The publication data currently available has been vetted by Vanderbilt faculty, staff, administrators and trainees. The data itself is retrieved directly from NCBI's PubMed and is automatically updated on a weekly basis to ensure accuracy and completeness.
If you have any questions or comments, please contact us.
There is a paucity of data on risk factors for lung cancer among never smokers. Here, we have carried out the first large study of circulating inflammation markers and lung cancer risk among female never smokers in Shanghai. A study of 248 lung cancer cases in female never smokers and 263 controls was nested within the Shanghai Women's Health Study (n = 75221), matched by dates of birth and blood collection (mean follow-up time = 7.5 years). Prediagnostic plasma levels of 65 inflammation markers were measured using a Luminex bead-based assay. Odds ratios (ORs) were estimated with multivariable logistic regression. Nine of 61 evaluable markers were statistically significantly associated with lung cancer risk among never smoking Chinese women (P-trend across categories <0.05). Soluble interleukin-6 receptor [sIL-6R; highest versus lowest category OR = 2.37; 95% confidence interval (CI) 1.40-4.02) and chemokine (C-C motif) ligand 2/monocyte chemotactic protein 1; (OR = 1.62; 95% CI 0.94-2.80) were associated with an increased risk of lung cancer, whereas interleukin (IL)-21 (OR = 0.53; 95%CI 0.31-0.93), chemokine (C-X3-C motif) ligand 1/fractalkine (OR = 0.54; 95% CI 0.30-0.96), soluble vascular endothelial growth factor receptor 2 (sVEGFR2, OR = 0.45; 95% CI 0.26-0.76), sVEGFR3 (OR = 0.53; 95% CI 0.32-0.90), soluble tumor necrosis factor receptor I (OR = 0.49; 95% CI 0.29-0.83), IL-10 (OR = 0.60; 95% CI 0.34-1.05) and C-reactive protein (OR = 0.63; 95% CI 0.37-1.06) were associated with a decreased risk. sIL-6R remained significantly associated with lung cancer risk >7.5 years prior to diagnosis. Markers involved in various aspects of the immune response were associated with subsequent lung cancer risk, implicating inflammation in the etiology of lung cancer among female never smokers.
Published by Oxford University Press 2017.
Clinicians have access to limited tools that predict which patients with early AKI will progress to more severe stages. In early AKI, urine output after a furosemide stress test (FST), which involves intravenous administration of furosemide (1.0 or 1.5 mg/kg), can predict the development of stage 3 AKI. We measured several AKI biomarkers in our previously published cohort of 77 patients with early AKI who received an FST and evaluated the ability of FST urine output and biomarkers to predict the development of stage 3 AKI (n=25 [32.5%]), receipt of RRT (n=11 [14.2%]), or inpatient mortality (n=16 [20.7%]). With an area under the curve (AUC)±SEM of 0.87±0.09 (P<0.0001), 2-hour urine output after FST was significantly better than each urinary biomarker tested in predicting progression to stage 3 (P<0.05). FST urine output was the only biomarker to significantly predict RRT (0.86±0.08; P=0.001). Regardless of the end point, combining FST urine output with individual biomarkers using logistic regression did not significantly improve risk stratification (ΔAUC, P>0.10 for all). When FST urine output was assessed in patients with increased biomarker levels, the AUC for progression to stage 3 improved to 0.90±0.06 and the AUC for receipt of RRT improved to 0.91±0.08. Overall, in the setting of early AKI, FST urine output outperformed biochemical biomarkers for prediction of progressive AKI, need for RRT, and inpatient mortality. Using a FST in patients with increased biomarker levels improves risk stratification, although further research is needed.
Copyright © 2015 by the American Society of Nephrology.
BACKGROUND - Undernourished, HIV-infected adults in sub-Saharan Africa have high levels of systemic inflammation, which is a risk factor for mortality and other adverse health outcomes. We hypothesized that microbial translocation, due to the deleterious effects of HIV and poor nutrition on intestinal defenses and mucosal integrity, contributes to heightened systemic inflammation in this population, and reductions in inflammation on antiretroviral therapy (ART) accompany reductions in translocation.
