\u003c/sup\u003e was compared with those of sCr, cCr, and eGFR in patients with EC. For urinary vanin-1, significant differences were observed on day 3, although significant differences in sCr level and eGFR were observed after day 4. Furthermore, urinary vanin-1 showed the highest AUC on day 3 and the non-AKI incidence below the cut-off value of urinary vanin-1 (3.17 ng/mg uCr) was 89.5%. Therefore, these results strongly suggested that urinary vanin-1 could also predict high-dose CDDP-induced AKI in patients receiving NAC for EC.\u003c/p\u003e \u003cp\u003eAKI is classified as acute tubular necrosis (ATN) or acute interstitial nephritis. Oxidative stress is one of the mechanisms underlying the development of ATN. Proximal tubular toxicity develops due to direct nephrotoxic effects, such as mitochondrial dysfunction, lysosomal hydrolase inhibition, phospholipid damage, and increased intracellular calcium concentration, leading to the formation of reactive oxygen species with injurious oxidative stress. Several drugs, such as CDDP, aminoglycosides (gentamycin, kanamycin, streptomycin, and tobramycin), amphotericin B, antiviral agents (adefovir, cidofovir, and tenofovir), radiocontrast agents, and bisphosphonates, have been reported to induce damage of renal proximal tubules.\u003c/p\u003e \u003cp\u003eVanin-1 is a GPI-anchored protein consisting of basic and nitrilase domains [20, 21]. Vanin-1 catalyzes the hydrolysis of pantetheine to pantothenic acid (vitamin B5) and cysteamine and is involved in the regulation of oxidative stress and inflammation [22, 23]. Yoshida \u003cem\u003eet al.\u003c/em\u003e showed that renal vanin-1 levels increased by approximately 2.7-fold after renal ischemia\u0026ndash;reperfusion in rats, a renal injury model that involves oxidative stress [24]. Moreover, Hosohata \u003cem\u003eet al.\u003c/em\u003e reported that the urinary excretion of vanin-1 increased before the urinary increase in KIM-1, NGAL, and NAG in rats with nephrotoxicant- and drug-induced renal tubular injury [18].\u003c/p\u003e \u003cp\u003eSignificant differences in urinary vanin-1 levels on day 3 after CDDP administration were also observed between the AKI- and non-AKI groups in patients with UC treated with the GC regimen [18]. Since urinary vanin-1 increased with oxidative stress following CDDP administration, urinary vanin-1 increased on day 3, even in the non-AKI group in our results. Therefore, these results indicate that oxidative stress associated with CDDP administration affects urinary vanin-1 excretion in both groups and that the sensitivity is greater in the AKI group than in the non-AKI group.\u003c/p\u003e \u003cp\u003eHosohata et al. reported that initial vanin-1 levels tended to be high in patients with AKI [18]. However, no significant difference in initial vanin-1 levels was observed between the AKI- and non-AKI groups in our study. UC is subject to a certain amount of oxidative stress due to the presence of cancerous lesions in the urinary tract, which may lead to the excretion of vanin-1. Hydronephrosis is a complication of UC, and it has been reported in animal experiments that urinary vanin-1 levels increase when hydronephrosis occurs [25]. Unlike UC, EC does not have cancerous lesions in the urinary tract; therefore, baseline vanin-1 levels may have been low, even in the AKI group.\u003c/p\u003e \u003cp\u003eRisk factors of CDDP-induced AKI include male sex, cardiac disease, and hypertension [26, 27]. Table\u0026nbsp;1 shows that all patients with CDDP-induced AKI were male, and the relative percentages of cardiac disease and hypertension in the AKI group were 37.5% and 62.5%, respectively.\u003c/p\u003e \u003cp\u003eSome clinical studies have found sex-associated renal toxicity with CDDP administration. Their studies showed that sex differences were not a predictor of CDDP-induced nephrotoxicity [28\u0026ndash;33]. Moreover, CDDP pharmacokinetics were not associated with age, sex, or measures of kidney dysfunction in patients undergoing chemotherapy [34]. However, in our study, all patients who developed AKI were male. According to a nationwide survey by the Japan Esophageal Society (8,019 cases treated in 2013 and analyzed in 2019), the male-to-female ratio in patients with EC is approximately 5.4:1, with more men than women.