Neuronal A2A receptor exacerbates synapse loss and memory deficits in APP/PS1 mice.

Early pathological upregulation of adenosine A2A receptors (A2ARs), one of the caffeine targets, by neurons is thought to be involved in the development of synaptic and memory deficits in Alzheimer's disease (AD) but mechanisms remain ill-defined. To tackle this question, we promoted a neuronal upregulation of A2AR in the hippocampus of APP/PS1 mice developing AD-like amyloidogenesis. Our findings revealed that the early upregulation of A2AR in the presence of an ongoing amyloid pathology exacerbates memory impairments of APP/PS1 mice. These behavioural changes were not linked to major change in the development of amyloid pathology but rather associated with increased phosphorylated tau at neuritic plaques. Moreover, proteomic and transcriptomic analyses coupled with quantitative immunofluorescence studies indicated that neuronal upregulation of the receptor promoted both neuronal and non-neuronal autonomous alterations, i.e. enhanced neuroinflammatory response but also loss of excitatory synapses and impaired neuronal mitochondrial function, presumably accounting for the detrimental effect on memory. Overall, our results provide compelling evidence that neuronal A2AR dysfunction, as seen in the brain of patients, contributes to amyloid-related pathogenesis and underscores the potential of A2AR as a relevant therapeutic target for mitigating cognitive impairments in this neurodegenerative disorder.

Dysregulated expression of cholesterol biosynthetic genes in Alzheimer's disease alters epigenomic signatures of hippocampal neurons.

Aging is the main risk factor of cognitive neurodegenerative diseases such as Alzheimer's disease, with epigenome alterations as a contributing factor. Here, we compared transcriptomic/epigenomic changes in the hippocampus, modified by aging and by tauopathy, an AD-related feature. We show that the cholesterol biosynthesis pathway is severely impaired in hippocampal neurons of tauopathic but not of aged mice pointing to vulnerability of these neurons in the disease. At the epigenomic level, histone hyperacetylation was observed at neuronal enhancers associated with glutamatergic regulations only in the tauopathy. Lastly, a treatment of tau mice with the CSP-TTK21 epi-drug that restored expression of key cholesterol biosynthesis genes counteracted hyperacetylation at neuronal enhancers and restored object memory. As acetyl-CoA is the primary substrate of both pathways, these data suggest that the rate of the cholesterol biosynthesis in hippocampal neurons may trigger epigenetic-driven changes, that may compromise the functions of hippocampal neurons in pathological conditions.

Caffeine consumption outcomes on amyotrophic lateral sclerosis disease progression and cognition.

Caffeine consumption outcomes on Amyotrophic Lateral Sclerosis (ALS) including progression, survival and cognition remain poorly defined and may depend on its metabolization influenced by genetic variants. 378 ALS patients with a precise evaluation of their regular caffeine consumption were monitored as part of a prospective multicenter study. Demographic, clinical characteristics, functional disability as measured with revised ALS Functional Rating Scale (ALSFRS-R), cognitive deficits measured using Edinburgh Cognitive and Behavioural ALS Screen (ECAS), survival and riluzole treatment were recorded. 282 patients were genotyped for six single nucleotide polymorphisms tagging different genes involved in caffeine intake and/or metabolism: CYP1A1 (rs2472297), CYP1A2 (rs762551), AHR (rs4410790), POR (rs17685), XDH (rs206860) and ADORA2A (rs5751876) genes. Association between caffeine consumption and ALSFRS-R, ALSFRS-R rate, ECAS and survival were statistically analyzed to determine the outcome of regular caffeine consumption on ALS disease progression and cognition. No association was observed between caffeine consumption and survival (p = 0.25), functional disability (ALSFRS-R; p = 0.27) or progression of ALS (p = 0.076). However, a significant association was found with higher caffeine consumption and better cognitive performance on ECAS scores in patients carrying the C/T and T/T genotypes at rs2472297 (p-het = 0.004). Our results support the safety of regular caffeine consumption on ALS disease progression and survival and also show its beneficial impact on cognitive performance in patients carrying the minor allele T of rs2472297, considered as fast metabolizers, that would set the ground for a new pharmacogenetic therapeutic strategy.

