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Importance: More than 3.5 million people worldwide and 540 000 individuals in the US receive maintenance hemodialysis or peritoneal dialysis for the treatment of chronic kidney failure. The 5-year survival rate is approximately 40% after initiation of maintenance dialysis., Observations: Hemodialysis and peritoneal dialysis remove metabolic waste and excess body water and rebalance electrolytes to sustain life. There is no recommended estimated glomerular filtration rate (eGFR) threshold for initiating dialysis, and patient-clinician shared decision-making should help determine when to initiate dialysis. Persistent signs and symptoms of uremia (eg, nausea, fatigue) and volume overload (eg, dyspnea, peripheral edema), worsening eGFR, metabolic acidosis, and hyperkalemia inform the timing of therapy initiation. A randomized clinical trial reported no mortality benefit to starting dialysis at higher eGFR (10-14 mL/min/1.73 m2) vs lower eGFR (5-7 mL/min/1.73 m2) levels. Observational data suggested no differences in 5-year mortality with use of hemodialysis vs peritoneal dialysis. Cardiovascular (eg, arrhythmias, cardiac arrest) and infection-related complications of maintenance dialysis are common. In the US, hemodialysis catheter-related bloodstream infections occur at a rate of 1.1 to 5.5 episodes per 1000 catheter-days and affect approximately 50% of patients within 6 months of catheter placement. Peritonitis occurs at a rate of 0.26 episodes per patient-year and affects about 30% of individuals in the first year of peritoneal dialysis therapy. Chronic kidney failure-related systemic complications, such as anemia, hyperphosphatemia, hypocalcemia, and hypertension, often require pharmacologic treatment. Hypotension during dialysis, refractory symptoms (eg, muscle cramps, itching), and malfunction of dialysis access can interfere with delivery of dialysis., Conclusions and Relevance: In 2021, more than 540 000 patients in the US received maintenance hemodialysis or peritoneal dialysis for treatment of chronic kidney failure. Five-year survival rate after initiation of maintenance dialysis is approximately 40%, and the mortality rate is similar with hemodialysis and peritoneal dialysis. Decisions about dialysis initiation timing and modality are influenced by patient symptoms, laboratory trajectories, patient preferences, and therapy cost and availability and should include shared decision-making.

Background: Consultation-liaison (CL) psychiatrists are frequently asked to consult on various abnormal movements (1). CL psychiatrists can be instrumental in aiding the primary teams to identify and manage these movement disorders. In this manuscript, we provide an illustrative case of a patient presenting with myoclonus and offer a review on this important topic. Myoclonus accompanied by delirium represents a rare post-transplant complication and can be associated with heightened morbidity and mortality. The incidence of this complication in solid organ transplant recipients is scarcely documented, and its pathophysiology remains inadequately understood. Potential etiologies in the intensive care unit are numerous and likely multifactorial. The literature lacks detailed descriptions of the correlation and association between myoclonus and uremia. Management of this condition requires a multimodal approach, focusing on resolving underlying metabolic disturbances and providing symptomatic treatment., Objective: This manuscript describes the clinical presentation of myoclonus in a liver transplant recipient accompanied by delirium and precipitated by uremia. We aim to highlight the diagnostic and therapeutic complexities, help providers distinguish myoclonus from other movement disorders, and aid appropriate management., Methods and Results: We present a case of acute myoclonus in an elderly female liver transplant recipient precipitated by uremia and improved after continuous renal replacement treatment. In addition, we conducted a systematic review utilizing EMBASSE and PubMed of reported cases of myoclonus, delirium, and/or encephalopathy accompanied by uremia. We included 12 manuscripts in our review and discussed their findings., Conclusions: CL psychiatrists are frequently consulted for a range of movement disorders in the intensive care unit, including myoclonus. Accurate diagnosis and identification of contributing etiologies are critical in these cases. Management typically involves addressing the underlying disorder, such as using dialysis for uremia, alongside symptomatic treatment with benzodiazepines to mitigate the frequency and amplitude of myoclonus. This approach helps to alleviate both the physical burden and psychological distress associated with the condition. This case underscores the pivotal role of the CL psychiatrist within a complex multidisciplinary team, contributing to diagnostic precision and optimization of management strategies for movement disorders., (Copyright © 2024 Academy of Consultation-Liaison Psychiatry. Published by Elsevier Inc. All rights reserved.)

Uremic pruritus, a severe complication in patients with chronic kidney disease, is associated with a high prevalence. It can cause depression and sleep disorders, and seriously affect the quality of life and the social relations of patients. Recently, there is growing evidence showing that κ-opioid receptor agonists, including nalfurafine, difelikefalin, and nalbuphine, can effectively and safely reduce itching symptoms in patients with refractory uremic pruritus. Herein, we reviewed the epidemiology, pathogenesis, clinical symptoms, and treatment strategies of uremic pruritus, and summarized in detail the progress in clinical research on the use of κ-opioid receptor agonists, including nalfurafine, difelikefalin, and nalbuphine, in the management of patients with uremic pruritus., Competing Interests: 利益冲突　所有作者均声明不存在利益冲突, (© 2024《四川大学学报（医学版）》编辑部 版权所有Copyright ©2024 Editorial Office of Journal of Sichuan University (Medical Sciences).)

Aims: This retrospective cohort study aimed to be the first to evaluate the association between plasma protein-bound uremic toxins (PBUTs) concentrations, echocardiographic parameters of heart failure (HF), and incident HF events in patients with chronic kidney disease (CKD) not on dialysis., Methods and Results: Retrospective, single-centre, cohort study at the Ghent University Hospital, Belgium. Adults with CKD stages G1-G5, not on dialysis, could be included. Exclusion criteria were ongoing pregnancy, age <18 years, active acute infection, active malignancy, history of transplantation, or a cardiovascular event within 3 months prior to inclusion. Free and total concentrations of five PBUTs were quantified at baseline: indoxyl sulfate (IxS), p-cresyl sulfate (pCS), p-cresyl glucuronide (pCG), indole-3 acetic acid (IAA), and hippuric acid (HA). Patients were grouped into three echocardiographic categories: normal left ventricular ejection fraction (LVEF) and normal left ventricular end-diastolic pressure (LVEDP), normal LVEF and increased LVEDP, and reduced LVEF, based on available echocardiographic data in a time interval of ±6 months around the plasma sample collection. A total of 523 patients were included between January 2011 and January 2014. Echocardiographic data within the predefined timeframe were available for 210 patients (40% of patients). Levels of pCG and pCS were significantly higher in patients with reduced (<50%) versus normal LVEF (P < 0.05). After a median follow-up 5.5 years, 43 (8.4%) patients reached the composite endpoint of hospitalization or mortality due to HF. Free fractions of IxS, pCS, and pCG showed the strongest association with clinical outcome: free IxS: HR 1.71 (95% CI 1.11-2.63; P = 0.015), free pCS: HR 1.82 (95% CI 1.11-3.01; P = 0.019), and free pCG: HR 1.67 (95% CI 1.08-2.58; P = 0.020), and these results were independent of age, gender, body mass index, diabetes, and systolic blood pressure. In models that were also adjusted for serum creatinine, the free fractions of these PBUTs remained significant., Conclusions: Elevated free concentrations of IxS, pCG, and pCS were independently associated with an increased risk of HF events in non-dialysed CKD patients. Further research is necessary to confirm these findings and investigate the potential impact of PBUT-lowering interventions on HF events in this patient group., (© 2023 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Introduction: Pruritus has been shown to be a common and burdensome complaint in the general population. In some diseases, there is an even higher rate and intensity of pruritus such as in chronic kidney diseases. In particular, patients requiring dialysis commonly suffer from pruritus with proportions between 22.0 and 90.0%. Few data on the characteristics and burden of such pruritus have been published. Therefore, the aim of this study was to investigate the extent and profiles of pruritus in such patients related to skin lesions and care., Methods: A non-interventional cross-sectional study in 14 centres for haemodialysis across Germany was conducted. The survey explored the prevalence, severity, and resulting burden of pruritus and skin lesions., Results: In total, 302 patients with uraemia (56.5% male, mean age 66.0 ± 14.4 years, mean duration of dialysis 3.9 ± 4.8 years) were included. Skin lesions appeared since start of dialysis in 50.0% of patients, with xerosis (94.7%) and desquamation (25.8%) being the most frequent and disturbing findings. Pruritus was reported by 60.9% of patients undergoing dialysis with a current mean numerical rating scale of 5.1 ± 2.4 occurring most frequently in the back, legs, and arms. About 89.0% of patients with xerosis and 69.0% with desquamation reported self-medication. However, only 40.0% and 28.0% sought medical help, respectively, indicating a remarkable lack of healthcare., Discussion: The current data suggest a more intensive focus on the skin symptoms and signs related to uraemia in the patients with dialysis and thus underline claims from a previous German large-scale study. Recommendations for early treatment and prevention of skin lesions in dialysis patients should be developed. Further research should be conducted focusing on recognizing subgroups of patients of particular vulnerability to pruritus and skin lesions, which may facilitate identifying patients at risk in an early moment. Moreover, a more specific tool for screening of skin lesions as well as pruritus may be useful since the existing instruments lack such specificity., (© 2021 S. Karger AG, Basel.)

