Neoantigen-targeted dendritic cell vaccination in lung cancer patients induces long-lived T cells exhibiting the full differentiation spectrum.

Non-small cell lung cancer (NSCLC) is known for high relapse rates despite resection in early stages. Here, we present the results of a phase I clinical trial in which a dendritic cell (DC) vaccine targeting patient-individual neoantigens is evaluated in patients with resected NSCLC. Vaccine manufacturing is feasible in six of 10 enrolled patients. Toxicity is limited to grade 1-2 adverse events. Systemic T cell responses are observed in five out of six vaccinated patients, with T cell responses remaining detectable up to 19 months post vaccination. Single-cell analysis indicates that the responsive T cell population is polyclonal and exhibits the near-entire spectrum of T cell differentiation states, including a naive-like state, but excluding exhausted cell states. Three of six vaccinated patients experience disease recurrence during the follow-up period of 2 years. Collectively, these data support the feasibility, safety, and immunogenicity of this treatment in resected NSCLC.

Detection and Scoring of Extracorporeal Circuit Clotting During Hemodialysis.

Maintaining patency of the extracorporeal hemodialysis (HD) circuit is a prerequisite to perform HD. Unfractionated heparin and low-molecular-weight heparins are the most used anticoagulants in maintenance HD, but their administration comes with a major trade-off of bleeding complications. This narrative review article discusses technical factors impacting on HD circuit patency, such as tubings, dialyzer membranes, priming practices, and treatment settings. Strategies for monitoring extracorporeal circuit clotting during and after treatment are also reviewed, as these are essential tools for optimizing anticoagulation.

The optimized anticoagulation strategy in prolonged hemodialysis.

Background: During extended (nocturnal) hemodialysis (ENHD), the dose of low-molecular-weight heparin (LMWH) can be administered as a single injection or as a divided dose over different time points. Our hypothesis was that a single injection might be sufficient to maintain dialyzer fiber patency. In addition, we investigated whether the biochemical clotting parameter anti-Xa accurately predicts fiber blocking. Methods: Our hypothesis was tested in 20 stable patients on ENHD in a random cross-over setting during two consecutive midweek sessions. The regular total dose of LMWH (i.e. enoxaparin, Clexane® 40-100  mg, Sanofi, Belgium) was either given (i) in a single injection at the dialysis start or (ii) divided over two injections, at the start and halfway the dialysis session. Blood samples were taken from the arterial blood line at different time points to determine plasma anti-Xa activity levels. Post-dialysis, the rinsed and dried hemodialyzers were scanned with a reference micro-computed tomography (µCT) scanning technique, and non-blocked fibers were counted in a central cross-section of the dialyzer outlet potting (ImageJ, NIH, USA). Results: The percentage of open fibers in the dialyzers after a single injection of LMWH [91 (61-96)%] versus divided administration [94 (79-98)%] was not different. Time averaged anti-Xa activity levels were clinically not significantly different between both sessions. Anti-Xa activity levels correlated with the administered anticoagulation doses normalized for body weight, but not with the percentages open fibers in the dialyzers. Conclusion: Our results indicate that there is no need to administer enoxaparin over two injections for ENHD up to 8 h. The usefulness of monitoring anti-Xa levels to predict fiber patency, assessed by µCT, can be questioned, but further clinical trials are needed.

Association between anticoagulation strategy and quality of life in chronic hemodialysis patients.

Prevention of clotting in hemodialysis (HD) is a concern, but tools to monitor anticoagulation strategies as well as data on bleeding and its impact on quality of life (QoL) are scant. In this prospective longitudinal observational study, bleeding tendency in 70 HD patients was scored with ISTH-BAT and HAS-BLED at week 0, 4, and 8. Patient's limbs were visually scored for bruises and hematomas, and Quality of Life (QoL) was assessed using EQ5D-3L and Visual Analogue Scale (VAS) questionnaires. At week 0, the used hemodialyzer was scanned in a micro-CT scanner to quantify the number of patent fibers. Bleeding scores were 0 [0; 1] and 3 [2; 4] for ISTH-BAT and HAS-BLED, and visual scoring showed 2 [0; 4] bruises/hematomas. QoL was 0.85 [0.77; 1.00] for EQ5D and 70 [60; 80] for VAS. Fiber patency was 81 [70; 90]%, but was not associated with anticoagulation dose (p = 0.103). Patients in the highest tertile of anticoagulation dose had a worse VAS score (p = 0.027), and patients identified as having bleeding tendency by ISTH also had a worse VAS score (p = 0.010). This supports our postulate that in maintenance HD patients the current personal anticoagulation dose regimens may be too high, leading to more mainly minor bleeding that may negatively impact health related quality of life.

