High-Density Lipoprotein Anti-Inflammatory Capacity and Acute Kidney Injury After Cardiac and Vascular Surgery: A Prospective Observational Study.

OBJECTIVES: Acute kidney injury (AKI) predicts death after cardiac and vascular surgery. Higher preoperative high-density lipoprotein (HDL) concentrations are associated with less postoperative AKI. In animals, HDL's anti-inflammatory capacity to suppress endothelial cell adhesion molecule expression reduces kidney damage due to ischemia and hemorrhagic shock. The objective of this study is to evaluate the statistical relationship between HDL anti-inflammatory capacity and AKI after major cardiac and vascular surgery. DESIGN: Prospective observational study. SETTING: Quaternary medical center. PATIENTS: One hundred adults with chronic kidney disease on long-term statin therapy undergoing major elective cardiac and vascular surgery. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Apolipoprotein B-depleted serum collected at anesthetic induction was incubated with tumor necrosis factor alpha stimulated human endothelial cells. Reverse transcriptase-polymerase chain reaction was used to measure intercellular adhesion molecule-1 (ICAM-1) messenger RNA. Enzyme-linked immunosorbent assay assays were used to measure apolipoprotein A-I and postoperative soluble ICAM-1 concentrations in patient plasma. HDL concentration did not correlate with HDL ICAM-1 suppression capacity (Spearman R = 0.05; p = 0.64). Twelve patients (12%) were found to have dysfunctional, pro-inflammatory HDL. Patients with pro-inflammatory HDL had a higher rate of postoperative AKI than patients with anti-inflammatory HDL (p = 0.046). After adjustment for AKI risk factors, a higher preoperative HDL capacity to suppress endothelial ICAM-1 was independently associated with lower odds of AKI (odds ratio, 0.88; 95% CI, 0.80-0.98; p = 0.016). The association between HDL anti-inflammatory capacity and postoperative AKI was independent of HDL concentration (p = 0.018). Further, a higher long-term statin dose was associated with higher HDL capacity to suppress endothelial ICAM-1 (p = 0.045). CONCLUSIONS: Patients with chronic kidney disease undergoing cardiac and vascular surgery who have dysfunctional, pro-inflammatory HDL have a higher risk of postoperative AKI compared with patients with anti-inflammatory HDL. Conversely, a higher HDL anti-inflammatory capacity is associated with a lower risk of postoperative AKI, independent of HDL concentration. Higher long-term statin dose is associated with higher HDL anti-inflammatory capacity.

Multi-axis fields boost SABRE hyperpolarization.

The inherently low signal-to-noise ratio of NMR and MRI is now being addressed by hyperpolarization methods. For example, iridium-based catalysts that reversibly bind both parahydrogen and ligands in solution can hyperpolarize protons (SABRE) or heteronuclei (X-SABRE) on a wide variety of ligands, using a complex interplay of spin dynamics and chemical exchange processes, with common signal enhancements between 103 and 104. This does not approach obvious theoretical limits, and further enhancement would be valuable in many applications (such as imaging mM concentration species in vivo). Most SABRE/X-SABRE implementations require far lower fields (µT-mT) than standard magnetic resonance (>1T), and this gives an additional degree of freedom: the ability to fully modulate fields in three dimensions. However, this has been underexplored because the standard simplifying theoretical assumptions in magnetic resonance need to be revisited. Here, we take a different approach, an evolutionary strategy algorithm for numerical optimization, multi-axis computer-aided heteronuclear transfer enhancement for SABRE (MACHETE-SABRE). We find nonintuitive but highly efficient multiaxial pulse sequences which experimentally can produce a sevenfold improvement in polarization over continuous excitation. This approach optimizes polarization differently than traditional methods, thus gaining extra efficiency.

NAD+ Biosynthesis Impairment and Acute Kidney Injury after Major Vascular Surgery.

