Association of proton pump inhibitors with renal adverse events in non-small cell lung cancer patients treated with PD-1 Inhibitor (APPIANI Study): study protocol for a randomized, assessor- blinded, controlled clinical trial

Abstract

Introduction: PD-1 inhibitor, an immune checkpoint inhibitor (ICI), is currently the standard first-line treatment for advanced non-small cell lung cancer (NSCLC). Immune-related adverse effects (irAEs), on the other hand, limit their use. Acid-suppressive drugs (ASDs), including proton pump inhibitors (PPIs) and histamine 2 receptor antagonist (H2RA), are well known as common concomitant drugs in the treatment of cancer. When coupled with ICIs, however, PPIs may increase the incidence of renal adverse events (AEs). The objective of this paper is seeing how commonly individuals with NSCLC developed acute kidney disease and renal dysfunction (AKD) after receiving PD-1 inhibitors and PPIs combined. 

Methods: This study is a randomized, assessor- blinded, controlled clinical trial. Participants who are diagnosed with NSCLC, and taking PPIs or H2RA are randomly assigned to the intervention (using PPIs) and control (using H2RA) groups for 12 weeks in a ratio of 1: 1, and will be followed up for another 12 weeks after treatment. The primary outcome is to explore whether there is a difference in the occurrence of renal AEs between patients with NSCLC treated with PPIs and those without PPIs. 

Discussion: Our findings will have significant implications for AKD prevention and control in the PD-1 inhibitor-treated patients with NSCLC. In addition, it may be valuable to improve policy development and PPIs clinical practice guidelines across China.

Trial registration: ClinicalTrials.gov ChiCTR2200057366. Registered on March 9, 2022

Administrative Information

Introduction

Background and rationale {6a}

Malignancies have emerged as a major public health issue that poses a threat to the population's health. Lung cancer is expected to kill over 1.5 million persons annually, making it the leading cause of cancer death worldwide [2, 3]. Non-small cell lung cancer (NSCLC) is the most frequent type of lung cancer (about 85 percent), with a significant morbidity and mortality rate around the world [4]. As a result, NSCLC incidence and metastasis are a pressing issue that must be addressed. In the treatment of NSCLC, PD-1/PD-L1 inhibitors have emerged as a first-line therapy [5, 6]. 

Normally, the immune system can exert surveillance on abnormal cells. Tumor cells, on the other hand, can acquire antigenic and other alterations as they mature, allowing them to evade immune system detection [7]. Immune checkpoints are molecules that function as a brake in the human immune system, preventing inflammatory damage caused by excessive T cell activation [8]. Tumor cells escape elimination by over-expressing immune checkpoint molecules, thereby promoting the growth of tumor cells [9]. CTLA-4, PD-1, and PD-L1 monoclonal antibodies are now the most commonly studied and used immune checkpoint inhibitors (ICIs), which work by suppressing the function of immunological checkpoints on tumor cells, resulting in an anti-tumor impact [10]. Conversely, ICIs, while activating T cells to enhance tumor immune response, may also lead to excessive activation of T cells, release a large number of inflammatory factors and the production of autoantibodies, resulting in immune-related adverse reactions (irAEs), such as renal adverse events (AEs) [6, 11, 12]. When utilizing ICIs to treat tumors, clinicians must additionally consider concomitant drugs including steroids, acid-suppressive drugs (ASDs), and antibiotics, which can impact the treatment's clinical result [13]. Proton pump inhibitors (PPIs) are a class of pharmaceuticals that reduce stomach acid secretion and are frequently used in conjunction with other anti-tumor therapies [14]. PPIs have been linked to an increased risk of acute kidney injury (AKI), chronic kidney disease (CKD), CKD progression, and even end-stage renal disease (ESRD) in recent studies [15-18]. Researchers found that PPIs contributed to renal tubular epithelial cells apoptosis in vitro [19]. Furthermore, a multi-center observational retrospective study showed that PPIs, as common concomitant medications, can be assumed to have immune modulating detrimental effects [13]. Therefore, we supposed that PD-1 inhibitors combined use with PPIs may lead to a higher risk of kidney injury. Another commonly used ASDs, histamine 2 receptor antagonist (H2RA) therapy, has not been found to have a similar risk of kidney injury to the authors' knowledge [20]. 