Chitinase-3-like protein 1 (CHI3L1) has been introduced as a marker of inflammation in different diseases, which can promote cell proliferation and differentiation. It has also been demonstrated that elevated serum CHI3L1 concentration can independently predict all-cause mortality in uremic patients. However, the impact of CHI3L1 on the early failure of autologous arteriovenous fistulas (AVFs) in uremic patients remains unknown. We conducted a prospective observational cohort study of 109 uremic patients (mean age 53.2 ± 14.7 years, 67.9% males), who received forearm AVF surgery, and were consecutively enrolled with a median follow-up time of 15 months. The early failure was defined as a fistula that never developed adequately for dialysis or that failed within the first 3 months of use. Serum CHI3L1 concentration was determined by the ELISA method. Among 109 uremic patients, 24 patients had AVF failure. The optimal cutoff value based on the receiver operating characteristics analysis of CHI3L1 was 122.6 ng/mL, with the area under the curve of 0.73 (P = 0.001). The Kaplan-Meier survival analysis demonstrated that patients with CHI3L1 < 122.6 ng/mL had better AVF patency than patients with CHI3L1 ≥ 122.6 ng/mL (Log-rank test, P = 0.001). Multivariable Cox proportional hazards regression analysis showed that baseline CHI3L1 level (≥ 122.6 ng/mL vs. < 122.6 ng/mL) was significantly associated with AVF failure after adjustment for confounders (adjusted hazard ratio [HR], 3.67; 95% CI, 1.44-9.36). The study demonstrated that Increased baseline serum level of CHI3L1 is independently associated with higher risk of the early failure of forearm AVFs., (© 2021 International Society for Apheresis, Japanese Society for Apheresis, and Japanese Society for Dialysis Therapy.)

Abstract: Systemic chronic microinflammation and altered cytokine signaling, with adjunct cardiovascular disease (CVD), endothelial maladaptation and dysfunction is common in dialysis patients suffering from end-stage renal disease and associated with increased morbidity and mortality. New hemodialysis filters might offer improvements. We here studied the impact of novel improved molecular cut-off hemodialysis filters on systemic microinflammation, uremia and endothelial dysfunction. Human endothelial cells (ECs) were incubated with uremic serum obtained from patients treated with two different hemodialysis regimens in the Permeability Enhancement to Reduce Chronic Inflammation (PERCI-II) crossover clinical trial, comparing High-Flux (HF) and Medium Cut-Off (MCO) membranes, and then assessed for their vascular endothelial growth factor (VEGF) production and angiogenesis. Compared to HF membranes, dialysis with MCO membranes lead to a reduction in proinflammatory mediators and reduced endothelial VEGF production and angiogenesis. Cytokine multiplex screening identified tumor necrosis factor (TNF) superfamily members as promising targets. The influence of TNF-α and its soluble receptors (sTNF-R1 and sTNF-R2) on endothelial VEGF promoter activation, protein release, and the involved signaling pathways was analyzed, revealing that this detrimental signaling was indeed induced by TNF-α and mediated by AP-1/c-FOS signaling. In conclusion, uremic toxins, in particular TNF-signaling, promote endothelial maladaptation, VEGF expression and aberrant angiogenesis, which can be positively modulated by dialysis with novel MCO membranes., Translational Perspective and Graphical Abstract: Systemic microinflammation, altered cytokine signaling, cardiovascular disease, and endothelial maladaptation/dysfunction are common clinical complications in dialysis patients suffering from end-stage renal disease. We studied the impact of novel improved medium-cut-off hemodialysis filters on uremia and endothelial dysfunction. We can show that uremic toxins, especially TNF-signaling, promote endothelial maladaptation, VEGF expression and aberrant angiogenesis, which can be positively modulated by dialysis with novel improved medium-cut-off membranes., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Catar, Moll, Kamhieh-Milz, Luecht, Chen, Zhao, Ernst, Willy, Girndt, Fiedler, Witowski, Morawietz, Ringdén, Dragun, Eckardt, Schindler and Zickler.)

Cardiovascular disease (CVD) is the leading cause of death in patients with chronic kidney disease (CKD). Endothelial cell (EC) dysfunction is a key CKD-specific risk factor; however, the mechanisms by which uremia harms the endothelium are still unclear. We report a role for excessive neutrophil extracellular trap (NET) formation induced by uremic serum on EC injury. Level of plasma nucleosome and myeloperoxidase-DNA, established in vivo markers of NETs, as well as intracellular adhesion molecule (ICAM)-1 were measured in hemodialysis (HD) patients and healthy volunteers (HV) and their prognostic role evaluated. For in vitro studies, HV-derived neutrophils and differentiated HL-60 cells by retinoic acid were used to determine the effect of uremic serum-induced NETs on human umbilical vein EC (HUVEC). The level of in vivo NETs was significantly higher in incident HD patients compared to HV, and these markers were strongly associated with ICAM-1. Specifically, nucleosome and ICAM-1 levels were independent predictors of a composite endpoint, all-cause mortality, or vascular access failure. In vitro, HD-derived uremic serum significantly increased NET formation both in dHL-60 and isolated neutrophils compared to control serum, and these NETs decreased EC viability and induced their apoptosis. In addition, the level of ICAM-1, E-selectin and von Willebrand factor in HUVEC supernatant was significantly increased by uremic serum-induced NETs compared to control serum-induced NETs. Dysregulated neutrophil activities in the uremic milieu may play a key role in vascular inflammatory responses. The high mortality and CVD rates in ESRD may be explained in part by excessive NET formation leading to EC damage and dysfunction., (© 2021. The Author(s).)

Uremic cardiomyopathy is characterized by diastolic dysfunction (DD), left ventricular hypertrophy (LVH), and fibrosis. Angiotensin-II plays a major role in the development of uremic cardiomyopathy via nitro-oxidative and inflammatory mechanisms. In heart failure, the beta-3 adrenergic receptor (β3-AR) is up-regulated and coupled to endothelial nitric oxide synthase (eNOS)-mediated pathways, exerting antiremodeling effects. We aimed to compare the antiremodeling effects of the angiotensin-II receptor blocker losartan and the β3-AR agonist mirabegron in uremic cardiomyopathy. Chronic kidney disease (CKD) was induced by 5/6th nephrectomy in male Wistar rats. Five weeks later, rats were randomized into four groups: (1) sham-operated, (2) CKD, (3) losartan-treated (10 mg/kg/day) CKD, and (4) mirabegron-treated (10 mg/kg/day) CKD groups. At week 13, echocardiographic, histologic, laboratory, qRT-PCR, and Western blot measurements proved the development of uremic cardiomyopathy with DD, LVH, fibrosis, inflammation, and reduced eNOS levels, which were significantly ameliorated by losartan. However, mirabegron showed a tendency to decrease DD and fibrosis; but eNOS expression remained reduced. In uremic cardiomyopathy, β3-AR, sarcoplasmic reticulum ATPase (SERCA), and phospholamban levels did not change irrespective of treatments. Mirabegron reduced the angiotensin-II receptor 1 expression in uremic cardiomyopathy that might explain its mild antiremodeling effects despite the unchanged expression of the β3-AR., (© 2021. The Author(s).)

