Cardiovascular Consequences of Uremic Metabolites: an Overview of the Involved Signaling Pathways.

The crosstalk of the heart with distant organs such as the lung, liver, gut, and kidney has been intensively approached lately. The kidney is involved in (1) the production of systemic relevant products, such as renin, as part of the most essential vasoregulatory system of the human body, and (2) in the clearance of metabolites with systemic and organ effects. Metabolic residue accumulation during kidney dysfunction is known to determine cardiovascular pathologies such as endothelial activation/dysfunction, atherosclerosis, cardiomyocyte apoptosis, cardiac fibrosis, and vascular and valvular calcification, leading to hypertension, arrhythmias, myocardial infarction, and cardiomyopathies. However, this review offers an overview of the uremic metabolites and details their signaling pathways involved in cardiorenal syndrome and the development of heart failure. A holistic view of the metabolites, but more importantly, an exhaustive crosstalk of their known signaling pathways, is important for depicting new therapeutic strategies in the cardiovascular field.

Role of the Microbiome in Gut-Heart-Kidney Cross Talk.

Homeostasis is a prerequisite for health. When homeostasis becomes disrupted, dysfunction occurs. This is especially the case for the gut microbiota, which under normal conditions lives in symbiosis with the host. As there are as many microbial cells in and on our body as human cells, it is unlikely they would not contribute to health or disease. The gut bacterial metabolism generates numerous beneficial metabolites but also uremic toxins and their precursors, which are transported into the circulation. Barrier function in the intestine, the heart, and the kidneys regulates metabolite transport and concentration and plays a role in inter-organ and inter-organism communication via small molecules. This communication is analyzed from the perspective of the remote sensing and signaling theory, which emphasizes the role of a large network of multispecific, oligospecific, and monospecific transporters and enzymes in regulating small-molecule homeostasis. The theory provides a systems biology framework for understanding organ cross talk and microbe-host communication involving metabolites, signaling molecules, nutrients, antioxidants, and uremic toxins. This remote small-molecule communication is critical for maintenance of homeostasis along the gut-heart-kidney axis and for responding to homeostatic perturbations. Chronic kidney disease is characterized by gut dysbiosis and accumulation of toxic metabolites. This slowly impacts the body, affecting the cardiovascular system and contributing to the progression of kidney dysfunction, which in its turn influences the gut microbiota. Preserving gut homeostasis and barrier functions or restoring gut dysbiosis and dysfunction could be a minimally invasive way to improve patient outcomes and quality of life in many diseases, including cardiovascular and kidney disease.

Disaster preparedness for people with kidney disease and kidney healthcare providers.

PURPOSE OF REVIEW: Man-made and natural disasters become more frequent and provoke significant morbidity and mortality, particularly among vulnerable people such as patients with underlying kidney diseases. This review summarizes strategies to minimize the risks associated with mass disasters among kidney healthcare providers and patients affected by kidney disease. RECENT FINDINGS: Considering patients, in advance displacement or evacuation are the only options to avoid harmful consequences of predictable disasters such as hurricanes. Following unpredictable catastrophes, one can only rely upon educational initiatives for disaster risk mitigation. Preparatory initiatives before disasters such as training courses should target minimizing hazards in order to decrease morbidity and mortality by effective interventions during and early after disasters. Retrospective evaluation of previous interventions is essential to identify adverse consequences of disaster-related health risks and to assess the efficacy of the medical response. However, preparations and subsequent responses are always open for ameliorations, even in well developed countries that are aware of disaster risks, and even after predictable disasters. SUMMARY: Adverse consequences of disasters in patients with kidney diseases and kidney healthcare providers can be mitigated by predisaster preparedness and by applying action plans and pragmatic interventions during and after disasters. Preparing clear, practical and concise recommendations and algorithms in various languages is mandatory.

Extracorporeal Techniques in Kidney Failure.