METHODS - HIV-infected, Zambian adults with a body mass index <18.5 kg/m2 were recruited for a pilot study to assess the relationships between microbial translocation and systemic inflammation over the first 12 weeks of ART. To assess microbial translocation we measured serum lipopolysaccharide binding protein (LBP), endotoxin core IgG and IgM, and soluble CD14, and to assess intestinal permeability we measured the urinary excretion of an oral lactulose dose normalized to urinary creatinine (Lac/Cr ratio). Linear mixed models were used to assess within-patient changes in these markers relative to serum C-reactive protein (CRP), tumor necrosis factor-α receptor 1 (TNF-α R1), and soluble CD163 over 12 weeks, in addition to relationships between variables independent of time point and adjusted for age, sex, and CD4+ count.
RESULTS - Thirty-three participants had data from recruitment and at 12 weeks: 55% were male, median age was 36 years, and median baseline CD4+ count was 224 cells/μl. Over the first 12 weeks of ART, there were significant decreases in serum levels of LBP (median change -8.7 μg/ml, p = 0.01), TNF-α receptor 1 (-0.31 ng/ml, p < 0.01), and CRP (-3.5 mg/l, p = 0.02). The change in soluble CD14 level over 12 weeks was positively associated with the change in CRP (p < 0.01) and soluble CD163 (p < 0.01). Pooling data at baseline and 12 weeks, serum LBP was positively associated with CRP (p = 0.01), while endotoxin core IgM was inversely associated with CRP (p = 0.01) and TNF-α receptor 1 (p = 0.04). The Lac/Cr ratio was not associated with any serum biomarkers.
CONCLUSIONS - In undernourished HIV-infected adults in Zambia, biomarkers of increased microbial translocation are associated with high levels of systemic inflammation before and after initiation of ART, suggesting that impaired gut immune defenses contribute to innate immune activation in this population.
Biomarker studies for early detection of acute kidney injury (AKI) have been limited by nonselective testing and uncertainties in using small changes in serum creatinine as a reference standard. Here we examine the ability of urine L-type fatty acid-binding protein (L-FABP), neutrophil gelatinase-associated lipocalin (NGAL), interleukin-18 (IL-18), and kidney injury molecule-1 (KIM-1) to predict injury progression, dialysis, or death within 7 days in critically ill adults with early AKI. Of 152 patients with known baseline creatinine examined, 36 experienced the composite outcome. Urine L-FABP demonstrated an area under the receiver-operating characteristic curve (AUC-ROC) of 0.79 (95% confidence interval 0.70-0.86), which improved to 0.82 (95% confidence interval 0.75-0.90) when added to the clinical model (AUC-ROC of 0.74). Urine NGAL, IL-18, and KIM-1 had AUC-ROCs of 0.65, 0.64, and 0.62, respectively, but did not significantly improve discrimination of the clinical model. The category-free net reclassification index improved with urine L-FABP (total net reclassification index for nonevents 31.0%) and urine NGAL (total net reclassification index for events 33.3%). However, only urine L-FABP significantly improved the integrated discrimination index. Thus, modest early changes in serum creatinine can help target biomarker measurement for determining prognosis with urine L-FABP, providing independent and additive prognostic information when combined with clinical predictors.
INTRODUCTION - Plasma neutrophil gelatinase-associated lipocalin (NGAL) is reportedly useful for post-cardiac surgery acute kidney injury (AKI). Although chronic kidney disease (CKD) is a strong risk factor for AKI development, no clinical evaluation of plasma NGAL has specifically examined AKI occurring in patients with CKD. This study evaluated plasma NGAL in AKI superimposed on CKD after cardiac surgery.
METHODS - This study prospectively evaluated 146 adult patients with scheduled cardiac surgery at 2 general hospitals. Plasma NGAL was measured before surgery, at ICU arrival after surgery (0 hours), and 2, 4, 12, 24, 36, and 60 hours after ICU arrival.