Background: Skin pruritus is a common complication in patients with uremia. When the hemodialysis time of patients is extended, and the probability of skin pruritus is greater. Patients often have the symptoms of skin pruritus intolerable, affecting the normal sleep and normal life of patients. The patients with uremic pruritus often constant scratching and pruritus skin, resulting in broken skin, and further symptoms such as infection, and subsequent skin shedding, prurigo nodularis, and other adverse complications, aggravating the patient's condition. Some patients will experience symptoms such as depression and insomnia due to skin pruritus, and simply scratching the skin lead to infection. Severely affected patients may even show suicidal tendency, endangering the physical and mental health of patients, and it is needed to give the effective treatment to patients. Hemodialysis is a common treatment for uremic pruritus, which can effectively relieve the pruritus symptoms of patients. The drugs can also relieve the symptoms and improve the degree of pruritus in patients. And some studies show that traditional Chinese medicine UCG combined with HFH in the treatment of uremic pruritus has a very good effect, Therefore, this study will systematically evaluate the clinical efficacy and safety of UCG combined with HFH and HFH alone in the treatment of uremic pruritus., Methods: Use computer to search English and Chinese databases, English databases include: PubMed, Web of Science, EMbase, The Cochrane Library. Chinese databases include: CNKI, CBM, WanFang Data and VIP databases, collecting the RCT on the clinical effectiveness and safety of UCG combined with HFH and HFH alone in the treatment of uremic pruritus. The retrieval time is from the beginning of each database to May 1, 2021. In order to improve the retrieval rate of the literature, the references cited in the included research are also collected and screened. Set Chinese and English as the search language. Two members of the research group independently collected, included and excluded the literatures. In case of disagreement, consulting the third party to assist in the judgment. For the literature with missing data, the original author should be contacted as far as possible to obtain complete data. Two evaluators evaluate the bias risk of included studies according to the Cochrane Handbook bias risk assessment tool for RCT. RevMan 5.3 software is used for statistical analysis and the forest plot is drawn to show the outcome indicators and funnel plot is drawn to show the publication bias., Results: This study evaluates the advantages and disadvantages of traditional Chinese medicine UCG combined with HFH and HFH alone in the treatment of uremic pruritus through the clinical effectiveness and safety-related indicators., Conclusion: This study will give a positive conclusion on the efficacy and safety of uremic clearance granule in the treatment of uremic pruritus, and the research results will be published in professional journals in the form of academic papers, thus benefiting more patients., Ethics and Dissemination: This study belongs to meta-analysis and all data comes from academic papers published publicly in formal academic journals, so there are no ethical issues involved in this study and no ethical review or approval is required., Osf Registration Number: DOI 10.17605/OSF.IO/W8P5G., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.)

The presence of toxins is believed to be a major factor in the development of uremia in patients with chronic kidney disease (CKD) and end-stage renal disease (ESRD). Uremic toxins have been divided into 3 groups: small substances dissolved in water, medium molecules: peptides and low molecular weight proteins, and protein-bound toxins. One of the earliest known toxins is urea, the concentration of which was considered negligible in CKD patients. However, subsequent studies have shown that it can lead to increased production of reactive oxygen species (ROS), and induce insulin resistance in vitro and in vivo, as well as cause carbamylation of proteins, peptides, and amino acids. Other uremic toxins and their participation in the damage caused by oxidative stress to biological material are also presented. Macromolecules and molecules modified as a result of carbamylation, oxidative stress, and their adducts with uremic toxins, may lead to cardiovascular diseases, and increased risk of mortality in patients with CKD.

Uremic toxins are suggested to be involved in the pathophysiology of hemodialysis (HD) patients. However, the profile of uremic solutes in HD patients has not been fully elucidated. In this study using capillary electrophoresis mass spectrometry (CE-MS), we comprehensively quantified the serum concentrations of 122 ionic solutes before and after HD in 11 patients. In addition, we compared the results with those in non-HD patients with chronic kidney disease (CKD) to identify HD patient-specific solutes. We identified 38 solutes whose concentrations were higher in pre-HD than in CKD stage G5. Ten solutes among them did not significantly accumulate in non-HD CKD patients, suggesting that these solutes accumulate specifically in HD patients. We also identified 23 solutes whose concentrations were lower in both pre- and post-HD than in CKD stage G5. The serum levels of 14 solutes among them were not affected by renal function in non-HD patients, suggesting that these solutes tend to be lost specifically in HD patients. Our data demonstrate that HD patients have a markedly different profile of serum uremic solute levels compared to that in non-HD CKD patients. The solutes identified in our study may contribute to the pathophysiology of HD patients.

The observation that unhealthy diets (those that are low in whole grains, fruits and vegetables, and high in sugar, salt, saturated fat and ultra-processed foods) are a major risk factor for poor health outcomes has boosted interest in the concept of 'food as medicine'. This concept is especially relevant to metabolic diseases, such as chronic kidney disease (CKD), in which dietary approaches are already used to ameliorate metabolic and nutritional complications. Increased awareness that toxic uraemic metabolites originate not only from intermediary metabolism but also from gut microbial metabolism, which is directly influenced by diet, has fuelled interest in the potential of 'food as medicine' approaches in CKD beyond the current strategies of protein, sodium and phosphate restriction. Bioactive nutrients can alter the composition and metabolism of the microbiota, act as modulators of transcription factors involved in inflammation and oxidative stress, mitigate mitochondrial dysfunction, act as senolytics and impact the epigenome by altering one-carbon metabolism. As gut dysbiosis, inflammation, oxidative stress, mitochondrial dysfunction, premature ageing and epigenetic changes are common features of CKD, these findings suggest that tailored, healthy diets that include bioactive nutrients as part of the foodome could potentially be used to prevent and treat CKD and its complications.

Background: Regional citrate anticoagulation has been recommended as first choice for anticoagulation of continuous renal replacement therapy. Precise calcium supplementation is important for the safety of regional citrate anticoagulation. In this study we aimed to provide an optimized calcium supplementation approach for regional citrate anticoagulation in post-dilution continuous venous-venous hemodiafiltration., Methods: Twenty-seven patients receiving post-dilution continuous venous-venous hemodiafiltration anticoagulated by citrate were included in this study. The ionized calcium levels were monitored and maintained in the targeted range. After linear regression analysis of the clearance of non-protein bound calcium and calculating the ratio of the non-protein bound calcium concentration to total calcium concentration, we concluded the mathematical model for calcium supplementation., Results: Positive correlations were found between the clearance of non-protein bound calcium and both dialysate flow rates (r = 0.647, p < 0.001) and ultrafiltration plus substitution fluid flow rates (r = 0.525, p = 0.005). The ratio of the non-protein bound calcium concentration to total calcium concentration values at the pre-filter point after infusion of citrate were constant about 0.83. Based on the clearance and the calcium ratio, the amount of extracorporeal calcium removal can be estimated with a simplified equation., Conclusions: We provided an optimized calcium supplementation approach for post-dilution continuous venous-venous hemodiafiltration anticoagulated by citrate which may help to estimate the amount of extracorporeal circuit removal of calcium with regard to different dosages of regional citrate anticoagulation.

Background: Healthcare institutions are confronted with large numbers of patient admissions during large-scale or long-term public health emergencies like pandemics. Appropriate and effective triage is needed for effective resource use., Objectives: To evaluate the effectiveness of the Pandemic Medical Early Warning Score (PMEWS), Simple Triage Scoring System (STSS) and Confusion, Uremia, Respiratory rate, Blood pressure and age ≥ 65 years (CURB-65) score in an emergency department (ED) triage setting., Design and Setting: Retrospective study in the ED of a tertiary-care university hospital in Düzce, Turkey., Methods: PMEWS, STSS and CURB-65 scores of patients diagnosed with COVID-19 pneumonia were calculated. Thirty-day mortality, intensive care unit (ICU) admission, mechanical ventilation (MV) need and outcomes were recorded. The predictive accuracy of the scores was assessed using receiver operating characteristic curve analysis., Results: One hundred patients with COVID-19 pneumonia were included. The 30-day mortality was 6%. PMEWS, STSS and CURB-65 showed high performance for predicting 30-day mortality (area under the curve: 0.968, 0.962 and 0.942, respectively). Age > 65 years, respiratory rate > 20/minute, oxygen saturation (SpO2) < 90% and ED length of stay > 4 hours showed associations with 30-day mortality (P < 0.05)., Conclusions: CURB-65, STSS and PMEWS scores are useful for predicting mortality, ICU admission and MV need among patients diagnosed with COVID-19 pneumonia. Advanced age, increased respiratory rate, low SpO2 and prolonged ED length of stay may increase mortality. Further studies are needed for developing the triage scoring systems, to ensure effective long-term use of healthcare service capacity during pandemics.

