The Clearance of Midazolam and Metabolites during Continuous Renal Replacement Therapy in Critically Ill Patients with COVID-19.

INTRODUCTION: Midazolam-based continuous intravenous sedation in patients admitted to the intensive care unit (ICU) was a necessity during the COVID-19 pandemic. However, benzodiazepine-based sedation is associated with a high incidence of benzodiazepine-related delirium and additional days on mechanical ventilation. Due to the requirement of high midazolam doses in combination with the impaired renal clearance (CL) of the pharmacological active metabolite 1-OH-midazolam-glucuronide (10% compared to midazolam), ICU patients with COVID-19 and continuous renal replacement therapy (CRRT) were at risk of unintended prolonged sedation. Several CRRT-related factors may have influenced the delivered CL of midazolam and its metabolites. Therefore, the aim of the study was to identify and describe these CRRT-related factors. METHODS: Pre-filter blood samples and ultrafiltrate samples were collected simultaneously. Midazolam, 1-OH-midazolam, and 1-OH-midazolam-glucuronide plasma samples were analyzed using an UPLC-MS/MS method. The prescribed CRRT dose was corrected for downtime and filter integrity using the urea ratio (urea concentration in effluent/urea concentration plasma). CL of midazolam and its metabolites were calculated with the delivered CRRT dose (corrected for downtime and saturation coefficient [SD]). RESULTS: Three patients on continuous venovenous hemodialysis (CVVHD) and 2 patients on continuous venovenous hemodiafiltration (CVVHDF) were included. Midazolam, 1-OH-midazolam, and 1-OH-midazolam-glucuronide concentrations were 2,849 (0-6,700) µg/L, 153 (0-295) µg/L, and 27,297 (1,727-39,000) µg/L, respectively. The SD was 0.03 (0.02-0.03) for midazolam, 0.05 (0.05-0.06) for 1-OH-midazolam, and 0.33 (0.23-0.43) for 1-OH-midazolam-glucuronide. The delivered CRRT CL was 1.4 (0-1.7) mL/min for midazolam, 2.7 (0-3.5) mL/min for 1-OH-midazolam, and 15.7 (4.0-27.7) mL/min for 1-OH-midazolam-glucuronide. CONCLUSIONS: Midazolam and 1-OH-midazolam were not removed during CVVHD and CVVHDF. However, 1-OH-midazolam-glucuronide was removed reasonably, approximately up to 43%. CRRT modality, filter integrity, and downtime affect this removal. These data imply a personalized titration of midazolam in critically ill patients with renal failure and awareness for the additional sedative effects of its active metabolites.

Pursuing the Real Vancomycin Clearance during Continuous Renal Replacement Therapy in Intensive Care Unit Patients: Is There Adequate Target Attainment?

INTRODUCTION: Vancomycin is used in intensive care unit (ICU) patients for the treatment of infections caused by gram-positive bacteria. The vancomycin pharmacokinetic/pharmacodynamic index is a ratio of the area under the concentration to the minimum inhibitory concentration ≥400-600 h*mg/L. This target can generally be achieved by a plasma concentration of 20-25 mg/L. Together with the pathophysiological alterations and pharmacokinetic variability associated with critical illness, the use of continuous renal replacement therapy (CRRT) may complicate the attainment of adequate vancomycin concentrations. The primary objective was the prevalence of attainment of vancomycin concentrations 20-25 mg/L after 24 h in adult ICU patients receiving CRRT. Secondary outcomes were to evaluate target attainment at days 2 and 3 and to calculate vancomycin clearance (CL) by CRRT and residual diuresis. METHODS: We performed a prospective observational study in adult ICU patients on CRRT, which received at least 24 h continuous infusion of vancomycin. Between May 2020 and February 2021, daily vancomycin residual blood gas and dialysate samples were collected from 20 patients, every 6 h and if possible vancomycin urine samples. Vancomycin was analysed with an immunoassay method. The CL by CRRT was calculated by a different approach correcting for the downtime and providing insight into the degree of filter patency. RESULTS: The proportion of patients with vancomycin concentrations <20 mg/L was 50% 24 h after starting vancomycin (n = 10). No differences were observed in patient characteristics. The target vancomycin concentration 20-25 mg/L was only achieved in 30% of the patients. On days 2 and 3, despite the use of TDM and albeit in lower percentages, sub- and supratherapeutic levels were still observed. Taking downtime and filter patency into account resulted in lower vancomycin CL. CONCLUSIONS: 50% of the studied ICU patients on CRRT showed subtherapeutic vancomycin concentrations 24 h after starting therapy. The results reveal that optimization of vancomycin dosage during CRRT therapy is needed.

