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.

A comparison of three commercial platforms for urinary NGAL in critically ill adults.

BACKGROUND: Early biomarkers for acute kidney injury (AKI) diagnosis are needed since an increase in serum creatinine levels is a late marker. Neutrophil gelatinase-associated lipocalin (NGAL) is one of the most promising AKI biomarkers. Prior to routine clinical use, it is necessary to evaluate and validate a high-throughput commercially available method for NGAL detection. The aim of this study was to do an independent validation and comparison of the analytical performance of three different commercially available urine NGAL (uNGAL) assays. METHODS: Urine samples (n=110) were obtained from various patient groups with and without AKI. All urine samples were processed using Architect NGAL assay, Siemens Advia® 2400 NGAL test, and Siemens Dimension Vista® NGAL Test™, based on the three different platforms. RESULTS: Overall, there was good agreement among the three assays: Spearman's rank correlation coefficient between Architect and Vista was 0.989 (95% confidence interval [CI], 0.983-0.993), between Architect and Advia, 0.962 (95% CI, 0.937-0.977), between Vista and Advia 2400, 0.975 (95% CI, 0.961-0.984). We observed a negative bias of Architect compared with the other assays: comparing Architect to Vista, the mean bias was -55.7 ng/mL (95% CI, -74.3 to -37.0 ng/mL); comparing Architect to Advia 2400, the mean bias was -40.9 ng/mL (95% CI, -56.4 to -25.4 ng/nL). The bias is proportional to the concentration of uNGAL and is more pronounced at higher levels, while irrelevant near the tested cutoff levels of 100 and 190 ng/mL. Comparing Vista and Advia 2400, the mean bias was 10.1 ng/mL (95% CI, 1.5-18.8 ng/mL). Intra-assay imprecision was generally acceptable across all assays; coefficient of variation ranged from 0.8% to 5.3%. CONCLUSIONS: All three methods for uNGAL showed acceptable performance for the tested parameters and are comparable with each other at clinically relevant cutoffs. However, Architect yields lower results than the other two methods, with a bias more pronounced at higher uNGAL concentrations, suggesting additional standardization efforts will likely be necessary to better harmonize the uNGAL methods at various clinically relevant cutoffs.

We Use Permcaths Instead of Peritoneal Catheters for Acute Kidney Injury and Urgent-Start Dialysis.

The rising tide of severe acute kidney injury requiring dialysis (AKI-D) and unplanned dialysis initiation for advanced CKD patients remains a major problem for the nephrology community worldwide. Hemodialysis (HD) through a central venous catheter remains the most common practice for both. Peritoneal dialysis (PD) remains greatly underutilized despite mounting evidence of equipoise with HD for a significant proportion of patients. PD is technically simpler, requires less infrastructure, and costs less. However, the structure of our healthcare system, hospital logistics, and the current state of nephrology training all contribute to the reflexive consult for a central venous catheter. As clinicians, we must ask ourselves if we are doing our patients and our healthcare system a disservice by not offering PD in AKI and urgent-start situations.

Pro-Apoptotic Effects of Plasma from Patients with Cardiorenal Syndrome on Human Tubular Cells.

BACKGROUND: The pathophysiology of Cardiorenal Syndrome Type 1 (CRS1) is widely studied, although the mechanisms by which renal tubular epithelial cells (TECs) cease to proliferate and embark upon terminal differentiation, following the initial insult of heart failure (HF), remain a key target. This study seeks to provide insight into the pathophysiological pathways in CRS1; we evaluated in vitro the effects of CRS1 plasma on TECs. METHODS: We enrolled 40 acute HF patients and 15 controls (CTR) without HF or acute kidney injury (AKI). Ten out of 40 HF patients exhibited AKI at the time of admission for HF or developed AKI during hospitalization and were classified as CRS1. In vitro, cell viability, DNA fragmentation and caspase-3 levels were investigated in TECs incubated with HF, CRS1, and CTR plasma. We assessed inflammatory cytokines and NGAL expression at the gene and protein levels. RESULTS: We observed a marked pro-apoptotic activity and a significantly increased in vitro level of apoptosis in TECs incubated with plasma from CRS1 patients compared to HF and CTR (p < 0.01). In the CRS1 group, the mRNA expression of IL-6, IL-18 and NGAL resulted significantly higher in TECs incubated with CRS1 plasma compared with those incubated with plasma from HF and CTR (p < 0.01). IL-6, IL-18, NGAL, and RANTES levels were significantly higher in TECs supernatant incubated with CRS1 plasma compared with HF patients and CTR plasma (p < 0.01). CONCLUSION: In vitro exposure to plasma from CRS1 patients altered the expression profile of TECs characterized by increases in proinflammatory mediators, release of tubular damage markers, and apoptosis.