 To our knowledge, very limited data is available regarding the incidence of acute kidney disease and renal dysfunction (AKD) after treatment of PD-1 inhibitors and PPIs. Therefore, we conducted a randomized controlled study to compare the PPIs group with the H2RA group in NSCLC patients using PD-1 inhibitors to evaluate the incidence of AKD. We, therefore, intend to conduct prospective, single-center, randomized, assessor- blinded clinical trial to identify the incidence of AKD. Furthermore, we advocate for the prudent use of PPIs in the clinical therapy of PD-1 inhibitors or choose alternative drugs, for example H2RA. 

Objectives {7}

Primary objective

To evaluate whether there is a difference in the occurrence of renal AEs between patients with NSCLC treated with PPIs and those without PPIs.  

Secondary objectives

To establish the indications and appropriate timing of PPIs use in clinical practice in the future. 

Trial design {8}

This is a prospective, randomized, assessor- blinded research, investigating whether there is a difference in renal AEs between NSCLC patients treated with PD-1 inhibitors combined with PPIs and those treated without PPIs. Eligible patients are divided into intervention group and control groups in a ratio of 1: 1 and renal AEs will be followed up. The overall flow chart of the trial are shown in Figure 1.

Methods: Participants, Interventions, And Outcomes

Study setting {9}

In this study, all participants with stage III-IV of NSCLC who received PD-1 inhibitors treatment and being prescribed ASDs in Changzhou, China from 1 April 2022to 31 December 2023 will be continuously included.  

Eligibility criteria {10}

Inclusion criteria

1. Diagnose as NSCLC stage III-IV.  

2. Treatment with PD-1 inhibitors.

3. Taking PPIs or H2RA.

4. Age between 18-65 years old.

5. Voluntarily participate in this study and sign an informed consent form. 

Exclusion criteria

1. Autoimmune diseases, such as systemic lupus erythematosus (SLE), Sjogren's syndrome (SS), vasculitis, etc. 

2. Underlying kidney disease (abnormal urine test, such as urine protein or urine occult blood, or estimated glomerular filtration rate (eGFR) <60ml/min/1.73m²). 

3. History of major organ allograft, especially kidney transplantation. 

4. History of previous long-term use of PPIs.

5. History of heart failure, uncontrolled angina, severe uncontrolled arrhythmias, or pericardial disease.

6. Infectious diseases, including active hepatitis B or C, syphilis, acquired immune deficiency syndrome (AIDS).

7. Severe infectious diseases. 

8. Expected survival time is less than half a year.

9. Psychiatric illness, including clinically defined depression and schizophrenia.

10. Any other conditions that can limit the ability of the patients to participate in the study. 

Exiting criteria

The participants are unwilling or unable to continue the study for any reason. 

Who will take informed consent? {26a}

 All patients informed consent will be signed. The study investigators should protect participants’ privacy and are responsible for the confidentiality of all private information.  

Additional consent provisions for collection and use of participant data and biological specimens {26b}

In this study, biological samples of participants will be collected as clinical indicators, which will be used to judge the occurrence of the AKD events. Informed consent form, which informs patients about the aim of biological samples and potential privacy issues, as well as obtaining their consent. 

Interventions

Explanation for the choice of comparators {6b}

 During the course of receiving PD-1 inhibitors patients developed gastrointestinal discomfort, and are given ASDs therapy by the physician according to the assessment of their condition. The administration of ASDs is based on clinical judgement of responsible physician, no intervention from researcher. To the authors' knowledge, H2RA has not been found to have a similar risk of renal harm. The control group received H2RA treatment and is free to take medicine as directed by their physicians. 

Intervention description {11a}

   Subjects are assigned to two groups, namely, the intervention group and the control group, in the experimental group, they received PPIs treatment and in the control group, H2RA treatment is given. PPIs treatment group is defined as using oral or intravenous PPIs (including omeprazole, pantoprazole, lansoprazole, rabeprazole, esomeprazole, etc.) at least once within 30 days before and after receiving PD-1 inhibitor treatment as recorded in the medical advice of electronic medical record information system.  

Criteria for discontinuing or modifying allocated interventions {11b}

In the following situations, subjects that have been enrolled but have not completed the clinical protocol should be deemed dropouts:

1. Patients withdrew from the trial on their own.

2. Lost to follow-up.

3. The study physician think that subjects are unable to perform the experiment because of some diseases. 

Strategies to improve adherence to interventions {11c}

During the study, researchers should make every effort to make the subjects complete the whole research. Whatever the reason, participants have the right to withdraw from the study at any time. This clinical study will pay for the relevant examination expenses (including blood routine, liver and kidney function) and transportation subsidies (transportation expenses in the city of Changzhou) during participation in this study. 