The use of AVF.SIM system for the surgical planning of arteriovenous fistulae in routine clinical practice.

BACKGROUND: The number of patients treated with hemodialysis (HD) in Europe is more than half a million and this number increases annually. The arteriovenous fistula (AVF) is the vascular access (VA) of first choice, but the clinical outcome is still poor. A consistent number of AVFs fails to reach the desired blood flow rate for HD treatment, while some have too high flow and risk for cardiac complications. Despite the skill of the surgeons and the possibility to use Ultrasound investigation for mapping arm vasculature, it is still not possible to predict the blood flow volume that will be obtained after AVF maturation. METHODS: We evaluated the potential of using a computational model (AVF.SIM) to predict the blood flow volume that will be achieved after AVF maturation, within a multicenter international clinical investigation aimed at assessing AVF.SIM predictive power. The study population included 231 patients, with data on AVF maturation in 124 patients, and on long-term primary patency in 180 patients. RESULTS: At 1 year of follow-up, about 60% of AVFs were still patent, with comparable primary patency in proximal and distal anastomosis. The correlation between predicted and measured blood flow volume in the brachial artery at 40 days after surgery was statistically significant, with an overall correlation coefficient of 0.58 (p < 0.001). The percent difference between measured and predicted brachial blood flow 40 days after surgery was less than 30% in 72% of patients investigated. CONCLUSIONS: The results indicate that the use of the AVF.SIM system allowed to predict with a good accuracy the blood flow volume achievable after VA maturation, for a given location and type of anastomosis. This information may help in AVF surgical planning, reducing the AVFs with too low or too high blood flow, thus improving AVF patency rate and clinical outcome of renal replacement therapy.

Impact of intradialytic fiber clotting on dialyzer extraction and solute removal: a randomized cross-over study.

Previous studies revealed the importance of biocompatibility, anticoagulation strategy, and dialysis mode and duration on fiber blocking at the end of a hemodialysis session. The present study was set up in ten hemodialysis patients to relate fiber patency to dialyzer extraction and removal of small and middle molecules. With only 1/4th of the regular anticoagulation dose, and using a Solacea 19H and FX800 CorDiax dialyzer, fiber patency was quantified using 3D micro-CT scanning for different dialysis durations (i.e. 60, 120 and 240 min). While Solacea showed enhanced fiber patency in all test sessions, fiber blocking in the FX800 CorDiax did not follow a linear process during dialysis, but was rather accelerated near the end of dialysis. Dialyzer extraction ratios were correlated with the percentages of open fibers. While the fiber blocking process affected extraction ratios (i.e. for phosphorus and myoglobin in the FX800 CorDiax), it had only minor impact on the removal of toxins up to at least 12 kDa.

Patients with Severe Lactic Acidosis in the Intensive Care Unit: A Retrospective Study of Contributing Factors and Impact of Renal Replacement Therapy.