During the last decades, various strategies have been optimized to enhance clearance of a variable spectrum of retained molecules to ensure hemodynamic tolerance to fluid removal and improve long-term survival in patients affected by kidney failure. Treatment effects are the result of the interaction of individual patient characteristics with device characteristics and treatment prescription. Historically, the nephrology community aimed to provide adequate treatment, along with the best possible quality of life and outcomes. In this article, we analyzed blood purification techniques that have been developed with their different characteristics.

Our shared responsibility: the urgent necessity of global environmentally sustainable kidney care.

In response to Earth's accelerating climate crisis, we, an international group of nephrologists, call on our global community to unite and align kidney care in accordance with United Nation's 26th Conference of the Parties health sector principles. We announce a global and inclusive initiative, "GREEN-K": Global Environmental Evolution in Nephrology and Kidney Care, with a vision of "sustainable kidney care for a healthy planet and healthy kidneys" and mission to "promote and support environmentally sustainable and resilient kidney care globally through advocacy, education, and collaboration." A patient-centric approach that permits climate change mitigation and adaptation is proposed. Multi-stakeholder GREEN-K action and focus areas will include education, sustainable clinical care, and advances toward environmentally sustainable innovations, procurement, and infrastructure. Mindful of the disproportionately high climate impact of kidney therapies, we welcome the opportunity to work together in shared accountability to patients and Earth's natural systems.

The European Kidney Health Alliance (EKHA) and the Decade of the KidneyTM.

The European Kidney Health Alliance (EKHA) is an advocacy organization that defends the case of the kidney patients and the nephrological community at the level of the European Union (EU), and from there, top to bottom, also at the national level of the EU member states and the EU-associated countries. The Decade of the KidneyTM is a global initiative launched by the American Association of Kidney Patients (AAKP) to create greater awareness and organize patient demands for long overdue innovation in kidney care. This article describes the medical and patient burden of kidney disease, the history of EKHA, its major activities and tools for policy action, and the need for innovation of kidney care. We then describe the Decade of the KidneyTM initiative, the rationale behind why EKHA joined this activity to emanate parallel action at the European side, the novel professionalized structure of EKHA, and its immediate targets. The final aim is to align all major stakeholders for an action plan on kidney disease comparable to Europe's successful Beating Cancer Plan, with the additional intent that the EKHA model is applied also by the respective national kidney-related societies to create a broad mobilization at all levels. The ultimate aims are that the EU considers chronic kidney disease (CKD) as a major health and health-economic problem, to consequently have CKD included as a key health research target by the European Commission, and to improve quality of life and outcomes for all kidney patients.

Factors influencing kidney transplantation rates: a study from the ERA Registry.

BACKGROUND: Large international differences exist in kidney transplantation (KT) rates. We aimed to investigate which factors may explain the total, deceased donor and living donor KT rates over the last decade. METHODS: KT experts from 39 European countries completed the Kidney Transplantation Rate Survey on measures and barriers and their potential effect on the KT rate in their country. In the analyses, countries were divided into low, middle and high KT rate countries based on the KT rate at the start of study period in 2010. RESULTS: Experts from low KT rate countries reported more frequently that they had taken measures regarding staff, equipment and facilities to increase the total KT rate compared with middle and high KT rate countries. For donor type-specific KT, the largest international differences in measures taken were reported for deceased donor KT, with middle and high KT rate countries taking more measures, such as the use of expanded criteria donor kidneys, the presence of transplantation coordinators and (inter)national exchange of donor kidneys. Once a measure was taken, experts' opinion on its success was similar across the low, middle and high KT rate countries. Experts from low KT rate countries more often reported potential barriers, such as patients' lack of knowledge and distrust in the healthcare system. CONCLUSIONS: Particularly in low KT rate countries, the KT rate might be stimulated by optimizing staff, equipment and facilities. In addition, all countries may benefit from measures specific to deceased and living donors.

Lessons learned during the war in Ukraine: a report from the Renal Disaster Relief Task Force of the ERA.

