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Background and Aims: Cholemic nephropathy is a cause of acute kidney injury occurring in patients with jaundice. The aim of this study was to evaluate early renal function impairment in patients with mild acute hyperbilirubinemia in the absence of alterations of the common parameters used in clinical practice (serum creatinine or urea) and with normal renal morphology. We studied urinary biomarkers of tubular damage urinary neutrophil gelatinase-associated lipocalin (u-NGAL), urinary beta-2-microglobulin (u-B2M), urinary osteopontin (u-OPN), urinary trefoil factor 3 (u-TFF3) and urinary Cystatin C (u-Cys)., Methods: This is a case-control study investigating the following urinary biomarkers of tubular damage: u-NGAL, u-B2M, u-OPN, u-TFF3 and u-Cys, in patients with mild acute hyperbilirubinemia. Seventy-four patients were included in this study: 36 patients with jaundice and 38 patients without jaundice., Results: Subjects with jaundice (total bilirubin 12.4 ± 7.3 mg/dL) showed higher u-NGAL, u-B2M, u-OPN, u-TFF3 and u-Cys compared with controls. After logistic regression analyses, including the following independent variables: age, estimated Glomerular Filtration Rate (eGFR), haemoglobin, diabetes, hypertension and jaundice, we observed a higher risk of elevated u-NGAL values (OR = 3.8, 95% CI 1.07-13.5, p = .03) and u-B2M (OR = 9.4, 95% CI 2.3-38.9, p = .0018) in jaundiced subjects. Moreover, urinary biomarkers had a direct correlation with serum cholestasis indexes., Conclusions: This study demonstrated increased urinary biomarkers of tubular damage (u-NGAL, u-B2M, u-OPN, u-TFF3, and u-Cys) in patients with mild hyperbilirubinemia in comparison with a control group. These findings suggest early renal tubular damage in the absence of alterations of the normal parameters used in clinical practice (eGFR, serum urea and renal morphology)., (© 2024 The Author(s). Liver International published by John Wiley & Sons Ltd.)

Rationale & Objective: β 2 -Microglobulin (B2M) and β-trace protein (BTP) are novel endogenous filtration markers that may improve the accuracy of estimated glomerular filtration rate (eGFR) beyond creatinine and cystatin C (eGFR cr-cys ), but they have not been assessed in patients with cancer., Study Design: Cross-sectional analysis., Setting & Participants: Prospective cohort of 1,200 patients with active solid tumors recruited between April 2015 and September 2017., Exposure: CKD-EPI equations without race combining B2M and/or BTP with creatinine with or without cystatin C (2-, 3-, or 4-marker panel eGFR)., Outcome: Performance of equations compared with eGFR cr-cys and non-GFR determinants of serum B2M and BTP (S B2M , and S BTP , respectively). Measured GFR (mGFR) was determined using the plasma clearance of chromium-51 labeled ethylenediamine tetraacetic acid ( 51 Cr-EDTA)., Analytical Approach: Bias was defined as the median of the differences between mGFR and eGFR, and 1-P 30 was defined as the percentage of estimates that differed by more than 30% from the mGFR (1-P 30 ). Linear regression was used to assess association of clinical and laboratory variables with S B2M , and S BTP after adjustment for mGFR., Results: Mean age and mGFR were 58.8±13.2 SD years and 78.4±21.7 SD mL/min/1.73m 2 , respectively. Performance of the 3-marker and 4-marker panel equations was better than eGFR cr-cys (lesser bias and 1-P 30 ). Performance of 2-marker panel equations was as good as eGFR cr-cys (lesser bias and similar 1-P 30 ). S B2M and S BTP were not strongly influenced by cancer site., Limitations: Participants may have had better clinical performance status than the general population of patients with solid tumors., Conclusions: B2M and BTP can improve the accuracy of eGFR and may be useful as confirmatory tests in patients with solid tumors, either by inclusion in a multimarker panel equation with creatinine and cystatin C, or by substituting for cystatin C in combination with creatinine., Plain-Language Summary: The most accurate method to assess estimate kidney function is estimated glomerular filtration rate (eGFR) using creatinine and cystatin C (eGFR cr-cys ). We studied whether using β2-microglobulin (B2M) and/or β-trace protein (BTP) with creatinine with or without cystatin C (2-, 3-, or 4-marker panel eGFR) might be useful in patients with active solid tumors. The performance of the 3-marker and 4-marker panel equations was better than eGFR cr-cys . Performance of 2-marker panel equations was as good as eGFR cr-cys . We conclude that B2M and BTP can improve the accuracy of eGFR and may be useful as a confirmatory test in patients with solid tumors either by inclusion in multimarker panel equation with creatinine and cystatin C or by substituting for cystatin C in combination with creatinine., (Copyright © 2024 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Introduction: Public training in cardiopulmonary resuscitation and treatment in emergency and intensive care unit have made tremendous progress. However, cardiac arrest remains a major health burden worldwide, with brain damage being a significant contributor to disability and mortality. Lipocalin-type prostaglandin D synthase (L-PGDS), which is mainly localised in the central nervous system, has been previously shown to inhibit postischemia neuronal apoptosis. Therefore, we aim to observe whether serum L-PGDS can serve as a potential biomarker and explore its role in determining the severity and prognosis of patients who have achieved restoration of spontaneous circulation (ROSC)., Methods and Analysis: This is a prospective observational study. The participants (n = 60) who achieve ROSC will be distributed into two groups (non-survivor and survivor) based on 28-day survival. Healthy volunteers (n = 30) will be enrolled as controls. Each individual's relevant information will be extracted from Electronic Medical Record System in Xinhua Hospital, including demographic characteristics, clinical data, laboratory findings and so on. On days 1, 3 and 7 after ROSC, blood samples will be drawn and batch tested on the level of serum neuron-specific enolase, soluble protein 100β, L-PGDS, procalcitonin, tumour necrosis factor-alpha and interleukin-6. The cerebral performance category score was assessed on the 28th day after ROSC., Ethics and Dissemination: This study was performed with the approval of the Clinical Ethical Committee of Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine (Approval No. XHEC-C-2023-130-1). The results will be published in a peer-reviewed journal., Trial Registration Number: Chinese Clinical Trial Registry (ChiCTR2300078564)., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: Circulating tissue transglutaminase immunoglobulin A concentration is a sensitive and specific indicator of celiac disease, but discrepancies between serologic and histologic findings occur. We hypothesized that fecal markers of inflammation and protein loss would be greater in patients with untreated celiac disease than in healthy controls. Our study aims to evaluate multiple fecal and plasma markers in celiac disease and correlate these findings with serologic and histologic findings as noninvasive means of evaluating disease activity., Methods: Participants with positive celiac serologies and controls with negative celiac serologies were prospectively enrolled before upper endoscopy. Blood, stool, and duodenal biopsies were collected. Concentrations of fecal lipocalin-2, calprotectin, and alpha-1-antitrypsin and plasma lipocalin-2 were determined. Biopsies underwent modified Marsh scoring. Significance was tested between cases and controls, modified Marsh score and tissue transglutaminase immunoglobulin A concentration., Results: Lipocalin-2 was significantly elevated in the stool ( P = 0.006) but not the plasma of participants with positive celiac serologies. There was no significant difference in fecal calprotectin or alpha-1 antitrypsin between participants with positive celiac serologies and controls. Fecal alpha-1 antitrypsin >100 mg/dL was specific, but not sensitive for biopsy-proven celiac disease., Discussion: Lipocalin-2 is elevated in the stool but not the plasma of patients with celiac disease suggesting a role of local inflammatory response. Calprotectin was not a useful marker in the diagnosis of celiac disease. While random fecal alpha-1 antitrypsin was not significantly elevated in cases compared with controls, an elevation of greater than 100 mg/dL was 90% specific for biopsy-proven celiac disease., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The American College of Gastroenterology.)

Competing Interests: Declaration of competing interest The authors have no conflicts of interest to disclose.