INTRODUCTION: Hyperlactatemia is a regular condition in the intensive care unit, which is often associated with adverse outcomes. Control of the triggering condition is the most effective treatment of hyperlactatemia, but since this is mostly not readily possible, extracorporeal renal replacement therapy (RRT) is often tried as a last resort. The present study aims to evaluate the factors that may contribute to the decision whether to start RRT or not and the potential impact of the start of RRT on the outcome in patients with severe lactic acidosis (SLA) (lactate ≥5 mmol/L). MATERIALS AND METHODS: We conducted a retrospective single-center cohort analysis over a 3-year period including all patients with a lactate level ≥5 mmol/L. Patients were considered as treated with RRT because of SLA if RRT was started within 24 h after reaching a lactate level ≥5 mmol/L. RESULTS: Overall, 90-day mortality in patients with SLA was 34.5%. Of the 1,203 patients who matched inclusion/exclusion criteria, 11% (n = 133) were dialyzed within 24 h. The propensity to receive RRT was related to the lactate level and to the SOFA renal and cardio score. The most frequently used modality was continuous RRT. Patients who were started on RRT versus those who did not have 2.3 higher odds of mortality, even after adjustment for the propensity to start RRT. CONCLUSIONS: Our analysis confirms the high mortality rate of patients with SLA. It adds that odds for mortality is even higher in patients who were started on RRT versus not. We suggest keeping an open mind to the factors that may influence the decision to start dialysis and bear in mind that without being a bridge to correction of the underlying condition, dialysis is unlikely to affect the outcome.

How biocompatible haemodialysers can conquer the need for systemic anticoagulation even in post-dilution haemodiafiltration: a cross-over study.

BACKGROUND: While systemic anticoagulation is most widely used in haemodialysis (HD), contraindications to its use might occur in particular settings. The Solacea™ haemodialyser with an asymmetric triacetate membrane claims improved biocompatibility and has already shown promising results when used in combination with only half dose of anticoagulation. To quantify the performance of the Solacea™ when further decreasing anticoagulation to zero, fibre blocking was assessed by micro-computed tomography (micro-CT). METHODS: Ten maintenance HD patients underwent six dialysis sessions at midweek using a Solacea™ 19H dialyser, consecutively in pre-dilution haemodiafiltration (pre-HDF), HD and post-dilution HDF (post-HDF). After the first three sessions with only a quarter of their regular anticoagulation dose (one-quarter), the last three sessions were performed without anticoagulation (zero). Dialyser fibre blocking was quantified in the dialyser outlet potting using a 3D micro-CT scanning technique post-dialysis. RESULTS: Even in case of reduced (one-quarter) anticoagulation, the relative number of open fibres post-dialysis was almost optimal, i.e. 0.96 (0.87-0.99) with pre-HDF, 0.99 (0.97-0.99) with HD and 0.97 (0.92-0.99) with post-HDF. Fibre patency was mildly decreased for pre-HDF and HD when anticoagulation was decreased from one-quarter to zero, i.e. to 0.76 (0.61-0.85) with pre-HDF (P = 0.004) and to 0.80 (0.77-0.89) with HD (P = 0.013). Comparing the results for zero anticoagulation, post-HDF [i.e. 0.94 (0.82-0.97)] performed as well as HD and pre-HDF. CONCLUSIONS: The Solacea™ dialyser provides promising results for use in conditions where systemic anticoagulation is contraindicated. Post-HDF, although inducing haemoconcentration in the dialyser, is equally effective for fibre patency in case of zero anticoagulation as pre-HDF and HD when using Solacea™.

The complexity of sleep disorders in dialysis patients.

BACKGROUND: Dialysis patients experience a high burden of physical and emotional symptoms directly affecting their sleep and quality of life. In this study, objective and subjective measurements to quantify sleep were performed, compared with those of healthy controls, and associated with burden of comorbidity and uraemic toxicity. METHODS: A total of 64 dialysis patients were included-10 peritoneal dialysis, 42 in-centre daytime haemodialysis (HD) and 12 in-centre nocturnal HD patients-as well as one-to-one age- and gender-matched healthy controls. Assumed and actual sleep time, sleep efficiency and fragmentation index were measured by actigraphy for at least two consecutive nights. Patients and controls also completed Insomnia Severity Index (ISI) and Pittsburgh Sleep Quality Index (PSQI) questionnaires. The patients' blood was sampled to determine concentrations of a representative series of uraemic toxins and the Davies-Stoke comorbidity index was derived from medical records. RESULTS: Apart from the assumed sleep time, all objectively and subjectively measured sleep parameters were worse in the dialysis group compared with the healthy controls. No differences were seen in any of the measured sleep parameters among the different dialysis groups. None of the objectively measured sleep parameters were associated with ISI or PSQI scores in dialysis patients, while sleep times were related to the subjective scores in the healthy cohort. Objectively assessed sleep parameters were associated to neither the uraemic toxicity load nor the Davies-Stoke score. CONCLUSIONS: Independent of the modality, dialysis patients have sleep quality much worse than age- and gender-matched healthy controls. The objectively measured sleep parameters could not be associated to the subjective score, uraemic toxicity or comorbidity score, highlighting the need for objective measurements of sleep and clinical guidelines to aid patient management.