Variation in risk and mortality of acute kidney injury in critically ill patients: a multicenter study.

BACKGROUND: Despite standardized definitions of acute kidney injury (AKI), there is wide variation in the reported rates of AKI and hospital mortality for patients with AKI. Variation could be due to actual differences in disease incidence, clinical course, or a function of data ascertainment and application of diagnostic criteria. Using standard criteria may help determine and compare the risk and outcomes of AKI across centers. METHODS: In this cohort study of critically ill patients admitted to the intensive care units at six hospitals in four countries, we used KDIGO criteria to define AKI. The main outcomes were the occurrence of AKI and hospital mortality. RESULTS: Of the 15,132 critically ill patients, 32% developed AKI based on serum creatinine criteria. After adjusting for differences in age, sex, and severity of illness, the odds ratio for AKI continued to vary across centers (odds ratio (OR), 2.57-6.04, p < 0.001). The overall, crude hospital mortality of patients with AKI was 27%, which also varied across centers after adjusting for KDIGO stage, differences in age, sex, and severity of illness (OR, 1.13-2.20, p < 0.001). The severity of AKI was associated with incremental mortality risk across centers. CONCLUSIONS: In this study, the absolute and severity-adjusted rates of AKI and hospital mortality rates for AKI varied across centers. Future studies should examine whether variation in the risk of AKI among centers is due to differences in clinical practice or process of care or residual confounding due to unmeasured factors.

Understanding acute kidney injury in low resource settings: a step forward.

Attention has recently been focused on addressing the problem of acute kidney injury in both the developed and developing world. Little information is actually available on the incidence and management of AKI in low resource settings. Thus, the paper by Bagasha in the current issue of BMC Nephrology makes an important contribution to our understanding of this serious and potentially remediable problem.

Potential use of biomarkers in acute kidney injury: report and summary of recommendations from the 10th Acute Dialysis Quality Initiative consensus conference.

Over the last decade there has been considerable progress in the discovery and development of biomarkers of kidney disease, and several have now been evaluated in different clinical settings. Although there is a growing literature on the performance of various biomarkers in clinical studies, there is limited information on how these biomarkers would be utilized by clinicians to manage patients with acute kidney injury (AKI). Recognizing this gap in knowledge, we convened the 10th Acute Dialysis Quality Initiative meeting to review the literature on biomarkers in AKI and their application in clinical practice. We asked an international group of experts to assess four broad areas for biomarker utilization for AKI: risk assessment, diagnosis, and staging; differential diagnosis; prognosis and management; and novel physiological techniques including imaging. This article provides a summary of the key findings and recommendations of the group, to equip clinicians to effectively use biomarkers in AKI.

Acute kidney injury: an increasing global concern.

Despite an increasing incidence of acute kidney injury in both high-income and low-income countries and growing insight into the causes and mechanisms of disease, few preventive and therapeutic options exist. Even small acute changes in kidney function can result in short-term and long-term complications, including chronic kidney disease, end-stage renal disease, and death. Presence of more than one comorbidity results in high severity of illness scores in all medical settings. Development or progression of chronic kidney disease after one or more episode of acute kidney injury could have striking socioeconomic and public health outcomes for all countries. Concerted international action encompassing many medical disciplines is needed to aid early recognition and management of acute kidney injury.

New trends in polymyxin B hemoperfusion: from 2006 to 2013.

Endotoxin, one of the principal components on the outer membrane of Gram-negative bacteria, is considered a key and early component in the pathogenesis of sepsis. Polymyxin B bound to polystyrene fibers (PMX) is a medical device capable of removing circulating endotoxin by adsorption. The most comprehensive analysis to date of clinical experience with this device remains a meta-analysis of 28 studies between 1998 and 2006. This showed that PMX hemoperfusion was associated with improved blood pressure and a reduction in dopamine dose, improved PaO2/FiO2 ratio and lower mortality. Since this meta-analysis, over 50 additional studies on PMX have been published. The majority are observational, with small sample sizes. Notable among the newer studies is the increasing interest in the use of PMX therapy in interstitial pneumonias and idiopathic pulmonary fibrosis, as well as in longer treatment duration and earlier initiation of PMX therapy in an attempt to further improve clinical outcomes. These observational data highlight important aspects of PMX therapy worthy of more rigorous investigation in future studies.

