Trajectory pattern of serially measured acute kidney injury biomarkers in critically ill patients: a prospective observational study.

BACKGROUND: The clinical value of the trajectory of temporal changes in acute kidney injury (AKI) biomarkers has not been well established among intensive care unit (ICU) patients. METHODS: This is a single-center, prospective observational study, performed at a mixed ICU in a teaching medical institute in Tokyo, Japan. Adult ICU patients with an arterial line and urethral catheter were enrolled from September 2014 to March 2015. Patients who stayed in the ICU for less than 48 h and patients with known end-stage renal disease were excluded from the study. Blood and urine samples were collected for measurement of AKI biomarkers at 0, 12, 24, and 48 h after ICU admission. The primary outcome was major adverse kidney events (MAKE) at discharge, defined as a composite of death, dialysis dependency, and persistent loss of kidney function (≥ 25% decline in eGFR). RESULTS: The study included 156 patients. Serum creatinine-based estimated glomerular filtration rate (eGFR), plasma neutrophil gelatinase-associated lipocalin (NGAL), and urinary liver-type fatty acid-binding protein (uL-FABP) were serially measured and each variable was classified into three groups based on group-based trajectory modeling analysis. While the trajectory curves moved parallel to each other (i.e., "low," "middle," and "high") for eGFR and plasma NGAL, the uL-FABP curves showed distinct trajectory patterns and moved in different directions ("low and constant," "high and exponential decrease," and "high and exponential increase"). These trajectory patterns were significantly associated with MAKE. MAKE occurred in 16 (18%), 16 (40%), and 9 (100%) patients in the "low and constant," "high and exponential decrease," and "high and exponential increase" groups, respectively, based on uL-FABP levels (p-value < 0.001). The initial value and the 12-h change in uL-FABP were both significantly associated with MAKE, even after adjusting for eGFR [Odds ratio (95% confidence interval): 1.45 (1.17-1.83) and 1.43 (1.12-1.88) for increase of initial value and 12-h change of log-transformed uL-FABP by 1 point, respectively]. CONCLUSIONS: Trajectory pattern of serially measured urinary L-FABP was significantly associated with MAKE in ICU patients.

Heterogeneity in the definition of major adverse kidney events: a scoping review.

Acute kidney injury (AKI) is associated with persistent renal dysfunction, the receipt of dialysis, dialysis dependence, and mortality. Accordingly, the concept of major adverse kidney events (MAKE) has been adopted as an endpoint for assessing the impact of AKI. However, applied criteria or observation periods for operationalizing MAKE appear to vary across studies. To evaluate this heterogeneity for MAKE evaluation, we performed a systematic scoping review of studies that employed MAKE as an AKI endpoint. Four major academic databases were searched, and we identified 122 studies with increasing numbers over time. We found marked heterogeneity in applied criteria and observation periods for MAKE across these studies, with some even lacking a description of criteria. Moreover, 13 different observation periods were employed, with 30 days and 90 days as the most common. Persistent renal dysfunction was evaluated by estimated glomerular filtration rate (34%) or serum creatinine concentration (48%); however, 37 different definitions for this component were employed in terms of parameters, cut-off criteria, and assessment periods. The definition for the dialysis component also showed significant heterogeneity regarding assessment periods and duration of dialysis requirement (chronic vs temporary). Finally, MAKE rates could vary by 7% [interquartile range: 1.7-16.7%] with different observation periods or by 36.4% with different dialysis component definitions. Our findings revealed marked heterogeneity in MAKE definitions, particularly regarding component assessment and observation periods. Dedicated discussion is needed to establish uniform and acceptable standards to operationalize MAKE in terms of selection and applied criteria of components, observation period, and reporting criteria for future trials on AKI and related conditions.

Serum myostatin at dialysis initiation may predict 1-year mortality and hospitalization.