Acute kidney injury (AKI) is a serious complication after vascular surgery. Reduced synthesis of nicotinamide adenine dinucleotide (NAD+) from tryptophan is associated with an increased risk of AKI in critically ill patients, patients hospitalized with COVID-19, and cardiac surgery patients, and is marked by elevated urinary quinolinate and quinolinate to tryptophan ratios. We measured quinolinate concentrations in vascular surgery patients to determine if impaired NAD+ synthesis was associated with AKI in this patient population. Eight preoperative and eight postoperative vascular surgery patients who developed AKI were selected from a parent study to participate in this single-center case-control study. They were matched with controls who did not develop AKI based on age, sex, BMI, eGFR, hypertension, and diabetes. Urinary quinolinate and tryptophan concentrations were measured at anesthetic induction and on postoperative day one. Two-sided Mann-Whitney U tests were used to compare quinolinate and quinolinate to tryptophan ratios. Multivariate linear regression modeling was used to estimate the relationship between quinolinate and serum creatinine. There was no difference in preoperative or postoperative urine quinolinate concentrations or the preoperative quinolinate to tryptophan ratio between patients that did and did not develop AKI (p = 0.07, 0.50, and 0.32, respectively). However, postoperative quinolinate to tryptophan ratios were higher in AKI patients (p = 0.04). Further, after adjustment for AKI risk factors, higher preoperative quinolinate concentrations and higher postoperative quinolinate to tryptophan ratios were associated with greater postoperative creatinine increases (p = 0.04 and 0.04, respectively). These data suggest that impaired NAD+ synthesis may contribute to AKI development in vascular surgery patients.

Prophylactic gabapentin during head and neck cancer therapy: a systematic review and meta-analysis.

PURPOSE: This review was designed to compile the currently available evidence on the prophylactic use of gabapentin in the head and neck cancer patient population. METHODS: A systematic search was conducted of PubMed, Web of Science, and Google Scholar to identify articles related to the use of prophylactic gabapentin in patients undergoing head and neck cancer therapy. Candidate studies were screened for inclusion and a subsequent bias assessment was conducted by multiple reviewers. Meta-analysis was conducted in cases in which the studies used compatible outcome measures. RESULTS: Ten studies were identified that met the inclusion criteria and were assessed for bias. Among the four small studies that examined pain prevention, 2 were positive and 2 were inconclusive. Three of the four studies examiniRDng opioid use noted less need for opioids in the treatment arm. Meta-analysis of the pertinent studies showed no difference in feeding tube placement (RD = 0.64%, 95%CI: (- 25.8%, 27.1%), p = 0.962) but substantially less weight loss among those in the treatment arm (p = 0.047). CONCLUSION: Prophylactic gabapentin appears to be a promising treatment option for preventing pain, reducing opioids, and reducing weight loss in patients undergoing head and neck cancer therapy. However, the studies on the treatment to date are small and several have a substantial risk of bias.

The Endourological Society Inaugural Census Report.

The Endourological Society, the premier urologic society encompassing endourology, robotics, and focal surgery, is composed of a diverse group of >1300 urologists. However, limited information has been collected about society members. Recognizing this need, a survey was initiated to capture data regarding current member practices, as well as help the Society shape the future direction of the organization. Presented herein is the inaugural Endourological Society census report as the beginning of a continued effort for global improvement in the field of endourology. Using a REDCap® database, an email survey was circulated to the membership of the Endourological Society from May through June 2021. Twenty questions were posed, categorizing member data in terms of epidemiology/demographics, practice patterns, member opinions, and future educational preferences. Responses were received from 534 members, representing 40.3% of membership. Data demonstrated that the average age, gender, race, and ethnicity of the typical Society member respondent is a 48-year-old Caucasian male working in the United States, with a mean of 25 years in practice. Retrograde endoscopy and percutaneous nephrolithotomy were identified as the most common practice skills, and 50% of members are involved in robotics. Importantly, the census confirmed that the World Congress of Endourology and Technology remains popular with Society members as a means of educational advancement. To sustain and advance the Society, information is required to understand the career interests and future educational desires of its members. This inaugural census provides crucial data regarding its membership and how the Society can achieve continued success and adjust its focus. Future census efforts will expand on the initial findings and stratify the data to elucidate changes in the needs of the Society as a whole. Circulating an annual census will allow for continued improvements in the field of endourology and, ultimately, better care for urologic patients.