Neutrophil gelatinase-associated lipocalin: ready for routine clinical use? An international perspective.

Acute kidney injury (AKI) remains a challenge in terms of diagnosis and classification, its morbidity and mortality remaining high in the face of improving clinical protocols. Current clinical criteria use serum creatinine (sCr) and urine output to classify patients. Ongoing research has identified novel biomarkers that may improve the speed and accuracy of patient evaluation and prognostication, yet the route from basic science to clinical practice remains poorly paved. International evidence supporting the use of plasma neutrophil gelatinase-associated lipocalin (NGAL) as a valuable biomarker of AKI and chronic kidney disease (CKD) for a number of clinical scenarios was presented at the 31st International Vicenza Course on Critical Care Nephrology, and these data are detailed in this review. NGAL was shown to be highly useful alongside sCr, urinary output, and other biomarkers in assessing kidney injury; in patient stratification and continuous renal replacement therapy (CRRT) selection in paediatric AKI; in assessing kidney injury in conjunction with sCr in sepsis; in guiding resuscitation protocols in conjunction with brain natriuretic peptide in burn patients; as an early biomarker of delayed graft function and calcineurin inhibitor nephrotoxicity in kidney transplantation from extended criteria donors; as a biomarker of cardiovascular disease and heart failure, and in guiding CRRT selection in the intensive care unit and emergency department. While some applications require further clarification by way of larger randomised controlled trials, NGAL nevertheless demonstrates promise as an independent biological marker with the potential to improve earlier diagnosis and better assessment of risk groups in AKI and CKD. This is a critical element in formulating quick and accurate decisions for individual patients, both in acute scenarios and in long-term care, in order to improve patient prognostics and outcomes.

Effects of fluid overload on heart rate variability in chronic kidney disease patients on hemodialysis.

BACKGROUND: While fluid overload (FO) and alterations in the autonomic nervous system (ANS) such as hypersympathetic activity, are known risk factors for cardiovascular morbidity and mortality in patients on chronic hemodialysis (HD), their relationship has not been thoroughly studied. METHODS: In this observational study involving 69 patients on chronic HD, FO was assessed by whole body bioimpedance measurements before the midweek HD session and ANS activity reflected by Heart Rate Variability (HRV) was measured using 24-hour Holter electrocardiogram recordings starting before the same HD treatment. In total, 13 different HRV indices were analyzed, comprising a mixture of time domain, frequency domain and complexity parameters. A correlation analysis was performed between the HRV indices and hydration status indices. Successively, patients were retrospectively assigned to a high FO (H, FO > 2.5 L) or low FO (L, FO ≤ 2.5 L) group and these were further compared also after stratification by diabetes mellitus. Finally, a small number of patients without diabetes with significant and persistent FO were followed up for 3 months post-study to investigate how normalization of fluid status affects HRV. RESULTS: SDANN, VLF, LZC and HF% parameters significantly correlate with FO (correlation coefficients were respectively r = -0.40, r = -0.37, r = -0.28 and r = 0.26, p-value < 0.05). Furthermore, LF% and LF/HF were inversely correlated with hydration status (correlation coefficients were respectively r = -0.31 and r = -0.33, p-value < 0.05). These results indicate an association between FO and reduced HRV, higher parasympathetic activation and reduced sympathetic response to the HD session. Indeed, group H tended to have lower values of SDANN, VLF and LZC, and higher values of HF% than patients in the L group. Finally, there was a trend towards lower LF% measured during the last 30 minutes of HD for the H group versus the L group. Reduction in FO achieved over 3 months by implementation of a strict fluid management plan resulted in an increase of HRV. CONCLUSIONS: Our results suggest that depressed HRV is associated with fluid overload and that normalization of hydration status is accompanied by improved HRV.

High-resolution melt as a screening method in autosomal dominant polycystic kidney disease (ADPKD).