\u003c/p\u003e \u003cp\u003eCDDP-induced AKI has been associated with comorbidities, such as cardiac disease, hypertension, and diabetes [35, 36]. In patients with cardiac diseases, a reduction in renal perfusion caused by decreased cardiac output may affect the clearance of CDDP by renal excretion [37, 38]. The renal clearance of teicoplanin and vancomycin is reduced in patients with heart disorders. Therefore, decreased renal perfusion, associated with cardiac disease, has been suggested to influence CDDP clearance.\u003c/p\u003e \u003cp\u003eA decrease in renal blood flow due to heart disorders reduces renal clearance, causing renal dysfunction, whereas chronic systemic hypertension accelerates kidney aging [39]. Atherosclerosis of the kidney is more common in patients with hypertension, and hypertensive nephrosclerosis is related to chronic ischemic damage to the tubulointerstitum, a major site of CDDP nephrotoxicity[40, 41]. The data suggested that the nephrotoxicity of high-dose CDDP is aggravated in patients with hypertension and that antihypertensive drugs may also affect nephrotoxicity in patients with a history of hypertension.\u003c/p\u003e \u003cp\u003eNevertheless, sex differences in the development of AKI after CDDP administration and the sensitivity of vanin-1 cannot be discussed in the small number of patients in the current study, which is a limitation of the study.\u003c/p\u003e \u003cp\u003eIn conclusion, urinary vanin-1 is a better biomarker than sCr, cCr, and eGFR, which are the biomarkers commonly used in clinical practice, for detecting early CDDP-induced AKI in patients with EC who are treated with the FP regimen. In future studies, the number of cases should be increased and the usefulness of vanin-1 in predicting AKI in patients receiving CDDP-containing regimens for EC should be examined. Since many high-dose CDDP regimens are used in cancer chemotherapy, the measurement of urinary vanin-1 levels for predicting CDDP-induced AKI may also be applicable to other high-dose CDDP regimens.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was partially supported by The Research Foundation for Pharmaceutical Sciences.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflict of interest\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare no conflicts of interest associated with this manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval and consent for participation\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study protocol was approved by the Institutional Review Board of Shizuoka General Hospital (approval number: SGH#2017049) and the University of Shizuoka (approval number: 29-46). Informed consent was obtained from all individual participants included in the study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and material\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets generated and/or analyzed in the current study are available from the corresponding author upon reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCode availability\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026rsquo; contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTomonobu Uchino and MasakazuTakagi designed and directed the project. Yasunori Miyazaki, Michiaki Nakajo, Misa Osawa, Erina Nagai, Yusuke Taki, Shinsuke Sato,\u0026nbsp;and Masaya Watanabe developed the trial design. Yuna Iwano performed the experiments and analyzed the data. Michiaki Nakajo and\u0026nbsp;Yasunori Miyazaki developed the analytical method for measuring urinary vanin-1. Tomonobu Uchino, Yuna Iwano, and Yasunori Miyazaki drafted the manuscript and designed the figures. All authors contributed to the writing of the final manuscript and read and approved the final manuscript for submission for publication.\u0026nbsp;\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eKitagawa Y, Ishihara R, Ishikawa H, et al (2023) Esophageal cancer practice guidelines 2022 edited by the Japan esophageal society: part 1. Esophagus 20:343\u0026ndash;372. https://doi.org/10.1007/s10388-023-00993-2\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTanaka Y, Yoshida K, Suetsugu T, et al (2018) Recent advancements in esophageal cancer treatment in Japan. 