Introduction: Sepsis-induced myocardial dysfunction (SIMD) is the most common complications of sepsis and septic shock with extremely high incidence and mortality. Lipocalin 10 (Lcn10) has recently been identified as a potential biomarker for heart failure, yet its relation to sepsis has not been investigated. The purpose of this study was to explore whether circulating Lcn10 could be used as a prognostic tool in patients with SIMD., Methods: In this single-center observational pilot study, seventy-five sepsis patients were enrolled after sepsis diagnosis or ICU admission (45.3% female, median age 60 years), and 35 patients (46.7%) developed myocardial dysfunction. Serum Lcn10 levels of septic patients were measured using the enzyme-linked immunosorbent assay (ELISA) at the time of admission. Other biomarkers of cardiac function and Lcn10 concentration were compared between SIMD and non-SIMD groups., Results: We observed that the median Lcn10 levels were 2.780 ng/mL in patients with SIMD and 2.075 ng/mL in patients without SIMD ( P < 0.05). The area under the receiver operating characteristic (ROC) curve for the diagnosis of SIMD was 0.797 ( P < 0.05). In addition, elevated serum Lcn10 levels at the time of admission were positively associated with 28-day mortality in septic patients., Conclusions: Our study indicates that circulating Lcn10 levels may serve as a novel biomarker for the diagnosis and prognosis of myocardial dysfunction induced by sepsis. An additional large multicenter study may be warranted to confirm the findings of this study., Competing Interests: No conflicting relationship exists for any author., (Copyright © 2021 Lu Wang et al.)

Persistence of damage induced by unhealthy diets during youth has been little addressed. Therefore, we investigated the impact of a short-term fructose-rich diet on liver metabolic activity in adolescent rats and the putative persistence of alterations after removing fructose from the diet. Adolescent rats were fed a fructose-rich diet for three weeks and then switched to a control diet for further three weeks. Body composition and energy balance were not affected by fructose-rich diet, while increased body lipids and lipid gain were found after the rescue period. Switching to a control diet reversed the upregulation of plasma fructose, uric acid, lipocalin, and haptoglobin, while plasma triglycerides, alanine aminotransferase, lipopolysaccharide, and tumor necrosis factor alpha remained higher. Hepatic steatosis and ceramide were increased by fructose-rich diet, but reversed by returning to a control diet, while altered hepatic response to insulin persisted. Liver fatty acid synthase and stearoyl-CoA desaturase (SCD) activities were upregulated by fructose-rich diet, and SCD activity remained higher after returning to the control diet. Fructose-induced upregulation of complex II-driven mitochondrial respiration, peroxisome proliferator-activated receptor-gamma coactivator 1 alpha, and peroxisome proliferator activated receptor α also persisted after switching to control diet. In conclusion, our results show prolonged fructose-induced dysregulation of liver metabolic activity.

Introduction: Estimation of kidney function is crucial in the evaluation of living kidney donor candidates. Despite the multitude of glomerular filtration rate (GFR) formulas, no equation is universal, and none were validated in the population of kidney donors. Novel biomarkers, including beta trace protein (BTP) and cystatin C, are studied to help estimate GFR and improve the safe qualification of living kidney donors., Aim: This study compares the accuracy of different formulas that estimate GFR with reference scintigraphy-measured GFR in the population of living kidney donor candidates., Material and Methods: This study enrolled 30 healthy living kidney donor candidates. GFR was measured using the following 11 different formulas. For reference, GFR was assessed using 99m-Technetium-diethylenetriaminepentaacetic acid., Results: The accuracy of estimation was generally low in all formulas. The strongest correlation between measured GFR (mGFR) and estimated GFR (eGFR) was achieved by the Nankivell formula (R = 0.47, P = .009); however, in the group of patients with a body mass index of >25 kg/m 2 , only the equations based on BTP had a statistically significant correlation with mGFR: White (R = 0.59; P = .016) and Poge (R = 0.53; P = .035). Bland-Altman plots revealed wide limits of agreement between eGFRs and mGFR in all groups of patients., Conclusion: In living kidney donor candidates, GFR estimation formulas should be chosen individually. White formula, which is based on BTP, may be a promising tool in estimating GFR in overweight potential living kidney donor candidates. More than 1 formula and personalized choice of GFR estimation method regarding the given patient should be performed in qualification of kidney donors., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Residual renal function is closely linked to quality of life, morbidity and mortality in dialysis patients. Beta-trace protein (BTP), a low molecular weight protein, has been suggested as marker of residual renal function, in particular in patients on hemodialysis. We hypothesized that BTP also serves as a marker of residual renal function in pertioneal dialysis patients., Methods: In this study 34 adult patients on peritoneal dialysis were included. BTP, creatinine, cystatin C and urea concentrations were analyzed simultaneously in serum and dialysate to calculate renal and peritoneal removal of the analytes., Results: In peritoneal dialysis patients with residual diuresis, mean serum BTP was 8.16 mg/l (SD ± 4.75 mg/l). BTP correlated inversely with residual diuresis (r s  = - 0.58, p < 0.001), residual creatinine clearance (Cl Cr ) (r s  = - 0.69, p < 0.001) and total urea clearance (Cl urea ) (r s  = - 0.56, p < 0.001). Mean peritoneal removal of BTP was 3.36 L/week/1.73m 2 (SD ± 1.38) and mean renal removal 15.14 L/week/1.73m 2 (SD ± 12.65) demonstrating a significant renal contribution to the total removal. Finally, serum BTP inversely correlated with alterations in residual diuresis (r = - 0.41, p = 0.035) and renal creatinine clearance over time (r = - 0.79, p = p < 0.001)., Conclusion: BTP measurement in the serum may be a simple tool to assess residual renal function in peritoneal dialysis patients.

Members of the lipocalin protein family serve as biomarkers for kidney disease and acute phase inflammatory reactions, and are under preclinical development for the diagnosis and therapy of allergies. However, none of the lipocalin family members has made the step into clinical development, mostly due to their complex biological activity and the lack of in-depth mechanistic knowledge. Here, we show that the hepatokine lipocalin 13 (LCN13) triggers glucose-dependent insulin secretion and cell proliferation of primary mouse islets. However, inhibition of endogenous LCN13 expression in lean mice did not alter glucose and lipid homeostasis. Enhanced hepatic secretion of LCN13 in either diet-induced or genetic obesity led to no discernible impact on systemic glucose and lipid metabolism, neither in preventive nor therapeutic setting. Of note, loss or forced LCN13 hepatic secretion did not trigger any compensatory regulation of related lipocalin family members. Together, these data are in stark contrast to the suggested gluco-regulatory and therapeutic role of LCN13 in obesity, and imply complex regulatory steps in LCN13 biology at the organismic level mitigating its principal insulinotropic effects., (© 2021 Bühler et al.)

Background: Establishment and improvement of glomerular filtration rate estimating equations requires accurate and precise laboratory measurement procedures (MPs) for filtration markers. The Advanced Research and Diagnostic Laboratory (ARDL) at the University of Minnesota, which has served as the central laboratory for the Chronic Kidney Disease Epidemiology Collaboration since 2009, has implemented several quality assurance measures to monitor the accuracy and stability of filtration marker assays over time., Methods: To assess longitudinal stability for filtration marker assays, a 40-sample calibration panel was created using pooled serum, divided into multiple frozen aliquots stored at -80 °C. ARDL monitored 4 markers-creatinine, cystatin C, beta-2-microglobulin (B2M) and beta-trace protein-measuring 15 calibration panel aliquots from 2009 to 2019. Initial target values were established using the mean of the first 3 measurements performed in 2009-10, and differences from target were monitored over time. New MPs for cystatin C and B2M were added in 2012, with target values established using the first measurement., Results: The mean percentage difference from mean target values across time was <2% for all original MPs (-0.59% for creatinine; -0.94% for cystatin C; -0.82% for B2M; 1.24% for beta-trace protein)., Conclusions: Close monitoring of filtration marker trends with a calibration panel at ARDL demonstrates remarkable long-term stability of the MPs. Routine use of a calibration panel for both research studies and clinical care is recommended for filtration markers where longitudinal monitoring is important to detect analytical biases, which can mask or confound true clinical trends in patients., (© American Association for Clinical Chemistry 2020. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objectives: The use of kidney function and injury markers for early detection of drug-related glomerular or tubular kidney injury in infants, children and adolescents requires age-specific data on reference intervals in a pediatric healthy population. This study characterizes serum values for eight kidney function and injury markers in healthy infants, children and adolescents., Methods: A single center prospective observational study was conducted between December 2018 and June 2019. Serum samples from 142 healthy infants, children and adolescents aged between 0 and ≤15 years were collected. Statistical analyses for eight markers (albumin (ALB), β2-microglobulin (B2M), β-trace protein (BTP), creatinine (SCR), cystatin C (CYSC), kidney injury molecule-1 (KIM-1), neutrophil gelatinase-associated lipocalin (NGAL), uromodulin (URO)) were performed to obtain reference intervals and associations with age, sex and weight were investigated (Pearson correlation, linear and piecewise regression)., Results: ALB and SCR increased with age (p<0.01), whereas B2M, BTP and KIM-1 values decreased with advancing age (p<0.05) in this healthy pediatric study population. CYSC showed dependency on sex (lower concentration in females) and decreased with age until reaching approximately 1.8 years; thereafter an increase with age was seen. NGAL and URO did not show any age-dependency., Conclusions: This study provides age appropriate reference intervals for key serum kidney function and injury markers determined in healthy infants, children and adolescents. Such reference intervals facilitate the interpretation of changes in kidney function and injury markers in daily practice, and allow early detection of glomerular and tubular injury in infancy, childhood and adolescence.