RESULTS - Based on the Kidney Disease Improving Global Outcomes (KDIGO) CKD guideline, 72 (49.3%) were diagnosed as having CKD. Of 146 patients, 53 (36.3%) developed AKI after surgery. Multiple logistic regression analysis revealed that preoperative plasma NGAL, estimated glomerular filtration rate (eGFR), and operation time are significantly associated with AKI occurrence after surgery. Plasma NGAL in AKI measured after surgery was significantly higher than in non-AKI irrespective of CKD complication. However, transient decrease of plasma NGAL at 0 to 4 hours was observed especially in AKI superimposed on CKD. Plasma NGAL peaked earlier than serum creatinine and at the same time in mild AKI and AKI superimposed on CKD with increased preoperative plasma NGAL (>300 ng/ml). Although AKI superimposed on CKD showed the highest plasma NGAL levels after surgery, plasma NGAL alone was insufficient to discriminate de novo AKI from CKD without AKI after surgery. Receiver operating characteristics analysis revealed different cutoff values of AKI for CKD and non-CKD patients.
CONCLUSIONS - Results show the distinct features of plasma NGAL in AKI superimposed on CKD after cardiac surgery: 1) increased preoperative plasma NGAL is an independent risk factor for post-cardiac surgery AKI; 2) plasma NGAL showed an earlier peak than serum creatinine did, indicating that plasma NGAL can predict the recovery of AKI earlier; 3) different cutoff values of post-operative plasma NGAL are necessary to detect AKI superimposed on CKD distinctly from de novo AKI. Further investigation is necessary to confirm these findings because this study examined a small number of patients.
Albuminuria is strongly associated with progressive kidney tubulo-interstitial damage and chronic kidney disease (CKD) progression. In proteinuric nephropathies, albumin reabsorption by the proximal tubule is saturated and the distal nephron is exposed to high concentrations of luminal albumin that may produce adverse effects. Since proximal tubular cells exposed to albuminuria exhibit a proinflammatory and profibrotic response, we assessed the effect of albuminuria in the collecting duct (CD). With the use of kidney sections and isolated cortical CDs (CCDs) from puromycin-aminonucleoside-induced nephrotic rats (PAN rats) exhibiting proteinuria, immunofluorescence microscopy revealed internalized albumin in CD cells. In these proteinuric rats, increased expression levels of cytokines and profibrotic signaling markers were detected in isolated CCDs and bands of inflammatory fibrosis could be observed around CDs. Albumin endocytosis was confirmed by FITC-albumin uptake in cultured murine CCD (mCCDcl1) cells. Exposure of mCCDcl1 cells to albumin induced NF-κB activation as assessed by luciferase reporter gene assay, nuclear translocation of NF-κB p65 subunit, and increased NF-κB target gene expression. Moreover, albuminuria-like condition results in transforming growth factor-β1 (TGF-β1) overexpression and the upregulation of profibrotic signaling markers such as Snail or vimentin via an autocrine mechanism. In mCCDcl1 cells, neutrophil gelatinase-associated lipocalin (NGAL)/lipocalin-2/24p3 receptor (24p3R) mediates albumin endocytosis as well as activation of NF-κB and TGF-β1 signaling pathways. Therefore, CD may play a key role in initiation and/or progression of inflammation and fibrosis in response to proteinuria.
The use of novel biomarkers to detect incident acute kidney injury (AKI) in the critically ill is hindered by heterogeneity of injury and the potentially confounding effects of prevalent AKI. Here we examined the ability of urine NGAL (NGAL), L-type fatty acid-binding protein (L-FABP), and cystatin C to predict AKI development, death, and dialysis in a nested case-control study of 380 critically ill adults with an eGFR over 60 ml/min per 1.73 m(2). One-hundred thirty AKI cases were identified following biomarker measurement and were compared with 250 controls without AKI. Areas under the receiver-operator characteristic curves (AUC-ROCs) for discriminating incident AKI from non-AKI were 0.58 (95% CI: 0.52-0.64), 0.59 (0.52-0.65), and 0.50 (0.48-0.57) for urine NGAL, L-FABP, and cystatin C, respectively. The combined AUC-ROC for NGAL and L-FABP was 0.59 (56-0.69). Both urine NGAL and L-FABP independently predicted AKI during multivariate regression; however, risk reclassification indices were mixed. Neither urine biomarker was independently associated with death or acute dialysis (NGAL hazard ratio 1.35 (95% CI: 0.93-1.96), L-FABP 1.15 (0.82-1.61)), although both independently predicted the need for acute dialysis alone (NGAL 3.44 (1.73-6.83), L-FABP 2.36 (1.30-4.25)). Thus, urine NGAL and L-FABP independently associated with the development of incident AKI and receipt of dialysis but exhibited poor discrimination for incident AKI using conventional definitions.