BACKGROUND: Autosomal dominant polycystic kidney disease (ADPKD) is an inherited condition caused by PKD1 and PKD2 mutations. Complete analysis of both genes is typically required in each patient. In this study, we explored the utility of High-Resolution Melt (HRM) as a tool for mutation analysis of the PKD2 gene in ADPKD families. METHODS: HRM is a mismatch-detection method based on the difference of fluorescence absorbance behavior during the melting of the DNA double strand to denatured single strands in a mutant sample as compared to a reference control. Our families were previously screened by linkage analysis. Subsequently, HRM was used to characterize PKD2-linked families. Amplicons that produced an overlapping profile sample versus wild-type control were not further evaluated, while those amplicons with profile deviated from the control were consequently sequenced. RESULTS: We analyzed 16 PKD2-linked families by HRM analysis. We observed ten different variations: six single-nucleotide polymorphisms and four mutations. The mutations detected by HRM and confirmed by sequencing were as follows: 1158T>A, 2159delA, 2224C>T, and 2533C>T. In particular, the same haplotype block and nonsense mutation 2533C>T was found in 8 of 16 families, so we suggested the presence of a founder effect in our province. CONCLUSIONS: We have developed a strategy for rapid mutation analysis of the PKD2 gene in ADPKD families, which utilizes an HRM-based prescreening followed by direct sequencing of amplicons with abnormal profiles. This is a simple and good technique for PKD2 genotyping and may significantly reduce the time and cost for diagnosis in ADPKD.

Fluid balance and urine volume are independent predictors of mortality in acute kidney injury.

INTRODUCTION: In ICUs, both fluid overload and oliguria are common complications associated with increased mortality among critically ill patients, particularly in acute kidney injury (AKI). Although fluid overload is an expected complication of oliguria, it remains unclear whether their effects on mortality are independent of each other. The aim of this study is to evaluate the impact of both fluid balance and urine volume on outcomes and determine whether they behave as independent predictors of mortality in adult ICU patients with AKI. METHODS: We performed a secondary analysis of data from a multicenter, prospective cohort study in 10 Italian ICUs. AKI was defined by renal sequential organ failure assessment (SOFA) score (creatinine >3.5 mg/dL or urine output (UO) <500 mL/d). Oliguria was defined as a UO <500 mL/d. Mean fluid balance (MFB) and mean urine volume (MUV) were calculated as the arithmetic mean of all daily values. Use of diuretics was noted daily. To assess the impact of MFB and MUV on mortality of AKI patients, multivariate analysis was performed by Cox regression. RESULTS: Of the 601 included patients, 132 had AKI during their ICU stay and the mortality in this group was 50%. Non-surviving AKI patients had higher MFB (1.31 ± 1.24 versus 0.17 ± 0.72 L/day; P <0.001) and lower MUV (1.28 ± 0.90 versus 2.35 ± 0.98 L/day; P <0.001) as compared to survivors. In the multivariate analysis, MFB (adjusted hazard ratio (HR) 1.67 per L/day, 95%CI 1.33 to 2.09; <0.001) and MUV (adjusted HR 0.47 per L/day, 95%CI 0.33 to 0.67; <0.001) remained independent risk factors for 28-day mortality after adjustment for age, gender, diabetes, hypertension, diuretic use, non-renal SOFA and sepsis. Diuretic use was associated with better survival in this population (adjusted HR 0.25, 95%CI 0.12 to 0.52; <0.001). CONCLUSIONS: In this multicenter ICU study, a higher fluid balance and a lower urine volume were both important factors associated with 28-day mortality of AKI patients.

Extracorporeal therapies in sepsis.

The treatment of sepsis is an ongoing challenge for clinicians; despite the wide choice of effective antibiotics to treat infection, sepsis remains the leading cause of morbidity and mortality for patients admitted to an intensive care unit. Dysregulation of the immune response is now recognized to be a key factor in multiple organ dysfunction, yet our therapy for inflammation remains ineffective. It has been advocated for more than a decade that cytokine reduction in blood compartment could lead to a reduction in mortality in sepsis. Over the years, multiple extracorporeal techniques have evolved, with the intent of influencing the circulating levels of inflammatory mediators like cytokines and chemokines, the complement system, as well as factors of the coagulation system. These include high-volume hemofiltration, use of high cutoff membranes, and systems based on adsorption, such as coupled plasma filtration adsorption and the polymyxin-B column. In addition, new experimental systems that utilize human phagocytic cells and immobilized antibodies for targeted immunomodulation have emerged. In the context of limited resources and growing expansion in the availability of technologies, a better understanding of these therapies is required before they can be properly integrated into standard clinical practice in the hope of influencing major clinical outcomes. In this article, we will provide a concise overview of selected extracorporeal modalities currently in clinical use and briefly introduce some new promising techniques for sepsis.

Genomics and biological activity of neutrophil gelatinase-associated lipocalin in several clinical settings.