The Seraph®-100 Microbind Affinity Blood Filter Does Not Affect Vancomycin, Tacrolimus, and Mycophenolic Acid Plasma Concentrations.

Extracorporeal blood purification is considered an adjunct therapy in critically ill patients with life-threatening conditions such as sepsis and septic shock. It consists of cytokine removal, removal of endotoxins, a combination of both, or the removal of pathogens themselves. The latter technique was introduced for clinical application very recently. This case study describes a case of a 69-year-old female lung transplant recipient patient with a persistent VV-ECMO-related septic deep vein thrombosis with continuous renal replacement therapy-dependent acute kidney injury initiated on the Seraph®-100 Microbind Affinity Filter in order to control the persistent bacteraemia with coagulase-negative staphylococci. Drug plasma concentrations (vancomycin, tacrolimus, and mycophenolic acid) were measured before and after the device to calculate absorber-related drug clearance.

Neutrophil Gelatinase-Associated Lipocalin Measured on Clinical Laboratory Platforms for the Prediction of Acute Kidney Injury and the Associated Need for Dialysis Therapy: A Systematic Review and Meta-analysis.

RATIONALE & OBJECTIVE: The usefulness of measures of neutrophil gelatinase-associated lipocalin (NGAL) in urine or plasma obtained on clinical laboratory platforms for predicting acute kidney injury (AKI) and AKI requiring dialysis (AKI-D) has not been fully evaluated. We sought to quantitatively summarize published data to evaluate the value of urinary and plasma NGAL for kidney risk prediction. STUDY DESIGN: Literature-based meta-analysis and individual-study-data meta-analysis of diagnostic studies following PRISMA-IPD guidelines. SETTING & STUDY POPULATIONS: Studies of adults investigating AKI, severe AKI, and AKI-D in the setting of cardiac surgery, intensive care, or emergency department care using either urinary or plasma NGAL measured on clinical laboratory platforms. SELECTION CRITERIA FOR STUDIES: PubMed, Web of Science, Cochrane Library, Scopus, and congress abstracts ever published through February 2020 reporting diagnostic test studies of NGAL measured on clinical laboratory platforms to predict AKI. DATA EXTRACTION: Individual-study-data meta-analysis was accomplished by giving authors data specifications tailored to their studies and requesting standardized patient-level data analysis. ANALYTICAL APPROACH: Individual-study-data meta-analysis used a bivariate time-to-event model for interval-censored data from which discriminative ability (AUC) was characterized. NGAL cutoff concentrations at 95% sensitivity, 95% specificity, and optimal sensitivity and specificity were also estimated. Models incorporated as confounders the clinical setting and use versus nonuse of urine output as a criterion for AKI. A literature-based meta-analysis was also performed for all published studies including those for which the authors were unable to provide individual-study data analyses. RESULTS: We included 52 observational studies involving 13,040 patients. We analyzed 30 data sets for the individual-study-data meta-analysis. For AKI, severe AKI, and AKI-D, numbers of events were 837, 304, and 103 for analyses of urinary NGAL, respectively; these values were 705, 271, and 178 for analyses of plasma NGAL. Discriminative performance was similar in both meta-analyses. Individual-study-data meta-analysis AUCs for urinary NGAL were 0.75 (95% CI, 0.73-0.76) and 0.80 (95% CI, 0.79-0.81) for severe AKI and AKI-D, respectively; for plasma NGAL, the corresponding AUCs were 0.80 (95% CI, 0.79-0.81) and 0.86 (95% CI, 0.84-0.86). Cutoff concentrations at 95% specificity for urinary NGAL were>580ng/mL with 27% sensitivity for severe AKI and>589ng/mL with 24% sensitivity for AKI-D. Corresponding cutoffs for plasma NGAL were>364ng/mL with 44% sensitivity and>546ng/mL with 26% sensitivity, respectively. LIMITATIONS: Practice variability in initiation of dialysis. Imperfect harmonization of data across studies. CONCLUSIONS: Urinary and plasma NGAL concentrations may identify patients at high risk for AKI in clinical research and practice. The cutoff concentrations reported in this study require prospective evaluation.