Pulmonary thromboembolism (PTE) is an acute emergency with high mortality and morbidity rates. This study aimed to investigate the importance of Lipocalin-type prostaglandin D synthase (L-PGDS) in predicting mortality and prognosis in PTE. The study prospectively included 90 patients who were admitted to the emergency department and in whom PTE was confirmed by computed tomographic pulmonary angiography as well as 40 healthy volunteers with no disease. L-PGDS levels in the venous blood were measured and compared. Pulmonary embolism severity index (PESI) prognosis scores of all patients and 1-month mortality rate were calculated. There was a statistically significant difference between the L-PGDS levels of the patient and control groups (P = 0.024), and 1-month mortality of patients diagnosed with PTE was 20% (n = 18). Furthermore, the patients were divided into two groups: patients deceased within 1 month following the diagnosis and survivors. L-PGDS levels of the deceased patients were significantly higher than those of the survivors (P < 0.001). Age, systolic blood pressure, pulse, shock index, lactate, and PESI scores were significantly different between the survivors and deceased patients. The cut-off value for L-PGDS obtained using receiver operating characteristic (ROC) curve analysis for 1-month mortality was 815.26 ng/mL (sensitivity: 83.33%; specificity: 79.17%; area under the curve: 0.851; 95% confidence interval 0.760-0.917; P < 0.001). Based on this cut-off value, logistic regression analysis revealed that increased L-PGDS, together with PESI, was an independent indicator of 1-month mortality. L-PGDS is associated with short-term mortality in patients with PTE; therefore, it can be used to predict mortality risk in patients with PTE.

Background: There are still limited studies comprehensively examining the diagnostic performance of neutrophil gelatinase-associated lipocalin (NGAL) and cystatin C in contrast-induced nephropathy (CIN). The study aimed to investigate and compare the predictive value of NGAL and cystatin C in the early diagnosis of CIN., Methods and Materials: We searched the PubMed, EMBASE and Cochrane Library databases until November 10, 2019. The methodological quality of the included studies was assessed by the Quality Assessment of Diagnostic Accuracy Studies 2 (QUADAS-2) tool. Bivariate modeling and hierarchical summary receiver operating characteristic (HSROC) modeling were performed to summarize and compare the diagnostic performance of blood/urine NGAL and serum cystatin C in CIN. Subgroup and meta-regression analyses were performed according to the study and patient characteristics., Results: Thirty-seven studies from thirty-one original studies were included (blood NGAL, 1840 patients in 9 studies; urine NGAL, 1701 patients in 10 studies; serum cystatin C, 5509 patients in 18 studies). Overall, serum cystatin C performed better than serum/urine NGAL (pooled DOR: 43 (95%CI: 12-152); AUROC: 0.93; λ: 3.79); serum and urine NGAL had a similar diagnostic performance (pooled DOR: 25 (95%CI: 6-108)/22(95%CI: 8-64); AUROC: 0.90/0.89; λ: 3.20/3.08). Meta-regression analysis indicated that the sources of heterogeneity might be CIN definition, assays, and nationalities., Conclusion: Both NGAL and cystatin C can serve as early diagnostic indicators of CIN, while cystatin C may perform better than NGAL., Competing Interests: The authors have declared that no competing interests exist.

Acute kidney injury (AKI) is a serious complication of pediatric cardiac surgery, with high morbidity and mortality. We aimed to evaluate the perioperative risk factors for AKI, and the validity of novel diagnostic urinary biomarkers after pediatric cardiac surgery. We analyzed 103 consecutive pediatric patients (≤ 18 years old), who underwent cardiac surgery. AKI was defined by ≥ 50% increase in serum creatinine levels from baseline. Urinary liver-type fatty acid binding protein (L-FABP) and neutrophil gelatinase-associated lipocalin (NGAL) were measured postoperatively at the intensive care unit (ICU) admission, subsequently at 4, 12, and 24 h. Areas under the receiver-operating characteristic curves (AUC) were calculated at each assessment time. AKI had developed in 47 patients (45.6%) by the second postoperative day. Univentricular status, aortic cross-clamping time, and intraoperative fluid balance were independently associated with AKI (p = 0.02, 0.01 and 0.01, respectively). Urinary L-FABP and NGAL were significantly higher in the AKI group at each point (p < 0.05). The predictive abilities of both biomarkers (AUC = 0.78-0.90) at ICU admission and 4 h after were especially high. The patients with L-FABP greater than the cutoff value at ICU admission and 4 h after ICU admission had significantly longer intubation and hospitalization periods (p < 0.05). Those with elevated NGAL levels at admission, and 4 h and 24 h after ICU admission, had significantly longer intubation, ICU stay, and hospitalization (p < 0.05). L-FABP and NGAL can be useful biomarkers for detecting early AKI after pediatric cardiac surgery and predicting adverse clinical outcomes.

The aim of this study was to determine the association between secretory phospholipase A2 group IIA (sPLA2-IIA) and eicosanoid pathway metabolites in patients with bacterial sepsis syndrome (BSS). Levels of sPLA2-IIA, eicosanoids prostaglandin (PG)E2, PGD synthase were quantified in the sera from patients confirmed to have bacterial sepsis (BS; N = 45), bacterial severe sepsis/septic shock (BSS/SS; N = 35) and healthy subjects (N = 45). Cyclooxygenase (COX)-1 and COX-2 activities were analyzed from cell lysate. Serum levels of sPLA2-IIA, PGE2, and PGDS increased significantly in patients with BS and BSS/SS compared to healthy subjects (p<0.05). COX-2 activity was significantly increased in patients with BS compared to healthy subjects (p<0.05), but not COX-1 activity. Binary logistic regression analysis showed that sPLA2-IIA and PGE2 were independent factors predicting BSS severity. In conclusion, high level of sPLA2-IIA is associated with eicosanoid metabolism in patients with BSS., Competing Interests: The authors have declared that no competing interests exist.

Objectives: The aim of this study was to investigate airway responsiveness and eosinophil and neutrophil inflammatory markers in clinically confirmed nonasthmatic adolescents with elevated fractional exhaled nitric oxide (FeNO), a marker of type-2 inflammation in the airways., Methodology: A total of 959 subjects from a general population, aged 12 to 15 years, answered a standardised questionnaire and underwent FeNO measurements at a screening visit at school. Adolescents without asthma, who had elevated FeNO (FeNO 100  > 15 ppb) (n = 19), and control subjects, with low FeNO (FeNO 100  < 5 ppb) and without reported symptoms of asthma or allergy (n = 28), participated in a follow-up study where FeNO 50 , airway responsiveness to methacholine (PD 20 ), blood eosinophil counts, and serum neutrophil lipocalin (HNL) and myeloperoxidase (MPO) levels were measured. Questionnaire follow-ups were performed 4 and 16 years later., Results: Airway responsiveness (PD 20 : 6.94 [1.87, 11.39] vs 11.42 [6.33, 59.4] µmol; P < .05) and blood eosinophil counts (0.31 [0.20, 0.44] vs 0.13 [0.1, 0.22] 10 9 /L; P < .001) (geometric mean [95% CI]) were higher among cases than controls. A significant correlation between blood eosinophils and FeNO was found (rho = 0.41; P = .005). In contrast, serum HNL and MPO were lower in cases than controls (P < .05 both), and there was a negative correlation between HNL and FeNO (r = -0.31; P = .04). At both follow-ups, a higher proportion of subjects reported allergic symptoms compared with baseline (P = .02, P = .01)., Conclusions: Elevated FeNO in nonasthmatic adolescents was associated with airway hyperresponsiveness, elevated blood eosinophil counts, and lower systemic activation of neutrophils., (© 2020 Wiley Periodicals, Inc.)

