Longitudinal NGAL and cystatin C plasma profiles present a high level of heterogeneity in a mixed ICU population.

BACKGROUND: NGAL and Cystatin C (CysC) as biomarkers for the early detection of AKI are subject to both pathophysiological, as well as patient related heterogeneity. The aim of this study was to investigate the timeline of plasma levels of NGAL and CysC during the first seven days of ICU admission in a mixed ICU population and to relate these to AKI severity during ICU stay. Via these means we aimed to bring clarity to the previously reported heterogeneity of these renal biomarkers. METHODS: Prospective Observation Cohort. Consecutive patients admitted to adult ICU at an academic hospital in the Netherlands between 18-02-2014 and 31-03-2014 were included. Urine output, serum creatinine, plasma NGAL and CysC were recorded during the first seven days of ICU admission. Biomarker expression was analyzed based on KDIGO score and time of AKI diagnosis. RESULTS: 335 patients were included, 110 met KDIGO criteria for AKI. NGAL and CysC plasma levels were higher in AKI patients compared to non-AKI, high variability in individual values resulted in 56% of AKI patients having a false negative, and 32% of non-AKI patients having a false positive. Individual biomarker levels were variable, and no pattern based on KDIGO score was observed. CONCLUSIONS: Plasma NGAL and CysC as biomarkers for the early AKI detection may be subject to pathophysiological, and patient related heterogeneity. Further understanding of individual biomarker profiles may help in their application amongst mixed ICU populations. TRIAL REGISTRATION: The need for informed consent was waived by the Institutional Ethical Review Board of the University Medical Center Groningen (METc 2013 - 174) by Prof. dr. W.A. Kamps on May 17th 2013.

How clinicians discuss patients' donor registrations of consent and presumed consent in donor conversations in an opt-out system: a qualitative embedded multiple-case study.

BACKGROUND: The Netherlands introduced an opt-out donor system in 2020. While the default in (presumed) consent cases is donation, family involvement adds a crucial layer of influence when applying this default in clinical practice. We explored how clinicians discuss patients' donor registrations of (presumed) consent in donor conversations in the first years of the opt-out system. METHODS: A qualitative embedded multiple-case study in eight Dutch hospitals. We performed a thematic analysis based on audio recordings and direct observations of donor conversations (n = 15, 7 consent and 8 presumed consent) and interviews with the clinicians involved (n = 16). RESULTS: Clinicians' personal considerations, their prior experiences with the family and contextual factors in the clinicians' profession defined their points of departure for the conversations. Four routes to discuss patients' donor registrations were constructed. In the Consent route (A), clinicians followed patients' explicit donation wishes. With presumed consent, increased uncertainty in interpreting the donation wish appeared and prompted clinicians to refer to "the law" as a conversation starter and verify patients' wishes multiple times with the family. In the Presumed consent route (B), clinicians followed the law intending to effectuate donation, which was more easily achieved when families recognised and agreed with the registration. In the Consensus route (C), clinicians provided families some participation in decision-making, while in the Family consent route (D), families were given full decisional capacity to pursue optimal grief processing. CONCLUSION: Donor conversations in an opt-out system are a complex interplay between seemingly straightforward donor registrations and clinician-family interactions. When clinicians are left with concerns regarding patients' consent or families' coping, families are given a larger role in the decision. A strict uniform application of the opt-out system is unfeasible. We suggest incorporating the four previously described routes in clinical training, stimulating discussions across cases, and encouraging public conversations about donation.

Criteria for Continuous Kidney Replacement Therapy Cessation in ICU Patients.

INTRODUCTION: In intensive care unit (ICU) patients with acute kidney injury, specific recommendations to guide the decision to cease continuous kidney replacement therapy (CKRT) are lacking. METHODS: We performed a survey to identify criteria currently used to cease CKRT in real-life clinical practice in the Netherlands. We used an online questionnaire with multiple choice questions designed with web-based software from SurveyMonkey. RESULTS: We received 169 completed questionnaires from intensivists (n = 126) and nephrologists (n = 43). Essential determinants for the cessation of CKRT were a spontaneously increasing diuresis (indicated by 92% of the respondents), absence of fluid overload (indicated by 88% of the respondents), and improvement in creatinine clearance (indicated by 61% of the respondents; intensivists 56%; nephrologists 77%, p = 0.03). Most often mentioned cut-off values used for increase in diuresis were 0.25 and 0.5 mL/kg/h (35% and 33%, respectively). Actual CKRT cessation was often postponed until the filter clots or until circuit disconnection is needed because of patient transport for diagnostic or intervention procedures (indicated by 58% of the respondents). Expected discharge from the ICU was the most frequently reported determinant to switch from CKRT to hemodialysis (indicated by 67% of the respondents). CONCLUSIONS: CKRT cessation in clinical practice is mostly based on spontaneously increasing diuresis, absence of fluid overload, and improvement in creatinine clearance and is often delayed until filter clotting or disconnection of the circuit because of logistic reasons.