Successful Reduction of Creatine Kinase and Myoglobin Levels in Severe Rhabdomyolysis Using Extracorporeal Blood Purification (CytoSorb®).

Rhabdomyolysis, if severe, can lead to acute kidney injury (AKI). Myoglobin is an iron and oxygen-binding protein that is freely filtered by the glomerulus. Precipitation of myoglobin in the nephrons' distal parts is responsible for tubular damage with AKI as a consequence. Extracorporeal clearance of myoglobin is conventionally attempted by the use of continuous renal replacement therapy (CRRT) with high cut-off dialysis membranes to limit the extent of the damage. We describe a case of a 56-year-old man with traumatic crush injury and a persistent source of muscle ischaemia unresponsive to high dose CRRT with EMiC-2 filter. Due to therapy failure, he was subsequently treated with the addition of a haemoadsorber (CytoSorb®) to the circuit. This reduced myoglobin and creatine kinase levels successfully despite ongoing tissue ischaemia. However, CytoSorb® was not enough to maintain microcirculatory perfusion, resulting in the eventual demise of the patient due to severity of the injury. Our report indicates that myoglobin was efficiently removed with CytoSorb® following exchange with the conventional high cut-off filter in continuous venovenous haemodialysis in severe traumatic rhabdomyolysis.

The aftermath of acute kidney injury: a narrative review of long-term mortality and renal function.

Acute kidney injury (AKI) is a frequent complication of hospitalization and is associated with an increased risk of chronic kidney disease (CKD), end-stage renal disease (ESRD), and mortality. While AKI is a known risk factor for short-term adverse outcomes, more recent data suggest that the risk of mortality and renal dysfunction extends far beyond hospital discharge. However, determining whether this risk applies to all patients who experience an episode of AKI is difficult. The magnitude of this risk seems highly dependent on the presence of comorbid conditions, including cardiovascular disease, hypertension, diabetes mellitus, preexisting CKD, and renal recovery. Furthermore, these comorbidities themselves lead to structural renal damage due to multiple pathophysiological changes, including glomeruloscleroses and tubulointerstitial fibrosis, which can lead to the loss of residual capacity, glomerular hyperfiltration, and continued deterioration of renal function. AKI seems to accelerate this deterioration and increase the risk of death, CDK, and ESRD in most vulnerable patients. Therefore, we strongly advocate adequate hemodynamic monitoring and follow-up in patients susceptible to renal dysfunction. Additionally, other potential renal stressors, including nephrotoxic medications and iodine-containing contrast fluids, should be avoided. Unfortunately, therapeutic interventions are not yet available. Additional research is warranted and should focus on the prevention of AKI, identification of therapeutic targets, and provision of adequate follow-up to those who survive an episode of AKI.

Successful Treatment of Severe Hyperammonaemia with Ultra-High Dose Continuous Veno-Venous Haemodiafiltration.

Hyperammonaemia is a severe condition and often requires a multimodal treatment regimen. Dialysis has been described as a potential treatment option, but currently it is not the standard of care. In this report, we describe a case of a 40-year-old postpartum woman who developed severe hyperammonaemia due to liver failure and acute kidney injury (AKI) combined with a large intra-abdominal haematoma producing nitrogen waste products. She was treated successfully with continuous veno-venous haemodiafiltration using an ultra-high effluent rate (100 mL/kg/h) and was discharged alive 32 days after the initial admission. Our report indicates that successful ammonia clearance in the setting of AKI can be obtained only by using this high effluent rate. This treatment modality should be considered in all patients with AKI and severe hyperammonaemia when other treatment modalities fail to lower ammonia levels within hours to prevent irreversible but preventable neurological damage.

Effect of Human Recombinant Alkaline Phosphatase on 7-Day Creatinine Clearance in Patients With Sepsis-Associated Acute Kidney Injury: A Randomized Clinical Trial.