People living with kidney disease are among the most vulnerable at times of natural or man-made disasters. In addition to their unpredictable course, armed conflicts impose a major threat given the disruption of infrastructure, sanitation and access to food, water and medical care. The ongoing war in Ukraine has once more demonstrated the importance of preparedness, organization, coordination and solidarity during disasters. People living with kidney disease face serious challenges given their dependence on life-sustaining treatment, irrespective of whether they remain in the war zone or are displaced internally or externally. This especially affects those requiring kidney replacement therapy, dialysis or transplantation, but also patients with other kidney diseases and the medical staff who care for them. Soon after the war started, the European Renal Association assigned a Renal Disaster Relief Task Force dedicated to support the people living with kidney disease and the nephrology community in Ukraine. This report summarizes the major challenges faced, actions taken and lessons learned by this task force. We anticipate that the experience will help to increase preparedness and mitigate the devastating effects of armed conflicts on the kidney community in the future and propose to establish an international collaboration to extend this effort to other parts of the world facing similar challenges.

Distribution, preparedness and management of Ukrainian adult refugees on dialysis-an international survey by the Renal Disaster Relief Task Force of the European Renal Association.

BACKGROUND: Due to the Russian-Ukrainian war, some of the about 10 000 adults requiring dialysis in Ukraine fled their country to continue dialysis abroad. To better understand the needs of conflict-affected dialysis patients, the Renal Disaster Relief Task Force of the European Renal Association conducted a survey on distribution, preparedness and management of adults requiring dialysis who were displaced due to the war. METHODS: A cross-sectional online survey was sent via National Nephrology Societies across Europe and disseminated to their dialysis centers. Fresenius Medical Care shared a set of aggregated data. RESULTS: Data were received on 602 patients dialyzed in 24 countries. Most patients were dialyzed in Poland (45.0%), followed by Slovakia (18.1%), Czech Republic (7.8%) and Romania (6.3%). The interval between last dialysis and the first in the reporting center was 3.1 ± 1.6 days, but was ≥4 days in 28.1% of patients. Mean age was 48.1 ± 13.4 years, 43.5% were females. Medical records were carried by 63.9% of patients, 63.3% carried a list of medications, 60.4% carried the medications themselves and 44.0% carried their dialysis prescription, with 26.1% carrying all of these items and 16.1% carrying none. Upon presentation outside Ukraine, 33.9% of patients needed hospitalization. Dialysis therapy was not continued in the reporting center by 28.2% of patients until the end of the observation period. CONCLUSIONS: We received information about approximately 6% of Ukrainian dialysis patients, who had fled their country by the end of August 2022. A substantial proportion were temporarily underdialyzed, carried incomplete medical information and needed hospitalization. The results of our survey may help to inform policies and targeted interventions to respond to the special needs of this vulnerable population during wars and other disasters in the future.

The European Green Deal and nephrology: a call for action by the European Kidney Health Alliance.

The world faces a dramatic man-made ecologic disaster and healthcare is a crucial part of this problem. Compared with other therapeutic areas, nephrology care, and especially dialysis, creates an excessive burden via water consumption, greenhouse gas emission and waste production. In this advocacy article from the European Kidney Health Alliance we describe the mutual impact of climate change on kidney health and kidney care on ecology. We propose an array of measures as potential solutions related to the prevention of kidney disease, kidney transplantation and green dialysis. For dialysis, several proactive suggestions are made, especially by lowering water consumption, implementing energy-neutral policies, waste triage and recycling of materials. These include original proposals such as dialysate regeneration, dialysate flow reduction, water distillation systems for dialysate production, heat pumps for unit climatization, heat exchangers for dialysate warming, biodegradable and bio-based polymers, alternative power sources, repurposing of plastic waste (e.g. incorporation in concrete), registration systems of ecologic burden and platforms to exchange ecologic best practices. We also discuss how the European Green Deal offers real potential for supporting and galvanizing these urgent environmental changes. Finally, we formulate recommendations to professionals, manufacturers, providers and policymakers on how this correction can be achieved.