End-of-life and bereavement support to families in cancer care: a cross-sectional survey with bereaved family members.

BACKGROUND: Losing a close other to cancer is an incisive experience that occurs after a long course of illness and intense family caregiving. Despite an evident need for family engagement and support and guidance on this, patients and family members may not receive the attention and support they need when a family unit is experiencing a disruption by death. A clear understanding of the quality of care that is currently provided and its ability to address family needs is necessary to improve end-of-life and bereavement support to families affected by cancer. The purpose of this study is to investigate the quality of support of end-of-life and bereavement care to families, their (un)met needs, grief experiences, and self-perceived health outcomes. METHODS: A multi-center, cross-sectional observational survey study with family members (n = 35) whose close other died of cancer in a health institution or their own home in German-speaking Switzerland. RESULTS: Bereaved family members were mostly satisfied with end-of-life care. Information on the grief process and services, and acknowledgment of their grief was experienced as helpful. Most coped with their grief drawing on family resources and exhibited resilience, but they reported unmet needs in relation to family togetherness and caregiving. CONCLUSION: This study with a small number of family members indicates that support provided to families across settings and illness trajectories is perceived as helpful, with specific needs related to family support. The findings suggest that improvements should focus on ensuring care that addresses the family as a unit and enables togetherness, mutual reflection, meaningful relationships, preparedness for death, resilience, and benefit-finding. PROTOCOL REGISTRATION: https://osf.io/j4kfh .

Characteristics and clinical challenges in patients with substance use disorder in palliative care-experience from a tertiary center in a high-income country.

BACKGROUND: Access to palliative care is often limited for challenging and vulnerable groups, including persons with substance use disorders. However, with optimized healthcare options and liberal substitution policies, this patient group is likely to increase over the upcoming years, and comorbidities will also influence the need for palliative support. Here, we aim at analyzing characteristics and specific challenges associated with substance use disorders (SUD) in palliative care. METHODS: We retrospectively reviewed all patients diagnosed with substance use disorder that were treated at our Competence Center Palliative Care within the University Hospital Zurich, Switzerland between 2015 and 2021. Patient characteristics, including age, gender, duration of hospitalization, as well as specific metrics like body mass index, distinct palliative care assessment scores, and in-hospital opioid consumption were retrieved from the electronic patient files. Demographics and clinical data were analyzed by descriptive statistics, and compared to those of a control group of palliative care patients without SUD. An opioid calculator was used to standardize opioid intake based on morphine equivalents for meaningful comparisons. RESULTS: The primary characteristics revealed that the majority of individuals were single (56%), had no children (83%), lived alone (39%), and were either unemployed or recipients of a disability pension (in total 50%). Nicotine (89%), opioids (67%), and alcohol (67%) were the most used substances. We identified various comorbidities including psychiatric illnesses alongside SUD (56%), hepatitis A, B, or C (33%), and HIV infection (17%). Patients with SUD were significantly younger (p < 0.5), predominantly male (p < 0.05), and reported a higher prevalence of pain (p < 0.5) compared to the standard cohort of palliative patients. Regarding the challenges most frequently reported by healthcare practitioners, non-compliance, multimorbidity, challenging communication, biographical trauma, lack of social support, and unstable housing situations played a key role. CONCLUSION: Patients with SUD represent a complex and vulnerable group dealing with multiple comorbidities that profoundly affect both their physical and psychological well-being. Understanding their unique characteristics is pivotal in providing precise and suitable palliative care.

Effects of dignity therapy on psychological distress and wellbeing of palliative care patients and family caregivers - a randomized controlled study.