Ectopic calcification is a risk of cardiovascular disease in chronic kidney disease (CKD) patients, and impaired endothelial nitric oxide synthase (eNOS) is involved in the CKD complications. However, whether eNOS dysfunction is a cause of ectopic calcification in CKD remains to be elucidated. To address this issue, we investigated the role of eNOS in ectopic calcification in mice with renal injury caused by an adenine and high-phosphorus (Ade + HP) diet. DBA/2J mice, a calcification-sensitive strain, were fed Ade + HP for 3 weeks. Expression levels of eNOS-related genes were reduced significantly in their calcified aorta. C57BL/6J is a calcification-resistant strain, and wild-type mice showed mild calcified lesions in the aorta and kidney when given an Ade + HP diet for 4 weeks. In contrast, a lack of eNOS led to the development of severe aortic calcification accompanied by an increase in runt-related transcription factor 2, an osteochondrogenic marker. Increased renal calcium deposition and the tubular injury score were remarkable in mice lacking eNOS-fed Ade + HP. Exacerbation of ectopic calcification by a lack of eNOS is associated with increased oxidative stress markers such as nicotinamide adenine dinucleotide phosphate oxidases. In conclusion, eNOS is critically important in preventing ectopic calcification. Therefore, the maintenance of eNOS is useful to reduce cardiovascular disease events and to improve prognosis in CKD patients., (Copyright © 2021 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Aim: The present study aimed to investigate the value of calcium-mediated parathyroid hormone (PTH) suppression test in evaluating the autonomic secretory function of parathyroid, and the management of uraemic secondary hyperparathyroidism (SHPT)., Methods: Calcium-mediated PTH suppression test was performed in dialysis with SHPT, who were candidates for parathyroidectomy from June 2017 to December 2019 in our hospital. The PTH inhibition rate (PTH-IR) was calculated, and the correlation between PTH-IR and clinical indicators was explored., Results: Fifty-one subjects were included. PTH-IR was negatively correlated with baseline PTH (r = -0.35, P = .012), it was also correlated with dialysis years, coronary artery calcification score (CACS) and parathyroid mass (r = -0.397, P = .004; r = -0.327, P = .028; r = -0.363, P = .015), which were not found for baseline PTH. Forty-four patients underwent surgical treatment. According to the histological results, 26 patients presented with parathyroid non-nodular hyperplasia, and 18 patients presented with parathyroid nodular hyperplasia. The mass of parathyroid of patients with nodular hyperplasia was higher than that of patients with non-nodular hyperplasia (ρ = 0.01). The difference of the PTH-IR was not found between the two groups (ρ = 0.296). During the test, the highest serum calcium was 2.9 ± 0.4 mmol/L, which dropped to normal at the end of the test., Conclusion: Parathyroid hormone inhibition rate might be a useful indicator in evaluating the autonomic secretory function of parathyroid and the progression of SHPT on top of intact PTH. Calcium-mediated PTH suppression test was safe in uraemic SHPT patients, but need to monitor for transient hypercalcaemia., (© 2020 Asian Pacific Society of Nephrology.)

Background: Uremic pruritus (UP) is a common and frustrating symptom in patients receiving hemodialysis (HD). The majority of patients have mild to moderate itching of the skin, and a small percentage have severe itching, which seriously affects their quality of life and survival rate. However, little is known about factors that influence the intensity of itching in patients., Methods: A cross-sectional study on uremic pruritus in male and female patients receiving HD was conducted in September 2019. This study included 148 eligible patients who received HD at the Blood Purification Center of Xinchang County People's Hospital, Zhejiang Province, China from March 2019 to June 2019. We collected general data consisted of age, sex, body mass index (BMI), place of residence, educational level, diabetes mellitus status and duration of HD; as well as clinical, biochemical indicators, including serum calcium (Ca), serum phosphorus (P), serum albumin (ALB), haemoglobin (Hb), serum intact parathyroid hormone (iPTH), pre-dialysis serum urea nitrogen (BUN), normalized protein catabolic rate (nPCR), urea nitrogen clearance index (KT/V), ferritin (FER) and pre-dialysis serum creatinine (sCR). We also assayed the inflammatory cytokine serum high sensitivity C-reactive protein (hs-CRP). The Five-Dimensional Itching Scale (5DIS) was used to evaluate the degree of skin itching (none, mild, moderate, or severe). We used multiple logistic regression to analyze influencing factors on the degree of skin itching in patients with UP., Results: Of the 148 patients, 60 had uremic pruritus (incidence rate, 40.54%). These included 22 cases of mild skin itching (14.86%), 30 of moderate skin itching (20.27%), and 8 of severe skin itching (5.41%). Compared with uremia patients without skin pruritus, patients with UP had higher levels of iPTH, Hb, BUN, nPCR, and hs-CRP. The composition ratio showed significant differences between urban and rural patients with different degrees of skin itching (P = 0.017); moreover, the difference of iPTH and hs-CRP levels were statistically significant (P = 0.009 and < 0.001, respectively). Using no itching as a reference, multiple logistic regression analysis showed that as hs-CRP level increased, the patient's risks of mild skin itching (odds ratio [OR] = 1.740; 95% confidence interval [CI], 1.061-2.854; P = 0.028), moderate skin itching (OR = 2.8838 95% CI, 1.744-4.718; P < 0.001), and severe skin itching (OR = 9.440; 95% CI, 3.547-25.124; P < 0.001) all increased as well. Compared with urban residents, rural residents have a higher risk of moderate itching (OR = 3.869; 95% CI, 1.099-13.622; P = 0.035)., Conclusion: Levels of hs-CRP were associated with the intensity of skin itching in patients with UP. Higher hs-CRP levels were closely related to severe skin itching. The relationship between the intensity of skin itching and the environment in maintenance hemodialysis patients needs further clarification., Competing Interests: The authors have declared that no competing interests exist.

Purpose of Review: Gut dysbiosis has been implicated in the pathogenesis of chronic kidney disease (CKD). Interventions aimed at restoring gut microbiota have emerged as a potential therapeutic option in CKD. This review summarizes the current evidence on gut microbiota-targeted strategies in patients with CKD., Recent Findings: A growing number of studies have shown that plant-based diets, low-protein diets, prebiotic, probiotic, and synbiotic supplementation, and constipation treatment may lead to favorable alterations in the gut microbiota. Current evidence suggests that the implementation of both plant-based and low-protein diets has potential benefits for the primary prevention of CKD, and for slowing CKD progression, with minimal risk of hyperkalemia and/or cachexia. The use of prebiotics, probiotics, and synbiotics and laxatives may have beneficial effects on uremic toxin generation, but their evidence is limited for the prevention and treatment of CKD. Recent advances in diagnostic technologies (e.g., high-throughput sequencing and nanotechnology) could enhance rapid diagnosis, monitoring, and design of effective therapeutic strategies for mitigating gut dysbiosis in CKD., Summary: Plant-based and low-protein diets, prebiotic, probiotic, and synbiotic supplementation, and constipation treatment represent novel gut microbiota-targeted strategies in the conservative management of CKD, which could improve clinical outcomes in CKD.

Chronic kidney disease (CKD) patients obtained high levels of uremic toxins progressively develop several complications including bone fractures. Protein-bound uremic toxins especially p-cresol and indoxyl sulfate are hardly eliminated due to their high molecular weight. Thus, the abnormality of bone in CKD patient could be potentially resulted from the accumulation of uremic toxins. To determine whether protein-bound uremic toxins have an impact on osteogenesis, mesenchymal stem cells were treated with either p-cresol or indoxyl sulfate under in vitro osteogenic differentiation. The effects of uremic toxins on MSC-osteoblastic differentiation were investigated by evaluation of bone phenotype. The results demonstrated that p-cresol and indoxyl sulfate down-regulated the transcriptional level of collagen type I, deceased alkaline phosphatase activity, and impaired mineralization of MSC-osteoblastic cells. Furthermore, p-cresol and indoxyl sulfate gradually increased senescence-associated beta-galactosidase positive cells while upregulated the expression of p21 which participate in senescent process. Our findings clearly revealed that the presence of uremic toxins dose-dependently influenced a gradual deterioration of osteogenesis. The effects partially mediate through the activation of senescence-associated gene lead to the impairment of osteogenesis. Therefore, the management of cellular senescence triggered by uremic toxins could be considered as an alternative therapeutic approach to prevent bone abnormality in CKD patients., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Competing Interests: Competing interests: None declared.