Acute and chronic histopathological findings in renal biopsies in COVID-19.

The dominant ICU admission diagnosis of COVID-19 patients is respiratory insufficiency, but 32-57% of hospitalized COVID-19 patients develop acute kidney injury (COVID-AKI). The renal histopathological changes accompanying COVID-AKI are not yet fully described. To obtain a detailed insight into renal histopathological features of COVID-19, we conducted a review including all studies reporting histopathological findings of diagnostic and postmortem kidney biopsies from patients with COVID-19 published between January 1, 2020, and January 31, 2021. A total of 89 diagnostic and 194 postmortem renal biopsies from individual patients in 39 published studies were investigated and were included in the analysis. In the diagnostic biopsy group, mean age was 56 years and AKI incidence was 96%. In the postmortem biopsy group, mean age was 69 years and AKI incidence was 80%. In the diagnostic biopsy group, the prevalence of acute glomerular diseases was 74%. The most common glomerular lesions were collapsing focal segmental glomerulosclerosis (c-FSGS) in 54% and thrombotic microangiopathy (TMA) in 9% of patients. TMA was also found in 10% of patients in the postmortem biopsy group. The most common acute tubular lesions was acute tubular necrosis (ATN) which was present in 87% of patients in the diagnostic and in 77% of patients in the postmortem biopsy group. Additionally, we observed a high prevalence of preexisting chronic lesions in both groups such as atherosclerosis and glomerulosclerosis. Histopathological changes in renal biopsies of COVID-19 patients show a heterogeneous picture with acute glomerular lesions, predominantly c-FSGS and TMA, and acute tubular lesions, predominantly ATN. In many patients, these lesions were present on a background of chronic renal injury.

Prospective Multicenter Observational Cohort Study on Time to Death in Potential Controlled Donation After Circulatory Death Donors-Development and External Validation of Prediction Models: The DCD III Study.

BACKGROUND: Acceptance of organs from controlled donation after circulatory death (cDCD) donors depends on the time to circulatory death. Here we aimed to develop and externally validate prediction models for circulatory death within 1 or 2 h after withdrawal of life-sustaining treatment. METHODS: In a multicenter, observational, prospective cohort study, we enrolled 409 potential cDCD donors. For model development, we applied the least absolute shrinkage and selection operator (LASSO) regression and machine learning-artificial intelligence analyses. Our LASSO models were validated using a previously published cDCD cohort. Additionally, we validated 3 existing prediction models using our data set. RESULTS: For death within 1 and 2 h, the area under the curves (AUCs) of the LASSO models were 0.77 and 0.79, respectively, whereas for the artificial intelligence models, these were 0.79 and 0.81, respectively. We were able to identify 4% to 16% of the patients who would not die within these time frames with 100% accuracy. External validation showed that the discrimination of our models was good (AUCs 0.80 and 0.82, respectively), but they were not able to identify a subgroup with certain death after 1 to 2 h. Using our cohort to validate 3 previously published models showed AUCs ranging between 0.63 and 0.74. Calibration demonstrated that the models over- and underestimated the predicted probability of death. CONCLUSIONS: Our models showed a reasonable ability to predict circulatory death. External validation of our and 3 existing models illustrated that their predictive ability remained relatively stable. We accurately predicted a subset of patients who died after 1 to 2 h, preventing starting unnecessary donation preparations, which, however, need external validation in a prospective cohort.

Comparison of renal histopathology and gene expression profiles between severe COVID-19 and bacterial sepsis in critically ill patients.