BACKGROUND: This study extended the original Dignity Therapy (DT) intervention by including partners and family caregivers (FCs) of terminally-ill cancer patients with the overall aim of evaluating whether DT can mitigate distress in both patients nearing the end of life and their FCs. METHODS: In this multicenter, randomized controlled trial (RCT), a total of 68 patients with life expectancy < 6 months and clinically-relevant stress levels (Hospital Anxiety Depression total score; HADStot ≥ 8) including their FCs were randomly assigned to DT, DT + (including their FCs), or standard palliative care (SPC) in a 1:1:1 ratio. Study participants were asked to complete a set of questionnaires pre- and post-intervention. RESULTS: The coalesced group (DT and DT +) revealed a significant increase in patients' perceived quality of life (FACIT-Pal-14) following the intervention (mean difference 6.15, SD = 1.86, p < 0.01). We found a statistically significant group-by-time interaction effect: while the HADStot of patients in the intervention group remained stable over the pre-post period, the control group's HADStot increased (F = 4.33, df = 1, 82.9; p < 0.05), indicating a protective effect of DT. Most patients and their FCs found DT useful and would recommend it to other individuals in their situation. CONCLUSIONS: The DT intervention has been well-received and shows the potential to increase HRQoL and prevent further mental health deterioration, illness burden and suffering in terminally-ill patients. The DT intervention holds the potential to serve as a valuable tool for facilitating end-of-life conversations among terminally-ill patients and their FCs. However, the implementation of DT within the framework of a RCT in a palliative care setting poses significant challenges. We suggest a slightly modified and less resource-intensive version of DT that is to provide the DT inventory to FCs of terminally-ill patients, empowering them to ask the questions that matter most to them over their loved one's final days. TRIAL REGISTRATION: This study was registered with Clinical Trial Registry (ClinicalTrials.gov -Protocol Record NCT02646527; date of registration: 04/01/2016). The CONSORT 2010 guidelines were used for properly reporting how the randomized trial was conducted.

Adoption of evidence-based end-of-life and bereavement support to families in cancer care: A contextual analysis study with health professionals.

AIMS: To investigate the level of adoption of evidence-based family engagement and support during end-of-life cancer care and subsequent bereavement and its contextual facilitators and barriers from health professionals' perspectives, and to explore differences between professional groups. DESIGN: Contextual analysis using an online cross-sectional survey. METHODS: This study was conducted in four Swiss hospitals and three home care oncology and palliative care services. Non-parametric testing was used to investigate the level of adoption and differences between nurses, physicians, occupational- and physiotherapists and psychosocial professionals (chaplains, onco-psychologists and social workers). The STROBE checklist for cross-sectional studies was followed. RESULTS: The majority of the 111 participating health professionals were nurses. Adoption was statistically significantly higher during end-of-life care than bereavement, with nurses and physicians reporting higher levels than the other professional groups. Guidance on end-of-life family care was available in about half of the cases, in contrast to a quarter for bereavement care. Self-perceived knowledge, skills and attitudes were moderate to high, with nurses and physicians reporting higher levels than others, except for general skills in working with families. Organisational structures were experienced as rather supportive, with the psychosocial group appraising the organisational context as significantly less conducive to fully implementing end-of-life and bereavement care than others, particularly during the end-of-life phase. CONCLUSION: Evidence-based family engagement and support were better adopted during end-of-life care than bereavement. Overall, nurses and physicians felt better enabled to care for families compared to other professional groups. PATIENT OR PUBLIC CONTRIBUTION: No patient or public contribution. PROTOCOL REGISTRATION: https://osf.io/j4kfh. IMPLICATIONS FOR THE PROFESSION AND/OR PATIENT CARE: Implementation and quality improvement efforts should focus particularly on the bereavement phase and be tailored to professional groups. IMPACT: The findings show that evidence-based family engagement and support practices during end-of-life were rather well adopted in contrast to subsequent bereavement care, with nurses and physicians better enabled than other professionals to provide care. A better understanding of health professionals' contributions and roles in family care is important to build interprofessional capacity for evidence-based end-of-life and bereavement support. REPORTING METHOD: The STROBE checklist for reports of cross-sectional studies was followed (von Elm et al., 2007).