Armed conflicts and kidney patients: a consensus statement from the Renal Disaster Relief Task Force of the ERA.

During conflicts, people with kidney disease, either those remaining in the affected zones or those who are displaced, may be exposed to additional threats because of medical and logistical challenges. Acute kidney injury developing on the battlefield, in field hospitals or in higher-level hospital settings is characterized by poor outcomes. People with chronic kidney disease may experience treatment interruptions, contributing to worsening kidney function. Patients living on dialysis or with a functioning graft may experience limitations of dialysis possibilities or availability of immunosuppressive medications, increasing the risk of severe complications including death. When patients must flee, these threats are compounded by unhealthy and insecure conditions both during displacement and/or at their destination. Measures to attenuate these risks may only be partially effective. Local preparedness for overall and medical/kidney-related disaster response is essential. Due to limitations in supply, adjustments in dialysis frequency or dose, switching between hemodialysis and peritoneal dialysis and changes in immunosuppressive regimens may be required. Telemedicine (if possible) may be useful to support inexperienced local physicians in managing medical and logistical challenges. Limited treatment possibilities during warfare may necessitate referral of patients to distant higher-level hospitals, once urgent care has been initiated. Preparation for disasters should occur ahead of time. Inclusion of disaster nephrology in medical and nursing curricula and training of patients, families and others on self-care and medical practice in austere settings may enhance awareness and preparedness, support best practices adapted to the demanding circumstances and prepare non-professionals to lend support.

Critical Appraisal of Limitations in the Current Definition/Classification of Uremic Toxins.

Progress in the identification and characterization of uremic retention solutes has refined our understanding of the pathophysiology of the uremic syndrome. Furthermore, the evolution of dialysis and other techniques designed to remove uremic retention solutes offers opportunities to provide a more personalized and targeted treatment for patients with chronic kidney disease (CKD) with an aim to improve outcomes. Considering these developments, a consensus report was recently published that readdressed the 2003 definition and classification of uremic toxins and formulated recommendations for future research to enhance the understanding of uremic retention solutes. In the present work, the authors of a work group that contributed to the consensus report provide a more detailed rationale for the recommendations related to their theme "Critical appraisal of limitations in the current definition/classification of uremic toxins." In summary, the authors propose that the current definition of uremic toxins should remain organized on hemodialysis strategies, membranes, and removal patterns since hemodialysis is the most frequently applied therapeutic strategy to reduce their concentration in advanced CKD. Nevertheless, the work group also acknowledges that any classification based on cutoff values and/or molecular spatial configurations is arbitrary and will likely need to be changed with therapeutic advancements. Furthermore, the current physicochemical classification might be extended to reflect the degree of toxicity of a specific toxin that is likely to support more personalized and targeted dialysis prescriptions and improve the outcomes for patients with CKD.

Uremic encephalopathy.

Uremic encephalopathy encompasses a wide range of central nervous system abnormalities associated with poor kidney function occurring with either progressive chronic kidney disease or acute kidney injury. The syndrome is likely caused by retention of uremic solutes, alterations in hormonal metabolism, changes in electrolyte and acid-base homeostasis, as well as changes in vascular reactivity, blood-brain barrier transport, and inflammation. There are no defining clinical, laboratory, or imaging findings, and the diagnosis is often made retrospectively when symptoms improve after dialysis or transplantation. The diagnosis is also made difficult because of the many confounding and overlapping conditions seen in patients with chronic kidney disease and acute kidney injury. Thus, institution of kidney replacement therapy should be considered as a trial to improve symptoms in the right clinical context. Neurological symptoms that do not improve after improvement in clearance should prompt a search for other explanations. Further knowledge linking possible uremic retention solutes with neurological symptoms is needed to better understand this syndrome as well as to develop more tailored treatments that aim to improve cognitive function.

Patient-reported factors influencing the choice of their kidney replacement treatment modality.