Hemodialysis (HD) majorly represents the global treatment option for patients with chronic kidney disease stage 5, and, despite advances in dialysis technology, these patients face a high risk of morbidity and mortality from malnutrition. We aimed to provide a novel view that malnutrition susceptibility in the global HD community is either or both of iatrogenic and of non-iatrogenic origins. This categorization of malnutrition origin clearly describes the role of each factor in contributing to malnutrition. Low dialysis adequacy resulting in uremia and metabolic acidosis and dialysis membranes and techniques, which incur greater amino-acid losses, are identified modifiable iatrogenic factors of malnutrition. Dietary inadequacy as per suboptimal energy and protein intakes due to poor appetite status, low diet quality, high diet monotony index, and/or psychosocial and financial barriers are modifiable non-iatrogenic factors implicated in malnutrition in these patients. These factors should be included in a comprehensive nutritional assessment for malnutrition risk. Leveraging the point of origin of malnutrition in dialysis patients is crucial for healthcare practitioners to enable personalized patient care, as well as determine country-specific malnutrition treatment strategies., Competing Interests: The authors declare no conflicts of interest.

A simple, rapid, reliable and sensitive ultra-high performance liquid chromatography tandem spectrometry (UHPLC-MS/MS) method was established for determination of eight serum protein-bound uremic toxins (hippuric acid, indoxyl sulfate, indole-3-acetic acid, kynurenic acid, L-kynurenine, melatonin, 3-carboxy-4-methyl-5-propyl-2-furanpropionic acid, 4-hydroxyhippuric acid) in serum from chronic kidney disease (CKD) dialysis patients. The chromatographic separation was achieved on an Atlantis T3 column (3 μm, 2.1 mm × 100 mm) using a gradient elution with acetonitrile (phase B) and 0.1% formic acid and 10 mmol/L ammonium acetate aqueous solution (phase A). The flow rate was 0.3 mL/min with analytical time of 5 min. The pretreatment procedure was developed with a simple protein precipitation and the hydrochlorothiazide was used as internal standard. The calibration ranges were set as 156.250-20000.000 ng/mL for indoxyl sulfate, hippuric acid, 3-carboxy-4-methyl-5-propyl-2-furanpropionic acid; 78.125-10000.000 ng/mL for L-kynurenine, indole-3-acetic acid and 4-hydroxyhippuricacid; 1.562-200.000 ng/mL for kynurenic acid; 0.078-10.000 ng/mL for melatonin. The UHPLC-MS/MS method for quantification of eight protein-bound uremic toxins was successfully developed and validated, and its clinical practicability was assessed on 81 serum samples from CKD patients., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Objectives: To assess whether salivary urea and creatinine levels accurately reflect their serum levels in blood samples of adults to detect chronic kidney disease., Materials and Methods: A systematic review was conducted in eight electronic databases. The protocol was registered in PROSPERO. Only diagnostic test studies were included. The JBI critical appraisal tools assessed the risk of bias. A meta-analysis of proportions was performed. The GRADE tool assessed the quality of evidence and strength of recommendation across the studies included., Results: Eight studies met the eligibility criteria and were included. Six studies assessed salivary urea, and six studies assessed salivary creatinine. All studies presented moderate risk of bias. The meta-analysis depicted an overall sensitivity of 93.3% (95% CI = 88.6; 97.9) for salivary creatinine levels and 87.5% (95% CI = 83.2; 91.8) for salivary urea levels, while the overall specificity was 87.1% (95% CI = 82.8; 91.3) and 83.2% (95% CI = 65.0; 101.4) for salivary creatinine and urea levels, respectively. The overall accuracy of salivary creatinine was 5.2 percentage points higher compared with salivary urea levels (90.8% vs. 85.6%). According to the GRADE tool, the analysed outcomes were classified as having low to moderate level of certainty., Conclusion: Compared with blood samples, salivary urea and creatinine levels presented high diagnostic values for chronic kidney disease screening, but should not be considered equivalent to levels obtained from blood at stages three, four, or five of the disease., Clinical Significance: Chronic kidney disease patients could receive a clinically significant benefit from replacing blood with saliva for potentially monitoring renal function. Saliva collection presents greater simplicity, comfort, safety, and lower collection cost.

Objectives: Information on sleep quality and its effective factors in the patients undergoing hemodialysis are important factors in future planning for improving sleep quality and ultimately the quality of life in these patients. The present study investigated the effect of omega-3 on the sleep quality of hemodialysis patients., Methods: The 52 hemodialysis patients were randomized into two groups and underwent two different treatment modes (A and B). The first group was given omega-3 and cetirizine and the second group only received cetirizine for six weeks. After one week wash out, the study was followed by crossover treatment in both groups for six weeks. Sleep quality and pruritus severity were evaluated in patients before the intervention and at the end of each treatment period using the Pittsburgh Sleep Quality Index and the Yosipovitch Itch Questionnaire. The collected data was analyzed using repeated measures ANOVA and the Pearson correlation coefficient., Results: The results of the study showed that majority of the patients (94.2%) had poor sleep quality (sleep score > 5 based on the questionnaire) and 5.8% of the patients had favorable sleep quality (sleep score < 5). Repeated measures ANOVA showed that sleep quality scores were different in two groups in phases 0, I and II (p <0.001)., Conclusions: Sleep quality improved in both modes but more improvement was observed in mode A. Therefore, omega-3 fatty acids can be used as a suitable method for improving sleep quality in hemodialysis patients., (© 2020 Walter de Gruyter GmbH, Berlin/Boston.)

Caloric restriction (CR) is known to have multiple beneficial effects on health and longevity. To study the effect of CR on phosphorus metabolism and vascular calcification (VC), rats were fed normal or restricted calories (67% of normal). The phosphorus content of the diets was adjusted to provide equal phosphorus intake independent of the calories ingested. After 50 days of CR, rats had negative phosphorus balance, lower plasma phosphorus, glucose, triglycerides, and leptin, and higher adiponectin than rats fed normal calories. Uremia was induced by 5/6 nephrectomy (Nx). After Nx, rats were treated with calcitriol (80 ng/kg ip every other day) and high-phosphorus diets (1.2% and 1.8%). No differences in aortic calcium content were observed between rats that ate normal or restricted calories before Nx in either rats that received 1.2% phosphorus (11.5 ± 1.7 vs. 10.9 ± 2.1 mg/g tissue) or in rats that received 1.8% phosphorus (12.5 ± 2.3 vs. 12.0 ± 2.9 mg/g of tissue). However, mortality was significantly increased in rats subjected to CR before Nx in both the 1.2% phosphorus groups (75% vs. 25%, P = 0.019) and 1.8% phosphorus groups (100% vs. 45%, P < 0.001). After calcitriol administration was stopped and phosphorus intake was normalized, VC regressed rapidly, but no significant differences in aortic calcium were detected between rats that ate normal or restricted calories during the regression phase (5.7 ± 2.7 and 5.2 ± 1.5 mg/g tissue). In conclusion, CR did not prevent or ameliorate VC and increased mortality in uremic rats.