Association of caffeine consumption with cerebrospinal fluid biomarkers in mild cognitive impairment and Alzheimer's disease: A BALTAZAR cohort study.

INTRODUCTION: We investigated the link between habitual caffeine intake with memory impairments and cerebrospinal fluid (CSF) biomarkers in mild cognitive impairment (MCI) and Alzheimer's disease (AD) patients. METHODS: MCI (N = 147) and AD (N = 116) patients of the Biomarker of AmyLoid pepTide and AlZheimer's diseAse Risk (BALTAZAR) cohort reported their caffeine intake at inclusion using a dedicated survey. Associations of caffeine consumption with memory impairments and CSF biomarkers (tau, p-tau181, amyloid beta 1-42 [Aß1-42], Aß1-40) were analyzed using logistic and analysis of covariance models. RESULTS: Adjusted on Apolipoprotein E (APOE ε4), age, sex, education level, and tobacco, lower caffeine consumption was associated with higher risk to be amnestic (OR: 2.49 [95% CI: 1.13 to 5.46]; p = 0.023) and lower CSF Aß1-42 (p = 0.047), Aß1-42/Aß1-40 (p = 0.040), and Aß1-42/p-tau181 (p = 0.020) in the whole cohort. DISCUSSION: Data support the beneficial effect of caffeine consumption to memory impairments and CSF amyloid markers in MCI and AD patients. HIGHLIGHTS: We studied the impact of caffeine consumption in the BALTAZAR cohort. Low caffeine intake is associated with higher risk of being amnestic in MCI/AD patients. Caffeine intake is associated with CSF biomarkers in AD patients.

[Loneliness at the end of life]. / Einsamkeit am Lebensende.

Advanced incurable diseases are often accompanied by numerous losses and burdens as the disease progresses, leading to a loss of autonomy, self-determination, and dignity for those affected, all of which can subsequently promote feelings of loneliness at the end of life. Declining health, increasing symptom burden, loss of social roles, and the fear of death and dying are among the key risk factors for loneliness towards the end of life. In this article, we provide an overview of the different dimensions of loneliness experienced at the end of life. We discuss existential loneliness alongside emotional and social loneliness, explore causes and health implications of loneliness at the end of life, suggest diagnostic tools for assessing loneliness, and finally provide recommendations for addressing emotional, social, and existential loneliness at the end of life. The loneliness of caregivers is also discussed. We suggest that addressing social and emotional loneliness early in the course of a terminal illness is crucial. Palliative, psychological, and spiritual support can strengthen interpersonal relationships, foster a sense of meaning and purpose, and alleviate the adverse effects of loneliness on mental and physical health as well as quality of life. In contrast, existential loneliness is considered an expression of profound emotional maturity and can offer opportunities for inner growth, contributing to a more refined sense of self while reinforcing identity, dignity, and transcendence at the end of life.

The Psychoneuroimmunological Model of Moral Distress and Health in Healthcare Workers: Toward Individual and System-Level Solutions.

Healthcare is presently experiencing a global workforce crisis, marked by the inability of hospitals to retain qualified healthcare workers. Indeed, poor working conditions and staff shortages have contributed to structural collapse and placed a heavy toll on healthcare workers' (HCWs) well-being, with many suffering from stress, exhaustion, demoralization, and burnout. An additional factor driving qualified HCWs away is the repeated experience of moral distress, or the inability to act according to internally held moral values and perceived ethical obligations due to internal and external constraints. Despite general awareness of this crisis, we currently lack an organized understanding of how stress leads to poor health, wellbeing, and performance in healthcare workers. To address this critical issue, we first review the literature on moral distress, stress, and health in HCWs. Second, we summarize the biobehavioral pathways linking occupational and interpersonal stressors to health in this population, focusing on neuroendocrine, immune, genetic, and epigenetic processes. Third, we propose a novel Psychoneuroimmunological Model of Moral Distress and Health in HCWs based on this literature. Finally, we discuss evidence-based individual- and system-level interventions for preventing stress and promoting resilience at work. Throughout this review, we underscore that stress levels in HCWs are a major public health concern, and that a combination of system-level and individual-level interventions are necessary to address preventable health care harm and foster resilience in this population, including new health policies, mental health initiatives, and additional translational research.