PURPOSE - Septic acute kidney injury (AKI) shows an unacceptably high mortality rate. Detection of sepsis is important for the clinical management of AKI patients. This study was undertaken to evaluate 2 biomarkers of neutrophil gelatinase-associated lipocalin (NGAL) and endotoxin activity (EA) assay and their combination for detecting sepsis in AKI.
MATERIALS AND METHODS - Adult intensive care unit patients consisting of 40 non-AKI, 65 AKI without sepsis, 10 non-AKI with sepsis, and 24 septic AKI were examined in a cross-sectional manner. Plasma NGAL and EA values in whole blood were measured at recruitment. We evaluated whether combining 2 different biomarkers would improve the performance of each biomarker using receiver operating characteristic analysis.
RESULTS - Plasma NGAL was significantly higher in septic AKI patients than in the other AKI patients and non-AKI patients, whereas EA values were higher in septic patients than nonseptic patients irrespective of AKI complication. Combination of plasma NGAL and EA value increased the area under the curve of the receiver operating characteristic curve and showed better performance compared with a clinical model consisting of clinically available variables.
CONCLUSION - Combinations of plasma NGAL and EA, which are operating via different pathological pathways, significantly improved their detection performance in complicated conditions of septic AKI.
Copyright © 2013 Elsevier Inc. All rights reserved.
Prerenal acute kidney injury (AKI) is thought to be a reversible loss of renal function without structural damage. Although prerenal and intrinsic AKI frequently coexist in clinical situations, serum creatinine and urine output provide no information to support their differentiation. Recently developed biomarkers reflect tubular epithelial injury; therefore, we evaluated urinary biomarker levels in an adult mixed intensive care unit (ICU) cohort of patients who had been clinically evaluated as having prerenal AKI. Urinary L-type fatty acid-binding protein (L-FABP), neutrophil gelatinase-associated lipocalin (NGAL), interleukin-18 (IL-18), N-acetyl-β-D-glucosaminidase (NAG), and albumin in patients with prerenal AKI showed modest but significantly higher concentrations than in patients with non-AKI. We also conducted a proof-of-concept experiment to measure urinary biomarker excretion in prerenal AKI caused by volume depletion. Compared with cisplatinum and ischemia-reperfusion models in mice, volume depletion in mice caused a modest secretion of L-FABP and NGAL into urine with more sensitive response of L-FABP than that of NGAL. Although no histological evidence of structural damage was identified by light microscopy, partial kidney hypoxia was found by pimonidazole incorporation in the volume depletion model. Thus, our study suggests that new AKI biomarkers can detect mild renal tubular damage in prerenal acute kidney injury.
AIMS - Reliable detectors of worsening renal function (WRF) in Emergency Department (ED) patients with acute heart failure (AHF) are limited. We hypothesized that initial urinary neutrophil gelatinase-associated lipocalcin (NGAL) levels, and changes in urinary NGAL levels after initial ED AHF therapy, would be associated with WRF and adverse events.
METHODS AND RESULTS - Urinary NGAL upon ED presentation and 12-24 h after ED treatment was measured in a cohort of ED patients with AHF. NGAL was corrected for urinary creatinine (uCr). WRF was defined as RIFLE stages 1, 2, or 3, or a creatinine increase of ≥0.3 mg/dL. Patients were prospectively followed for 5- and 30-day adverse cardiovascular events. The 399 patients had a median age of 63 years, 50% were Caucasian, and 62% were male. Those with WRF at 72-96 h were more likely to have a higher initial NGAL value (71 vs. 32 ng NGAL/mg uCr) (P = 0.005), and a higher NGAL level at 12-24 h after ED therapy (107 vs. 25ng NGAL/mg uCr, P < 0.001). In a multivariable model, NGAL at 12-24 h remained a significant predictor of WRF (P = 0.012). Of all variables available 12-24 h after initial therapy, the only significant predictor of 30-day events was an elevated urinary NGAL level (P = 0.02).
CONCLUSIONS - Urinary NGAL levels determined 12-24 h after ED therapy are significantly associated with both WRF at 72-96 h and 30-day adverse events. This suggests that early management strategies may have an impact on subsequent WRF and outcomes. If confirmed, NGAL may have a role for guiding therapeutic decisions.