OBJECTIVE: Myostatin, which is known as a negative skeleton muscle regulator, is associated with mortality in maintenance hemodialysis patients. However, the significance of serum myostatin concentrations at dialysis initiation has not been established. We investigated the relation between serum myostatin concentrations and mortality or hospitalization within one year in incident dialysis patients. METHODS: After a patient initiating hemodialysis or peritoneal dialysis during 2016-2018 was enrolled, the patient's serum myostatin at dialysis initiation was measured. Composite outcomes comprising mortality and hospitalization within 1 year after dialysis initiation were compared between two groups divided according to myostatin levels. The Cox proportional hazards model was used to assess significant relations between myostatin and outcomes. RESULTS: This study examined 104 incident dialysis patients with mean age of 65.5±14.0 (68% male). Kaplan-Meier analyses indicated the 1-year hospitalization-free and survival rate as significantly lower in the lower myostatin group than in the higher myostatin group (p = .0020). Cox proportional hazards regression analyses revealed that the value of myostatin logarithm at dialysis initiation was inversely associated with the occurrence of a composite outcome, independently of age (hazard ratio 0.16, 95% confidence interval 0.05-0.57). Receiver operating characteristic (ROC) analysis showed the area under the curve of serum myostatin for predicting death or hospitalization within 1 year as higher than those of clinical indices of nutritional disturbance and frailty. CONCLUSION: Serum myostatin concentration at dialysis initiation is inversely associated with adverse outcomes in these dialysis-initiated patients.

Impact of renal dysfunction on the diagnosis of acute pancreatitis using urinary trypsinogen-2: A retrospective study.

AIM: Early diagnosis of acute pancreatitis is crucial, and urinary trypsinogen has been recently reported as a useful biomarker for diagnosing acute pancreatitis. We aimed to evaluate the impact of renal dysfunction on the diagnostic performance of urinary trypsinogen-2 for acute pancreatitis. METHODS: We conducted a retrospective study using the clinical data of patients who visited the Department of Emergency and Critical Care at the University of Tokyo Hospital between 1 October, 2021, and 30 June, 2022. Patients with available data on qualitative urinary trypsinogen-2 levels were identified. We compared the urinary trypsinogen-2 levels among patients who were clinically diagnosed with acute pancreatitis. We further stratified the patients according to renal function parameters, such as serum creatinine level, blood urea nitrogen level, and estimated glomerular filtration rate, and evaluated the performance of urinary trypsinogen-2 as a biomarker for acute pancreatitis. RESULTS: Within 9 months, 35 patients were identified. Of them, 22 patients showed positive results and 13 showed negative results on the urinary trypsinogen-2 test. The sensitivity, specificity, positive predictive value, and negative predictive value were 0.80, 0.40, 0.18, and 0.92, respectively. Based on the blood urea nitrogen level and estimated glomerular filtration rate, the prevalence of false-positive results was significantly higher in patients with reduced renal function than in those with normal renal function. CONCLUSION: In patients with reduced renal function, the urinary trypsinogen-2 qualitative test results might be interpreted with caution when used for diagnosing acute pancreatitis.

Dose of nafamostat mesylate during continuous kidney replacement therapy in critically ill patients: a two-centre observational study.

BACKGROUND: Nafamostat mesylate is an anticoagulant used for critically ill patients during continuous kidney replacement therapy (CKRT), characterised by its short half-life. However, its optimal dosage remains unclear. This study aimed to explore the optimal dosage of nafamostat mesylate during CKRT. METHODS: We conducted a two-centre observational study. We screened all critically ill adult patients who required CKRT in the intensive care unit (ICU) from September 2013 to August 2021; we included patients aged ≥ 18 years who received nafamostat mesylate during CKRT. The primary outcome was filter life, defined as the time from CKRT initiation to the end of the first filter use due to filter clotting. The secondary outcomes included safety and other clinical outcomes. The survival analysis of filter patency by the nafamostat mesylate dosage adjusted for bleeding risk and haemofiltration was performed using a Cox proportional hazards model. RESULTS: We included 269 patients. The mean dose of nafamostat mesylate was 15.8 mg/hr (Standard deviation (SD), 8.8; range, 5.0 to 30.0), and the median filter life was 18.3 h (Interquartile range (IQR), 9.28 to 36.7). The filter survival analysis showed no significant association between the filter life and nafamostat mesylate dosage (hazard ratio 1.12; 95 CI 0.74-1.69, p = 0.60) after adjustment for bleeding risk and addition of haemofiltration to haemodialysis. CONCLUSIONS: We observed no dose-response relationship between the dose of nafamostat mesylate (range: 5 to 30 mg/h) and the filter life during CKRT in critically ill patients. The optimal dose to prevent filter clotting safely needs further study in randomised controlled trials. TRIAL REGISTRATION: Not applicable.