BACKGROUND: Access to various kidney replacement therapy (KRT) modalities for patients with end-stage kidney disease differs substantially within Europe. METHODS: European adults on KRT filled out an online or paper-based survey about factors influencing and experiences with modality choice (e.g. information provision, decision-making and reasons for choice) between November 2017 and January 2019. We compared countries with low, middle and high gross domestic product (GDP). RESULTS: In total, 7820 patients [mean age 59 years, 56% male, 63% on centre haemodialysis (CHD)] from 38 countries participated. Twenty-five percent had received no information on the different modalities, and only 23% received information >12 months before KRT initiation. Patients were not informed about home haemodialysis (HHD) (42%) and comprehensive conservative management (33%). Besides nephrologists, nurses more frequently provided information in high-GDP countries, whereas physicians other than nephrologists did so in low-GDP countries. Patients from low-GDP countries reported later information provision, less information about other modalities than CHD and lower satisfaction with information. The majority of modality decisions were made involving both patient and nephrologist. Patients reported subjective (e.g. quality of life and fears) and objective reasons (e.g. costs and availability of treatments) for modality choice. Patients had good experiences with all modalities, but experiences were better for HHD and kidney transplantation and in middle- and high-GDP countries. CONCLUSION: Our results suggest European differences in patient-reported factors influencing KRT modality choice, possibly caused by disparities in availability of KRT modalities, different healthcare systems and varying patient preferences. Availability of home dialysis and kidney transplantation should be optimized.

EDTAKI: a Nephrology and Public Policy Committee platform call for more European involvement in acute kidney injury.

BACKGROUND: Acute kidney injury (AKI) is an often neglected but crucial element of clinical nephrology. The aim of the Nephrology and Public Policy Committee (NPPC) of the European Renal Association-European Dialysis and Transplant Association is to promote several key aspects of European nephrology. One of the targets proposed by the NPPC was to advance European nephrology involvement in AKI. METHODS: We undertook a literature analysis to define the current position of European nephrology in the field of AKI compared with other regions and to determine how different European countries compare with each other. RESULTS: It appeared that vis-à-vis countries with a comparable socio-economic status (the USA, Australia, New Zealand and Canada), the European contribution was almost 50% less. Within Europe, Central and Eastern Europe and countries with a lower gross domestic product showed lower scientific output. Nephrologists contributed to less than half of the output. There was no trend of a change over the last decade. CONCLUSIONS: There is room to improve the contribution of European nephrology in the field of AKI. We propose a model on how to promote clinical collaboration on AKI across Europe and the creation of a pan-European nephrology network of interested units to improve clinical outcomes, increase nephrologist involvement and awareness outside nephrology and stimulate research on AKI in Europe. Accordingly, we also propose a list of research priorities and stress the need for more European funding of AKI research.

Kidney transplantation during mass disasters - from COVID-19 to other catastrophes A Consensus Statement by the DESCARTES Working Group and Ethics Committee of the ERA.

Mass disasters are characterized by a disparity between health care demand and supply, which hampers complex therapies like kidney transplantation. Considering scarcity of publications on previous disasters, we reviewed transplantation practice during the recent COVID-19 pandemic, and dwelled upon this experience for guiding transplantation strategies in the future pandemic and non-pandemic catastrophes. We strongly suggest continuing transplantation programs during mass disasters, if medical and logistic operational circumstances are appropriate. Postponing transplantations from living donors and referral of urgent cases to safe regions or hospitals are justified. Specific preventative measures in anticipated disasters (such as vaccination programs during pandemics or evacuation in case of hurricanes or wars) may be useful to minimize risks. Immunosuppressive therapies should consider stratifying risk status and avoiding heavy immune suppression in patients with a low probability of therapeutic success. Discharging patients at the earliest convenience is justified during pandemics, whereas delaying discharge is reasonable in other disasters, if infrastructural damage results in unhygienic living environments for the patients. In the outpatient setting, telemedicine is a useful approach to reduce the patient load to hospitals, to minimize the risk of nosocomial transmission in pandemics and the need for transport in destructive disasters. If it comes down to save as many lives as possible, some ethical principles may vary in function of disaster circumstances, but elementary ethical rules are non-negotiable. Patient education is essential to minimize disaster-related complications and to allow for an efficient use of health care resources.