Relevant concomitant care permitted or prohibited during the trial {11d}

During the trial, other drugs affecting renal function can be used according to the doctor’s advice. If used, detailed records are required.  

Provisions for post-trial care {30}

There are no expected harms resulting from the trial. After this trial, the subjects can be informed of the relevant experimental conclusions, and the indications and side effects of routine drug use can be publicized. 

Outcomes {12}

The endpoint of our study is defined as AKD during the treatment of PD-1 inhibitor. AKD: kidney injury within 3 months, including AKI (increased serum creatinine ≥ 50% within 7 days, or increased serum creatinine ≥ 26.5μmol/l within 48 hours, or oliguria), or GFR < 60ml/min/1.73m2 within 3 months, or decreased GFR ≥ 35%, or increased Scr > 50% [21]. 

Participant timeline {13}

The participant timeline is presented in Table 1. 

Table 1 

Time schedule of enrollment, interventions, and assessments

Sample size {14}

According to the results of small sample size in our center, the incidence of AKD in the control group (PD-1 inhibitor + H2RA) was estimated to be about 18%, and that in the intervention group (PD-1 inhibitor + PPIs) was about 32%. The sample size calculations are derived from Power Analysis and Sample Size (PASS) software where the alpha and minimum required power is fixed at 0.05 and higher than 0.80 respectively. Finally, 190 cases in PPIs group and 190 cases in H2RA group are needed in our study. 

Recruitment {15}

Three hundred and eighty participants with stage III-IV of NSCLC who received PD-1 inhibitors treatment in Changzhou, China from 1 April 2022 to 31 December 2022 will be continuously included. 

Assignment of interventions: allocation

Sequence generation {16a}

The subjects who meet the eligibility criteria will be assigned to each group following the randomization schedule generated by an independent statistician using the statistical analysis system (SAS).  

Concealment mechanism {16b}

The generated sequences will be placed in serialized, opaque, sealed envelopes (to ensure concealment of allocation from the evaluators). 

Implementation {16c}

The randomisation list will be sealed in opaque sealed envelopes with continuous numbers. Envelopes will be stored in a locked cabinet and will only be opened by the practitioner to assign participants to the experimental or controlled group only after obtaining informed consent and eligibility screening. The opened envelope will again be stored separately in another cabinet with locks and managed by a dedicated research assistant. 

Assignment of interventions: blinding 

Who will be blinded {17a}

In this trial, participant blindness cannot be achieved because informed consent is required for inclusion and grouping of subjects. In addition, it is impossible for practitioners involved in the treatment process to achieve blindness. After all, practitioners need to make professional judgments to adjust the treatment plan. However, data analysts and outcome assessors are not involved in PPIs treatment management and are unaware of grouping. 

Procedure for unblinding if needed {17b}

Unblinding will only be allowed under emergencies such as the incidence of serious adverse effects. 

Data collection and management

Plans for assessment and collection of outcomes {18a}

We conduct baseline surveys through the electronic medical record system of our hospital, including basic individual information and clinical indicators.

 Basic information

1. Demographic information: age, sex, race, height, weight. 
2. Information about diseases: history of disease (including cardiovascular and cerebrovascular diseases, smoking and drinking history, diabetes, hypertension). 
3. Information about drugs: chemotherapy drugs (such as cisplatin, vinorelbine, paclitaxel, carboplatin, pemetrexed, etc.), epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) (such as gefitinib, erlotinib, afatinib, orhitinib, etc.), PPIs, H2RA, angiotensin-converting enzyme inhibitor (ACEI) or angiotensin receptor block (ARB), non-steroidal anti-inflammatory drugs (NSAIDs), antibiotics (especially nephrotoxic drugs), and contrast agents.

Clinically indicators 

1. Blood tests: white blood cells, red blood cells, hemoglobin, platelets, lymphocytes, alanine aminotransferase (ALT), aspartate aminotransferase (AST), albumin, serum creatinine (Scr), blood urea nitrogen (BUN), uric acid (UA), and C-reactive protein (CRP). 
2. Urine test: urine protein, urine occult blood, urine white blood cells, urine red blood cells.  