: Background: Kidney function in preterm newborns may be impaired by many factors., Methods: 71 newborns with gestational age (GA) < 32 weeks were enrolled. Serum creatinine (sCr), cystatin C (CysC), beta-trace protein (BTP) and urea were measured at T0 (3 rd day of life) and T36 (GA 36 weeks), and estimated glomerular filtration rate (eGFR) was calculated according to different formulas at T36. Pre-natal and post-natal kidney injury risk scores were calculated., Results: Newborns with GA ≤ 28 weeks had higher sCr at T0, and lower sCr, BTP and higher urea levels at T36 ( p = 0.007, p = 0.005 and p = 0.029, respectively). eGFR values were not different according to GA when calculated by the formulas using only CysC, but were higher in subjects with GA ≤ 28 weeks according to the other formulas. The post-natal score was positively correlated with eGFR according to sCr-based formulas, but the correlations did not persist when adjusted for urea levels and GA., Conclusions: CysC-based eGFR values are not influenced by GA. Post-natal score shows a direct correlation with eGFR according to sCr-based formulas, not persisting after adjustment for GA and urea levels, implying the importance of the nutritional status, since more premature subjects receive a more aggressive nutritional regimen, testified by higher urea levels., Competing Interests: The authors declare no conflict of interest.

The link between cystatin C and mortality independent of glomerular filtration rate (GFR) in adults has prompted the "Shrunken Pore Syndrome" (SPS) hypothesis, where high serum cystatin C with normal creatinine is explained by smaller glomerular pores, through which creatinine can pass freely, while the larger cystatin C, beta-trace protein (BTP) and pro-inflammatory molecules are retained. This study set out to apply the definition of SPS to children. In 294 children who underwent inulin clearance (Cin) test, serum creatinine, cystatin C and BTP were measured. For all three markers eGFR x was calculated using the full age spectrum equations. The ratio eGFR cys /eGFR crea was plotted against the error of eGFR BTP (%) (i.e. eGFR BTP -Cin)/Cin*100%). Patients with and without SPS according to different cut-off points of eGFRcys/eGFRcrea and eGFR cys /Cin (i.e. ≤0.6,0.7,0.8) were compared in terms of eGFR x , Cin, error of eGFRx(%) and eGFR BTP /eGFR crea -ratio. The ratio eGFR cys /eGFR crea and error of eGFR BTP (%) were positively correlated. The prevalence of SPS by eGFR cys /eGFR crea with a cut-off of 0.6 was 4.8%. Patients with SPS had a more negative error of eGFR cys (%) and eGFR BTP (%) and higher Cin regardless of the definition. Overestimation of eGFR crea in patients with SPS was only present when using the eGFR cys /eGFR crea rather than the eGFR cys /Cin definition. Cystatin C and BTP are related independent of creatinine, suggesting glomerular pore size as a common denominator. The prevalence of SPS in children is comparable to adults. For research in SPS, a definition based on eGFR cys /exogenous clearance study may be useful to study the effect of SPS on creatinine metabolism.

Background & Aims: Renal function assessed by creatinine is a key prognostic factor in cirrhotic patients. However, creatinine is influenced by several factors, rendering interpretation difficult in some situations. This is especially important in early stages of renal dysfunction where renal impairment might not be accompanied by an increase in creatinine. Other parameters, such as cystatin C (CysC) and beta-trace protein (BTP), have been evaluated to fill this gap. However, none of these studies have considered the role of the patient's sex. The present study analysed CysC and BTP to evaluate their prognostic value and differentiate them according to sex., Patients and Methods: CysC and BTP were measured in 173 transjugular intrahepatic portosystemic shunt (TIPS)-patients from the NEPTUN-STUDY(NCT03628807) and analysed their relationship with mortality and sex. Propensity score for age, MELD, etiology and TIPS indication was used., Results: Cystatin C and BTP showed excellent correlations with creatinine values at baseline and follow-up. CysC was an independent predictor of overall mortality (HR = 1.66(1.33-2.06)) with an AUC of 0.75 and identified a cut-off of 1.55 mg/L in the whole cohort. Interestingly, CysC was significantly lower in females, also after propensity score matching. In males, the only independent predictor was the creatinine level (HR = 1.54(1.25-1.58)), while in females CysC levels independently predicted mortality (HR = 3.17(1.34-7.52))., Conclusion: This study demonstrates for the first time that in TIPS-patients creatinine predicts mortality in males better than in females, whereas CysC is a better predictor of mortality in females. These results may influence future clinical decisions on therapeutic options for example, allocation for liver transplantation in TIPS-patients., (© 2019 The Authors. Liver International published by John Wiley & Sons Ltd.)

Background: Human neutrophil lipocalin (HNL) is used as a novel biomarker for infections. However, only a few studies have focused on the usefulness of HNL. The purpose of this study was to evaluate the diagnostic efficiency of HNL for identifying bacterial infections and to compare HNL with procalcitonin (PCT) and C-reactive protein (CRP)., Methods: Hospital patients with acute infections of bacterial origin (n = 439), viral origin (n = 71), and healthy volunteers (n = 67) were included in the study. The infection status of each patient was verified using microbiological, serological, and PCR testing. Additionally, CRP, HNL, and PCT levels were measured by established methods., Results: In distinguishing bacterial and viral infections, area under the curve (AUC) analysis showed that, with a value of 0.81 (95% CI, 0.76-0.86), HNL was superior to CRP at 0.73 (0.68-0.79) and PCT at 0.64 (0.58-0.70). Interestingly, the combination of HNL, PCT, and CRP improved the diagnostic potential significantly with an AUC of 0.86 (0.82-0.90, P < 0.05). Furthermore, when comparing different infection site subgroups with healthy patients, HNL levels were higher in all bacterial groups, albeit to widely varying degrees (P < 0.0001), and HNL reached a higher level in bloodstream and abdominal infections. CRP levels showed the same trend as HNL levels. PCT levels were significantly increased in bloodstream infections, abdominal infections, and in bacterial pneumonia (P < 0.0001), while no significant differences were found in soft tissue (P = 0.4378) or urinary tract infections (P = 0.423). There was no difference in HNL and CRP levels between patients with Gram-negative bacterial (GNB) or Gram-positive bacterial infections. However, compared with controls, PCT was only increased in GNB-infected patients., Conclusion: HNL detection can help diagnose patients with infectious diseases, and the diagnostic efficacy of HNL is not affected by the infected site or by pathogenic bacterial species. The combination of HNL, PCT, and CRP has a superior performance at identifying bacterial infections compared with traditional biomarkers., (Copyright © 2019 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.)

Aim: Exertional heastroke (EHS) can lead to acute kidney injury. Oral rehydration solution III (ORS III), recommended by WHO in 2004, is used to rehydrate children with gastroenteritis. This study aimed to characterize the renoprotective effect of ORS III in EHS rats., Methods: Rats were randomly divided into Group Control, Group EHS, Group EHS + Water, and Group EHS + ORS. Thirty minutes before the experiment, ORS III was orally administrated to Group EHS + ORS, Water was given to Group EHS + Water. Rats from Group EHS, Group EHS + Water and Group EHS + ORS were then forced to run until they fatigued. Core temperature (Tc) was monitored and 40.5 °C was considered as the onset of heatstroke. Serum creatinine (SCr), blood urea nitrogen (BUN) were measured using an automated biochemical analyzer. Serum neutrophil gelatinase-associated lipocalin (NGAL) was measured using an NGAL ELISA Kit. Light microscopy was used for kidney structural analysis., Results: SCr level in Group EHS was no different from Group Control (p > .05), while BUN and NGAL levels in Group EHS were higher than Group Control (p <.001, p < .001). SCr, BUN and NGAL concentrations in group EHS + Water were no different from Group EHS (p > .05). SCr, BUN levels in Group EHS + ORS were no different from Group EHS (p > .05). But NGAL levels were significant in these two groups (p = .012). Renal histopathologies of rats in Group EHS and Group EHS + Water showed flattened lumens filled with eosinophilic materials. The damage was milder in Group EHS + ORS, in which injured tubules showed degeneration of the tubular epithelium and sloughing of the brush border membrane., Conclusion: ORS III could alleviate the kidney injury in EHS rats.

Objectives: The distinction between bacterial and viral causes of acute infections is a major clinical challenge. In this report we investigate the diagnostic performance in this regard of nine candidate biomarkers together with HNL (Human Neutrophil Lipocalin)., Methods: Blood was obtained from patients with symptoms of infectious (n = 581). HNL was measured in whole blood (B-HNL) after pre-activation with the neutrophil activator fMLP or in plasma (P-HNL). Azurocidin also known as heparin-binding protein (HBP), Calprotectin, PMN-CD64, CRP (C-reactive protein), IP-10 (Interferon γ-induced Protein 10 kDa), PCT (Procalcitonin), TK1 (Thymidine kinase 1), TRAIL (TNF-related apoptosis-inducing ligand) were measured in plasma/serum. Area under the ROC (receiver operating characteristics) curve (AuROC) was used for the evaluation of the clinical performance of the biomarkers., Results: Side-by-side comparisons of the ten biomarkers showed large difference in the AuROC with B-HNL being the superior biomarker (0.91, 95% CI 0.86-0.95) and with the other nine biomarkers varying from AuROC of 0.63-0.79. The combination of B-HNL with IP-10 and/or TRAIL increased the diagnostic performance further to AuROCs of 0.94-0.97. The AuROCs of the combination of CRP with IP-10 and/or TRAIL were significantly lower than combinations with B-HNL 0.87 (95% CI 0.83-0.91)., Conclusion: The diagnostic performance of whole blood activated HNL was superior in the distinction between bacterial or viral infections. The addition of IP-10 and/or TRAIL to the diagnostic algorithm increased the performance of B-HNL further. The rapid analysis of HNL, reflecting bacterial infections, together with biomarkers reflecting viral infections may be the ideal combination of diagnostic biomarkers of acute infections., (Copyright © 2019 Elsevier B.V. All rights reserved.)