Quantitative magnetic resonance imaging to aid clinical decision making in autoimmune hepatitis.

Background: In autoimmune hepatitis (AIH), clinical practice and treatment guidelines frequently diverge as a reflection of disease heterogeneity and challenges in achieving standardised care. We sought to explore the utility of multiparametric (mp) MR in patients with AIH, and the impact of this technology on physicians' decision making and intended patient management. Methods: 82 AIH patients, recruited from two sites between June and November 2019 as part of an observational cohort study, underwent non-contrast MRI alongside their standard clinical investigations. Correlations between iron-corrected T1 (cT1) and other markers of disease were investigated alongside the utility of imaging markers to risk stratify patients in biochemical remission. The impact of mpMR on clinical decision making was evaluated using pairwise t-tests. The discriminatory ability of the imaging markers was assessed using area under the receiver operating characteristic curves (AUCs). Findings: cT1 had a significant impact on clinician intended patient management (p<0.0001). cT1 correlated with ALT (p = 0.0005), AST (p<0.001), IgG (p = 0.0005), and liver stiffness (p<0.0001). Patients in deep biochemical remission (N = 11; AST/ALT <50% upper limit of normal [ULN] and IgG <12 g/L) had low cT1, while 7/34 in normal biochemical remission (AST/ALT between 50 and 100% of ULN) had high cT1 and were at risk of disease flare. cT1 measures of disease heterogeneity, ALP and bilirubin made the best predictor of those not in biochemical remission (AUC:0.85). Interpretation: This study investigates the impact of mpMR results on intended clinical management in a real world setting. Findings showed that mpMR demonstrated a significant impact on clinical management of AIH and has the potential to inform patient risk stratification. Funding: This paper presents independent research supported by the Innovate UK grant (104,915).

Fine-scale plasticity in nest placement can compensate for poor quality junipers as nesting trees for gray vireos.

Understanding the interactions between behavior and habitat characteristics can have important implications for species of conservation concern. Gray vireos (Vireo vicinior) are one example of a species of conservation concern that is understudied in terms of nest survival probabilities and the habitat characteristics that influence them. Our objective was to determine if habitat features such as juniper density, juniper foliage density, or tree height influence nest survival probabilities, and if gray vireo nest placement can mitigate habitat risks. Based on previous work, we expected daily nest survival probabilities to be associated with nest height and surrounding vegetation. We monitored 89 nests in central New Mexico from 2016-2018 to estimate daily nest survival probabilities. We compared variation in nest placement, nest tree characteristics, and surrounding vegetation between failed and successful nests using logistic exposure models and Akaike Information Criteria. Daily and cumulative nest survival probability were 0.983 (95% CI [0.973-0.989]) and 0.575 (95% CI [0.444-0.702]), respectively. Top models predicting nest survival included a negative interaction between nest-tree foliage density and the distance of the nest from the edge of the nesting tree. This suggests that gray vireos can mitigate risks associated with low nest concealment by nesting closer to the interior of the nesting tree.

High-Density Lipoproteins in Kidney Disease.