Plans to promote participant retention and complete follow-up {18b}

 All participants will sign informed consent forms. The consent form will describe the study and its objectives, potential benefits and risks, indicate that participants are free to withdraw at any time and safeguards will be taken to maintain confidentiality of data. During 12 weeks of PD-1 inhibitor treatment, blood and urine tests will be examined before each course of treatment (21 ± 3 days). After 12 weeks of PD-1 inhibitor treatment, the follow-up time will be extended to 12 ± 1 weeks. In addition, the information about drug use at each stage will be recorded. Of course, if there is a decrease in urine volume (< 400 ml/d), edema, nausea, vomiting, unplanned hospital visits are required. 

Data management {19}

The electronic data capture (EDC) system is used for data collection, and EpiData entry is also used for the double-key data entry and the program control of the data entry. The monitors ensure that the data recorded in the case report form (CRF) are consistent with the source files and that the entire research process conforms to the approved scheme. 

Confidentiality {27}

All patients’ data are kept confidential and not disclosed. The organizers were equipped with clinical research coordinator (CRC) and clinical research associate (CRA), which will be mainly used for quality control (QC) and supervision of the inclusion of research subjects, selection of treatment schemes, laboratory index detection and other aspects. 

Plans for collection, laboratory evaluation, and storage of biological specimens for genetic or molecular analysis in this trial/future use {33}

After signing the informed consent form, the baseline blood sample and urine sample of the patient will be obtained. During the follow-up period, the changes of blood routine, liver and kidney function, urine routine and CRP will be used as evaluation indexes to judge the occurrence of AKD events. Blood and urine samples are properly stored at -80 ℃ and not used by any other means than this study. Meanwhile, existing and further sample specific studies will be carried out with the approval of the Ethics Committee. If there are any remaining research specimens, biological specimens will be allowed for future research. 

Statistical methods

Statistical methods for primary and secondary outcomes {20a}

Analyses were conducted using SPSS. All data were first checked for normality of distribution using the Kolmogorov-Smirnov test. Normally distributed data are presented as the mean ± standard deviation. Non-normally distributed data are represented as the median (inter-quartile range). The comparison of continuous variables uses Welch's t-test or Kruskall-Wallis test, depending on the distribution of data. Chi-square test is used to compared categorical data. In observational studies, it is difficult to guarantee the credibility of test results due to data bias and confounding variables for various reasons. We use univariate logistic regression models to initially determine which factors might have an impact on outcomes. Second, multivariate logistic regression models are established to assess potential confounding factors and reveal adjusted RR, and to adjust the confounding factors. In addition, we use propensity score matching to further estimate the incidence of AKD while accounting for covariate imbalances in populations. First, logsitic regression model is established to estimate propensity score according to the independent variable (AKD incidence) converted into dependent variable and the control variables (age, sex, hypertension, diabetes, cancer stage etc.) converted into independent variables. Select the nearest neighbor matching method to match the propensity score in a 1:1 ratio, and finally the balance groups of PPIs users and H2RA users are obtained. The Kaplan-Meier method and the log-rank test were used to estimate the survival rate of patients. A two-sided p value of <0.05 was considered to indicate statistical significance.

 Interim analyses {21b}

There are no interim analyses planned. 

Methods for additional analyses (e.g., subgroup analyses) {20b}

Patient characteristics of interest that might potentially influence the results. Possible confounding factors, such as age, cancer stage, disease history and medication history will be identified and summarised at baseline. Details are as follows.

1. Age: 18-50 or 50-65 years old. 
2. Cancer stage: stage III or IV (refer to NCCN Guidelines for Non-Small Cell Lung Cancer in 2021, Fourth Edition). 
3. Diabetes: yes or no (refer to 2021 ADA Guidelines-Updates in T2DM Care). 
4. Hypertension: yes or No (refer to 2018 Chinese Guidelines for Prevention and Treatment of Hypertension). 
5. Medications with possible risks of AKD: yes or no (including ACEI / ARB, NSAIDs, contrast agents, aminoglycosides, etc.). 

We may perform subgroup analysis based on the relevant age, sex, and cancer stage according to the above confounding factors. 

Methods in analysis to handle protocol non-adherence and any statistical methods to handle missing data {20c}

Participants with missing primary outcome data are excluded. 

Plans to give access to the full protocol, participant level data, and statistical code {31c}

The datasets analyzed during the current study are available from the corresponding author on reasonable request. 