BACKGROUND: The mechanisms driving acute kidney injury (AKI) in critically ill COVID-19 patients are unclear. We collected kidney biopsies from COVID-19 AKI patients within 30 min after death in order to examine the histopathology and perform mRNA expression analysis of genes associated with renal injury. METHODS: This study involved histopathology and mRNA analyses of postmortem kidney biopsies collected from patients with COVID-19 (n = 6) and bacterial sepsis (n = 27). Normal control renal tissue was obtained from patients undergoing total nephrectomy (n = 12). The mean length of ICU admission-to-biopsy was 30 days for COVID-19 and 3-4 days for bacterial sepsis patients. RESULTS: We did not detect SARS-CoV-2 RNA in kidney biopsies from COVID-19-AKI patients yet lung tissue from the same patients was PCR positive. Extensive acute tubular necrosis (ATN) and peritubular thrombi were distinct histopathology features of COVID-19-AKI compared to bacterial sepsis-AKI. ACE2 mRNA levels in both COVID-19 (fold change 0.42, p = 0.0002) and bacterial sepsis patients (fold change 0.24, p < 0.0001) were low compared to control. The mRNA levels of injury markers NGAL and KIM-1 were unaltered compared to control tissue but increased in sepsis-AKI patients. Markers for inflammation and endothelial activation were unaltered in COVID-19 suggesting a lack of renal inflammation. Renal mRNA levels of endothelial integrity markers CD31, PV-1 and VE-Cadherin did not differ from control individuals yet were increased in bacterial sepsis patients (CD31 fold change 2.3, p = 0.0006, PV-1 fold change 1.5, p = 0.008). Angiopoietin-1 mRNA levels were downregulated in renal tissue from both COVID-19 (fold change 0.27, p < 0.0001) and bacterial sepsis patients (fold change 0.67, p < 0.0001) compared to controls. Moreover, low Tie2 mRNA expression (fold change 0.33, p = 0.037) and a disturbed VEGFR2/VEGFR3 ratio (fold change 0.09, p < 0.0001) suggest decreased microvascular flow in COVID-19. CONCLUSIONS: In a small cohort of postmortem kidney biopsies from COVID-19 patients, we observed distinct histopathological and gene expression profiles between COVID-19-AKI and bacterial sepsis-AKI. COVID-19 was associated with more severe ATN and microvascular thrombosis coupled with decreased microvascular flow, yet minimal inflammation. Further studies are required to determine whether these observations are a result of true pathophysiological differences or related to the timing of biopsy after disease onset.

A new tool to assess Clinical Diversity In Meta-analyses (CDIM) of interventions.

OBJECTIVE: To develop and validate Clinical Diversity In Meta-analyses (CDIM), a new tool for assessing clinical diversity between trials in meta-analyses of interventions. STUDY DESIGN AND SETTING: The development of CDIM was based on consensus work informed by empirical literature and expertise. We drafted the CDIM tool, refined it, and validated CDIM for interrater scale reliability and agreement in three groups. RESULTS: CDIM measures clinical diversity on a scale that includes four domains with 11 items overall: setting (time of conduct/country development status/units type); population (age, sex, patient inclusion criteria/baseline disease severity, comorbidities); interventions (intervention intensity/strength/duration of intervention, timing, control intervention, cointerventions); and outcome (definition of outcome, timing of outcome assessment). The CDIM is completed in two steps: first two authors independently assess clinical diversity in the four domains. Second, after agreeing upon scores of individual items a consensus score is achieved. Interrater scale reliability and agreement ranged from moderate to almost perfect depending on the type of raters. CONCLUSION: CDIM is the first tool developed for assessing clinical diversity in meta-analyses of interventions. We found CDIM to be a reliable tool for assessing clinical diversity among trials in meta-analysis.

External Validation of the DCD-N Score and a Linear Prediction Model to Identify Potential Candidates for Organ Donation After Circulatory Death: A Nationwide Multicenter Cohort Study.