Decades of epidemiological studies have established the strong inverse relationship between high-density lipoprotein (HDL)-cholesterol concentration and cardiovascular disease. Recent evidence suggests that HDL particle functions, including anti-inflammatory and antioxidant functions, and cholesterol efflux capacity may be more strongly associated with cardiovascular disease protection than HDL cholesterol concentration. These HDL functions are also relevant in non-cardiovascular diseases, including acute and chronic kidney disease. This review examines our current understanding of the kidneys' role in HDL metabolism and homeostasis, and the effect of kidney disease on HDL composition and functionality. Additionally, the roles of HDL particles, proteins, and small RNA cargo on kidney cell function and on the development and progression of both acute and chronic kidney disease are examined. The effect of HDL protein modification by reactive dicarbonyls, including malondialdehyde and isolevuglandin, which form adducts with apolipoprotein A-I and impair proper HDL function in kidney disease, is also explored. Finally, the potential to develop targeted therapies that increase HDL concentration or functionality to improve acute or chronic kidney disease outcomes is discussed.

Perioperative high density lipoproteins, oxidative stress, and kidney injury after cardiac surgery.

Oxidative stress promotes acute kidney injury (AKI). Higher HDL cholesterol concentrations are associated with less AKI. To test the hypothesis that HDL antioxidant activity is associated with AKI after cardiac surgery, we quantified HDL particle (HDL-P) size and number, paraoxonase-1 (PON-1) activity, and isofuran concentrations in 75 patients who developed AKI and 75 matched control patients. Higher preoperative HDL-P was associated with less AKI (OR: 0.80; 95% CI, 0.71-0.91; P = 0.001), higher PON-1 activity ( P < 0.001), and lower plasma concentrations of isofurans immediately after surgery (P = 0.02). Similarly, higher preoperative small HDL-P was associated with less AKI, higher PON-1 activity, and lower isofuran concentrations. Higher intraoperative particle losses were associated with less AKI (OR: 0.79; 95% CI 0.67-0.93; P = 0.005), and with decreased postoperative isofuran concentrations (P = 0.04) . Additionally, higher preoperative small HDL-P and increased intraoperative small particle loss were associated with improved long-term renal function (P = 0.003, 0.01, respectively). In conclusion, a higher preoperative concentration of HDL-P, particularly small particles, is associated with lower oxidative damage and less AKI. Perioperative changes in HDL-P concentrations are also associated with AKI. Small HDL-P may represent a novel modifiable risk factor for AKI.

Selective Uptake of Carboxylated Multi-Walled Carbon Nanotubes by Class A Type 1 Scavenger Receptors and Impaired Phagocytosis in Alveolar Macrophages.

The production and applications of multi-walled carbon nanotubes (MWNTs) have increased despite evidence that MWNTs can be toxic. Recently, we reported that the binding of Pluronic® F-108 (PF108)-coated carboxylated MWNTs (C-MWNTs) to macrophages is inhibited by class A scavenger receptors (SR-As) antagonists (R. Wang et al., 2018. Nanotoxicology 12:677-690). The current study investigates the uptake of PF108-coated MWNTs by macrophages lacking SR-A1 and by CHO cells that ectopically express SR-A1. Macrophages without SR-A1 failed to take up C-MWNTs and CHO cells that expressed SR-A1 did take up C-MWNTs, but not pristine MWNTs (P-MWNTs) or amino-functionalized MWNTs (N-MWNTs). The dependence of C-MWNT uptake on SR-A1 is strong evidence that SR-A1 is a receptor for C-MWNTs. The consequences of SR-A1-dependent C-MWNT accumulation on cell viability and phagocytic activity in macrophages were also studied. C-MWNTs were more toxic than P-MWNTs and N-MWNTs in cell proliferation and colony formation tests. C-MWNTs reduced surface SR-A1 levels in RAW 264.7 cells and impaired phagocytic uptake of three known SR-A1 ligands, polystyrene beads, heat-killed E. coli, and oxLDL. Altogether, results of this study confirmed that SR-A1 receptors are important for the selective uptake of PF108-coated C-MWNTs and that accumulation of the C-MWNTs impairs phagocytic activity and cell viability in macrophages.

Reactive Dicarbonyl Scavenging Effectively Reduces MPO-Mediated Oxidation of HDL and Restores PON1 Activity.