Importance: Sepsis-associated acute kidney injury (AKI) adversely affects long-term kidney outcomes and survival. Administration of the detoxifying enzyme alkaline phosphatase may improve kidney function and survival. Objective: To determine the optimal therapeutic dose, effect on kidney function, and adverse effects of a human recombinant alkaline phosphatase in patients who are critically ill with sepsis-associated AKI. Design, Setting, and Participants: The STOP-AKI trial was an international (53 recruiting sites), randomized, double-blind, placebo-controlled, dose-finding, adaptive phase 2a/2b study in 301 adult patients admitted to the intensive care unit with a diagnosis of sepsis and AKI. Patients were enrolled between December 2014 and May 2017, and follow-up was conducted for 90 days. The final date of follow-up was August 14, 2017. Interventions: In the intention-to-treat analysis, in part 1 of the trial, patients were randomized to receive recombinant alkaline phosphatase in a dosage of 0.4 mg/kg (n = 31), 0.8 mg/kg (n = 32), or 1.6 mg/kg (n = 29) or placebo (n = 30), once daily for 3 days, to establish the optimal dose. The optimal dose was identified as 1.6 mg/kg based on modeling approaches and adverse events. In part 2, 1.6 mg/kg (n = 82) was compared with placebo (n = 86). Main Outcomes and Measures: The primary end point was the time-corrected area under the curve of the endogenous creatinine clearance for days 1 through 7, divided by 7 to provide a mean daily creatinine clearance (AUC1-7 ECC). Incidence of fatal and nonfatal (serious) adverse events ([S]AEs) was also determined. Results: Overall, 301 patients were enrolled (men, 70.7%; median age, 67 years [interquartile range {IQR}, 59-73]). From day 1 to day 7, median ECC increased from 26.0 mL/min (IQR, 8.8 to 59.5) to 65.4 mL/min (IQR, 26.7 to 115.4) in the recombinant alkaline phosphatase 1.6-mg/kg group vs from 35.9 mL/min (IQR, 12.2 to 82.9) to 61.9 mL/min (IQR, 22.7 to 115.2) in the placebo group (absolute difference, 9.5 mL/min [95% CI, -23.9 to 25.5]; P = .47). Fatal adverse events occurred in 26.3% of patients in the 0.4-mg/kg recombinant alkaline phosphatase group; 17.1% in the 0.8-mg/kg group, 17.4% in the 1.6-mg/kg group, and 29.5% in the placebo group. Rates of nonfatal SAEs were 21.0% for the 0.4-mg/kg recombinant alkaline phosphatase group, 14.3% for the 0.8-mg/kg group, 25.7% for the 1.6-mg/kg group, and 20.5% for the placebo group. Conclusions and Relevance: Among patients who were critically ill with sepsis-associated acute kidney injury, human recombinant alkaline phosphatase compared with placebo did not significantly improve short-term kidney function. Further research is necessary to assess other clinical outcomes. Trial Registration: ClinicalTrials.gov Identifier: NCT02182440.

Targeting Oliguria Reversal in Goal-Directed Hemodynamic Management Does Not Reduce Renal Dysfunction in Perioperative and Critically Ill Patients: A Systematic Review and Meta-Analysis.

BACKGROUND: We investigated whether resuscitation protocols to achieve and maintain urine output above a predefined threshold-including oliguria reversal as a target--prevent acute renal failure (ARF). METHODS: We performed a systematic review and meta-analysis using studies found by searching MEDLINE, EMBASE, and references in relevant reviews and articles. We included all studies that compared "conventional fluid management" (CFM) with "goal-directed therapy" (GDT) using cardiac output, urine output, or oxygen delivery parameters and reported the occurrence of ARF in critically ill or surgical patients. We divided studies into groups with and without oliguria reversal as a target for hemodynamic optimization. We calculated the combined odds ratio (OR) and 95% confidence intervals (CIs) using random-effects meta-analysis. RESULTS: We based our analyses on 28 studies. In the overall analysis, GDT resulted in less ARF than CFM (OR, 0.58; 95% CI, 0.44-0.76; P < 0.001; I = 34.3%; n = 28). GDT without oliguria reversal as a target resulted in less ARF (OR, 0.45; 95% CI, 0.34-0.61; P < 0.001; I = 7.1%; n = 7) when compared with CFM with oliguria reversal as a target. The studies comparing GDT with CFM in which the reversal of oliguria was targeted in both or in neither group did not provide enough evidence to conclude a superiority of GDT (targeting oliguria reversal in both protocols: OR, 0.63; 95% CI, 0.36-1.10; P = 0.09; I = 48.6%; n = 9, and in neither protocol: OR, 0.66; 95% CI, 0.37-1.16; P = 0.14; I = 20.2%; n = 12). CONCLUSIONS: Current literature favors targeting circulatory optimization by GDT without targeting oliguria reversal to prevent ARF. Future studies are needed to investigate the hypothesis that targeting oliguria reversal does not prevent ARF in critically ill and surgical patients.