Background: The relationships between digestive bacterial translocation, uremic toxins, oxidative stress and microinflammation in a population of chronic kidney disease (CKD) patients without metabolic nor inflammatory disease are unknown., Methods: Bacterial translocation, uremic toxins, oxidative stress, and inflammation were assessed by measuring plasma levels of 16S  ribosomal DNA (16S rDNA), p-cresyl sulfate (PCS), indoxyl sulfate (IS), indole acetic acid (IAA), F2-isoprostanes, hsCRP and receptor I of TNFα (RITNFα) in patients without metabolic nor inflammatory disease. 44 patients with CKD from stage IIIB to V and 14 controls with normal kidney function were included from the nephrology outpatients. 11 patients under hemodialysis (HD) were also included. Correlations between each factor and microinflammation markers were studied., Results: 16S rDNA levels were not increased in CKD patients compared to controls but were decreased in HD compared to non-HD stage V patients (4.7 (3.9-5.3) vs 8.6 (5.9-9.7) copies/μl, p = 0.002). IS, PCS and IAA levels increased in HD compared to controls (106.3 (73.3-130.4) vs 3.17 (2.4-5.1) μmol/l, p < 0.0001 for IS; 174.2 (125-227.5) vs 23.7 (13.9-52.6) μmol/l, p = 0.006 for PCS; and 3.7 (2.6-4.6) vs 1.3 (1.0-1.9) μmol/l, p = 0.0002 for IAA). Urea increased in non-HD stage V patients compared to controls (27.6 (22.7-30.9) vs 5.4 (4.8-6.4) mmol/l, p < 0.0001) and was similar in HD and in non-HD stage V (19.3 (14.0-24.0) vs 27.6 (22.7-30.9) mmol/l, p = 0.7). RITNFα levels increased in HD patients compared to controls (12.6 (9.6-13.3) vs 1.1 (1.0-1.4) ng/ml, p < 0.0001); hsCRP levels increased in non-HD stage V patients compared to controls (2.9 (1.4-8.5) vs 0.8 (0.5-1.7) mg/l, p = 0.01) and remained stable in HD patients (2.9 (1.4-8.5) vs 5.1 (0.9-11.5) mg/l, p = 1). F2-isoprostanes did not differ in CKD patients compared to controls. Among uremic toxins, IS and urea were correlated to RITNFα (r = 0.8, p < 0.0001 for both). PCS, IS and urea were higher in patients with hsCRP≧5 mg/l (p = 0.01, 0.04 and 0.001 respectively). 16S rDNA, F2-isoprostanes were not correlated to microinflammation markers in our study., Conclusions: In CKD patients without any associated metabolic nor inflammatory disease, only PCS, IS, and urea were correlated with microinflammation. Bacterial translocation was decreased in patients under HD and was not correlated to microinflammation.

Background and Objectives: Residual kidney function is important to the health and wellbeing of patients with ESKD. We tested whether the kidney clearances of proximal tubular secretory solutes are associated with burden of uremic and heart failure symptoms among patients on peritoneal dialysis with residual kidney function., Design, Setting, Participants, & Measurements: We enrolled 29 patients on incident peritoneal dialysis with residual urine output >250 ml daily. We used targeted liquid chromatography-mass spectrometry to quantify plasma, 24-hour urine, and peritoneal dialysate concentrations of ten tubular secretory solutes. We calculated the kidney and peritoneal dialysis clearances of each secretory solute, creatinine, and urea, and we estimated a composite kidney and peritoneal secretion score. We assessed for uremic symptoms using the Dialysis Symptom Index and heart failure-related symptoms using the Kansas City Cardiomyopathy Questionnaire. We used linear regression to determine associations of composite secretory solute clearances and GFR urea+Cr with Dialysis Symptom Index symptom score and Kansas City Cardiomyopathy Questionnaire summary score., Results: Mean residual kidney clearances of creatinine and urea were 8±5 and 9±6 ml/min per 1.73 m 2 , respectively, and mean GFR urea+Cr was 8±5 ml/min per 1.73 m 2 . The residual kidney clearances of most secretory solutes were considerably higher than creatinine and urea clearance, and also, they were higher than their respective peritoneal dialysis clearances. After adjustments for age and sex, each SD higher composite kidney secretion score was associated with an 11-point lower Dialysis Symptom Index score (95% confidence interval, -20 to -1; P =0.03) and a 12-point higher Kansas City Cardiomyopathy Questionnaire score (95% confidence interval, 0.5- to 23-point higher score; P =0.04). Composite peritoneal dialysis secretion score was not associated with either symptom assessment., Conclusions: Residual kidney clearances of secretory solutes are higher than peritoneal dialysis clearances. Kidney clearances of secretory solutes are associated with patient-reported uremic and heart failure-related symptoms., (Copyright © 2020 by the American Society of Nephrology.)

Uremic pruritus is one of the most prevalent and bothersome dermatologic symptoms in patients with end-stage renal disease. Some studies suggest a possible neuropathic cause of uremic pruritus. Gabapentin, an anticonvulsant, may control pruritus with neuropathic origin. The objectives of this study were to assess the efficacy of gabapentin in reducing pruritus scores of patients with uremic pruritus and evaluate its safety among dialysis patients. Meta-analysis of randomized controlled trials, using gabapentin as treatment for uremic pruritus among hemodialysis patients was included and analyzed using Review Manager Version 5.1.4 software. Seven out of 17 screened articles were included, with a total of 315 participants. Meta-analysis of the incidence of improved pruritus scores after treatment from four studies (n = 171) showed that treatment with gabapentin decreased the severity of uremic pruritus as compared to the placebo (risk ratio = 0.18; 95% confidence interval: 0.09, 0.33; I 2  = 4%: P =< 0.00001). Six studies (n = 290) presented with incidence of adverse drug events such as dizziness, drowsiness, and somnolence. In the pooled analysis, treatment with gabapentin was associated with a higher incidence of adverse drug events compared to the comparator drugs, but the results were not significant (risk ratio = 1.3, 95% confidence interval: 0.81, 2.11; P = 0.28, I 2  = 37%). The results of this systematic review suggest that gabapentin is efficacious and safe in improving uremic pruritus among dialysis patients., (© 2019 The International Society of Dermatology.)

Parathyroid hormone (PTH) has an important role in the maintenance of serum calcium levels. It activates renal 1α-hydroxylase and increases the synthesis of the active form of vitamin D (1,25[OH] 2 D 3 ). PTH promotes calcium release from the bone and enhances tubular calcium resorption through direct action on these sites. Hallmarks of secondary hyperparathyroidism associated with chronic kidney disease (CKD) include increase in serum fibroblast growth factor 23 (FGF-23), reduction in renal 1,25[OH] 2 D 3 production with a decline in its serum levels, decrease in intestinal calcium absorption, and, at later stages, hyperphosphatemia and high levels of PTH. In this paper, we aim to critically discuss severe CKD-related hyperparathyroidism, in which PTH, through calcium-dependent and -independent mechanisms, leads to harmful effects and manifestations of the uremic syndrome, such as bone loss, skin and soft tissue calcification, cardiomyopathy, immunodeficiency, impairment of erythropoiesis, increase of energy expenditure, and muscle weakness., Competing Interests: The authors declare no conflict of interest.

Bardet- biedl syndrome (BBS) is a rare heterogenous autosomal recessive disease due to defects in primary cilia which until now, up to 21 types have been detected. A few reports of BBS in Iran have been published but this is the first type 9 genotyped and clinically discussed case. This type can cause severe and delayed onset renal failure.

Introduction: Removal of uremic toxins is a main objective of hemodialysis; however, whether high-flux and medium cut-off (MCO) membranes differ as regards removal of middle and large uremic toxins is not clear., Objective: To compare medium cut-off and high-flux dialyzers as regards their intra- and interdialysis effect on circulating levels of middle and large uremic toxins and serum albumin., Methods: Fifty-two patients were randomized to have hemodialysis with either 3 months of high-flux dialyzer followed by 3 months of MCO or vice versa. Blood samples were taken before and after dialysis at the first and last sessions of each dialyzer for analyses of middle and large uremic toxins including inflammatory mediators and vascular endothelial growth factor (VEGF), and serum albumin., Results: Reduction rates were higher, and postdialysis levels of β-2 microglobulin, free kappa and lambda light chains, and myoglobulin were lower at the first and last sessions with MCO dialyzers compared to high-flux dialyzers (p < 0.05 for all). Last session predialysis levels of β-2 microglobulin, free kappa light chain, and free lambda light chain were lower than first session predialysis levels in MCO dialyzers as compared to high-flux dialyzers (p < 0.05 for all). Last session levels of interleukin-6, interleukin-10, interleukin-17, and interferon-gamma did not differ between dialyzers (p > 0.05 for all). VEGF level was lower in the MCO group compared to the high-flux group (p = 0.043). Last session level of serum albumin with MCO dialyzers was lower than that with high-flux dialyzers (3.62 [3.45-3.88] vs. 3.78 [3.58-4.02] g/L) (p = 0.04) and 6.7% lower (p < 0.001) than at the first session of MCO dialyzers., Conclusion: The decline in circulating levels of several middle and large uremic toxins including VEGF following hemodialysis was more pronounced when using MCO membranes as compared to high-flux membranes while their effect on inflammatory molecules was similar., (© 2020 S. Karger AG, Basel.)