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BMC Nephrol 19:219. https://doi.org/10.1186/s12882-018-1022-2\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTekce BK, Uyeturk U, Tekce H, et al (2015) Does the kidney injury molecule-1 predict cisplatin-induced kidney injury in early stage? Ann Clin Biochem 52:88\u0026ndash;94. https://doi.org/10.1177/0004563214528312\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGhadrdan E, Ebrahimpour S, Sadighi S, et al (2020) Evaluation of urinary neutrophil gelatinase-associated lipocalin and urinary kidney injury molecule-1 as biomarkers of renal function in cancer patients treated with cisplatin. J Oncol Pharm Pract Off Publ Int Soc Oncol Pharm Pract 26:1643\u0026ndash;1649. https://doi.org/10.1177/1078155220901756\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHosohata K, Ando H, Fujiwara Y, Fujimura A (2011) Vanin-1; a potential biomarker for nephrotoxicant-induced renal injury. Toxicology 290:82\u0026ndash;88. https://doi.org/https://doi.org/10.1016/j.tox.2011.08.019\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHosohata K, Ando H, Fujimura A (2012) Urinary Vanin-1 As a Novel Biomarker for Early Detection of Drug-Induced Acute Kidney Injury. J Pharmacol Exp Ther 341:656 LP \u0026ndash; 662. https://doi.org/10.1124/jpet.112.192807\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHosohata K, Washino S, Kubo T, et al (2016) Early prediction of cisplatin-induced nephrotoxicity by urinary vanin-1 in patients with urothelial carcinoma. Toxicology 359\u0026ndash;360:71\u0026ndash;75. https://doi.org/10.1016/j.tox.2016.06.011\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKidney Disease: Improving Global Outcomes (KDIGO) Acute Kidney Injury Work Group (2012) Section 2: AKI Definition. Kidney Int Suppl 2:19\u0026ndash;36. https://doi.org/https://doi.org/10.1038/kisup.2011.32\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAurrand-Lions M, Galland F, Bazin H, et al (1996) Vanin-1, a novel GPI-linked perivascular molecule involved in thymus homing. Immunity 5:391\u0026ndash;405. https://doi.org/10.1016/s1074-7613(00)80496-3\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePitari G, Malergue F, Martin F, et al (2000) Pantetheinase activity of membrane-bound Vanin-1: lack of free cysteamine in tissues of Vanin-1 deficient mice. FEBS Lett 483:149\u0026ndash;154. https://doi.org/10.1016/s0014-5793(00)02110-4\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBerruyer C, Martin FM, Castellano R, et al (2004) Vanin-1-/- mice exhibit a glutathione-mediated tissue resistance to oxidative stress. Mol Cell Biol 24:7214\u0026ndash;7224. https://doi.org/10.1128/MCB.24.16.7214-7224.2004\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHosohata K (2016) Role of Oxidative Stress in Drug-Induced Kidney Injury. Int J Mol Sci 17:. https://doi.org/10.3390/ijms17111826\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eYoshida T, Kurella M, Beato F, et al (2002) Monitoring changes in gene expression in renal ischemia-reperfusion in the rat. Kidney Int 61:1646\u0026ndash;1654. https://doi.org/10.1046/j.1523-1755.2002.00341.x\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHosohata K, Jin D, Takai S, Iwanaga K (2018) Vanin-1 in Renal Pelvic Urine Reflects Kidney Injury in a Rat Model of Hydronephrosis. Int J Mol Sci 19:. https://doi.org/10.3390/ijms19103186\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMiyoshi T, Uoi M, Omura F, et al (2021) Risk Factors for Cisplatin-Induced Nephrotoxicity: A Multicenter Retrospective Study. Oncology 99:105\u0026ndash;113. https://doi.org/10.1159/000510384\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eUchida M, Kondo Y, Suzuki S, Hosohata K (2019) Evaluation of Acute Kidney Injury Associated With Anticancer Drugs Used in Gastric Cancer in the Japanese Adverse Drug Event Report Database. Ann Pharmacother 53:1200\u0026ndash;1206. https://doi.org/10.1177/1060028019865870\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eOgura N, Mera T, Sato F, Ishikawa