Targeting oliguria reversal in perioperative restrictive fluid management does not influence the occurrence of renal dysfunction: A systematic review and meta-analysis.

BACKGROUND: Interest in perioperative fluid restriction has increased, but it could lead to hypovolaemia. Urine output is viewed as a surrogate for renal perfusion and is frequently used to guide perioperative fluid therapy. However, the rationale behind targeting oliguria reversal - achieving and maintaining urine output above a previously defined threshold by additional fluid boluses - is often questioned. OBJECTIVE: We assessed whether restrictive fluid management had an effect on oliguria, acute renal failure (ARF) and fluid intake. We also investigated whether targeting oliguria reversal affected these parameters. DESIGN: Systematic review of randomised controlled trials with meta-analyses. We used the definitions of restrictive and conventional fluid management as provided by the individual studies. DATA SOURCES: We searched MEDLINE (1966 to present), EMBASE (1980 to present), and relevant reviews and articles. ELIGIBILITY CRITERIA: We included randomised controlled trials with adult patients undergoing surgery comparing restrictive fluid management with a conventional fluid management protocol and also reporting the occurrence of postoperative ARF. RESULTS: We included 15 studies with a total of 1594 patients. There was insufficient evidence to associate restrictive fluid management with an increase in oliguria [restrictive 83/186 vs. conventional 68/230; odds ratio (OR) 2.07; 95% confidence interval (CI), 0.97 to 4.44; P = 0.06; I = 23.7%; Nstudies = 5]. The frequency of ARF in restrictive and conventional fluid management was 20/795 and 20/799, respectively (OR 1.07; 95% CI, 0.60 to 1.92; P = 0.8; I = 17.5%; Nstudies = 15). There was no statistically significant difference in ARF occurrence between studies targeting oliguria reversal and not targeting oliguria reversal (OR 0.31; 95% CI, 0.08 to 1.22; P = 0.088). Intraoperative fluid intake was 1.89 l lower in restrictive than in conventional fluid management when not targeting oliguria reversal (95% CI, -2.59 to -1.20 l; P < 0.001; I = 96.6%; Nstudies = 7), and 1.63 l lower when targeting oliguria reversal (95% CI, -2.52 to -0.74 l; P < 0.001; I = 96.6%; Nstudies = 6). CONCLUSION: Our data suggest that, even though event numbers are small, perioperative restrictive fluid management does not increase oliguria or postoperative ARF while decreasing intraoperative fluid intake, irrespective of targeting reversal of oliguria or not.

Vitamin D deficiency as a risk factor for infection, sepsis and mortality in the critically ill: systematic review and meta-analysis.

INTRODUCTION: In Europe, vitamin D deficiency is highly prevalent varying between 40% and 60% in the healthy general adult population. The consequences of vitamin D deficiency for sepsis and outcome in critically ill patients remain controversial. We therefore systematically reviewed observational cohort studies on vitamin D deficiency in the intensive care unit. METHODS: Fourteen observational reports published from January 2000 to March 2014, retrieved from Pubmed and Embase, involving 9,715 critically ill patients and serum 25-hydroxyvitamin D3 (25 (OH)-D) concentrations, were meta-analysed. RESULTS: Levels of 25 (OH)-D less than 50 nmol/L were associated with increased rates of infection (risk ratio (RR) 1.49, 95% (confidence interval (CI) 1.12 to 1.99), P = 0.007), sepsis (RR 1.46, 95% (CI 1.27 to 1.68), P <0.001), 30-day mortality (RR 1.42, 95% (CI 1.00 to 2.02), P = 0.05), and in-hospital mortality (RR 1.79, 95% (CI 1.49 to 2.16), P <0.001). In a subgroup analysis of adjusted data including vitamin D deficiency as a risk factor for 30-day mortality the pooled RR was 1.76 (95% CI 1.37 to 2.26, P <0.001). CONCLUSIONS: This meta-analysis suggests that vitamin D deficiency increases susceptibility for severe infections and mortality of the critically ill.

Acute normovolemic hemodilution in the pig is associated with renal tissue edema, impaired renal microvascular oxygenation, and functional loss.