Outpatient Palliative Care Service Involvement: A Five-Year Experience from a Tertiary Hospital in Switzerland.

Background: The value of early integration of palliative care has been demonstrated increasingly for the past years in both oncological and nononcological diseases. Outpatient palliative care services might represent a feasible approach to implement supportive care in early disease. In this study, we aimed at evaluating which patients use and benefit from outpatient palliative care services, which symptoms are addressed most, and which support services are installed in this early phase of disease. Methods: We retrospectively analyzed the entire patient collective of a recently developed palliative care outpatient clinic within the leading university hospital in Switzerland for a period of five years. Sociodemographics, symptoms, and information on disease as well as patient-reported outcomes were retrieved from the electronic patient files. Demographic and clinical data were analyzed by descriptive statistics between groups and survival was analyzed by means of Kaplan-Meier estimates and log-rank test. Results: We report on 642 consultations of 363 patients between 2016 and 2020. Patients had a mean of 1.8 visits (range 1-10), with n = 340 patients (93.7%) of patients suffering from an oncological disease. Overall symptom load was high, with n = 401 (73.7%) of patient-reported outcomes reporting two or more symptoms. Distress levels of 5 or higher were reported in n = 78 (30.4%) of available patient-reported outcomes. Independent of the origin of primary disease and the length of the disease trajectory, patients were referred to the palliative care service in median only four months before death. Conclusion: We identify high symptom load and distress in the outpatient palliative patient population. Patients benefitted from supportive medication, improvement of ambulatory support systems and advance care planning, and more than one-third of patients remained in follow-up, indicating a good acceptance of the service. Overcoming the overall late referral could, however, further increase the quality of life at earlier stages of disease.

Hub and Spokes-Implementation of Basic Palliative Care into University Hospital Practice-A Pilot Study.

Background: The aim is to implement knowledge of basic palliative care in selected departments by the Hub and Spokes model. Methods: Implementation of basic palliative care was designed as a stepwise training model by skills lectures over a time period of 2 years. In each of the six selected oncological and nononcological departments, one physician and two nurses were trained in semi-annual half-day meetings as expert representatives within their departments. Results: Semi-structured interviews were conducted to assess implementation outcomes with 12 nurses and 6 physicians. Overall acceptability was high for all departments and professions. Feasibility was given in all departments. Adoption and penetration of a trained expert representative differed between medical and nursing professions. Implementation was more appropriate in the stationary sector. Implementation costs were low. Conclusion: Expansion of the system into a second follow-up period, including more departments, is planned to ensure sustainability.

Contextual determinants of guideline-based family support during end-of-life cancer care and subsequent bereavement care: A cross-sectional survey of registered nurses.