Atheroprotective functions of high-density lipoproteins (HDL) are related to the activity of HDL-associated enzymes such as paraoxonase 1 (PON1). We examined the impact of inhibition of myeloperoxidase (MPO)-mediated HDL oxidation by PON1 on HDL malondialdehyde (MDA) content and HDL function. In the presence of PON1, crosslinking of apoAI in response to MPO-mediated oxidation of HDL was abolished, and MDA-HDL adduct levels were decreased. PON1 prevented the impaired cholesterol efflux capacity of MPO-oxidized HDL from Apoe-/- macrophages. Direct modification of HDL with MDA increased apoAI crosslinking and reduced the cholesterol efflux capacity. MDA modification of HDL reduced its anti-inflammatory function compared to native HDL. MDA-HDL also had impaired ability to increase PON1 activity. Importantly, HDL from subjects with familial hypercholesterolemia (FH-HDL) versus controls had increased MDA-apoAI adducts, and PON1 activity was also impaired in FH. Consistently, FH-HDL induced a pro-inflammatory response in Apoe-/- macrophages and had an impaired ability to promote cholesterol efflux. Interestingly, reactive dicarbonyl scavengers, including 2-hydroxybenzylamine (2-HOBA) and pentyl-pyridoxamine (PPM), effectively abolished MPO-mediated apoAI crosslinking, MDA adduct formation, and improved cholesterol efflux capacity. Treatment of hypercholesterolemic mice with reactive dicarbonyl scavengers reduced MDA-HDL adduct formation and increased HDL cholesterol efflux capacity, supporting the therapeutic potential of reactive carbonyl scavenging for improving HDL function.

High-Density Lipoproteins and Acute Kidney Injury.

High-density lipoprotein (HDL) particles, best known for their anti-atherosclerotic effects, also may play a beneficial role during acute renal stress. HDL from healthy human beings also shows anti-inflammatory and anti-oxidant capacities, promotes endothelial function and repair, and serves as a systemic signaling mechanism facilitating rapid interorgan communication during times of physiologic stress. Higher concentrations of HDL are associated with less acute kidney injury after sepsis, cardiac and vascular surgery, and contrast-exposure during percutaneous coronary interventions. A better understanding of the interplay between HDL and the kidney both under homeostatic conditions and under acute physiologic stress could lead to the identification of novel risk factors and therapeutic targets for acute kidney injury prevention and treatment in the future.

Influence of the Conservation Reserve Program (CRP) and playa wetlands on pollinator communities in the Southern High Plains, USA.

Numerous studies have documented that invertebrate pollinator services are critical to the world economy. Factors including habitat loss and agricultural practices, however, threaten pollinator populations. Many counties in the Southern High Plains were identified as at risk for a shortage of pollination service from wild bees. This region also has one of the highest concentrations of Conservation Reserve Program (CRP) contracts in the US. The CRP is the largest, voluntary, private lands conservation program in the US and was targeted as a program to improve pollinator habitat. Our objective was to determine how the predominant land uses in the SHP (native grassland, CRP, and cropland) affect pollinator abundance and species richness, and more specifically if the CRP can provide quality habitat for pollinators. We also examined how the keystone habitat, playa wetlands, embedded within these land uses contribute to pollinator habitat (land type: uplands vs. wetland). We used blue vane traps placed in playa basins and adjacent uplands to determine Hymenoptera abundance and richness from April to October in 2013 and 2014. The CRP had lower abundance than cropland and native grassland, and generally less richness. Uplands and playa wetlands had little difference in Hymenoptera abundance and richness. Patch size negatively influenced abundance but had a positive influence on richness. The interaction of vegetation height and percent bare ground positively influenced abundance in cropland and native grasslands, and positively influenced richness in all land uses. In the CRP, vegetation height negatively influenced Hymenoptera abundance and percent bare ground had a positive influence. The years sampled in this study were during a severe extended drought; therefore, these results may be reflective of poor floral resources. The CRP has potential to create valuable habitat for pollinators if land managers incorporate a diversity of native grasses and native forbs into plantings to enhance pollinator foraging and nesting habitat.