Oversight and monitoring

Composition of the coordinating center and trial steering committee {5d}

The organizers were equipped with CRC and CRA, which will be mainly used for QC and supervision of the inclusion of research subjects, selection of treatment schemes, laboratory index detection and other aspects. There are several CRCs at each study center. Study coordinators play a role in coordination and study management. At the start-up meeting of clinical trials, all participants who are preparing to be authorized need to attend the training of the start-up meeting and carry out special training for relevant personnel according to the authorized authority. 

Composition of the data monitoring committee, its role and reporting structure {21a}

The data security and monitoring board (DSMB) is composed of researchers from the Department of Oncology and Nephrology of the Third Affiliated Hospital of Soochow University. Members should have professional knowledge in medicine, pharmacy and health statistics, and be familiar with relevant laws and regulations of clinical trials. The Committee monitors the eligibility, integrity, security and validity of the research center data through the EDC system.  

Adverse event reporting and harms {22}

All AEs will be recorded throughout the study period. We define AEs as any hospitalization behavior related to treatment. Researchers will determine whether AEs occur by following up subjects or inquiring by electronic medical record information system. We divide the severity of AEs into ‘general AEs (GAEs)’ and ‘severe AEs (SAEs)’. 

GAEs: No special reports are required, but they need to be recorded in CRF. The DSMB and institutional review board (IRB) will review them in regular meetings. 

SAEs: Fill in the SAE report form within 24 hours, send it to the project leader in PDF form, and then submit it to the data monitoring committee (DMC). The risk is assessed by DSMB, and finally the hospital ethics committee makes decision.

 When it is not appropriate to rate the severity of AEs, we judge them as unexpected AEs (UAEs), and divide them into ‘possibly related to research intervention’, ‘possibly not related to research intervention’, and ‘definitely not related to research intervention’.

Possibly related to research intervention: report within 24 hours.

Possibly not related to research intervention: report within 5 working days.

Definitely not related to research intervention: report within 10 working days. 

Frequency and plans for auditing trial conduct {23}

The supervisor meet monthly to ensure that the study is being conducted in accordance with the study protocol. 

Plans for communicating important protocol amendments to relevant parties (e.g., trial participants, ethical committees) {25}

All changes to the study will be notified to the Ethics Committee of Soochow University. Non-material changes will be recorded and archived. If the modification involves or affects participants in any way, they will be informed of the change. If necessary, additional consent will be requested and registered. In addition, the online test registry will be updated accordingly. 

Dissemination plans {31a} 

The findings will be disseminated in conferences and peer-reviewed publications, and hope to attract the attention of oncologists, nephrologists and other peers. Our study findings will have significant implications for AKD prevention and control in the PD-1 inhibitor-treated patients with NSCLC.

Conclusion

ICIs have become the first-line treatment of NSCLC, but the irAEs limit their use [5, 22–24]. ICIs-associated kidney injury can have serious consequences for patients including discontinuation of ICIs therapy, irreversible loss of kidney function.[25–27] PPIs are often used to prevent gastrointestinal symptoms undergoing anti-tumor therapy [14]. However, PPIs may cause acute interstitial nephritis (AIN) [18, 19, 28], therefore raise the risk of renal AEs when combined use with ICIs [29]. However, there are few studies to confirm the incidence of AKD when combined use of PD-1 inhibitors and PPIs. Our cohort study is the first to compare the incidence of AKD with or without concomitant PPIs when treated with PD-1 inhibitors in China. Our findings will have significant implications for AKD prevention and control in the PD-1 inhibitor-treated patients with NSCLC. In addition, it may be valuable to improve policy development and PPIs clinical practice guidelines across China.

Abbreviations

ICI: immune checkpoint inhibitor; NSCLC: non-small cell lung cancer; irAEs: immune-related adverse effects; ASDs: acid-suppressive drugs; PPIs: proton pump inhibitors; H2RA: histamine 2 receptor antagonist; AEs: adverse events; AKD: acute kidney disease and renal dysfunction; AKI: acute kidney injury; CKD: chronic kidney disease; ESRD: end-stage renal disease; SLE: systemic lupus erythematosus; SS: Sjogren's syndrome; eGFR: estimated glomerular filtration rate; AIDS: acquired immune deficiency syndrome; SAS: statistical analysis system; PASS: Power Analysis and Sample Size; EGFR-TKIs: epidermal growth factor receptor-tyrosine kinase inhibitors; ACEI: angiotensin-converting enzyme inhibitor; ARB: angiotensin receptor block; NSAIDs: non-steroidal anti-inflammatory drugs; ALT: alanine aminotransferase; AST: aspartate aminotransferase; Scr: serum creatinine; BUN: blood urea nitrogen; UA: uric acid; CRP: C-reactive protein; CRC: clinical research coordinator; CRA: clinical research associate; QC: quality control; GAEs: general adverse events; SAEs: severe adverse events; CRF: case report form; DSMB: data security and monitoring board; IRB: institutional review board; DMC: data monitoring committee; UAEs: unexpected adverse events; EDC: electronic data capture; AIN: acute interstitial nephritis. 