Phase-3 trial of recombinant human alkaline phosphatase for patients with sepsis-associated acute kidney injury (REVIVAL).

PURPOSE: Ilofotase alfa is a human recombinant alkaline phosphatase with reno-protective effects that showed improved survival and reduced Major Adverse Kidney Events by 90 days (MAKE90) in sepsis-associated acute kidney injury (SA-AKI) patients. REVIVAL, was a phase-3 trial conducted to confirm its efficacy and safety. METHODS: In this international double-blinded randomized-controlled trial, SA-AKI patients were enrolled < 72 h on vasopressor and < 24 h of AKI. The primary endpoint was 28-day all-cause mortality. The main secondary endpoint was MAKE90, other secondary endpoints were (i) days alive and free of organ support through day 28, (ii) days alive and out of the intensive care unit (ICU) through day 28, and (iii) time to death through day 90. Prior to unblinding, the statistical analysis plan was amended, including an updated MAKE90 definition. RESULTS: Six hundred fifty patients were treated and analyzed for safety; and 649 for efficacy data (ilofotase alfa n = 330; placebo n = 319). The observed mortality rates in the ilofotase alfa and placebo groups were 27.9% and 27.9% at 28 days, and 33.9% and 34.8% at 90 days. The trial was stopped for futility on the primary endpoint. The observed proportion of patients with MAKE90A and MAKE90B were 56.7% and 37.4% in the ilofotase alfa group vs. 64.6% and 42.8% in the placebo group. Median [interquartile range (IQR)] days alive and free of organ support were 17 [0-24] and 14 [0-24], number of days alive and discharged from the ICU through day 28 were 15 [0-22] and 10 [0-22] in the ilofotase alfa and placebo groups, respectively. Adverse events were reported in 67.9% and 75% patients in the ilofotase and placebo group. CONCLUSION: Among critically ill patients with SA-AKI, ilofotase alfa did not improve day 28 survival. There may, however, be reduced MAKE90 events. No safety concerns were identified.

A case of hypervirulent K1-ST23 Klebsiella pneumoniae endocarditis and papillary muscle rupture secondary to multiple site abscesses.

Hypervirulent Klebsiella pneumoniae (hvKP) causes multisite infections and abscesses. However, endocarditis is a rare presentation of hvKP infection. Herein, we report a case of K. pneumoniae native valve infective endocarditis secondary to community-acquired liver and prostate abscesses. The patient developed papillary muscle rupture, leading to mitral regurgitation, and underwent emergent mitral valve replacement. The diagnosis of endocarditis was confirmed microbiologically and histologically. The causative strain belonged to the hypermucoid K1 capsular genotype and possessed the rmpA gene. The genome sequence was deposited in GenBank under the accession number JAQZBZ000000000.

COVID-19 vaccine effectiveness against severe COVID-19 requiring oxygen therapy, invasive mechanical ventilation, and death in Japan: A multicenter case-control study (MOTIVATE study).