PURPOSE: In end-of-life cancer care, 10-20% of bereaved family members experience adverse mental health effects, including prolonged grief disorder. Despite great efforts, evidence-based recommendations to support their grieving process and well-being are often not successfully adopted into routine clinical care. This study identified facilitators and barriers using implementation science methodology. METHODS: 81 registered nurses working in cancer care from four hospitals and three home care services in Switzerland assessed their current family support practices in end-of-life care and bereavement care. They then assessed organisational attributes of their institution and their own individual characteristics and skills regarding literature-based factors of potential relevance. Facilitators and barriers to guideline-based family support were determined using fractional logistic regression. RESULTS: Service specialisation in palliative care, a culture that supports change, the availability of family support guidelines, billing/reimbursement of bereavement support services, and individual knowledge of family support and skill were systematically associated with higher adoption of guideline-based family support practices. Lack of privacy with families and insufficient training acted as significant barriers. CONCLUSIONS: While several potentially relevant factors have emerged in the literature, certain organisational and individual determinants actually empirically predict guideline-based family support according to nurses in end-of-life cancer care, with some determinants having much stronger implications than others. This provides crucial guidance for focussing quality improvement and implementation efforts through tailored strategies, especially with scarce resources. Furthermore, adoption is lower in bereavement care than in end-of-life care, suggesting a particular need for supportive organisational cultures including specific training and billing/reimbursement options.

Proteomics of human platelet lysates and insight from animal studies on platelet protein diffusion to hippocampus upon intranasal administration.

Human platelet lysates (HPLs) from allogeneic platelet concentrates (PCs) are biomaterials, which are rich in various trophic factors, increasingly used in regenerative medicine and biotherapy. Understanding how preparation methods influence the HPL protein profile, biological function, and clinical outcomes is crucial. Our study sheds light on the proteomes and functionality of different HPLs, with the aim of advancing their scientifically grounded clinical applications. To achieve this, PCs suspended in plasma underwent three distinct processing methods, resulting in seven HPL types. We used three characterization techniques: label-free proteomics and tandem mass tag (TMT)-based quantitative proteomics, both before and after the immunodepletion of abundant plasma proteins. Bioinformatic tools assessed the proteome, and western blotting validated our quantitative proteomics data. Subsequent pre-clinical studies with fluorescent labeling and label-free proteomics were used as a proof of concept for brain diffusion. Our findings revealed 1441 proteins detected using the label-free method, 952 proteins from the TMT experiment before and after depletion, and 1114 proteins from the subsequent TMT experiment on depleted HPLs. Most detected proteins were cytoplasmic, playing key roles in catalysis, hemostasis, and immune responses. Notably, the processing methodologies significantly influenced HPL compositions, their canonical pathways, and, consequently, their functionality. Each HPL exhibited specific abundant proteins, providing valuable insight for tailored clinical applications. Immunoblotting results for selected proteins corroborated our quantitative proteomics data. The diffusion and differential effects to the hippocampus of a neuroprotective HPL administered intranasally to mice were demonstrated. This proteomics study advances our understanding of HPLs, suggesting ways to standardize and customize their production for better clinical efficacy in regenerative medicine and biotherapy. Proteomic analyses also offered objective evidence that HPPL, upon intranasal delivery, not only effectively diffuses to the hippocampus but also alters protein expression in mice, bolstering its potential as a treatment for memory impairments.

Acceptance of Digital Health Technologies in Palliative Care Patients.

Background: Digital health technologies have potential to transform palliative care (PC) services. The global aging population poses unique challenges for PC, which digital health technologies may help overcome. Evaluation of attitudes and perceptions combined with quantification of prior use habits favor an understanding of psychological barriers to PC patient acceptance of digital health technologies including artificial intelligence (AI). Objectives: We aimed to evaluate the attitudes and perceptions of PC patients regarding a broad range of digital health technologies used in their routine monitoring and treatment and identify barriers to use. Methods: We used a 39-item questionnaire to evaluate acceptance and use of smartphone-based electronic patient report outcome measures, wearables, AI, data privacy, and virtual reality (VR) in 29 female and male PC inpatients. Results: A majority of patients indicated an interest in (69.0%) and positive attitude toward (75.9%) digital health technologies. Nearly all (93.1%) patients believe that digital health technologies will become more important in medicine in the future. Most patients would consider using their smartphone (79.3%) or wearable (69.0%) more often for their health. The most feasible technologies were smartphones, wearables, and VR. Barriers to acceptance included unfamiliarity, data security, errors in data interpretation, and loss of personal interaction through AI. Conclusion: In this patient survey, acceptance of new technologies in a PC patient population was high, encouraging its use also at the end-of-life.

