The utility of biomarker excretion rates in acute kidney injury

INTRODUCTION: The concentration of urinary biomarkers of acute kidney injury (AKI) is influenced by variation in urinary concentration within and between individuals.1 Normalisation to urine creatinine concentration is commonly used to account for this variation.2 The accuracy of this method is compromised by tubular secretion of creatinine, and variations in urine creatinine excretion in non-steady state when glomerular filtration rate (GFR) changes.1 Alternatives to normalisation to creatinine include using the absolute biomarker concentration or quantifying the biomarker excretion rate. Intuitively, the excretion rate may also account for variation in water reabsorption and urine flow rate. In addition, total biomarker excretion in AKI might more accurately reflect the mass of injured tubular cells, a function of both severity and duration, parameters associated with long-term mortality.3 OBJECTIVE: To compare the performance of biomarker excretion rate and the absolute and normalized biomarker concentration in diagnosis of AKI, prediction of AKI, death and the need for renal replacement therapy (RRT) in adult intensive care patients. This will assists in the comparison of biomarkers between trials and guide clinicians on how it should be utilized in clinical practice. METHODS: Urinary concentrations of alkaline phosphatase (AP), γ-glutamyl transpeptidase (GGT), cystatin C (CysC), neutrophil gelatinase-associated-lipocalin (NGAL), kidney-injury molecule-1 (KIM 1), and interleukin-18(IL-18) were measured on ICU admission, at 12 and 24 hours in the EARLYARF trial.4, 5 The average urine flow rate was calculated from 4-hour creatinine clearance measurements obtained at the same time points, which allowed calculation of biomarker excretion rate. The normalised biomarker concentrations were derived by dividing the biomarker concentration by the urinary creatinine concentration. The total excretion over 24 hours for each biomarker (i.e. integration of excretion rate with respect to time) was determined using the trapezoidal rule. The performance of absolute and normalised biomarker concentration, and biomarker excretion rate on admission to the ICU in diagnosis or prediction of outcome was assessed by comparison of the area under the curve (AUC) of receiver-operator characteristic curves (ROC) for each parameter using the DeLong method.6, 7 The association of total biomarker excretion with AKI severity (maximum AKIN stages within 48 hours), and 1-year survival were assessed with one-way ANOVA and Kaplan Meier survival analysis. RESULTS: Of 528 recruited patients, 484 had 4h-creatinine clearance measurements on ICU admission from which urine output volumes could be obtained for the calculation of biomarker excretion rates. For diagnosis of AKI on ICU admission, biomarker concentration performed better than normalised concentration or excretion rate. Normalised concentrations performed best in prediction of 7-day mortality and the need of RRT. Excretion rate did not diagnose or predict outcomes better than absolute or normalised concentration. In the cohort of patients without AKI on ICU admission (n=339), there were no differences in performance between absolute and normalised biomarker concentration in prediction of development of AKI within 48 hours (AKIN48) or sustained AKI within 7 days of admission (RIFLE 24). However, here also the normalised concentrations had higher AUCs than excretion rates (Figure 1). The total biomarker excretion in the first 24 hours increased with severity of injury for all biomarkers except AP. For NGAL alone, post-hoc analysis also demonstrated significant differences between successive AKIN stages of increasing severity AKI (p≤0.02) (Figure 2). Patient survival was assessed according to extent of biomarker excretion ranked by tertiles Only NGAL demonstrated a significant association between total excretion and survival over 365 days (log-rank test, p=0.04). After adjusting for age, gender, sepsis, APACHE II and SOFA scores, patients with higher excretion of NGAL (higher tertile, total excretion >184µg) had a higher 1-year mortality compared to those with a lower tertile of NGAL excretion (total excretion of <40µg) (Hazard ratio of 2.15 (95% CI: 1.23 to 3.73), p=0.007) (Figure 3). . CONCLUSIONS: Normalisation to urine creatinine provides no advantage in diagnosis of AKI, but improves prediction of AKI and outcome. Periodic excretion rates did not improve performance, but total excretion in the first 24hr was strongly associated with AKI severity, and for NGAL with survival. The ideal method for standardizing urinary AKI biomarkers depends on the outcome being assessed

Development and validation of a frailty index compatible with three interRAI assessment instruments

BACKGROUND: a Frailty Index (FI) calculated by the accumulation of deficits is often used to quantify the extent of frailty in individuals in specific settings. This study aimed to derive a FI that can be applied across three standardised international Residential Assessment Instrument assessments (interRAI), used at different stages of ageing and the corresponding increase in support needs. METHODS: deficit items common to the interRAI Contact Assessment (CA), Home Care (HC) or Long-Term Care Facilities assessment (LTCF) were identified and recoded to form a cumulative deficit FI. The index was validated using a large dataset of needs assessments of older people in New Zealand against mortality prediction using Kaplan Meier curves and logistic regression models. The index was further validated by comparing its performance with a previously validated index in the HC cohort. RESULTS: the index comprised 15 questions across seven domains. The assessment cohort and their mean frailty (SD) were: 89,506 CA with 0.26 (0.15), 151,270 HC with 0.36 (0.15) and 83,473 LTCF with 0.41 (0.17). The index predicted 1-year mortality for each of the CA, HC and LTCF, cohorts with area under the receiver operating characteristic curves (AUCs) of 0.741 (95% confidence interval, CI: 0.718-0.762), 0.687 (95%CI: 0.684-0.690) and 0.674 (95%CI: 0.670-0.678), respectively. CONCLUSIONS: the results for this multi-instrument FI are congruent with the differences in frailty expected for people in the target settings for these instruments and appropriately associated with mortality at each stage of the journey of progressive ageing.</p