To identify neuroinflammatory biomarkers in patients with various severity of autism spectrum disorder (ASD) increases the insight about the pathogenesis and pathophysiology of this neurodevelopmental disorder. The aim of the present study was to analyze the levels in plasma of TGFβ2, Heat shock protein 70 (HSP70), and hematopoietic prostaglandin D2 synthase (H-PGDS) in Saudi ASD children and healthy age-matched neurotypical controls. Also, it was in the present study examined the correlation among these neuroinflammatory biomarkers and the sensory deficit exhibited by the ASD children. Blood samples from 38 Saudi children with ASD and 32 age-matched neurotypical controls were withdrawn after an overnight fast. For the blood taking 3 mL EDTA containing blood collection tubes was used. The samples were centrifuged for 20 min (4 °C; 3000×g) directly after the blood sampling. The harvested plasma was used for in vitro quantification of TGF-β2, HSP70, and H-PGDS by using the sandwich enzyme immunoassay. Receiver operating characteristic (ROC) analysis and predictiveness curves showed that each of TGF-β2, HSP70 or H-PGDS alone could not be used as a predictive neuroinflammatory biomarker for ASD. However, when TGF-β2 and HSP70 were combined in one ROC curve, the AUC was increased to an appreciable value that makes them together robust predictors of variation between the ASD and neurotypical control groups. Overall, it was in the present study found significant differences for TGF-β2 and HSP70 when the ASD and neurotypical control groups were compared, independently of the sensory deficit level. In conclusion, the present study highlights the usefulness of TGF-β2, HSP70, and H-PGDS as diagnostic tools to differentiate between ASD and neurotypical control children, but not among subgroups of ASD children exhibiting different severity levels of sensory dysfunction. The presented data also suggest the effectiveness of ROC as a powerful statistical tool, which precisely can measure a combined effect of neuroinflammatory biomarkers intended for diagnostic purposes.

Objective: To evaluate the nephro-protective effects of berberine and/or pentoxifylline on the reduction of diclofenac-induced acute kidney injury in rats., Methods: The experimental study was conducted at the Department of Pharmacology, College of Medicine, Mustansiriya University, Baghdad, Iraq, from February to April, 2018, and comprised fifty male Sprague-Dawley rats aged 3-4 months and weighing 250-400 grams each. They were divided into five equal groups and were treated for 12 days. Group 1 rats were treated with distilled water plus normal saline, Group 2 with distilled water plus diclofenac, Group 3 with berberine plus diclofenac, Group 4 with pentoxifylline plus diclofenac, and Group 5 rats were treated with berberine, pentoxifylline and diclofenac. Blood urea, creatinine, Neutrophil Gelatinase Associated Lipocalin (NGAL), kidney injury molecules (KIM-1) and cystatin-C were used to measure the severity of AKI., Results: Diclofenac led to significant AKI by significant elevation of blood urea, serum creatinine level, KIM-1, NGAL. Treatment with berberine showed no significant effect on all biomarkers level compared to diclofenac group except on serum KIM-1 level which was also seen in pentoxifylline group. Whereas, combination of berberine and pentoxifylline led to more significant effect in reduction of all renal biomarkers., Conclusions: Combination of berberine with pentoxifylline led to more significant reno-protective than either berberine or pentoxifylline when used alone on diclofenac induced-AKI.

Background and Purpose- Current European guidelines for the management of atrial fibrillation suggest using biomarkers to refine the risk stratification process. However, it is unclear whether ≥2 biomarkers incrementally improve risk prediction beyond 1 biomarker alone. We investigated whether the predictive performance of CHA 2 DS 2 -VASc and HAS-BLED scores could be enhanced by incrementally adding consecutive different biomarkers in real-world atrial fibrillation patients taking vitamin K antagonists therapy. Methods- We included 940 atrial fibrillation patients stable on vitamin K antagonists (international normalized ratio, 2.0-3.0) for at least the previous 6 months. At inclusion, VWF (von Willebrand factor), high-sensitivity troponin T, NT-proBNP (N-terminal pro-B-type natriuretic peptide), high-sensitivity IL (interleukin)-6, fibrin monomers, and BTP (β-trace protein) concentrations were quantified. During follow-up, all adverse events were recorded, and biomarkers were added to CHA 2 DS 2 -VASc and HAS-BLED scores depending on the C index. Results- During 6.5 (4.3-7.9) years, there were 98 ischemic strokes (1.60% per year) and 172 major bleeds (1.60% per year). After the addition of biomarkers, the predictive performance of CHA 2 DS 2 -VASc was not significantly increased, although the model with 3 biomarkers (ie, NT-proBNP+BTP+VWF) showed a low gain in sensitivity (integrated discrimination improvement, 2.70%; P<0.001). The predictive performance of HAS-BLED was enhanced in all biomarker-based models, with the best prediction shown by the model with 3 biomarkers (ie, VWF+NT-proBNP+high-sensitivity IL-6; C index, 0.600 [95% CI, 0.561-0.625] versus 0.639 [95% CI, 0.607-0.669]; P=0.025). This model also confirmed an increased sensitivity (integrated discrimination improvement, 5.20%; P<0.001) and positive reclassification (net reclassification improvement, 19.20%; P=0.020). Conclusions- By adding consecutive biomarkers, the predictive ability of CHA 2 DS 2 -VASc for ischemic stroke was not increased, whereas the predictive ability of HAS-BLED for major bleeding was only slightly enhanced. The net benefit and clinical usefulness of the biomarker-based models were marginal in comparison to the original scores based on clinical factors.

Current therapies have not shown benefit in organ damage reversal in Fabry disease (FD), but biomarkers could help risk stratification and prognosis. We investigated if several biomarkers of cardiac fibrosis, cardiac wall stress, myocardial injury, renal function and inflammation, are associated with early cardiac affectation in FD patients. We included FD patients from four cardiology outpatient clinics of southeastern Spain. At inclusion, Galectin-3 (Gal-3), N-terminal proB-type natriuretic peptide, high sensitivity troponin T (hsTnT), β-trace protein (BTP) and interleukin-6 concentrations were measured. The relation of biomarkers concentrations with clinical features, cardiac involvement and organ affectation according to the Mainz Severity Score Index (MSSI) was investigated. 44 FD patients (n = 21 affected and n = 23 unaffected) were compared to age and sex-respectively matched healthy controls. Significant differences in biomarkers' concentration between FD groups were observed. Importantly, Gal-3 and BTP levels were higher in unaffected patients when compared with age and sex-matched healthy controls (both p < 0.05). All the biomarkers correlated with clinical features. When cut-off values for clinical affectation (measured as MSSI ≥ 20) were established, only hsTnT (OR 30.69, 95% CI 2.70-348.42) and male sex (OR 8.17, 95% CI 1.16-57.75) were independently associated with cardiac damage by multivariate regression analysis. Gal-3 and BTP levels are increased in unaffected FD patients compared to healthy controls. This suggests that these biomarkers could be useful for the early detection of cardiac affectation in FD patients. On the other hand, hsTnT and male sex are independent risk factors for established clinical cardiac damage in FD.