BACKGROUND: The authors investigated the impact of acute normovolemic hemodilution (ANH) on intrarenal oxygenation and its functional short-term consequences in pigs. METHODS: Renal microvascular oxygenation (µPO2) was measured in cortex, outer and inner medulla via three implanted optical fibers by oxygen-dependent quenching of phosphorescence. Besides systemic hemodynamics, renal function, histopathology, and hypoxia-inducible factor-1α expression were determined. ANH was performed in n = 18 pigs with either colloids (hydroxyethyl starch 6% 130/0.4) or crystalloids (full electrolyte solution), in three steps from a hematocrit of 30% at baseline to a hematocrit of 15% (H3). RESULTS: ANH with crystalloids decreased µPO2 in cortex and outer medulla approximately by 65% (P < 0.05) and in inner medulla by 30% (P < 0.05) from baseline to H3. In contrast, µPO2 remained unaltered during ANH with colloids. Furthermore, renal function decreased by approximately 45% from baseline to H3 (P < 0.05) only in the crystalloid group. Three times more volume of crystalloids was administered compared with the colloid group. Alterations in systemic and renal regional hemodynamics, oxygen delivery and oxygen consumption during ANH, gave no obvious explanation for the deterioration of µPO2 in the crystalloid group. However, ANH with crystalloids was associated with the highest formation of renal tissue edema and the highest expression of hypoxia-inducible factor-1α, which was mainly localized in distal convoluted tubules. CONCLUSIONS: ANH to a hematocrit of 15% statistically significantly impaired µPO2 and renal function in the crystalloid group. Less tissue edema formation and an unimpaired renal µPO2 in the colloid group might account for a preserved renal function.

Time of injury affects urinary biomarker predictive values for acute kidney injury in critically ill, non-septic patients.

BACKGROUND: The predictive value of acute kidney injury (AKI) urinary biomarkers may depend on the time interval following tubular injury, thereby explaining in part the heterogeneous performance of these markers that has been reported in the literature. We studied the influence of timing on the predictive values of tubular proteins, measured before the rise of serum creatinine (SCr) in critically ill, non-septic patients. METHODS: Seven hundred adult critically ill patients were prospectively included for urine measurements at four time-points prior to the rise in serum creatinine (T = 0, -16, -20 and -24 h). Patients with sepsis and or AKI at ICU entry were excluded. The urinary excretion of the proteins, neutrophil gelatinase-associated lipocalin (NGAL) and kidney injury molecule-1 (KIM-1), which are up-regulated in the distal and proximal tubules, respectively, were measured as well as the constitutive cytoplasmatic enzymes, π- and α-glutathione-S-transferase (GST), which are released by the distal and proximal tubules, respectively. RESULTS: Five hundred and forty-three subjects were eligible for further analyses; however, 49 developed AKI in the first 48 h. Both NGAL (P = 0.001 at T = -24 vs. non-AKI patients) and KIM-1 (P < 0.0001 at T = 0 vs. non-AKI patients) concentrations gradually increased until AKI diagnosis, whereas π- and α-GST peaked at T = -24 before AKI (P = 0.006 and P = 0.002, respectively vs. non-AKI patients) and showed a rapid decline afterwards. The predictive values at T = -24 prior to AKI were modest for π- and α-GST, whereas NGAL sufficiently predicted AKI at T = -24 and its predictive power improved as the time interval to AKI presentation decreased (area under the receiver operating characteristic curve; AUC = 0.79, P < 0.0001). KIM-1 was a good discriminator at T = 0 only (AUC = 0.73, P < 0.0001). CONCLUSIONS: NGAL, KIM-1, pi- and alpha-GST displayed unique and mutually incomparable time dependent characteristics during the development of non-sepsis related AKI. Therefore, the time-relationship between the biomarker measurements and the injurious event influences the individual test results.

Neutrophil gelatinase-associated lipocalin at ICU admission predicts for acute kidney injury in adult patients.