Background: Protein-bound uremic toxins (PBUTs) have received extensive attention, as their accumulation leads to pleiotropic toxic biological effects, while the removal of these solutes by conventional dialysis therapies is severely hampered. This study aimed to examine whether increased removal of PBUTs could be achieved with intravenous lipid emulsion (ILE)., Methods: PBUTs such as 3-carboxy-4-methyl-5-propyl-2-furanpropionic acid (CMPF), p-cresyl sulfate (PCS) and indoxyl sulfate (IS) were spiked with human serum albumin (HSA) solution and the inhibitory effects of free fatty acid (FFA) on the binding of CMPF, PCS and IS to HSA were examined separately in vitro by ultrafiltration. In vitro dialysis of albumin solution was then performed to investigate the effects of fatty acid (FAs) mixtures infusion on the fractional removal of PBUTs. Finally, the inhibitory effect of FFA on the binding of PBUTs to albumin was examined in uremic rats, and blood purification therapy was conducted to calculate the reduction ratio (RR) and the total solute removal (TSR) of solutes., Results: The percentage protein binding of CMPF, PCS and IS decreased significantly with increasing FFAs concentrations, and the inhibitory effect was more remarkable with the addition of oleic acid or linoleic acid than that of eicosapentaenoic acid and docosahexaenoic acid. In vitro infusion of FAs increased the fractional removal of CMPF to 14.40 ± 2.38%. PCS, IS and indole-3-acetic acid removal increased from 8.00 ± 2.43%, 11.68 ± 1.54% and 15.38 ± 3.97%, respectively, at baseline to 28.21 ± 5.99%, 35.42 ± 5.27% and 40.18 ± 5.05%, respectively, when FAs were present. In vivo, rat serum concentrations of free PBUTs were significantly higher in the ILE group than in the control group, and administration of ILE resulted in higher RRs and more TSR for PBUTs after 3 h of hemodialysis (HD) therapy compared with the control group., Conclusions: Administration of ILE effectively increased the dialytic removal of PBUTs. This method could be applied to current HD therapy., (© The Author(s) 2019. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.)

Background: Hemodialysis (HD) sessions induce changes in plasma electrolytes that lead to modifications of QT interval, virtually associated with dangerous arrhythmias. It is not known whether such a phenomenon occurs even during peritoneal dialysis (PD). The aim of the study is to analyze the relationship between dialysate and plasma electrolyte modifications and QT interval during a PD exchange., Methods: In 15 patients, two manual PD 4-h exchanges were performed, using two isotonic solutions with different calcium concentration (Ca ++ 1.25 and Ca1.75 ++  mmol/L). Dialysate and plasma electrolyte concentration and QT interval (ECG Holter recording) were monitored hourly. A computational model simulating the ventricular action potential during the exchange was also performed., Results: Dialysis exchange induced a significant plasma alkalizing effect (p < 0.001). Plasma K + significantly decreased at the third hour (p < 0.05). Plasma Na + significantly decreased (p < 0.001), while plasma Ca ++ slightly increased only when using the Ca 1.75 ++  mmol/L solution (p < 0.01). The PD exchange did not induce modifications of clinical relevance in the QT interval, while a significant decrease in heart rate (p < 0.001) was observed. The changes in plasma K + values were significantly inversely correlated to QT interval modifications (p < 0.001), indicating that even small decreases of K + were consistently paralleled by small QT prolongations. These results were perfectly confirmed by the computational model., Conclusions: The PD exchange guarantees a greater cardiac electrical stability compared to the HD session and should be preferred in patients with a higher arrhythmic risk. Moreover, our study shows that ventricular repolarization is extremely sensitive to plasma K + changes, also in normal range.

Competing Interests: Competing interests: None declared.

Background: Cardiovascular disease is the most common complication and leading cause of death in maintenance hemodialysis patients. The protection mechanism of hydrogen sulfide (H 2 S) and the specific role of conventional protein kinase C βII (cPKCβII)/Akt signaling pathway in the formation of atherosclerosis is still controversial., Methods: 8-week-old male ApoE -/- mice were treated with 5/6 nephrectomy and high-fat diet to make uremia accelerated atherosclerosis (UAAS) model. Mice were divided into normal control group (control group), sham operation group (sham group), UAAS group, L-cysteine group (UAAS+L-cys group), sodium hydrosulfide group (UAAS+NaHS group), and propargylglycine group (UAAS+PPG group). Western blot was used to detect cPKCβII activation, Akt phosphorylation and endothelial nitric oxide synthase (eNOS) expression in mice aorta., Results: The membrane translocation of cPKCβII in UAAS group was higher than sham group, and L-cys or NaHS injection could suppress the membrane translocation, but PPG treatment resulted in more membrane translocation of cPKCβII (P < 0.05, n = 6 per group). Akt phosphorylation and the eNOS expression in UAAS group was lower than sham group, and L-cys or NaHS injection could suppress the degradation of Akt phosphorylation and the eNOS expression, but PPG treatment resulted in more decrease in the Akt phosphorylation and the eNOS expression (P < 0.05, n = 6 per group)., Conclusion: Endogenous cystathionine-γ-lyase (CSE)/H 2 S system protected against the formation of UAAS via cPKCβII/Akt signal pathway. The imbalance of CSE/H 2 S system may participate in the formation of UAAS by affecting the expression of downstream molecule eNOS, which may be mediated by cPKCβII/Akt signaling pathway.

Activin A is a new fascinating player in chronic kidney disease-mineral and bone disorder (CKD-MBD), which is implicated in progressive renal disease, vascular calcification, and osteodystrophy. Plasma activin A rises early in the progression of renal disease. Disruption of circadian rhythms is related to increased risk of several diseases and circadian rhythms are observed in mineral homeostasis, bone parameters, and plasma levels of phosphate and PTH. Therefore, we examined the circadian rhythm of activin A and CKD-MBD-related parameters (phosphate, PTH, FGF23, and klotho) in healthy controls and CKD rats (5/6 nephrectomy) on high-, standard- and low-dietary phosphate contents as well as during fasting conditions. Plasma activin A exhibited circadian rhythmicity in healthy control rats with fourfold higher values at acrophase compared with nadir. The rhythm was obliterated in CKD. Activin A was higher in CKD rats compared with controls when measured at daytime but not significantly when measured at evening/nighttime, stressing the importance of time-specific reference intervals when interpreting plasma values. Plasma phosphate, PTH, and FGF23 all showed circadian rhythms in control rats, which were abolished or disrupted in CKD. Plasma klotho did not show circadian rhythm. Thus, the present investigation shows, for the first time, circadian rhythm of plasma activin A. The rhythmicity is severely disturbed by CKD and is associated with disturbed rhythms of phosphate and phosphate-regulating hormones PTH and FGF23, indicating that disturbed circadian rhythmicity is an important feature of CKD-MBD.

The accumulation of uremic solutes in kidney failure may impair mental function. The present study profiled the accumulation of uremic solutes in the cerebrospinal fluid (CSF) in acute renal failure. CSF and plasma ultrafiltrate were obtained from rats at 48 h after sham operation (control; n = 10) or bilateral nephrectomy ( n = 10) and analyzed using an established metabolomic platform. Two hundred forty-eight solutes were identified as uremic based on their accumulation in the plasma ultrafiltrate of nephrectomized compared with control rats. CSF levels of 124 of these solutes were sufficient to allow calculation of CSF-to-plasma ultrafiltrate concentration ratios. Levels of many of the uremic solutes were normally lower in the CSF than in the plasma ultrafiltrate, indicating exclusion of these solutes from the brain. CSF levels of the great majority of the uremic solutes increased in renal failure. The increase in the CSF was, however, relatively less than in the plasma ultrafiltrate for most solutes. In particular, for the 31 uremic solutes with CSF-to-plasma ultrafiltrate ratios of <0.25 in control rats, the average CSF-to-plasma ultrafiltrate ratio decreased from 0.13 ± 0.07 in control rats to 0.09 ± 0.06 in nephrectomized rats, revealing sustained ability to exclude these solutes from the brain. In summary, levels of many uremic solutes are normally kept lower in the CSF than in the plasma ultrafiltrate by the action of the blood-brain and blood-CSF barriers. These barriers remain functional but cannot prevent accumulation of uremic solutes in the CSF when the kidneys fail.