A thumbwheel mechanism for APOA1 activation of LCAT activity in HDL.

APOA1 is the most abundant protein in HDL. It modulates interactions that affect HDL's cardioprotective functions, in part via its activation of the enzyme, LCAT. On nascent discoidal HDL, APOA1 comprises 10 α-helical repeats arranged in an anti-parallel stacked-ring structure that encapsulates a lipid bilayer. Previous chemical cross-linking studies suggested that these APOA1 rings can adopt at least two different orientations, or registries, with respect to each other; however, the functional impact of these structural changes is unknown. Here, we placed cysteine residues at locations predicted to form disulfide bonds in each orientation and then measured APOA1's ability to adopt the two registries during HDL particle formation. We found that most APOA1 oriented with the fifth helix of one molecule across from fifth helix of the other (5/5 helical registry), but a fraction adopted a 5/2 registry. Engineered HDLs that were locked in 5/5 or 5/2 registries by disulfide bonds equally promoted cholesterol efflux from macrophages, indicating functional particles. However, unlike the 5/5 registry or the WT, the 5/2 registry impaired LCAT cholesteryl esterification activity (P < 0.001), despite LCAT binding equally to all particles. Chemical cross-linking studies suggest that full LCAT activity requires a hybrid epitope composed of helices 5-7 on one APOA1 molecule and helices 3-4 on the other. Thus, APOA1 may use a reciprocating thumbwheel-like mechanism to activate HDL-remodeling proteins.

High-Density Lipoprotein Cholesterol Concentration and Acute Kidney Injury After Cardiac Surgery.

BACKGROUND: Acute kidney injury (AKI) after cardiac surgery is associated with increased short- and long-term mortality. Inflammation, oxidative stress, and endothelial dysfunction and damage play important roles in the development of AKI. High-density lipoproteins (HDLs) have anti-inflammatory and antioxidant properties and improve endothelial function and repair. Statins enhance HDL's anti-inflammatory and antioxidant capacities. We hypothesized that a higher preoperative HDL cholesterol concentration is associated with decreased AKI after cardiac surgery and that perioperative statin exposure potentiates this association. METHODS AND RESULTS: We tested our hypothesis in 391 subjects from a randomized clinical trial of perioperative atorvastatin to reduce AKI after cardiac surgery. A 2-component latent variable mixture model was used to assess the association between preoperative HDL cholesterol concentration and postoperative change in serum creatinine, adjusted for known AKI risk factors and suspected confounders. Interaction terms were used to examine the effects of preoperative statin use, preoperative statin dose, and perioperative atorvastatin treatment on the association between preoperative HDL and AKI. A higher preoperative HDL cholesterol concentration was independently associated with a decreased postoperative serum creatinine change (P=0.02). The association between a high HDL concentration and an attenuated increase in serum creatinine was strongest in long-term statin-using patients (P=0.008) and was further enhanced with perioperative atorvastatin treatment (P=0.004) and increasing long-term statin dose (P=0.003). CONCLUSIONS: A higher preoperative HDL cholesterol concentration was associated with decreased AKI after cardiac surgery. Preoperative and perioperative statin treatment enhanced this association, demonstrating that pharmacological potentiation is possible during the perioperative period. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique Identifier: NCT00791648.

Melittofauna and Other Potential Pollinators in Wetland and Uplands in South Central Nebraska (Insecta: Apoidea).

Our objective was to document potential wild pollinating insects in south central Nebraska. This intensively cultivated region is known as the Rainwater Basin and contains some of the most endangered wetland systems in North America. We used blue vane traps to passively collect insects and insect nets to actively collect on flowering plants from April through October in 2014 and 2015. Habitat types included playa wetlands, adjacent mixed and tallgrass prairies, and agricultural fields. Over 112,000 insects were collected; Hymenoptera represented 78% of the total, and the families Apidae and Halictidae comprised 99% of the total melittofauna. Insects from 13 orders were collected, but Hymenoptera, Diptera, and Coleoptera were the most abundant potential pollinators.