INTRODUCTION: Since the SARS-CoV-2 Omicron variant became dominant, assessing COVID-19 vaccine effectiveness (VE) against severe disease using hospitalization as an outcome became more challenging due to incidental infections via admission screening and variable admission criteria, resulting in a wide range of estimates. To address this, the World Health Organization (WHO) guidance recommends the use of outcomes that are more specific to severe pneumonia such as oxygen use and mechanical ventilation. METHODS: A case-control study was conducted in 24 hospitals in Japan for the Delta-dominant period (August-November 2021; "Delta") and early Omicron (BA.1/BA.2)-dominant period (January-June 2022; "Omicron"). Detailed chart review/interviews were conducted in January-May 2023. VE was measured using various outcomes including disease requiring oxygen therapy, disease requiring invasive mechanical ventilation (IMV), death, outcome restricting to "true" severe COVID-19 (where oxygen requirement is due to COVID-19 rather than another condition(s)), and progression from oxygen use to IMV or death among COVID-19 patients. RESULTS: The analysis included 2125 individuals with respiratory failure (1608 cases [75.7%]; 99.2% of vaccinees received mRNA vaccines). During Delta, 2 doses provided high protection for up to 6 months (oxygen requirement: 95.2% [95% CI:88.7-98.0%] [restricted to "true" severe COVID-19: 95.5% {89.3-98.1%}]; IMV: 99.6% [97.3-99.9%]; fatal: 98.6% [92.3-99.7%]). During Omicron, 3 doses provided high protection for up to 6 months (oxygen requirement: 85.5% [68.8-93.3%] ["true" severe COVID-19: 88.1% {73.6-94.7%}]; IMV: 97.9% [85.9-99.7%]; fatal: 99.6% [95.2-99.97]). There was a trend towards higher VE for more severe and specific outcomes. CONCLUSION: Multiple outcomes pointed towards high protection of 2 doses during Delta and 3 doses during Omicron. These results demonstrate the importance of using severe and specific outcomes to accurately measure VE against severe COVID-19, as recommended in WHO guidance in settings of intense transmission as seen during Omicron.

Solute Clearance Evaluation and Filter Clotting Prediction in Continuous Renal Replacement Therapy.

Unexpected filter clotting is a major problem in continuous renal replacement therapy (CRRT). Reduced solute clearance is observed prior to filter clotting. This single-center, retrospective, observational study aimed to determine whether reduced solute clearance of low- and medium-molecular-weight molecules in CRRT can predict filter clotting. Solute clearances of urea and myoglobin (Mb) were measured at 24 h after initiation of continuous hemodiafiltration (CHDF). Clearance per flow (CL/F) was calculated. The primary outcome was clotting of the filter in the subsequent 24 h, and 775 CHDF treatments conducted on 230 patients for at least 24 consecutive hours in our ICU were analyzed. Filter clotting was observed in 127 treatments involving 39 patients. Urea and Mb CL/F at 24 h were significantly lower in the patients who experienced clotting. Further analysis was limited to the first CHDF treatment of each patient to adjust for confounding factors. Multivariate logistic regression analysis revealed that both urea CL/F < 94% and Mb CL/F < 64% were significant predictors of clotting within the next 24 h. Lower urea and Mb CL/F measured at 24 h after CRRT initiation were associated with filter clotting in the next 24 h. Further study is necessary to ascertain whether measurement of urea and MB CL/F will help with avoiding unexpected filter clotting.

Sympathetic Nerve Activation in Acute Kidney Injury and Cardiorenal Syndrome.

The interactions between the kidney and heart are well studied and frequently lumped together as cardiorenal syndrome. It is believed that the sympathetic nervous system is involved in the mechanism of kidney injury caused by heart failure, but direct evidence is still lacking. In chronic renal fibrosis, sympathetic nerve activation was demonstrated to be harmful by unilateral ureteral obstruction and post-ischemia reperfusion injury models. On the other hand, sympathetic nerve activation seemed protective in acute kidney injury models such as ischemia reperfusion injury and lipopolysaccharide injection. Our recent investigation showed that post-ischemic renal fibrosis was attenuated when preexisting heart failure was induced by transverse aortic constriction surgery and renal denervation canceled this protection. These findings suggest sympathetic nerve activation in cardiorenal syndrome may be protective on chronic renal fibrosis development caused by ischemic an insult.

Different Roles of Functional and Structural Renal Markers Measured at Discontinuation of Renal Replacement Therapy for Acute Kidney Injury.