Aims: As a source of growth factors and with its cytoprotective properties, platelet-rich plasma (PRP) received considerable attention in regenerative medicine. Thus, this study was designed to evaluate the protective efficacy of PRP against γ-radiation-induced nephrotoxicity., Main Methods: Forty male rats were distributed in four groups: 1) control, 2) PRP, 3) Radiation, and 4) PRP + radiation. Nephrotoxicity was examined in rats after a whole body γ-irradiation at a single dose of 8 Gy. Activated PRP (0.5 ml/kg BW) was injected subcutaneously twice weekly for three successive weeks prior to γ-irradiation. At the end of the experiment, creatinine, urea, albumin, and neutrophil gelatinase-associated lipocalin (NGAL) serum levels, as well as renal relative gene expression level of kidney injury molecule-1 (KIM-1) were estimated. Further, malondialdehyde level, nitric oxide content and reduced glutathione content in addition to superoxide dismutase and catalase activities were measured. Moreover, the expression levels of B-cell lymphoma 2 (Bcl-2), Bcl-2-associated X (Bax), and caspase-3 proteins were assayed., Key Findings: PRP pre-treatment significantly reduced the radiation-induced abnormalities in kidney histology and attenuated the induced cell injury. Furthermore, PRP notably ameliorated the state of oxidative stress and appeared to inhibit the induced apoptosis., Significance: This study lends a probable protective role of PRP against γ-radiation-induced nephrotoxicity which can highlight the possibilities of its application as a complementary procedure during radiotherapy., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: Diagnosis, prognostication and treatment in chronic kidney disease is often informed by an estimate of the glomerular filtration rate (GFR). Commonly used GFR estimation (eGFR) equations are based on serum creatinine (Cr) concentrations and display suboptimal precision and accuracy. Newer equations incorporating additional endogenous markers such as β-Trace Protein (BTP), β 2 -Microglobulin (B2M) and cystatin C (cysC) have been developed but require validation., Methods: This prospective cohort study evaluated the performance of 6 eGFR equations developed by the chronic kidney disease - epidemiology collaboration group (CKD-EPI) against urinary inulin clearance GFR in patients recruited from outpatient nephrology clinics., Results: Mean biases were negligible and similar between equations. The eGFR-EPI Cr/cysC had the best precision and accuracy of all the equations and the best agreement with inulin mGFR when classifying participants into GFR categories. The BTP and B2M equations displayed the worst precisions and accuracies and showed the least consistent performance across levels of GFR. Thus, the eGFR-EPI Cr/cysC is the least biased, most precise and has the highest accuracy as compared to other eGFR-EPI equations., Conclusions: The BTP and B2M equations are the worst performing of the eGFR-EPI equations, and no benefit is observed with the addition of BTP or B2M to Cr/cysC., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Introduction: Beta-trace protein (BTP) is a low molecular weight protein, produced mainly in the cerebrospinal fluid. It has been proposed as a marker for kidney function. Recently, a new method for GFR estimation using mean normal values to rescale GFR marker concentrations has been described for creatinine and cystatin C, two commonly used endogenous markers for kidney function. The aim of this study is to apply this approach to BTP in children., Method: We retrospectively analyzed serum concentrations of creatinine, cystatin C and BTP measured during inulin clearance tests in children. BTP was measured using a particle-enhanced immunonephelometric assay (Siemens Healthcare). A novel BTP-based eGFR equation was developed using published normal values for children: eGFR BTP [ml/min/1.73m 2 ] = 107.3/BTP/Q BTP with Q BTP  = 0.69. Performance of this equation was compared to the established creatinine-based full age spectrum equation FASage and the cystatin C-based FAScys equations as well as the BTP-based Benlamri equation in terms of bias, % prediction error and P 30 and P 10 accuracy rates., Results: 322 inulin clearance tests were studied. Overall, our novel equation performed comparably to the creatinine-based FASage and the BTP-based Benlamri equations but was less accurate than FAScys (P 30 : 79.2 vs 86.3%, p = .008). Combining markers significantly enhanced performance compared to the single marker equations, with the exception of FAScys., Conclusion: Rescaled BTP concentrations are a simple method for estimating GFR in children. However, the additional value of BTP for the estimation of GFR compared to rescaled creatinine and cystatin C still remains to be demonstrated., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Rationale & Objective: Determining whether a change in estimated glomerular filtration rate (eGFR) or albuminuria is clinically significant requires knowledge of short-term within-person variability of the measurements, which few studies have addressed in the setting of chronic kidney disease., Study Design: Cross-sectional study with multiple collections over less than 4 weeks., Setting & Participants: Clinically stable outpatients with chronic kidney disease (N=50; mean age, 56.8 years; median eGFR, 40mL/min/1.73m 2 ; median urinary albumin-creatinine ratio (UACR), 173mg/g)., Exposure: Repeat measurements from serially collected samples across 3 study visits., Outcomes: Measurements of urine albumin concentration (UAC), UACR, and plasma creatinine, cystatin C, β 2 -microglobulin (B2M), and beta trace protein (BTP)., Analytical Approach: We calculated within-person coefficients of variation (CV w ) values and corresponding reference change positive and negative (RCV pos and RCV neg ) values using log-transformed measurements., Results: Median CV w (RCV pos ; RCV neg ) values of filtration markers were 5.4% (+16%; -14%) for serum creatinine, 4.1% (+12%; -11%) for cystatin C, 7.4% (+23%; -18%) for BTP, and 5.6% (+17%; -14%) for B2M. Results for albuminuria were 33.2% (+145%; -59%) for first-morning UAC, 50.6% (+276%; -73%) for random spot UAC, 32.5% (+141%; -58%) for first-morning UACR, and 29.7% (124%; -55%) for random spot UACR. CV w values for filtration markers were comparable across the range of baseline eGFRs. CV w values for UAC and UACR were comparable across the range of baseline albuminuria values., Limitations: Small sample size limits the ability to detect differences in variability across markers. Participants were recruited and followed up in a clinical and not research setting, so some preanalytical factors could not be controlled., Conclusions: eGFR markers appear to have relatively low short-term within-person variability, whereas variability in albuminuria appears to be high, making it difficult to distinguish random variability from meaningful biologic changes., (Copyright © 2018 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Tubulointerstitial fibrosis is a common feature of kidney disease. Histone deacetylase (HDAC) inhibitors have been reported to attenuate renal fibrosis progression. Here, we investigated the effect of CG200745, a novel HDAC inhibitor, on renal fibrosis development in a mouse model of unilateral ureteral obstruction (UUO). To examine the effects of CG200745 on renal fibrosis in UUO, C57BL/6 J male mice were divided into three groups: control, UUO, and CG200745 (30 mg/kg/day)-treated UUO groups. CG 200745 was administered through drinking water for 1 week. Human proximal tubular epithelial (HK-2) cells were also treated with CG200745 (10 µM) with or without TGF-β (2 ng/mL). Seven days after UUO, plasma creatinine did not differ among the groups. However, plasma neutrophil gelatinase-associated lipocalin (NGAL) levels were markedly increased in the UUO group, which were attenuated by CG200745 treatment. UUO kidneys developed marked fibrosis as indicated by collagen deposition and increased α-smooth muscle actin (SMA) and fibronectin expression. CG200745 treatment attenuated these fibrotic responses and suppressed UUO-induced production of transforming growth factor-beta1 (TGF-β) and phosphorylation of Smad-2/3. CG200745 treatment also attenuated UUO-induced inflammation as indicated by the expression of inflammatory markers. Furthermore, CG200745 attenuated phosphorylation of p38 mitogen-activated protein kinase in UUO kidneys. In HK-2 cells, TGF-β induced the expression of α-SMA and fibronectin, which were attenuated by CG200745 cotreatment. These results demonstrate that CG200745, a novel HDAC inhibitor, has a renoprotective effect by suppressing renal fibrosis and inflammation in a UUO mouse model.

Bacterial and viral infections often present with similar symptoms. Etiologic misdiagnosis can alter the trajectory of patient care, including antibiotic overuse. A host-protein signature comprising tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), interferon gamma-induced protein-10 (IP-10), and C-reactive protein (CRP) was validated recently for differentiating bacterial from viral disease. However, a focused head-to-head comparison of its diagnostic performance against other biomarker candidates for this indication was lacking in patients with respiratory infection and fever without source. We compared the signature to other biomarkers and prediction rules using specimens collected prospectively at two secondary medical centers from children and adults. Inclusion criteria included fever > 37.5 °C, symptom duration ≤ 12 days, and presentation with respiratory infection or fever without source. Comparator method was based on expert panel adjudication. Signature and biomarker cutoffs and prediction rules were predefined. Of 493 potentially eligible patients, 314 were assigned unanimous expert panel diagnosis and also had sufficient specimen volume. The resulting cohort comprised 175 (56%) viral and 139 (44%) bacterial infections. Signature sensitivity 93.5% (95% CI 89.1-97.9%), specificity 94.3% (95% CI 90.7-98.0%), or both were significantly higher (all p values < 0.01) than for CRP, procalcitonin, interleukin-6, human neutrophil lipocalin, white blood cell count, absolute neutrophil count, and prediction rules. Signature identified as viral 50/57 viral patients prescribed antibiotics, suggesting potential to reduce antibiotic overuse by 88%. The host-protein signature demonstrated superior diagnostic performance in differentiating viral from bacterial respiratory infections and fever without source. Future utility studies are warranted to validate potential to reduce antibiotic overuse.