Next-Generation Field Guides

To conserve species, we must first identify them. Field researchers, land managers, educators, and citizen scientists need up-to-date and accessible tools to identify organisms, organize data, and share observations. Emerging technologies complement traditional, book-form field guides by providing users with a wealth of multimedia data. We review technical innovations of next-generation field guides, including Web-based and stand-alone applications, interactive multiple-access keys, visual-recognition software adapted to identify organisms, species checklists that can be customized to particular sites, online communities in which people share species observations, and the use of crowdsourced data to refine machine-based identification algorithms. Next-generation field guides are user friendly; permit quality control and the revision of data; are scalable to accommodate burgeoning data; protect content and privacy while allowing broad public access; and are adaptable to ever-changing platforms and browsers. These tools have great potential to engage new audiences while fostering rigorous science and an appreciation for nature.Organismic and Evolutionary Biolog

Heart Fatty Acid Binding Protein and cardiac troponin: development of an optimal rule-out strategy for acute myocardial infarction

Background: Improved ability to rapidly rule-out Acute Myocardial Infarction (AMI) in patients presenting with chest pain will promote decongestion of the Emergency Department (ED) and reduce unnecessary hospital admissions. We assessed a new commercial Heart Fatty Acid Binding Protein (H-FABP) assay for additional diagnostic value when combined with cardiac troponin (using a high sensitivity assay). Methods: H-FABP and high-sensitivity troponins I (hs-cTnI) and T (hs-cTnT) were measured in samples taken on-presentation from patients, attending the ED, with symptoms triggering investigation for possible acute coronary syndrome. The optimal combination of H-FABP with each hs-cTn was defined as that which maximized the proportion of patients with a negative test (low-risk) whilst maintaining at least 99 % sensitivity for AMI. A negative test comprised both H-FABP and hs-cTn below the chosen threshold in the absence of ischemic changes on the ECG. Results: One thousand seventy-nine patients were recruited including 248 with AMI. H-FABP 99 % sensitivity for AMI whilst classifying 40.9 % of patients as low-risk. The combination of H-FABP < 3.9 ng/mL and hs-cTnT < 7.6 ng/L with a negative ECG maintained the same sensitivity whilst classifying 32.1 % of patients as low risk. Conclusions: In patients requiring rule-out of AMI, the addition of H-FABP to hs-cTn at presentation (in the absence of new ischaemic ECG findings) may accelerate clinical diagnostic decision making by identifying up to 40 % of such patients as low-risk for AMI on the basis of blood tests performed on presentation. If implemented this has the potential to significantly accelerate triaging of patients for early discharge from the ED

The Drug Burden Index and Level of Frailty as Determinants of Healthcare Costs in a Cohort of Older Frail Adults in New Zealand

OBJECTIVES: Frailty is common in older people and is associated with increased use of healthcare services and ongoing use of multiple medications. This study provides insights into the healthcare cost structure of a frail group of older adults in Aotearoa, New Zealand. Furthermore, we investigated the relationship between participants' anticholinergic and sedative medication burden and their total healthcare costs to explore the viability of deprescribing interventions within this cohort.METHODS: Healthcare cost analysis was conducted using data collected during a randomized controlled trial within a frail, older cohort. The collected information included participant demographics, medications used, frailty, cost of service use of aged residential care and outpatient hospital services, hospital admissions, and dispensed medications.RESULTS: Data from 338 study participants recruited between 25 September 2018 and 30 October 2020 with a mean age of 80 years were analyzed. The total cost of healthcare per participant ranged from New Zealand $15 (US dollar$10) to New Zealand $270 681 (US dollar$175 943) over 6 months postrecruitment into the study. Four individuals accounted for 26% of this cohort's total healthcare cost. We found frailty to be associated with increased healthcare costs, whereas the drug burden was only associated with increased pharmaceutical costs, not overall healthcare costs.CONCLUSIONS: With no relationship found between a patient's anticholinergic and sedative medication burden and their total healthcare costs, more research is required to understand how and where to unlock healthcare cost savings within frail, older populations.</p

Kidney damage biomarkers detect acute kidney injury but only functional markers predict mortality after paraquat ingestion

Acute kidney injury (AKI) is common following paraquat ingestion. The diagnostic performance of injury biomarkers was investigated in serial blood and urine samples from patients from 5 Sri Lankan hospitals. Functional AKI was diagnosed using serum creatinine (sCr) or serum cystatin C (sCysC). The 95th centile in healthy subjects defined the urinary biomarker cutoffs for diagnosing structural AKI. 50 poisoned patients provided 2 or more specimens, 76% developed functional AKI [AKIN stage 1 (n=12), 2 (n=7) or 3 (n=19)]; 19/26 patients with AKIN stage 2/3 also had functional AKI by sCysC criteria (≥50% increase). Urinary cystatin C (uCysC), clusterin (uClu) and NGAL (uNGAL) increased within 24h of ingestion compared with NoAKI patients and healthy controls. Each biomarker demonstrated moderate diagnostic utility [AUC-ROC: uCysC 0.79, uNGAL 0.79, uClu 0.68] for diagnosis of functional AKI at 16h. Death occurred only in subjects with functional AKI. Structural biomarker-based definitions detected more AKI than did sCr or sCysC, but did not independently predict death. Renal injury biomarkers did not add clinical value to patients who died rapidly due to multi-organ failure. Use of injury biomarkers within 16-24h may guide early intervention for reno-protection in less severe paraquat poisoning.NHMRC project grant 101177