Prevention of tunneled cuffed catheter dysfunction with prophylactic use of a taurolidine urokinase lock: A randomized double-blind trial.

BACKGROUND: The efficacy and cost-effectiveness of prophylactic thrombolytic locks in hemodialysis patients at high-risk of thrombotic dialysis catheter dysfunction is uncertain. We investigated this question in a double-blinded randomized controlled study. METHODS: Prevalent hemodialysis patients from 8 Belgian hemodialysis units, with ≥2 separate episodes of thrombotic dysfunction of their tunneled cuffed catheter during the 6 months before inclusion, were randomized to either: taurolidine heparin locks thrice weekly (control arm) or the same locks twice a week combined with taurolidine urokinase locks once a week before the longest interval without HD (TaurolockU arm). The primary efficacy outcome was the incidence rate of catheter thrombotic dysfunction requiring thrombolytic locks to restore function. RESULTS: 68 hemodialysis patients (32 controls, 36 urokinase) were followed during 9875 catheter days between May 2015 and June 2017. Incidence rate of thrombotic catheter dysfunction was 4.8 in TaurolockU vs 12.1/1000 catheter days in control group (rate ratio 0.39; 95%CI 0.23-0.64). 15/36 (42%) catheters in the treatment group required at least one therapeutic urokinase lock vs 23/32 (72%) in the control group (P = 0.012). The two groups did not differ significantly in catheter-related bloodstream infection and combined cost of prophylactic and therapeutic catheter locks. The TaurolockU group had a numerically higher number of episodes of refractory thrombosis. CONCLUSIONS: Prophylactic use of urokinase locks is highly effective in reducing the number of thrombotic catheter dysfunctions in catheters with a history of recurring dysfunction. Prophylactic use of urokinase locks did not reduce the overall costs associated with catheter locks and was associated with a numerically higher number of episodes of refractory thrombosis. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02036255.

Erratum: A randomized cross-over study with objective quantification of the performance of an asymmetric triacetate and a polysulfone dialysis membrane using different anticoagulation strategies.

[This corrects the article DOI: 10.1093/ckj/sfz163.][This corrects the article DOI: 10.1093/ckj/sfz163.].

A randomized cross-over study with objective quantification of the performance of an asymmetric triacetate and a polysulfone dialysis membrane using different anticoagulation strategies.

BACKGROUND: Different strategies can be used to counteract coagulation of extracorporeal systems. Systemic anticoagulation is most widely used in routine clinical practice, but can be contraindicated in specific settings. The Solacea™ dialyser, containing the asymmetric triacetate membrane, claims improved biocompatibility, which should result in decreased tendency for coagulation. We quantified the performance of the Solacea™ versus the FX800CORDIAX dialyser regarding resistance to fibre blocking as assessed by micro-computed tomography (CT). METHODS: This cross-over study with four arms randomized consecutively 10 maintenance haemodialysis patients to a 4-h post-dilution haemodiafiltration session at midweek, using either Solacea™ 19 H or FX800CORDIAX, with either regular or half dose of anticoagulation (EC2017/1459-NCT03820401). Dialyser fibre blocking was visualized in the dialyser outlet potting using a 3D CT scanning technique on micrometre resolution. Extraction ratios of middle molecules [myoglobin, lambda and kappa free light chains (FLCs)] were determined. RESULTS: The relative number of open fibres post-dialysis was lower in FX800CORDIAX versus Solacea™ dialyser, and this was irrespective of the anticoagulation dose used or the threshold for counting open fibres. Extraction ratios of FLCs were not different at regular anticoagulation between Solacea™ and FX800CORDIAX (21% ± 4% for kappa and 32% ± 8% for lambda with Solacea™ versus 23% ± 7% and 38% ± 6% for FX800CORDIAX), but were superior with the Solacea™ (34% ± 12% versus 22% ± 8% with FX800CORDIAX; P = 0.02) for myoglobin in case of halving anticoagulation dose. No clinically relevant albumin loss was detected. CONCLUSIONS: The Solacea™ dialyser seems to be promising for use in conditions where systemic anticoagulation is contraindicated, as even under conditions of low systemic anticoagulation, virtually no signs of fibre blocking could be observed using the sensitive micro-CT scanning technique. This finding is in line with its presumed good performance in terms of biocompatibility.