Recent literature has shown that neutrophil gelatinase-associated lipocalin (NGAL) is one of the most interesting and promising biomarkers in case of acute kidney injury. However, several studies indicated that this protein may be applied beyond the boundaries of renal pathophysiology and may be used in other pathophysiological settings since it is also expressed in neutrophils, and respiratory, bowel and prostate epithelia. In this review, we report NGAL genomics and biology and its possible use in several clinical settings. In particular, we review the genomic organization of the NGAL gene, the lipocalin family structure, the interaction between NGAL and ligands, and the induction and expression of NGAL in different conditions.

Fluid management in the intensive care unit: bioelectrical impedance vector analysis as a tool to assess hydration status and optimal fluid balance in critically ill patients.

BACKGROUND: Fluid balance disorders are a relevant risk factor for morbidity and mortality in critically ill patients. Volume assessment in the intensive care unit (ICU) is thus of great importance, but there are currently few methods to obtain an accurate and timely assessment of hydration status. Our aim was to evaluate the hydration status of ICU patients via bioelectric impedance vector analysis (BIVA) and to investigate the relationship between hydration and mortality. METHODS: We evaluated 280 BIVA measurements of 64 patients performed daily in the 5 days following their ICU admission. The observation period ranged from a minimum of 72 h up to a maximum of 120 h. We observed the evolution of the hydration status during the ICU stay in this population, and analyzed the relationship between mean and maximum hydration reached and mortality--both in the ICU and at 60 days--using logistic regression. RESULTS: A state of overhydration was observed in the majority of patients (70%) on admission, which persisted during the ICU stay. Patients who required continuous renal replacement therapy (CRRT) were more likely to be overhydrated starting from the 2nd day of observation. Logistic regression showed a strong and significant correlation between mean/maximum hydration reached and mortality, both independently and correcting for severity of prognosis. CONCLUSIONS: Fluid overload measured by BIVA is a frequent condition in critically ill patients--whether or not they undergo CRRT--and a significant predictor of mortality. Hence, hydration status should be considered as an additional prognosticator in the clinical management of the critically ill patient. KEY MESSAGES: (i) On the day of ICU admittance, patients showed a marked tendency to overhydration (>70% of total). This tendency was more pronounced in patients on CRRT. (ii) Hyperhydration persisted during the ICU stay. Patients who underwent CRRT showed significantly higher hyperhydration from the 2nd day of hospitalization. (iii) Nonsurvivors showed worse hyperhydration patterns in comparison to survivors in logistic univariate analysis (p < 0.05). This relationship between hydration and mortality is confirmed even when controlling for the effect of a worse prognosis approximated by any of three ICU scoring systems (APACHE II, SAPS II and SOFA). Mean and maximum hydration levels present a stronger correlation with mortality than with mean and maximum cumulative fluid balance reached during the observation period.

Effects of dialysate flow configurations in continuous renal replacement therapy on solute removal: computational modeling.

BACKGROUND/AIMS: Continuous renal replacement therapy (CRRT) is commonly used for critically ill patients with acute kidney injury. During treatment, a slow dialysate flow rate can be applied to enhance diffusive solute removal. However, due to the lack of the rationale of the dialysate flow configuration (countercurrent or concurrent to blood flow), in clinical practice, the connection settings of a hemodiafilter are done depending on nurse preference or at random. METHODS: In this study, we investigated the effects of flow configurations in a hemodiafilter during continuous venovenous hemodialysis on solute removal and fluid transport using computational fluid dynamic modeling. We solved the momentum equation coupling solute transport to predict quantitative diffusion and convection phenomena in a simplified hemodiafilter model. RESULTS: Computational modeling results showed superior solute removal (clearance of urea: 67.8 vs. 45.1 ml/min) and convection (filtration volume: 29.0 vs. 25.7 ml/min) performances for the countercurrent flow configuration. Countercurrent flow configuration enhances convection and diffusion compared to concurrent flow configuration by increasing filtration volume and equilibrium concentration in the proximal part of a hemodiafilter and backfiltration of pure dialysate in the distal part. In clinical practice, the countercurrent dialysate flow configuration of a hemodiafilter could increase solute removal in CRRT. Nevertheless, while this configuration may become mandatory for high-efficiency treatments, the impact of differences in solute removal observed in slow continuous therapies may be less important. Under these circumstances, if continuous therapies are prescribed, some of the advantages of the concurrent configuration in terms of simpler circuit layout and simpler machine design may overcome the advantages in terms of solute clearance. CONCLUSION: Different dialysate flow configurations influence solute clearance and change major solute removal mechanisms in the proximal and distal parts of a hemodiafilter. Advantages of each configuration should be balanced against the overall performance of the treatment and its simplicity in terms of treatment delivery and circuit handling procedures.