INTRODUCTION: Severe acute kidney injury (AKI) requiring renal replacement therapy (RRT) has been associated with an unacceptably high mortality of 50% or more. Successful discontinuation of RRT is thought to be linked to better outcomes. Although functional and structural renal markers have been evaluated in AKI, little is known about their roles in predicting outcomes at the time of RRT discontinuation. METHODS: In this prospective single-center cohort study, we analyzed patients who received continuous RRT (CRRT) for AKI between August 2016 and March 2018 in the intensive care unit of the University of Tokyo Hospital (Tokyo, Japan). Clinical parameters and urine samples were obtained at CRRT discontinuation. Successful CRRT discontinuation was defined as neither resuming CRRT for 48 h nor receiving intermittent hemodialysis for 7 days from the CRRT termination. Major adverse kidney events (MAKEs) were defined as death, requirement for dialysis, or a decrease in the estimated glomerular filtration rate (eGFR) of more than 25% from the baseline at day 90. RESULTS: Of 73 patients, who received CRRT for AKI, 59 successfully discontinued CRRT and 14 could not. Kinetic eGFR, urine volume, urinary neutrophil gelatinase-associated lipocalin (NGAL), and urinary L-type fatty acid binding protein were predictive for CRRT discontinuation. Of these factors, urine volume had the highest area under the curve (AUC) 0.91 with 95% confidence interval [0.80-0.96] for successful CRRT discontinuation. For predicting MAKEs at day 90, the urinary NGAL showed the highest AUC 0.76 [0.62-0.86], whereas kinetic eGFR and urine volume failed to show statistical significance (AUC 0.49 [0.35-0.63] and AUC 0.59 [0.44-0.73], respectively). CONCLUSIONS: Our prospective study confirmed that urine volume, a functional renal marker, predicted successful discontinuation of RRT and that urinary NGAL, a structural renal marker, predicted long-term renal outcomes. These observations suggest that the functional and structural renal makers play different roles in predicting the outcomes of severe AKI requiring RRT.

BENEFIT OF HIGHER BLOOD PRESSURE TARGET IN SEVERE ACUTE KIDNEY INJURY TREATED BY CONTINUOUS RENAL REPLACEMENT THERAPY.

ABSTRACT: Introduction : The optimal target of mean arterial pressure (MAP) during continuous renal replacement therapy (CRRT) is unknown. Method : We retrospectively collected the hourly MAP data in acute kidney injury patients requiring CRRT who admitted to the intensive care unit in the University of Tokyo hospital during 2011-2019. Patients who died within 48 h of CRRT start and whose average value of hourly MAPs during the first 48 h was <65 mm Hg were excluded. When the average value of MAP was ≤75 mm Hg or >75 mm Hg, patients were allocated to the low or high target group. We estimated the effect of MAP on mortality and RRT independence at 90 days, using multivariable the Cox regression model and Fine and Gray model. Result : Of the 275 patients we analyzed, 95 patients were in the low group. There are no differences in sex, baseline kidney function, and disease severity. At 90 days, the low target group had higher mortality with 38 deaths (40.0%) compared with 57 deaths (31.7%) in the high target group ( P < 0.05). The adjusted hazard ratio of the low target group (≤75 mm Hg) for mortality was 1.72 (95% CI, 1.08-2.74). In addition, the low target group had a lower rate of RRT independence, with 60 patients (63.2%) compared with 136 patients (75.6%) in the high target group ( P < 0.05). The multivariable analysis revealed that the adjusted hazard ratio of the low target group for RRT independence was 0.74 (95% CI, 0.54-1.01). Conclusion : This study found the association with low MAP and mortality. The association with low MAP and delayed renal recovery was not revealed.

Bite wound and mauling of a zookeeper by a gorilla.

The majority of bite wounds that we encounter in the emergency department are caused by dogs, cats and humans, but bite injuries can be caused by a variety of animals. Here, we describe a case of bite wound and trauma caused by a large gorilla (Western lowland gorilla) weighing over 170 kg. Gorilla bites are rare, and the patient had an open fracture of the right distal radioulna in addition to multiple bite wounds. Treatment required careful consideration of gorilla antigenicity and a literature review to guide the selection of appropriate antimicrobial agents. Furthermore, trauma inflicted by large animals tends to require systemic traumatological screening, and patients can develop acute stress disorder because of a fear of being attacked again; therefore, early psychiatric intervention is important.