Objective: The effect of lipoxin receptor agonist BML-111 on acute kidney injury and AKI in rats with hemorrhagic shock (HS) and its mechanism were investigated., Materials and Methods: A model of hemorrhagic shock in Sprague-Dawley (SD) rats was established, and recovered after 30 min of shock. 1 mg/kg BML-111 was intraperitoneally injected at the beginning of resuscitation in group BML-111. The concentration of serum creatinine, serum KIM-1 content, NGAL and inflammatory factors were detected. Renal tissue injury was examined by HE staining; TUNEL staining was used to detect the apoptosis of rat kidney cells. Western blot was performed for the detection of the expression level of MAPK (mitogen-activated protein kinase), Bax, cytochrome C and caspase-3,9 in rat renal tissue., Results: HE staining showed pathological changes in groups group comparing to sham group. BML-111 group had a significant decrease in renal tissue injury. The scores of renal injury in each group were in accordance with the histological changes. The expression level of inflammatory factors in HS group was significantly higher than that in sham group (p<0.05). After BML-111 intervention, the levels of inflammatory factors in renal tissue were significantly lower than those in HS group (p<0.05). Meanwhile, NGAL and KIM-1 also showed the same trend. TUNEL staining showed that compared with sham group, the number of apoptotic cells in renal tissue of HS group increased significantly, and the apoptosis rate of renal tissue cells in group BML-111 decreased significantly. Western blot showed that the expression level of JNK, p38MAPK, and apoptosis-related protein in HS group was significantly increased, whereas the expression level of p38MAPK and JNK in group BML-111 was significantly decreased., Conclusions: BML-111 can reduce the inflammatory response and apoptosis of renal tissue by inhibiting the activation of MAPK signaling pathway in acute renal injury induced by hemorrhagic shock.

Background: Beta trace protein (BTP) is a novel renal biomarker that has emerged as potential alternative or addition to serum creatinine (Scr) and serum cystatin C (ScysC). We analyzed BTP's diagnostic ability to detect impaired kidney function by rescaling it and we tested whether rescaling BTP allowed us to expand the Full-Age-Spectrum (FAS)-equation to BTP., Methods: 566 participants aged ≥70 years with measured glomerular filtration rate (mGFR), Scr, ScysC and BTP from the population-based Berlin Initiative Study (BIS) were considered. We developed a single and combined FAS-equation using rescaled BTP (BTP/0.60) and calculated its sensitivity (S) and specificity (Sp) to identify kidney disease using a fixed (60 mL/min/1.73 m 2 ) and age-dependent threshold for mGFR., Results: Rescaled BTP shared the same reference interval with rescaled Scr and ScysC and showed acceptable diagnostic performance (S = 73.1%, Sp = 86.5%), comparable to Scr (S = 71.0%, Sp = 90.5%) and ScysC (S = 80.7%, Sp = 92.9%). Rescaled BTP can be used in the FAS-equation with comparable performance as Scr and ScysC, but the Scr/ScysC/BTP-combined FAS-eq. (P10 = 57.8%, P30 = 96.6%) did not outperform the Scr/ScysC-combined FAS-eq. (P10 = 57.1%, P30 = 96.3%)., Conclusions: Rescaled BTP is a valid alternative to Scr or ScysC to diagnose kidney function. The FAS-concept can be applied to BTP or the combination of BTP, Scr and ScysC., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: Beta Trace Protein (BTP) is a promising marker of glomerular filtration rate (GFR). Equations to estimate GFR using BTP have been proposed. Very little is known about BTP's production and metabolism. It has been hypothesized that the liver metabolizes certain BTP isoforms. As such, hepatic dysfunction may influence serum levels independently of GFR. This would impact on the accuracy and precision of GFR estimates using BTP. The purpose of this study was to assess the impact of cirrhosis on serum BTP concentrations., Methods: BTP, cystatin C (cysC) and creatinine (Cr) were measured in 99 cirrhotic subjects and in matched controls. BTP/cysC and Cr/cysC ratios were compared between cases and controls. This was repeated after stratification by Child Pugh category. Comparisons of ratios between Child Pugh category A and combined B and C case subjects were also performed., Results: There were no differences in BTP/cysC ratios between cases and controls for the entire cohort (0.80 vs 0.79) or for any of the Child Pugh categories (p > 0.10). There were significant differences between cases (1.09) and controls (0.73) for the BTP/Cr ratios (p < 0.001). The BTP/Cr ratio was higher in those with more advanced cirrhosis as compared to those with less severe cirrhosis (1.20 vs 1.03, p < 0.01). There were no differences in BTP/cysC ratios between those with less severe and more advanced cirrhosis (p = 0.25)., Conclusions: This study suggests that hepatic dysfunction does not influence serum BTP levels and argues against a significant role for the liver in BTP metabolism. Confirmation in a larger group of patients with advanced cirrhosis is required.

Background: Iron deficiency anemia is common in patients with chronic kidney disease (CKD). Neutrophil gelatinase-associated lipocalin (NGAL), a biomarker of acute kidney injury, is known to be associated with iron metabolism. We investigated whether plasma NGAL level is associated with iron status in pre-dialysis CKD patients with anemia., Methods: This study included 419 patients who had anemia. The subjects were into categorized into a pre-dialysis group (estimated glomerular filtration rate [eGFR] <60 ml/min/1.73 m 2 , n = 288) and a non-CKD group (eGFR >60 ml/min/1.73 m 2 , n = 131). The associations between plasma NGAL and iron status (serum ferritin and transferrin saturation [TSAT]), eGFR, albumin, uric acid, total cholesterol, calcium, phosphate, and C-reactive protein (CRP) were assessed., Results: In non-CKD group, plasma NGAL was not associated with any baseline variables including iron indices (TSAT and serum ferritin). In pre-dialysis group, univariate analysis showed plasma NGAL correlated with eGFR, CRP, TSAT, and serum ferritin. In multivariate analysis, plasma NGAL was independently associated with TSAT. However, serum ferritin lost its association with plasma NGAL. In ROC analysis for identifying iron deficiency, the plasma NGAL (best cut-off value ≤394 ng/ml) was superior to the serum ferritin (suggested cut-off value ≤500 ng/ml) in both sensitivity and specificity., Conclusions: Plasma NGAL is associated with iron status in anemic patients with pre-dialysis CKD. Further studies are needed to demonstrate the role of plasma NGAL in assessing the iron deficiency and in guiding the iron therapy for pre-dialysis CKD patients.

Background: The pharmacological blockade of galectin-3 (Gal-3), a β-galactoside-binding lectin, reduces renal impairment in acute kidney injury, hyperaldosteronism or nephropathy. We herein investigated the effects of pharmacological Gal-3 inhibition by modified citrus pectin (MCP) in renal damage in spontaneously hypertensive rats (SHRs)., Methods and Results: Gal-3 inhibition did not modify blood pressure levels in 30-week-old SHR. Kidney weight was higher in SHR, with no effect of MCP treatment (100 mg/kg/day in the drinking water). Plasma creatinine and albuminuria were slightly but significantly increased in SHR and reduced by MCP, as well as plasma and urinary neutrophil gelatinase-associated lipocalin. In kidney from SHR, Gal-3 was upregulated, as well as the fibrotic markers (collagen type I, TGF-β and connective tissue growth factor) and tubulointerstitial fibrosis. MCP treatment reduced Gal-3 levels and fibrosis. The epithelial-mesenchymal transition (EMT) molecules (fibronectin, α-smooth muscle actin and β-catenin) were modified in SHR and normalized by Gal-3 inhibition. The inflammatory mediators (monocyte chemoattractant protein-1, osteopontin, cd68, cd80, cd44 and cd45) were elevated in SHR and attenuated by MCP. Renal damage markers (neutrophil gelatinase-associated lipocalin and kidney injury molecule-1) were augmented in SHR and improved by MCP. In renal epithelial normal rat kidney-52E cells, Gal-3 treatment induced EMT markers, whereas Gal-3 silencing attenuated EMT., Conclusion: Gal-3 inhibition attenuated early renal damage in SHR as indicated by reduced albuminuria, improved renal function and decreased renal fibrosis, EMT and inflammation, independently of blood pressure levels. These data suggest that Gal-3 could be a potential therapeutic candidate for the prevention of early renal alterations in hypertension.