Declarations

Acknowledgments 

We are very grateful to all the patients who participated in the study and the staff who contributed to the study. 

Contributors 

HZ and MY conceptualised the study. XM, AW, and PL provided additional methodological and/or clinical advice. MY is the principal investigator of the project and provides strategic advice. XM and AW drafted the protocol. All authors read, critically revised and approved the final draft. 

Funding 

This work was supported by grants from the National Natural Science Foundation of China (82000684) and Changzhou Sci & Tech Program (CJ20200025). 

Availability of data and materials 

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request. 

Ethics approval and consent to participate {24}

This study was approved by the Ethics Committee of the Third Affiliated Hospital of Soochow University, China (number: #27/2013). Written informed consent to participate will be obtained from all participants.  

Consent for publication {32}

Details are visible in the additional files. 

Competing interests 

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

References

1. Colombo M, Valo E, McGurnaghan SJ, Sandholm N, Blackbourn LAK, Dalton RN, et al: Biomarker panels associated with progression of renal disease in type 1 diabetes. Diabetologia. 2019;62(9):1616-27.
2. Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A: Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68(6):394-424.
3. Cheng TY, Cramb SM, Baade PD, Youlden DR, Nwogu C, Reid ME: The International Epidemiology of Lung Cancer: Latest Trends, Disparities, and Tumor Characteristics. J Thorac Oncol. 2016;11(10):1653-71.
4. Fan H, Shao ZY, Xiao YY, Xie ZH, Chen W, Xie H, et al: Incidence and survival of non-small cell lung cancer in Shanghai: a population-based cohort study. BMJ Open. 2015;5(12):e009419.
5. Arrieta O, Barrón F, Ramírez-Tirado LA, Zatarain-Barrón ZL, Cardona AF, Díaz-García D, et al: Efficacy and Safety of Pembrolizumab Plus Docetaxel vs Docetaxel Alone in Patients With Previously Treated Advanced Non-Small Cell Lung Cancer: The PROLUNG Phase 2 Randomized Clinical Trial. JAMA Oncol. 2020;6(6):856-64.
6. Reck M, Rodríguez-Abreu D, Robinson AG, Hui R, Csőszi T, Fülöp A, et al: Pembrolizumab versus Chemotherapy for PD-L1-Positive Non-Small-Cell Lung Cancer. The New England journal of medicine. 2016;375(19):1823-33.
7. Purtilo DT, Linder J: Oncological consequences of impaired immune surveillance against ubiquitous viruses. J Clin Immunol. 1983;3(3):197-206.
8. Kalbasi A, Ribas A: Tumour-intrinsic resistance to immune checkpoint blockade. Nat Rev Immunol. 2020;20(1):25-39.
9. Shankar B, Zhang J, Naqash AR, Forde PM, Feliciano JL, Marrone KA, et al: Multisystem Immune-Related Adverse Events Associated With Immune Checkpoint Inhibitors for Treatment of Non-Small Cell Lung Cancer. JAMA Oncol. 2020;6(12):1952-56.
10. Sharma P, Pachynski RK, Narayan V, Flechon A, Gravis G, Galsky MD, et al: Nivolumab Plus Ipilimumab for Metastatic Castration-Resistant Prostate Cancer: Preliminary Analysis of Patients in the CheckMate 650 Trial. Cancer Cell. 2020;38(4):489-99.e3.
11. Berner F, Bomze D, Diem S, Ali OH, Fässler M, Ring S, et al: Association of Checkpoint Inhibitor-Induced Toxic Effects With Shared Cancer and Tissue Antigens in Non-Small Cell Lung Cancer. JAMA Oncol. 2019;5(7):1043-47.