Factors influencing the toxicity of Headline® fungicides to terrestrial stage toads.

Amphibians are susceptible to exposure from contaminants via multiple pathways. Pyraclostrobin fungicides have been shown to be toxic to terrestrial amphibians at environmentally relevant concentrations; however, these studies did not account for factors that may influence exposure and effects, such as fungicide formulation, age of the individual, exposure route, and physiological state of the individual. We examined Headline® and Headline AMP® fungicide toxicity to adult Anaxyrus cognatus and Anaxyrus woodhousii by direct overspray, as well as acute toxicity of Headline AMP to juvenile A. cognatus through direct overspray, previously exposed soils, and diet. We also assessed effects of hydration state on fungicide toxicity in juvenile A. cognatus and sublethal effects of fungicide exposure on prey-orientation ability of juvenile A. cognatus. Neither formulation of Headline caused mortality of adult A. cognatus and A. woodhousii at up to 5 times the maximum label rate in North American corn (1052 and 879 mL formulation/ha for Headline AMP and Headline fungicides, respectively, corresponding to 1.52 and 2.2 µg pyraclostrobin/cm2 , respectively). Exposures of juvenile A. cognatus to Headline AMP via direct overspray and previously exposed soils (2 types) resulted in median lethal rate (LR50) values of 2.4, 3.34, and 3.61 µg pyraclostrobin/cm2 , respectively. Dietary Headline AMP exposure was not toxic, prey-orientations were not influenced by exposure, and effects were similar between dehydrated and hydrated treatments (LR50 = 2.4 and 2.3 µg pyraclostrobin/cm2 , respectively). These results, combined with exposure concentrations reported in previous studies, suggest that risk of acute mortality for amphibians in terrestrial environments is low and is dictated by body size and site-specific factors influencing exposure. Environ Toxicol Chem 2017;36:2679-2688. © 2017 SETAC.

Latent variable modeling improves AKI risk factor identification and AKI prediction compared to traditional methods.

BACKGROUND: Acute kidney injury (AKI) is diagnosed based on postoperative serum creatinine change, but AKI models have not consistently performed well, in part due to the omission of clinically important but practically unmeasurable variables that affect creatinine. We hypothesized that a latent variable mixture model of postoperative serum creatinine change would partially account for these unmeasured factors and therefore increase power to identify risk factors of AKI and improve predictive accuracy. METHODS: We constructed a two-component latent variable mixture model and a linear model using data from a prospective, 653-subject randomized clinical trial of AKI following cardiac surgery (NCT00791648) and included established AKI risk factors and covariates known to affect serum creatinine. We compared model fit, discrimination, power to detect AKI risk factors, and ability to predict AKI between the latent variable mixture model and the linear model. RESULTS: The latent variable mixture model demonstrated superior fit (likelihood ratio of 6.68 × 1071) and enhanced discrimination (permutation test of Spearman's correlation coefficients, p < 0.001) compared to the linear model. The latent variable mixture model was 94% (-13 to 1132%) more powerful (median [range]) at identifying risk factors than the linear model, and demonstrated increased ability to predict change in serum creatinine (relative mean square error reduction of 6.8%). CONCLUSIONS: A latent variable mixture model better fit a clinical cohort of cardiac surgery patients than a linear model, thus providing better assessment of the associations between risk factors of AKI and serum creatinine change and more accurate prediction of AKI. Incorporation of latent variable mixture modeling into AKI research will allow clinicians and investigators to account for clinically meaningful patient heterogeneity resulting from unmeasured variables, and therefore provide improved ability to examine risk factors, measure mechanisms and mediators of kidney injury, and more accurately predict AKI in clinical cohorts.