Kidney transplantation during mass disasters - from COVID-19 to other catastrophes.

Mass disasters are characterized by a disparity between health care demand and supply, which hampers complex therapies like kidney transplantation. Considering scarcity of publications on previous disasters, we reviewed transplantation practice during the recent COVID-19 pandemic, and dwelled upon this experience for guiding transplantation strategies in the future pandemic and non-pandemic catastrophes. We strongly suggest continuing transplantation programs during mass disasters, if medical and logistic operational circumstances are appropriate. Postponing transplantations from living donors and referral of urgent cases to safe regions or hospitals are justified. Specific preventative measures in anticipated disasters (such as vaccination programs during pandemics or evacuation in case of hurricanes or wars) may be useful to minimize risks. Immunosuppressive therapies should consider stratifying risk status and avoiding heavy immune suppression in patients with a low probability of therapeutic success. Discharging patients at the earliest convenience is justified during pandemics, whereas delaying discharge is reasonable in other disasters, if infrastructural damage results in unhygienic living environments for the patients. In the outpatient setting, telemedicine is a useful approach to reduce the patient load to hospitals, to minimize the risk of nosocomial transmission in pandemics and the need for transport in destructive disasters. If it comes down to save as many lives as possible, some ethical principles may vary in function of disaster circumstances, but elementary ethical rules are non-negotiable. Patient education is essential to minimize disaster-related complications and to allow for an efficient use of health care resources.

Study protocol for Vascular Access outcome measure for function: a vaLidation study In hemoDialysis (VALID) : A multi-center, multinational validation study to assess the accuracy and feasibility of measuring vascular access function in clinical practice.

BACKGROUND: A functioning vascular access (VA) is crucial to providing adequate hemodialysis (HD) and considered a critically important outcome by patients and healthcare professionals. A validated, patient-important outcome measure for VA function that can be easily measured in research and practice to harvest reliable and relevant evidence for informing patient-centered HD care is lacking. Vascular Access outcome measure for function: a vaLidation study In hemoDialysis (VALID) aims to assess the accuracy and feasibility of measuring a core outcome for VA function established by the international Standardized Outcomes in Nephrology (SONG) initiative. METHODS: VALID is a prospective, multi-center, multinational validation study that will assess the accuracy and feasibility of measuring VA function, defined as the need for interventions to enable and maintain the use of a VA for HD. The primary objective is to determine whether VA function can be measured accurately by clinical staff as part of routine clinical practice (Assessor 1) compared to the reference standard of documented VA procedures collected by a VA expert (Assessor 2) during a 6-month follow-up period. Secondary outcomes include feasibility and acceptability of measuring VA function and the time to, rate of, and type of VA interventions. An estimated 612 participants will be recruited from approximately 10 dialysis units of different size, type (home-, in-center and satellite), governance (private versus public), and location (rural versus urban) across Australia, Canada, Europe, and Malaysia. Validity will be measured by the sensitivity and specificity of the data acquisition process. The sensitivity corresponds to the proportion of correctly identified interventions by Assessor 1, among the interventions identified by Assessor 2 (reference standard). The feasibility of measuring VA function will be assessed by the average data collection time, data completeness, feasibility questionnaires and semi-structured interviews on key feasibility aspects with the assessors. DISCUSSION: Accuracy, acceptability, and feasibility of measuring VA function as part of routine clinical practice are required to facilitate global implementation of this core outcome across all HD trials. Global use of a standardized, patient-centered outcome measure for VA function in HD research will enhance the consistency and relevance of trial evidence to guide patient-centered care. TRIAL REGISTRATION: Clinicaltrials.gov: NCT03969225. Registered on 31st May 2019.