BACKGROUND: Donation after circulatory death (DCD) is a procedure in which after planned withdrawal of life-sustaining treatment (WLST), the dying process is monitored. A DCD procedure can only be continued if the potential organ donor dies shortly after WLST. This study performed an external validation of 2 existing prediction models to identify potentially DCD candidates, using one of the largest cohorts. METHODS: This multicenter retrospective study analyzed all patients eligible for DCD donation from 2010 to 2015. The first model (DCD-N score) assigned points for absence of neurological reflexes and oxygenation index. The second model, a linear prediction model (LPDCD), yielded the probability of death within 60 min. This study determined discrimination (c-statistic) and calibration (Hosmer and Lemeshow test) for both models. RESULTS: This study included 394 patients, 283 (72%) died within 60 min after WLST. The DCD-N score had a c-statistic of 0.77 (95% confidence intervals, 0.71-0.83) and the LPDCD model 0.75 (95% confidence intervals, 0.68-0.81). Calibration of the LPDCD 60-min model proved to be poor (Hosmer and Lemeshow test, P < 0.001). CONCLUSIONS: The DCD-N score and the LPDCD model showed good discrimination but poor calibration for predicting the probability of death within 60 min. Construction of a new prediction model on a large data set is needed to obtain better calibration.

A Method to Improve Continuous Renal Replacement Therapy Circuit Survival Time in Critically Ill Coronavirus Disease 2019 Patients With Acute Kidney Injury.

OBJECTIVES: Optimizing continuous renal replacement therapy circuit survival in coronavirus disease 2019 patients admitted to the ICU. DESIGN: Single-center prospective observational cohort study. SETTING: Tertiary academic teaching ICU. PATIENTS: Between March 19, 2020, and May 18, 2020, 11 out of 101 coronavirus disease 2019 patients were treated with continuous renal replacement therapy comprising 127 continuous renal replacement therapy days. INTERVENTIONS: A nonrandomized observational comparison of circuit anticoagulation modalities using standard regional citrate anticoagulation, continuous IV heparin anticoagulation, or the combination of regional citrate anticoagulation with either continuous IV heparin or therapeutic dose nadroparin. MEASUREMENTS AND MAIN RESULTS: Circuit patency was shorter than 24 hours using standard regional citrate anticoagulation or continuous IV heparin anticoagulation. Median circuit survival increased with at least 165% when the combination of regional citrate anticoagulation with either continuous IV heparin or therapeutic dose nadroparin was applied. CONCLUSIONS: Continuous renal replacement therapy circuit patency is diminished in coronavirus disease 2019 ICU patients. Combining regional citrate anticoagulation with either continuous IV heparin or therapeutic dose nadroparin increases filter survival as compared with regional citrate anticoagulation alone in this nonrandomized observational study.

[The new Dutch Donor Act and Organ Donation]. / De nieuwe donorwet en orgaandonatie.

On 1 July 2020, the new Dutch Donor Act with an Active Donor Registration system will become effective. Consequent changes in clinical practice and matters related to dealing with a patient's family are described by means of an illustrative case history of a 53-year-old fictive female patient. Furthermore, the implications of an earlier change in the Dutch Donor Act in 2013 are discussed.

Determining the impact of timing and of clinical factors during end-of-life decision-making in potential controlled donation after circulatory death donors.

Controlled donation after circulatory death (cDCD) occurs after a decision to withdraw life-sustaining treatment and subsequent family approach and approval for donation. We currently lack data on factors that impact the decision-making process on withdraw life-sustaining treatment and whether time from admission to family approach, influences family consent rates. Such insights could be important in improving the clinical practice of potential cDCD donors. In a prospective multicenter observational study, we evaluated the impact of timing and of the clinical factors during the end-of-life decision-making process in potential cDCD donors. Characteristics and medication use of 409 potential cDCD donors admitted to the intensive care units (ICUs) were assessed. End-of-life decision-making was made after a mean time of 97 hours after ICU admission and mostly during the day. Intracranial hemorrhage or ischemic stroke and a high APACHE IV score were associated with a short decision-making process. Preserved brainstem reflexes, high Glasgow Coma Scale scores, or cerebral infections were associated with longer time to decision-making. Our data also suggest that the organ donation request could be made shortly after the decision to stop active treatment and consent rates were not influenced by daytime or nighttime or by the duration of the ICU stay.

Urinary creatinine excretion is related to short-term and long-term mortality in critically ill patients.