I (1991) Longitudinal observation of cementum regeneration through multiple fluorescent labeling. J Periodontol 62:284\u0026ndash;291. https://doi.org/10.1902/jop.1991.62.4.284\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eChen C-Y, Chen K-Y, Shih J-Y, Yu C-J (2020) Clinical factors associated with treatment toxicity of pemetrexed plus platinum in elderly patients with non-small cell lung cancer. J Formos Med Assoc 119:1506\u0026ndash;1513. https://doi.org/10.1016/j.jfma.2019.12.007\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCubillo A, Cornide M, L\u0026oacute;pez JL, et al (2001) Renal tolerance to cisplatin in patients 70 years and older. Am J Clin Oncol 24:192\u0026ndash;197. https://doi.org/10.1097/00000421-200104000-00018\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGalfetti E, Cerutti A, Ghielmini M, et al (2020) Risk factors for renal toxicity after inpatient cisplatin administration. BMC Pharmacol Toxicol 21:19. https://doi.org/10.1186/s40360-020-0398-3\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCampbell AB, Kalman SM, Jacobs C (1983) Plasma platinum levels: relationship to cisplatin dose and nephrotoxicity. Cancer Treat Rep 67:169\u0026ndash;172\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLagrange JL, M\u0026eacute;decin B, Etienne MC, et al (1997) Cisplatin nephrotoxicity: a multivariate analysis of potential predisposing factors. Pharmacotherapy 17:1246\u0026ndash;1253\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ede Jongh FE, Gallo JM, Shen M, et al (2004) Population pharmacokinetics of cisplatin in adult cancer patients. Cancer Chemother Pharmacol 54:105\u0026ndash;112. https://doi.org/10.1007/s00280-004-0790-5\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMizuno T, Ishikawa K, Sato W, et al (2013) The risk factors of severe acute kidney injury induced by cisplatin. Oncology 85:364\u0026ndash;369. https://doi.org/10.1159/000356587\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMotwani SS, McMahon GM, Humphreys BD, et al (2018) Development and Validation of a Risk Prediction Model for Acute Kidney Injury After the First Course of Cisplatin. J Clin Oncol 36:682\u0026ndash;688. https://doi.org/10.1200/JCO.2017.75.7161\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTeramachi H, Hatakeyama H, Matsushita R, et al (2002) Evaluation of predictability for vancomycin dosage regimens by the Bayesian method with Japanese population pharmacokinetic parameters. Biol Pharm Bull 25:1333\u0026ndash;1338. https://doi.org/10.1248/bpb.25.1333\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFukumoto K, Shimamoto Y, Tsuchishita Y, et al (2007) Evaluation of Teicoplanin pharmacokinetics in neonates and infanst. Jpn J Ther Drug Monit 24:128\u0026ndash;132\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHill GS (2008) Hypertensive nephrosclerosis. Curr Opin Nephrol Hypertens 17:266\u0026ndash;270. https://doi.org/10.1097/MNH.0b013e3282f88a1f\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFine LG, Orphanides C, Norman JT (1998) Progressive renal disease: the chronic hypoxia hypothesis. Kidney Int Suppl 65:S74-8\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eOhta Y, Fujii K, Arima H, et al (2005) Increased renal resistive index in atherosclerosis and diabetic nephropathy assessed by Doppler sonography. J Hypertens 23:1905\u0026ndash;1911. https://doi.org/10.1097/01.hjh.0000181323.44162.01\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTable 1 is available in the Supplementary Files section.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"cancer-chemotherapy-and-pharmacology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ccap","sideBox":"Learn more about [Cancer Chemotherapy and Pharmacology](http://link.springer.com/journal/280)","snPcode":"280","submissionUrl":"https://submission.nature.com/new-submission/280/3","title":"Cancer Chemotherapy and Pharmacology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"acute kidney injury, cisplatin, creatinine clearance, estimated glomerular filtration rate, serum creatinine, vanin-1","lastPublishedDoi":"10.21203/rs.3.rs-5164399/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-5164399/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003ePurpose\u003c/h2\u003e \u003cp\u003eCisplatin (CDDP) induces acute kidney injury (AKI) as a side effect during neoadjuvant chemotherapy (NAC). Urinary vanin-1 excretion might increase during CDDP treatment. We investigated whether urinary vanin-1 may be an early biomarker of CDDP-induced AKI.