12. Perazella MA, Shirali AC: Nephrotoxicity of Cancer Immunotherapies: Past, Present and Future. Journal of the American Society of Nephrology : JASN. 2018;29(8):2039-52.
13. Cortellini A, Tucci M, Adamo V, Stucci LS, Russo A, Tanda ET, et al: Integrated analysis of concomitant medications and oncological outcomes from PD-1/PD-L1 checkpoint inhibitors in clinical practice. J Immunother Cancer. 2020;8(2):e001361.
14. Smelick GS, Heffron TP, Chu L, Dean B, West DA, Duvall SL, et al: Prevalence of acid-reducing agents (ARA) in cancer populations and ARA drug-drug interaction potential for molecular targeted agents in clinical development. Mol Pharm. 2013;10(11):4055-62.
15. Hart E, Dunn TE, Feuerstein S, Jacobs DM: Proton Pump Inhibitors and Risk of Acute and Chronic Kidney Disease: A Retrospective Cohort Study. Pharmacotherapy. 2019;39(4):443-53.
16. Lazarus B, Chen Y, Wilson FP, Sang Y, Chang AR, Coresh J, et al: Proton Pump Inhibitor Use and the Risk of Chronic Kidney Disease. JAMA Intern Med. 2016;176(2):238-46.
17. Xie Y, Bowe B, Li T, Xian H, Balasubramanian S, Al-Aly Z: Proton Pump Inhibitors and Risk of Incident CKD and Progression to ESRD. J Am Soc Nephrol. 2016;27(10):3153-63.
18. Xu X, Nie S, Zhang A, Mao J, Liu H-P, Xia H, et al: Acute Kidney Injury among Hospitalized Children in China. Clinical journal of the American Society of Nephrology : CJASN. 2018;13(12):1791-800.
19. Fontecha-Barriuso M, Martin-Sanchez D, Martinez-Moreno JM, Cardenas-Villacres D, Carrasco S, Sanchez-Nino MD, et al: Molecular pathways driving omeprazole nephrotoxicity. Redox Biol. 2020;32:101464.
20. Qiu T, Zhou J, Zhang C: Acid-suppressive drugs and risk of kidney disease: A systematic review and meta-analysis. J Gastroenterol Hepatol. 2018.
21. Lameire NH, Levin A, Kellum JA, Cheung M, Jadoul M, Winkelmayer WC, et al: Harmonizing acute and chronic kidney disease definition and classification: report of a Kidney Disease: Improving Global Outcomes (KDIGO) Consensus Conference. Kidney Int. 2021;100(3):516-26.
22. Ramos-Casals M, Brahmer JR, Callahan MK, Flores-Chavez A, Keegan N, Khamashta MA, et al: Immune-related adverse events of checkpoint inhibitors. Nat Rev Dis Primers. 2020;6(1):38.
23. Reck M, Rodriguez-Abreu D, Robinson AG, Hui R, Csoszi T, Fulop A, et al: Pembrolizumab versus Chemotherapy for PD-L1-Positive Non-Small-Cell Lung Cancer. N Engl J Med. 2016;375(19):1823-33.
24. Tang SQ, Tang LL, Mao YP, Li WF, Chen L, Zhang Y, et al: The Pattern of Time to Onset and Resolution of Immune-Related Adverse Events Caused by Immune Checkpoint Inhibitors in Cancer: A Pooled Analysis of 23 Clinical Trials and 8,436 Patients. Cancer Res Treat. 2021;53(2):339-54.
25. Cortazar FB, Marrone KA, Troxell ML, Ralto KM, Hoenig MP, Brahmer JR, et al: Clinicopathological features of acute kidney injury associated with immune checkpoint inhibitors. Kidney Int. 2016;90(3):638-47.
26. Mamlouk O, Selamet U, Machado S, Abdelrahim M, Glass WF, Tchakarov A, et al: Nephrotoxicity of immune checkpoint inhibitors beyond tubulointerstitial nephritis: single-center experience. J Immunother Cancer. 2019;7(1):2.
27. Wanchoo R, Karam S, Uppal NN, Barta VS, Deray G, Devoe C, et al: Adverse Renal Effects of Immune Checkpoint Inhibitors: A Narrative Review. Am J Nephrol. 2017;45(2):160-69.
28. Moledina DG, Perazella MA: Proton Pump Inhibitors and CKD. J Am Soc Nephrol. 2016;27(10):2926-28.
29. Bruzzi P: Non-drug industry funded research. BMJ. 2008;336(7634):1-2.