PURPOSE: Patients with reduced muscle mass have a worse outcome, but muscle mass is difficult to quantify in the ICU. Urinary creatinine excretion (UCE) reflects muscle mass, but has not been studied in critically ill patients. We evaluated the relation of baseline UCE with short-term and long-term mortality in patients admitted to our ICU. METHODS: Patients who stayed ≥ 24 h in the ICU with UCE measured within 3 days of admission were included. We excluded patients who developed acute kidney injury stage 3 during the first week of ICU stay. As muscle mass is considerably higher in men than women, we used sex-stratified UCE quintiles. We assessed the relation of UCE with both in-hospital mortality and long-term mortality. RESULTS: From 37,283 patients, 6151 patients with 11,198 UCE measurements were included. Mean UCE was 54% higher in males compared to females. In-hospital mortality was 17%, while at 5-year follow-up, 1299 (25%) patients had died. After adjustment for age, sex, estimated glomerular filtration rate, body mass index, reason for admission and disease severity, patients in the lowest UCE quintile had an increased in-hospital mortality compared to the patients in the highest UCE quintile (OR 2.56, 95% CI 1.96-3.34). For long-term mortality, the highest risk was also observed for patients in the lowest UCE quintile (HR 2.32, 95% CI 1.89-2.85), independent of confounders. CONCLUSIONS: In ICU patients without severe renal dysfunction, low urinary creatinine excretion is associated with short-term and long-term mortality, independent of age, sex, renal function and disease characteristics, underscoring the role of muscle mass as risk factor for mortality and UCE as relevant biomarker.

RAte Control Efficacy in permanent atrial fibrillation: a comparison between lenient versus strict rate control in patients with and without heart failure. Background, aims, and design of RACE II.

BACKGROUND: Recent studies demonstrated that rate control is an acceptable alternative for rhythm control in patients with persistent atrial fibrillation (AF). However, optimal heart rate during AF is still unknown. OBJECTIVE: To show that in patients with permanent AF, lenient rate control is not inferior to strict rate control in terms of cardiovascular mortality, morbidity, neurohormonal activation, New York Heart Association class for heart failure, left ventricular function, left atrial size, quality of life, and costs. METHODS: The RACE II study is a prospective multicenter trial in The Netherlands that will randomize 500 patients with permanent AF (< or = 12 months) to strict or lenient rate control. Strict rate control is defined as a mean resting heart rate < 80 beats per minute (bpm) and heart rate during minor exercise < 110 bpm. After reaching the target, a 24-hour Holter monitoring will be performed. If necessary, drug dose reduction and/or pacemaker implantation will be performed. Lenient rate control is defined as a resting heart rate < 110 bpm. Patients will be seen after 1, 2, and 3 months (for titration of rate control drugs) and yearly thereafter. We anticipate a 25% 2.5-year cardiovascular morbidity and mortality in both groups. RESULTS: Enrollment started in January 2005 in 29 centers in The Netherlands and is expected to be concluded in June 2006. Follow-up will be at least 2 years with a maximum of 3 years. CONCLUSION: This study should provide data how to treat patients with permanent AF.

Usefulness of preoperative C-reactive protein and soluble intercellular adhesion molecule-1 level for predicting future cardiovascular events after coronary artery bypass grafting.

High levels of C-reactive protein and soluble intercellular adhesion molecule-1 are associated with increased risk for cardiovascular events. No long-term data are available on predictive value of preoperative levels of C-reactive protein and soluble intercellular adhesion molecule-1 on outcome after coronary artery bypass grafting. We measured baseline levels of C-reactive protein and soluble intercellular adhesion molecule-1 in preoperative serum stored at -80 degrees C in 87 patients with coronary artery disease before undergoing isolated coronary artery bypass grafting. Follow-up was performed after a mean duration of 7.6+/-0.1 years, and all cardiovascular events were recorded. Data were analyzed by categorizing patients into 2 groups according to median value of C-reactive protein and soluble intercellular adhesion molecule-1. During follow-up, 16 patients developed a cardiovascular event. In patients with C-reactive protein above the median (1.9 mg/L), the cumulative cardiovascular event incidence was 29% compared with 9% in patients with levels below the median (p=0.048). In Cox regression analysis that was corrected for age, gender, and conventional risk factors, the adjusted relative risk of cardiovascular events of C-reactive protein above the median was 3.9 (95% confidence interval 1.1 to 13.9, p <0.05). Soluble intercellular adhesion molecule-1 level above the median (136 microg/L) was associated with a cumulative cardiovascular event incidence of 21% versus 16% below the median (p=0.48). In conclusion, in patients who undergo coronary artery bypass grafting, high preoperative levels of C-reactive protein levels, but not of soluble intercellular adhesion molecule-1, were associated with long-term risk of cardiovascular events, independent of other cardiac risk factors.