Evaluation with micro-CT of different anticoagulation strategies during hemodialysis in patients with thrombocytopenia: A randomized crossover study.

In patients with enhanced risk for bleeding, heparin-free hemodialysis (HD) with conventional dialyzers is routinely used. To explore the potential benefit of using heparin-coated dialyzers, we used a reference CT-scanning technique and registered different clotting parameters to quantify coagulation with heparin-coated versus non-coated dialyzers. Six HD patients with thrombocytopenia were dialyzed 240 min in a randomized crossover study with Evodial 1.3 or FX600 Cordiax, each without anticoagulation. Blood samples were taken from the vascular access predialysis, and from the dialyzer inlet and outlet at 5 and 240 min after dialysis start. Predialysis blood samples were analyzed for hemoglobin, hematocrit, thrombocytes, fibrinogen, and activated partial thromboplastin time. On dialyzer inlet and outlet blood samples, a viscoelastic measurement of blood coagulation was performed using a Sonoclot analyzer. After dialysis, dialyzers were visually scored, subsequently dried for 24 h, weighed, and scanned with micro-CT at a resolution of 25 µm. After image reconstruction, the open, non-coagulated fibers were counted in a representative cross-section at the dialyzer outlet. No sessions were terminated prematurely for circuit clotting. Heparin-coated dialyzers had more patent fibers on micro-CT versus non-coated dialyzers and also had a better score of subjective visual assessment of fiber clotting. There was no difference in subjective assessment of clotting at the venous drip chamber. With both dialyzers, all ACT values remained in the normal range, and were lower at the dialyzer outlet versus inlet. In conclusion, dialysis with a heparin-coated versus non heparin-coated membrane results in substantially less coagulated fibers during 4 h hemodialysis without systemic anticoagulation. Eventual leaching of heparin, immobilized on the fiber membrane, does not result in measurable systemic anticoagulation.

Evaluation of Different Dialyzers and the Impact of Predialysis Albumin Priming in Intermittent Hemodialysis With Reduced Anticoagulation.

INTRODUCTION: Systemic anticoagulation is widely used in routine clinical hemodialysis, but can be contraindicated in specific settings. Anticoagulant-free treatment regimens are prone to failure even in chronic intermittent hemodialysis. We quantified fiber blocking in settings of reduced anticoagulation to assess performance of different dialyzers and the potential benefit of albumin priming. METHODS: This crossover study included 10 patients performing 4 hours of hemodialysis at midweek in 7 different settings: that is, using Solacea 19H and FX800, both with regular and half dose of anticoagulation, Evodial 1.3 without systemic anticoagulation, and FX800 (half dose) and Evodial (no anticoagulation) when primed with a human albumin solution. Dialyzer fiber blocking was visualized in the dialyzer outlet potting using a 3-dimensional computed tomography (CT) scanning technique on micrometer resolution. RESULTS: No sessions had to be prematurely interrupted because of circuit clotting. The relative number of open fibers post dialysis was not influenced by the reduction of anticoagulation in the Solacea making this dialyzer superior in fiber patency in this setting above both the FX800 with reduced anticoagulation and the Evodial with no anticoagulation. Furthermore, no differences in relative number of open fibers were found in the FX800 and Evodial dialyzers with versus without albumin priming. CONCLUSION: In situations in which reduced anticoagulation is indicated, the asymmetric triacetate ATA Solacea dialyzer outperforms a dialyzer with a conventional polysulfone membrane (FX800) or with the heparin-coated polyacrylonitrile membrane (Evodial). The use of human albumin to prime the dialysis circuit did not improve dialyzer patency.