RATIONALE: Measured at intensive care unit admission (ICU), the predictive value of neutrophil gelatinase-associated lipocalin (NGAL) for severe acute kidney injury (AKI) is unclear. OBJECTIVES: To assess the ability of plasma and urine NGAL to predict severe AKI in adult critically ill patients. METHODS: Prospective-cohort study consisting of 632 consecutive patients. MEASUREMENTS AND MAIN RESULTS: Samples were analyzed by Triage immunoassay for NGAL expression. The primary outcome measure was occurrence of AKI based on Risk-Injury-Failure (RIFLE) classification during the first week of ICU stay. A total of 171 (27%) patients developed AKI. Of these 67, 48, and 56 were classified as RIFLE R, I, and F, respectively. Plasma and urine NGAL values at ICU admission were significantly related to AKI severity. The areas under the receiver operating characteristic curves for plasma and urine NGAL were for RIFLE R (0.77 ± 0.05 and 0.80 ± 0.04, respectively), RIFLE I (0.80 ± 0.06 and 0.85 ± 0.04, respectively), and RIFLE F (0.86 ± 0.06 and 0.88 ± 0.04, respectively) and comparable with those of admission estimated glomerular filtration rate (eGFR) (0.84 ± 0.04, 0.87 ± 0.04, and 0.92 ± 0.04, respectively). Plasma and urine NGAL significantly contributed to the accuracy of the "most efficient clinical model" with the best four variables including eGFR, improving the area under the curve for RIFLE F prediction to 0.96 ± 0.02 and 0.95 ± 0.01. Serial NGAL measurements did not provide additional information for the prediction of RIFLE F. CONCLUSIONS: NGAL measured at ICU admission predicts the development of severe AKI similarly to serum creatinine-derived eGFR. However, NGAL adds significant accuracy to this prediction in combination with eGFR alone or with other clinical parameters and has an interesting predictive value in patients with normal serum creatinine.

Biomarker strategies to predict need for renal replacement therapy in acute kidney injury.

The early detection and diagnosis of acute kidney injury (AKI) with the standardization of novel kidney-injury-specific biomarkers is one of the highest research priorities in nephrology. Accordingly, the majority of studies of novel AKI biomarkers have focused on the early diagnosis of AKI using serum creatinine-based definitions as the gold standard. However, another potential application of kidney-injury-specific biomarkers is for guiding decisions on when to initiate renal replacement therapy (RRT). The purpose of this review is to summarize recent findings concerning some of the more promising AKI biomarkers on their capacity, either alone or integrated with traditional surrogate measures of kidney injury, for early prediction of whether patients will develop severe AKI requiring RRT. Some studies that have examined neutrophil gelatinase-associated lipocalin, cystatin-C, N-acetyl-ß-d-glucosaminidase, kidney injury molecule-1, and α(1)-microglobulin, among others, have suggested that these novel biomarkers have the potential to distinguish patients in whom RRT will be needed. This would imply that these biomarkers may be integrated into clinical decision algorithms and could synergistically improve our current ability to predict worsening AKI and need for RRT. However, published studies have many recognized limitations, which preclude our ability to adapt their findings into clinical practice today. While currently available data are not sufficient to conclude that biomarkers should be used routinely for clinical decision making for RRT initiation, additional data may in the future significantly modify the clinical variability for initiation of RRT, and potentially translate into improved outcomes and cost-effectiveness. Finally, we propose a potential approach to future biomarker strategies for RRT initiation, integrating these biomarkers with "traditional" clinical factors.

COVID outcome prediction in the emergency department (COPE): using retrospective Dutch hospital data to develop simple and valid models for predicting mortality and need for intensive care unit admission in patients who present at the emergency department with suspected COVID-19.

OBJECTIVES: Develop simple and valid models for predicting mortality and need for intensive care unit (ICU) admission in patients who present at the emergency department (ED) with suspected COVID-19. DESIGN: Retrospective. SETTING: Secondary care in four large Dutch hospitals. PARTICIPANTS: Patients who presented at the ED and were admitted to hospital with suspected COVID-19. We used 5831 first-wave patients who presented between March and August 2020 for model development and 3252 second-wave patients who presented between September and December 2020 for model validation. OUTCOME MEASURES: We developed separate logistic regression models for in-hospital death and for need for ICU admission, both within 28 days after hospital admission. Based on prior literature, we considered quickly and objectively obtainable patient characteristics, vital parameters and blood test values as predictors. We assessed model performance by the area under the receiver operating characteristic curve (AUC) and by calibration plots. RESULTS: Of 5831 first-wave patients, 629 (10.8%) died within 28 days after admission. ICU admission was fully recorded for 2633 first-wave patients in 2 hospitals, with 214 (8.1%) ICU admissions within 28 days. A simple model-COVID outcome prediction in the emergency department (COPE)-with age, respiratory rate, C reactive protein, lactate dehydrogenase, albumin and urea captured most of the ability to predict death. COPE was well calibrated and showed good discrimination for mortality in second-wave patients (AUC in four hospitals: 0.82 (95% CI 0.78 to 0.86); 0.82 (95% CI 0.74 to 0.90); 0.79 (95% CI 0.70 to 0.88); 0.83 (95% CI 0.79 to 0.86)). COPE was also able to identify patients at high risk of needing ICU admission in second-wave patients (AUC in two hospitals: 0.84 (95% CI 0.78 to 0.90); 0.81 (95% CI 0.66 to 0.95)). CONCLUSIONS: COPE is a simple tool that is well able to predict mortality and need for ICU admission in patients who present to the ED with suspected COVID-19 and may help patients and doctors in decision making.