Single cell transcriptome analysis of the THY-Tau22 mouse model of Alzheimer's disease reveals sex-dependent dysregulations.

Alzheimer's disease (AD) progression and pathology show pronounced sex differences, but the factors driving these remain poorly understood. To gain insights into early AD-associated molecular changes and their sex dependency for tau pathology in the cortex, we performed single-cell RNA-seq in the THY-Tau22 AD mouse model. By examining cell type-specific and cell type-agnostic AD-related gene activity changes and their sex-dimorphism for individual genes, pathways and cellular sub-networks, we identified both statistically significant alterations and interpreted the upstream mechanisms controlling them. Our results confirm several significant sex-dependent alterations in gene activity in the THY-Tau22 model mice compared to controls, with more pronounced alterations in females. Both changes shared across multiple cell types and cell type-specific changes were observed. The differential genes showed significant over-representation of known AD-relevant processes, such as pathways associated with neuronal differentiation, programmed cell death and inflammatory responses. Regulatory network analysis of these genes revealed upstream regulators that modulate many of the downstream targets with sex-dependent changes. Most key regulators have been previously implicated in AD, such as Egr1, Klf4, Chchd2, complement system genes, and myelin-associated glycoproteins. Comparing with similar data from the Tg2576 AD mouse model and human AD patients, we identified multiple genes with consistent, cell type-specific and sex-dependent alterations across all three datasets. These shared changes were particularly evident in the expression of myelin-associated genes such as Mbp and Plp1 in oligodendrocytes. In summary, we observed significant cell type-specific transcriptomic changes in the THY-Tau22 mouse model, with a strong over-representation of known AD-associated genes and processes. These include both sex-neutral and sex-specific patterns, characterized by consistent shifts in upstream master regulators and downstream target genes. Collectively, these findings provide insights into mechanisms influencing sex-specific susceptibility to AD and reveal key regulatory proteins that could be targeted for developing treatments addressing sex-dependent AD pathology.

Daily Caffeine Consumption May Increase the Risk of Acute Kidney Injury Related to Platinum-Salt Chemotherapy in Thoracic Cancer Patients: A Translational Study.

Although their efficacy has been well-established in Oncology, the use of platinum salts remains limited due to the occurrence of acute kidney injury (AKI). Caffeine has been suggested as a potential pathophysiological actor of platinum-salt-induced AKI, through its hemodynamic effects. This work aims to study the association between caffeine consumption and the risk of platinum-salt-induced AKI, based on both clinical and experimental data. The clinical study involved a single-center prospective cohort study including all consecutive thoracic cancer patients receiving a first-line platinum-salt (cisplatin or carboplatin) chemotherapy between January 2017 and December 2018. The association between daily caffeine consumption (assessed by a validated auto-questionnaire) and the risk of platinum-salt induced AKI or death was estimated by cause-specific Cox proportional hazards models adjusted for several known confounders. Cellular viability, relative renal NGAL expression and/or BUN levels were assessed in models of renal tubular cells and mice co-exposed to cisplatin and increasing doses of caffeine. Overall, 108 patients were included (mean age 61.7 years, 65% men, 80% tobacco users), among whom 34 (31.5%) experienced a platinum-salt-induced AKI (67% Grade 1) over a 6-month median follow-up. The group of high-caffeine consumption (≥386 mg/day) had a two-fold higher hazard of AKI (adjusted HR [95% CI], 2.19 [1.05; 4.57]), without any significant association with mortality. These results are consistent with experimental data confirming enhanced cisplatin-related nephrotoxicity in the presence of increasing doses of caffeine, in both in vitro and in vivo models. Overall, this study suggests a potentially deleterious effect of high doses of daily caffeine consumption on the risk of platinum-salt-related AKI, in both clinical and experimental settings.