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eThirty patients were administrated 80 mg/m\u003csup\u003e2\u003c/sup\u003e CDDP on day 1 as NAC for esophageal cancer. Blood and urine samples were collected on days 1, 2, 3, 4 and 6 after CDDP administration. Serum creatinine (sCr) and urinary vanin-1 were measured. Creatinine clearance (cCr) and estimated glomerular filtration rate (eGFR) were calculated from sCr. Based on the change of sCr after CDDP administration, AKI and non-AKI groups were defined using the Kidney Disease Improving Global Outcomes classification. Changes in sCr, cCr, eGFR, and urinary vanin-1 were compared between the two groups.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eA gradual increase in sCr and decrease in eGFR were observed over time post-CDDP administration, with differences between the two groups becoming significant by day 4. However, urinary vanin-1 levels increased on day 3 after CDDP administration, and the difference between the two groups was already significant on day 3. Receiver operating characteristic curves of urinary vanin-1 on day 3 revealed that a cut-off value of 3.17 ng urinary vanin-1/mg urinary creatinine yielded an area under the curve, sensitivity, and specificity of 0.83 (P\u0026thinsp;\u0026lt;\u0026thinsp;0.05), 75.0%, and 22.7%, respectively. The non-AKI incidence below the cut-off value of urinary vanin-1 of 3.17 ng/mg uCr was 89.5%.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eUrinary vanin-1 is a superior minimally invasive biomarker for early prediction of CDDP-induced AKI.\u003c/p\u003e","manuscriptTitle":"Evaluation of urinary vanin-1 for the early prediction of cisplatin-induced acute kidney injury during neoadjuvant chemotherapy for esophageal cancer","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-12-09 08:19:05","doi":"10.21203/rs.3.rs-5164399/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2024-11-25T10:41:56+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-11-24T01:18:13+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"295973965312789975165756024462438095683","date":"2024-11-10T06:59:37+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"11156689700076447362888665546662121956","date":"2024-09-29T14:45:44+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-09-28T10:16:28+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-09-28T06:16:28+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-09-28T06:14:10+00:00","index":"","fulltext":""},{"type":"submitted","content":"Cancer Chemotherapy and Pharmacology","date":"2024-09-27T10:31:52+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"cancer-chemotherapy-and-pharmacology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ccap","sideBox":"Learn more about [Cancer Chemotherapy and Pharmacology](http://link.springer.com/journal/280)","snPcode":"280","submissionUrl":"https://submission.nature.com/new-submission/280/3","title":"Cancer Chemotherapy and Pharmacology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"dce534b1-7bc4-4ec0-a995-701571933802","owner":[],"postedDate":"December 9th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2024-12-30T16:04:14+00:00","versionOfRecord":{"articleIdentity":"rs-5164399","link":"https://doi.org/10.1007/s00280-024-04737-6","journal":{"identity":"cancer-chemotherapy-and-pharmacology","isVorOnly":false,"title":"Cancer Chemotherapy and Pharmacology"},"publishedOn":"2024-12-23 15:57:13","publishedOnDateReadable":"December 23rd, 2024"},"versionCreatedAt":"2024-12-09 08:19:05","video":"","vorDoi":"10.1007/s00280-024-04737-6","vorDoiUrl":"https://doi.org/10.1007/s00280-024-04737-6","workflowStages":[]},"version":"v1","identity":"rs-5164399","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-5164399","identity":"rs-5164399","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}