Clinical Characteristics and Outcomes of Drug-Induced Acute Kidney Injury Cases.

Introduction: Drug-induced acute kidney injury (DI-AKI) is a frequent adverse event. The identification of DI-AKI is challenged by competing etiologies, clinical heterogeneity among patients, and a lack of accurate diagnostic tools. Our research aims to describe the clinical characteristics and predictive variables of DI-AKI. Methods: We analyzed data from the Drug-Induced Renal Injury Consortium (DIRECT) study (NCT02159209), an international, multicenter, observational cohort study of enriched clinically adjudicated DI-AKI cases. Cases met the primary inclusion criteria if the patient was exposed to at least 1 nephrotoxic drug for a minimum of 24 hours prior to AKI onset. Cases were clinically adjudicated, and inter-rater reliability (IRR) was measured using Krippendorff's alpha. Variables associated with DI-AKI were identified using L1 regularized multivariable logistic regression. Model performance was assessed using the area under the receiver operating characteristic curve (ROC AUC). Results: A total of 314 AKI cases met the eligibility criteria for this analysis, and 271 (86%) cases were adjudicated as DI-AKI. The majority of the AKI cases were recruited from the United States (68%). The most frequent causal nephrotoxic drugs were vancomycin (48.7%), nonsteroidal antiinflammatory drugs (18.2%), and piperacillin/tazobactam (17.8%). The IRR for DI-AKI adjudication was 0.309. The multivariable model identified age, vascular capacity, hyperglycemia, infections, pyuria, serum creatinine (SCr) trends, and contrast media as significant predictors of DI-AKI with good performance (ROC AUC 0.86). Conclusion: The identification of DI-AKI is challenging even with comprehensive adjudication by experienced nephrologists. Our analysis identified key clinical characteristics and outcomes of DI-AKI compared to other AKI etiologies.

Neutrophil gelatinase-associated lipocalin as a biomarker of cardiovascular disease: a systematic review.

BACKGROUND: Neutrophil gelatinase-associated lipocalin (NGAL) is a biomarker of acute kidney injury (AKI). Recently, elevated NGAL levels have also been reported in heart failure, coronary heart disease, and stroke. Other studies demonstrate that NGAL is upregulated in failing myocardium and in atherosclerotic plaque. Our aim was to synthesize the current evidence on NGAL and cardiovascular disease (CVD), and to clarify the prognostic significance of systemic NGAL levels in CVD. METHODS: We performed a systematic review to identify experimental and human studies on NGAL and CVD. We excluded articles which specifically dealt with AKI or renal endpoints. RESULTS: We identified 22 studies, including both animal and human data. NGAL is highly expressed in the heart, both in failing myocardium and myocarditis, and is also expressed in atherosclerotic plaques. Areas of co-localization of NGAL and matrix metalloproteinase (MMP)-9 exhibited increased MMP-9 proteolytic activity. Systemic NGAL levels correlated with renal function and severity of CVD in several, but not all, studies. An association between elevated systemic NGAL levels and clinical outcomes (e.g., death, hospital readmissions) were reported in six CVD studies, but these had limited adjustment for potential confounders. CONCLUSIONS: There is ample literature to support a putative role of NGAL in the pathophysiology of CVD, but at present there is insufficient data regarding the clinical utility of systemic NGAL levels in the management of CVD. Available evidence regarding NGAL as a predictor of outcomes in CVD is very limited.

Extracorporeal carbon dioxide removal: the future of lung support lies in the history.

Extracorporeal organ support in patients with dysfunction of vital organs like the kidney, heart, and liver has proven helpful in bridging the patients to recovery or more definitive therapy. Mechanical ventilation in patients with respiratory failure, although indispensable, has been associated with worsening injury to the lungs, termed ventilator-induced lung injury. Application of lung-protective ventilation strategies are limited by inevitable hypercapnia and hypercapnic acidosis. Various alternative extracorporeal strategies, proposed more than 30 years ago, to combat hypercapnia are now more readily available. In particular, the venovenous approach to effective carbon dioxide removal, which involves minimal invasiveness comparable to renal replacement therapy, appears to be very promising. The clinical applications of these extracorporeal carbon dioxide removal therapies may extend beyond just lung protection in ventilated patients. This article summarizes the rationale, technology and clinical application of various extracorporeal lung assist techniques available for clinical use, and some of the future perspectives in the field.