Acute kidney injury after liver transplantation: Recent insights and future perspectives.

Acute kidney injury (AKI) is a common postoperative complication after liver transplantation (LT). The occurrence of postoperative AKI after LT (Post-LT AKI) is associated with inferior patient and graft outcomes. Post-LT AKI is multifactorial in origin and has been related to the severity of liver disease, pre-LT renal dysfunction, graft quality, perioperative events and toxicity of immunosuppressive therapy. Furthermore it is thought that hepatic ischaemia reperfusion injury might be a driving force in the aetiology of post-LT AKI. Novel biomarkers for AKI are emerging and can be useful for early identification and characterization of AKI. There is a clear need for strategies aimed at preventing or treating post-LT AKI. Several pharmacological and non-pharmacological interventions have been studied, but so far failed to show any benefit in the prevention of post-LT AKI. Further studies are needed to develop and evaluate new interventions aimed at preventing post-LT AKI and improve patient outcomes.

Neutrophil Gelatinase-Associated Lipocalin as a Diagnostic Marker for Acute Kidney Injury in Oliguric Critically Ill Patients: A Post-Hoc Analysis.

BACKGROUND: Oliguria occurs frequently in critically ill patients, challenging clinicians to distinguish functional adaptation from serum-creatinine-defined acute kidney injury (AKIsCr). We investigated neutrophil gelatinase-associated lipocalin (NGAL)'s ability to differentiate between these 2 conditions. METHODS: This is a post-hoc analysis of a prospective cohort of adult critically ill patients. Patients without oliguria within the first 6 h of admission were excluded. Plasma and urinary NGAL were measured at 4 h after admission. AKIsCr was defined using the AKI network criteria with pre-admission serum creatinine or lowest serum creatinine value during the admission as the baseline value. Hazard ratios for AKIsCr occurrence within 72 h were calculated using Cox regression and adjusted for risk factors such as sepsis, pre-admission serum creatinine, and urinary output. Positive predictive values (PPV) and negative predictive values (NPV) were calculated for the optimal cutoffs for NGAL. RESULTS: Oliguria occurred in 176 patients, and 61 (35%) patients developed AKIsCr. NGAL was a predictor for AKIsCr in univariate and multivariate analysis. When NGAL was added to a multivariate model including sepsis, pre-admission serum creatinine and lowest hourly urine output, it outperformed the latter model (plasma p = 0.001; urinary p = 0.048). Cutoff values for AKIsCr were 280 ng/ml for plasma (PPV 80%; NPV 79%), and 250 ng/ml for urinary NGAL (PPV 58%; NPV 78%). CONCLUSIONS: NGAL can be used to distinguish oliguria due to the functional adaptation from AKIsCr, directing resources to patients more likely to develop AKIsCr.

The cardiac surgery-associated neutrophil gelatinase-associated lipocalin (CSA-NGAL) score: A potential tool to monitor acute tubular damage.

Acute kidney injury (AKI), defined as a rise in serum creatinine (functional AKI), is a frequent complication after cardiac surgery. The expression pattern of acute tubular damage biomarkers such as neutrophil gelatinase-associated lipocalin (NGAL) has been shown to precede functional AKI and, therefore, may be useful to identify very early tubular damage. The term subclinical AKI represents acute tubular damage in the absence of functional AKI (biomarker positivity without a rise in serum creatinine) and affects hard outcome measures. This potentiates an tubular-damage-based identification of renal injury, which may guide clinical management, allowing for very early preventive-protective strategies. The aim of this paper was to review the current available evidence on NGAL applicability in adult cardiac surgery patients and combine this knowledge with the expert consensus of the authors to generate an NGAL based tubular damage score: The cardiac surgery-associated NGAL Score (CSA-NGAL score). The CSA-NGAL score might be the tool needed to improve awareness and enable interventions to possibly modify these detrimental outcomes. In boldly doing so, it is intended to introduce a different approach in study designs, which will undoubtedly expand our knowledge and will hopefully move the AKI biomarker field forward.