Supplemented ERA-EDTA Registry data evaluated the frequency of dialysis, kidney transplantation, and comprehensive conservative management for patients with kidney failure in Europe.

The aims of this study were to determine the frequency of dialysis and kidney transplantation and to estimate the regularity of comprehensive conservative management (CCM) for patients with kidney failure in Europe. This study uses data from the ERA-EDTA Registry. Additionally, our study included supplemental data from Armenia, Germany, Hungary, Ireland, Kosovo, Luxembourg, Malta, Moldova, Montenegro, Slovenia and additional data from Israel, Italy, Slovakia using other information sources. Through an online survey, responding nephrologists estimated the frequency of CCM (i.e. planned holistic care instead of kidney replacement therapy) in 33 countries. In 2016, the overall incidence of replacement therapy for kidney failure was 132 per million population (pmp), varying from 29 (Ukraine) to 251 pmp (Greece). On 31 December 2016, the overall prevalence of kidney replacement therapy was 985 pmp, ranging from 188 (Ukraine) to 1906 pmp (Portugal). The prevalence of peritoneal dialysis (114 pmp) and home hemodialysis (28 pmp) was highest in Cyprus and Denmark respectively. The kidney transplantation rate was nearly zero in some countries and highest in Spain (64 pmp). In 28 countries with five or more responding nephrologists, the median percentage of candidates for kidney replacement therapy who were offered CCM in 2018 varied between none (Slovakia and Slovenia) and 20% (Finland) whereas the median prevalence of CCM varied between none (Slovenia) and 15% (Hungary). Thus, the substantial differences across Europe in the frequency of kidney replacement therapy and CCM indicate the need for improvement in access to various treatment options for patients with kidney failure.

Free p-cresyl sulfate shows the highest association with cardiovascular outcome in chronic kidney disease.

BACKGROUND: Several protein-bound uraemic toxins (PBUTs) have been associated with cardiovascular (CV) and all-cause mortality in chronic kidney disease (CKD) but the degree to which this is the case per individual PBUT and the pathophysiological mechanism have only partially been unraveled. METHODS: We compared the prognostic value of both total and free concentrations of five PBUTs [p-cresyl sulfate (pCS), p-cresyl glucuronide, indoxyl sulfate, indole acetic acid and hippuric acid] in a cohort of 523 patients with non-dialysis CKD Stages G1-G5. Patients were followed prospectively for the occurrence of a fatal or non-fatal CV event as the primary endpoint and a number of other major complications as secondary endpoints. In addition, association with and the prognostic value of nine markers of endothelial activation/damage was compared. RESULTS: After a median follow-up of 5.5 years, 149 patients developed the primary endpoint. In multivariate Cox regression models adjusted for age, sex, systolic blood pressure, diabetes mellitus and estimated glomerular filtration rate, and corrected for multiple testing, only free pCS was associated with the primary endpoint {hazard ratio [HR]1.39 [95% confidence interval (CI) 1.14-1.71]; P = 0.0014}. Free pCS also correlated with a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (r = -0.114, P < 0.05), angiopoietin-2 (ANGPT2) (r = 0.194, P < 0.001), matrix metallopeptidase 7 (MMP-7; (r = 0.238, P < 0.001) and syndecan 1 (r = 0.235, P < 0.001). Of these markers of endothelial activation/damage, ANGPT2 [HR 1.46 (95% CI 1.25-1.70); P < 0.0001] and MMP-7 [HR 1.31 (95% CI 1.08-1.59); P = 0.0056] were also predictive of the primary outcome. CONCLUSIONS: Among PBUTs, free pCS shows the highest association with CV outcome in non-dialysed patients with CKD. Two markers of endothelial activation/damage that were significantly correlated with free pCS, ANGPT2 and MMP-7 were also associated with CV outcome. The hypothesis that free pCS exerts its CV toxic effects by an adverse effect on endothelial function deserves further exploration.