Study Objective: Confusion, uremia, elevated respiratory rate, hypotension, and aged 65 years or older (CURB-65) is a clinical prediction rule intended to stratify patients with pneumonia by expected mortality. We assess the predictive performance of CURB-65 for the proximal endpoint of receipt of critical care intervention in emergency department (ED) patients admitted with community-acquired pneumonia., Methods: We performed a retrospective analysis of electronic health records from a single tertiary center for ED patients admitted as inpatients with a primary diagnosis of pneumonia from 2010 to 2014. Patients with a history of malignancy, tuberculosis, bronchiectasis, HIV, or readmission within 14 days were excluded. We assessed the predictive accuracy of CURB-65 for receipt of critical care interventions (ie, vasopressors, large-volume intravenous fluids, invasive catheters, assisted ventilation, insulin infusions, or renal replacement therapy) and inhospital mortality. Logistic regression was performed to assess the increase in odds of critical care intervention or inhospital mortality by increasing CURB-65 score., Results: There were 2,322 patients admitted with community-acquired pneumonia in the study cohort; 630 (27.1%) were admitted to the ICU within 48 hours of ED triage and 343 (14.8%) received a critical care intervention. Of patients with a CURB-65 score of 0 to 1, 181 (15.6%) were admitted to the ICU, 74 (6.4%) received a critical care intervention, and 7 (0.6%) died. Of patients with a CURB-65 score of 2, 223 (27.0%) were admitted to the ICU, 127 (15.4%) received a critical care intervention, and 47 (5.7%) died. Among patients with CURB-65 score greater than or equal to 3, 226 (67.0%) were admitted to the ICU, 142 (42.1%) received a critical care intervention, and 43 (12.8%) died. The areas under the receiver operating characteristic for CURB-65 as a predictor of critical care intervention and mortality were 0.73 and 0.77, whereas sensitivity of CURB-65 score greater than or equal to 2 in predicting critical care intervention was 78.4%; for mortality, 92.8%., Conclusion: Patients with CURB-65 score less than or equal to 2 were often admitted to the ICU and received critical care interventions. Given this finding and the relatively low sensitivity of CURB-65 for critical care intervention, clinicians should exercise caution when using CURB-65 to guide disposition. Future ED-based clinical prediction rules may benefit from calibration to proximal endpoints., (Copyright © 2018 American College of Emergency Physicians. Published by Elsevier Inc. All rights reserved.)

Background: The epidemiology and prognosis of chronic kidney disease (CKD) differ by sex. We aimed to compare symptom prevalence and the clinical state in women and men of ≥65 years of age with advanced CKD receiving routine nephrology care., Methods: The European QUALity study on treatment in advanced chronic kidney disease (EQUAL) study follows patients from six European countries of ≥65 years of age  years whose estimated glomerular filtration rate (eGFR) dropped to ≤20 mL/min/1.73 m2 for the first time during the last 6 months. The Dialysis Symptom Index was used to assess the prevalence and severity of 33 uraemic symptoms. Data on the clinical state at baseline were collected from medical records. Prevalence was standardized using the age distribution of women as the reference., Results: The results in women (n = 512) and men (n = 967) did not differ with age (77.0 versus 75.7 years) or eGFR (19.0 versus 18.5). The median number of symptoms was 14 [interquartile range (IQR) 9-19] in women, and 11 (IQR 7-16) in men. Women most frequently reported fatigue {39% [95% confidence interval (CI) 34-45]} and bone/joint pain [37% (95% CI 32-42)] as severe symptoms, whereas more men reported difficulty in becoming sexually aroused [32% (95% CI 28-35)] and a decreased interest in sex [31% (95% CI 28-35)]. Anaemia [73% (95% CI 69-77) versus 85% (95% CI 82-87)] was less common in women than in men, as were smoking history and cardiovascular comorbidity. However, a diagnosis of liver disease other than cirrhosis, psychiatric disease and mild malnutrition were more common among women., Conclusions: Women in secondary care with an incident eGFR ≤20 mL/min/1.73 m2 reported a higher symptom burden, while their clinical state was considered similar or even more favourable as compared with men., (© The Author(s) 2018. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.)

Elucidation of molecular and cellular mechanisms of the uremic syndrome is a very challenging task. More than 130 substances are now considered to be "uremic toxins" and represent a very diverse group of molecules. The toxicity of these molecules affects many cellular processes, and expectably, some of them are able to disrupt mitochondrial functioning. However, mitochondria can be the source of uremic toxins as well, as the mitochondrion can be the site of complete synthesis of the toxin, whereas in some scenarios only some enzymes of the pathway of toxin synthesis are localized here. In this review, we discuss the role of mitochondria as both the target and source of pathological processes and toxic compounds during uremia. Our analysis revealed about 30 toxins closely related to mitochondria. Moreover, since mitochondria are key regulators of cellular redox homeostasis, their functioning might directly affect the production of uremic toxins, especially those that are products of oxidation or peroxidation of cellular components, such as aldehydes, advanced glycation end-products, advanced lipoxidation end-products, and reactive carbonyl species. Additionally, as a number of metabolic products can be degraded in the mitochondria, mitochondrial dysfunction would therefore be expected to cause accumulation of such toxins in the organism. Alternatively, many uremic toxins (both made with the participation of mitochondria, and originated from other sources including exogenous) are damaging to mitochondrial components, especially respiratory complexes. As a result, a positive feedback loop emerges, leading to the amplification of the accumulation of uremic solutes. Therefore, uremia leads to the appearance of mitochondria-damaging compounds, and consecutive mitochondrial damage causes a further rise of uremic toxins, whose synthesis is associated with mitochondria. All this makes mitochondrion an important player in the pathogenesis of uremia and draws attention to the possibility of reducing the pathological consequences of uremia by protecting mitochondria and reducing their role in the production of uremic toxins.

Background: Despite universal administration of erythropoiesis-stimulating agents, patients with end-stage renal disease (ESRD) are at high risk for presenting persistent anemia. Due to ambiguities in optimal hemoglobin targets and evidence of recombinant human erythropoietin (EPO)-related toxicity, an increase in blood transfusions has been observed in chronic renal disease over the past years. The probable effects of uremic plasma on the performance of stored red blood cells (RBCs) after transfusion have not been investigated., Study Design and Methods: Leukoreduced RBCs after short or long storage in CPD-SAGM (n = 5) were assessed for hemolysis, surface removal signaling, reactive oxygen species (ROS) accumulation, and shape distortions before and after reconstitution with healthy (n = 10) or uremic plasma from ESRD patients (n = 20) for 24 hours at physiologic temperature, by using a previously reported in vitro model of transfusion., Results: Temperature and cell environment shifts from blood bag to plasma independently and in synergy affected the RBC physiology. Outcome measures at transfusion-simulating conditions might not be analogous to timing of storage lesion. The uremic plasma ameliorated the susceptibility of stored RBCs to hemolysis, phosphatidylserine externalization, and ROS generation after stimulation by oxidants, but negatively affected shape homeostasis versus healthy plasma. Creatinine, uric acid, and EPO levels had correlations with the performance of stored RBCs in ESRD plasma., Conclusion: Renal insufficiency and EPO supplementation likely affect the recovery of donor RBCs and the reactivity of RBCs after transfusion by exerting both toxic and cytoprotective influences on them. ESRD patients constitute a specific recipient group that deserves further examination., (© 2019 AABB.)

Purpose: Several lines of evidence suggest that renal dysfunction is associated with cardiovascular toxicity through the action of uremic toxins. The levels of those uremic toxins can be reportedly reduced by the spherical carbon adsorbent AST-120. Because heart failure (HF) causes renal dysfunction by low cardiac output and renal edema, the removal of uremic toxins could be cardioprotective., Method: To determine whether blood levels of the uremic toxin indoxyl sulfate (IS) increase in HF and whether AST-120 can reduce those levels and improve HF. We induced HF in 12 beagle dogs by 6 weeks of rapid right ventricular pacing at 230 beats per min. We treated six dogs with a 1-g/kg/day oral dosage of AST-120 for 14 days from week 4 after the start of rapid ventricular pacing. The other six dogs did not receive any treatment (control group)., Results: In the untreated dogs, IS levels increased as cardiac function deteriorated. In contrast, plasma IS levels in the treated dogs decreased to baseline levels, with both left ventricular fractional shortening and pulmonary capillary wedge pressure also improving when compared with untreated dogs. Finally, AST-120 treatment was shown to reduce both myocardial apoptosis and fibrosis along with decreases in extracellular signal-regulated kinase phosphorylation, the Bax/Bcl-2 ratio, and TGF-β1 expression and increases in AKT phosphorylation., Conclusions: IS levels are increased in HF. AST-120 treatment reduces the levels of IS and improves the pathophysiology of HF in a canine model. AST-120 could be a novel candidate for the treatment of HF.