Micro-computed tomography for the quantification of blocked fibers in hemodialyzers.

A novel technique based on micro-CT scanning is developed to quantify coagulation in fibers of hemodialyzers. This objectivation is needed to allow accurate assessment of thrombogenicity of dialyzers used during hemodialysis, for example when comparing different strategies to avoid coagulation and/or fiber blocking. The protocol allowed imaging at a resolution of 25 µm, making it possible to count the open, non-coagulated fibers in a non-invasive way. In 3 fresh, non-used FX600 hemodialyzers, patent fiber counts were extremely consistent (10748 ± 2). To illustrate the potential of this technique, different dialysis parameters currently used as surrogates for fiber blocking were evaluated during 20 hemodialysis sessions. After dialysis, the FX600 dialyzers were visually scored for clotting, dried and subsequently weighed and scanned. The number of patent fibers (10003 [8763,10330], range 534-10692) did not correlate with any of the recorded surrogate parameters. Micro-CT scanning is a feasible, objective, non-invasive, accurate and reproducible tool for quantification of the degree of fiber blocking in a hemodialyzer after use, making it a potential gold standard for use in studies on fiber blocking during renal replacement therapies.

Selecting a strategy for prevention of contrast-induced nephropathy in clinical practice: an evaluation of different clinical practice guidelines using the AGREE tool.

BACKGROUND: Contrast-induced acute kidney injury (CI-AKI) is a potential complication of radio-contrast investigations. Many organisations have published guidance documents on the prevention of CI-AKI. Our aim is to explore the scope, content, consistency, practicality in clinical practice and reasons for eventual underlying discrepancies of these documents. METHODS: We searched the literature for guidance documents developed to guide prevention of CI-AKI up to 09/2014. Four reviewers appraised guideline quality using the 23-item AGREE-II instrument, which rates reporting of the guidance development process across six domains: scope and purpose, stakeholder involvement, rigour of development, clarity of presentation, applicability and editorial independence. Total scores were calculated as standardised averages by domain. RESULTS: Twenty-four guidance documents were evaluated. The guidance documents were produced by radiologists (N = 7), intensivists (N = 2), nephrologists (N = 6) or multidisciplinary teams (N = 9). One document did not mention the background of the authors. Only guidance documents (N = 15) that were not mere adaptations of existing guidelines were evaluated more in depth, using the AGREE tool. Overall, quality was mixed: only one clinical practice guidance document obtained an average score of >50% for all domains. The evidence was rated in a systematic way in only 11, and only 7 graded the strength of the recommendations. The Kidney Diseases Improving Global Outcomes guideline was the only one recommended without adaptions by all assessors. The guidance documents agreed in recommending pre-hydration as the main preventive measure, but there was difference in recommended total volumes, composition, rate and duration of the infused solutions. There was no consensus on the use of NaHCO3, with eight recommending it, six considering it and one not. Five guidance documents mentioned oral pre-hydration as a possibility, and none recommended N-acetylcysteine as solitary preventive measure. More recent guidance documents recommend avoiding hypertonic contrast media, but did not recommend preference of iso-osmolar over low-osmolar contrast media. Most guidance documents recognised pre-existing chronic kidney disease, diabetes, age and cardiovascular comorbidity as risk factors. CONCLUSIONS: There seems to be a relative consensus on the need for adequate pre-hydration to avoid CI-AKI, but recommendations to define at-risk populations for whom these measures should be applied and how they should be implemented differ substantially. Based on accumulating evidence, more recent guidelines do not recommend iso-osmolar over low-osmolar contrast media, whereas all recommend avoiding hypertonic agents.