Introduction: Compared to the conventional methods, serum beta-trace protein (BTP) has been shown to be more helpful for estimating glomerular filtration rate; however, its value is remained unclear in neonates. The present study aimed to investigate the range of serum BTP level in healthy term neonates and its value to estimate glomerular filtration rate., Materials and Methods: This cross-sectional study was conducted on 50 healthy term neonates without underlying cardiovascular or kidney disorders who were admitted to Ali Asghar hospital in 2013. Serum BTP was measured using an automated nephelometric immunoassay. Glomerular filtration rate was assessed using the Schwartz equation based on serum creatinine level., Results: The mean age of the neonates was 6.2 ± 3.6 days (range, 2 to 17 days), their mean gestational age was 38.02 ± 0.20 weeks, and their mean height was 49.8 ± 1.7 cm. The mean serum BTP level was 0.41 ± 0.11 mg/L (range, 0.19 mg/L to 0.92 mg/L). The mean serum creatinine level was 0.49 ± 0.16 mg/dL (range, 0.3 mg/dL to 1.0 mg/dL). The mean estimated GFR was 48.90 ± 15.88 mL/min. A positive correlation was observed between the reciprocal concentrations of BTP and GFR (r = 0.383, P = .006). Furthermore, the reciprocal concentrations of BTP was associated with the reciprocal concentrations of serum creatinine level (r = 0.365, P = .009)., Conclusions: Measurement of serum BTP can be a reliable tool for detecting kidney function in neonates. Further studies are warranted to design a suitable formula for GFR estimation based on serum BTP in neonates.

Background: MicroRNAs (miRNA) have been identified to exert a wide range of biological functions in acute kidney injury (AKI) after deep hypothermic circulatory arrest (DHCA). We sought to investigate the renoprotection of miRNA-106b-5p in a rat model of DHCA by targeting phosphatase and tensin homolog (PTEN)., Methods: Overexpression of miRNA-106b-5p in vivo was conducted by directly injection of lentivirus vectors containing pre-miRNA-106b-5p into the renal parenchyma of the animals under the ultrasound guidance 7 days before DHCA. The vehicle or control lentivirus vectors were given to the control group or the control vector group, respectively. Renal function and apoptosis activity were evaluated by serum cystatin C, serum/tissue neutrophil gelatinase-associated lipocalin (NGAL), and terminal deoxynucleotidyl transferase dUTP nick-end labeling assay (TUNEL) at 24 hours after surgery. Expressions of miRNA-106b-5p, PTEN, and caspase-3 in the kidney were evaluated by quantitative real-time polymerase chain reaction and western blot analysis., Results: Transfection of pre-miRNA-106b-5p significantly enhanced the expression of miRNA-106b-5p and dramatically downregulated the expressions of PTEN in the kidney compared with the control group. Renal functions were markedly protected by pretreatment with pre-miRNA-106b-5p as evidenced by decreases in serum cystatin C and serum/tissue neutrophil gelatinase-associated lipocalin at 24 hours after surgery. The pre-miRNA-106b-5p group showed significantly fewer apoptotic cells and lower levels of caspase-3 activation than the control group., Conclusions: Overexpression of miRNA-106b-5p attenuates kidney injuries after DHCA, possibly by inhibition of PTEN., Competing Interests: Conflict of Interest: None., (Georg Thieme Verlag KG Stuttgart · New York.)

Chronic kidney disease (CKD) is known to involve inflammation, oxidative stress and apoptosis. Here, we investigated the impact of curcumin (diferuloyl methane, a phenolic turmeric pigment), which has strong antioxidant, anti-inflammatory and anti-apoptotic activities on kidney structure and function in rats with adenine-induced CKD. Rats were treated for 5 weeks with adenine to induce CKD-like renal damage and combined with three doses of curcumin. Markers of kidney function and oxidative stress were quantified in plasma, urine, renal homogenates and on kidney tissue. Curcumin was found to significantly abate adenine-induced toxic effects such as reduced creatinine clearance, elevated neutrophil gelatinase-associated lipocalin levels and raised urinary N-acetyl-β-D-glucosaminidase activities. Curcumin markedly reduced renal morphological damage and histopathological markers of inflammation, fibrosis and apoptosis. Curcumin further reduced adenine-induced hypertension, urinary albumin, the inflammatory cytokines IL-1β, IL-6 and TNF-α, cystatin C and adiponectin. It restored plasma sclerostin concentrations and lowered oxidative stress in renal homogenates. In animals treated with the two higher curcumin concentrations, alone or in combination with adenine, an increased expression of the antioxidative transcription factor Nrf2 was found as well as up-regulation of the activity of its direct target glutathione reductase, and of an indirect target, the glutathione level. In conclusion, curcumin exhibits salutary effects against adenine-induced CKD in rats by reducing inflammation and oxidative stress via up-regulation of the transcription factor Nrf2., (© 2017 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).)

Despite extensive investigations, the process of development of chronic subdural hematoma (CSDH) is not known. The present study aims to investigate CSDH by measuring biomarkers in it, gas analysis, and immunohistochemical examination. A total of 42 patients with symptomatic CSDH who underwent burr-hole drainage were enrolled. Intraoperatively, hematoma fluid and peripheral venous blood (PV CSDH ) were simultaneously collected. As controls, peripheral venous blood (PV Control ) and intracranial cerebrospinal fluid (CSF) were collected from other subjects during other surgeries. CatK, lipocalin-type prostaglandin D synthase (PGDS), and cystatin C (CysC) present in these specimens were measured using enzyme-linked immunosorbent assay. Data obtained were statistically analyzed after age correction. In 15 patients, gas analysis was performed for CSDH and PV CSDH . Furthermore, immunohistochemical examination for the outer membrane was performed for four patients. CatK, PGDS, and CysC levels were markedly elevated in the CSF and CSDH. CatK levels in PV CSDH were significantly higher than in PV Control (P<0.0001). In contrast, CysC levels in PV CSDH were significantly lower than in PV Control (P=0.004). The gas analysis revealed that the internal environment of CSDH is characterized by marked hypoxia, hypoglycemia, and lactic acidosis. Furthermore, the outer membrane consistently showed a diffuse staining for CatK. Based on these, CatK was thought to play a role in the development of CSDH, with the levels in peripheral venous blood elevated in patients with CSDH., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Despite intense research the optimal endogenous biomarker for glomerular filtration rate (GFR) estimation has not been identified yet. We analyzed if ß-trace protein (BTP) improved GFR estimation in elderly. 566 participants aged 70+ from the population-based Berlin Initiative Study were included in a cross-sectional validation study. BTP, standardized creatinine and cystatin C were measured in participants with iohexol clearance measurement as gold standard method for measured GFR (mGFR). In a double logarithmic linear model prediction of mGFR by BTP was assessed. Analyses with BTP only and combined with creatinine and cystatin C were performed. Additionally, performance of GFR estimating equations was compared to mGFR. We found that the combination of all three biomarkers showed the best prediction of mGFR (r 2  = 0.83), whereat the combination of creatinine and cystatin C provided only minimally diverging results (r 2  = 0.82). Single usage of BTP showed worst prediction (r 2  = 0.67) within models with only one biomarker. Subgroup analyses (arterial hypertension, diabetes, body mass index ≤23 and >30) demonstrated a slight additional benefit of including BTP into the prediction model for diabetic, hypertensive and lean patients. Among BTP-containing GFR equations the Inker BTP-based equation showed superior performance. Especially the use of cystatin C renders the addition of BTP unnecessary.

Objective: To evaluate the gene expression of beta-trace protein in urine of diabetic patients, with no reduction in glomerular filtration rate, which was defined as below 60mL/min/1.73m2., Methods: Type 2 diabetes mellitus patients were recruited, and a group of non-diabetic individuals served as control. Beta-trace protein gene expression was analyzed by quantitative PCR. Blood samples were collected to establish glucose levels and baseline kidney function. Accuracy was analyzed using ROC curves., Results: Ninety type 2 diabetes mellitus patients and 20 non-diabetic individuals were recruited. The area under the curve was 0.601, sensitivity of 20% and specificity of 89.47%. Among diabetic participants, 18% showed an expression above the cutoff point., Conclusion: These results of accuracy of beta-trace protein gene expression in urine of diabetic patients are promising, although they did not achieve a higher area under the curve level.

Aim: To optimize the transurethral endoscopic management of patients with ureterolithiasis by measuring biomarkers of renal parenchymal damage., Materials and Methods: One hundred fifty-one patients with solitary ureteral stones were tested for levels of cystatin C, neutrophil gelatinase-associated lipocalin, 2-microglobulin and interleukin 18., Results: An increase in the levels of markers of renal injury was observed both in the preoperative period and after CULT. Differences in the values of these indices depended on the timing of the CULT, the size and location of the stone and the type of lithotripter., Conclusions: All patients were found to have damage to the renal tubular system. The established critical values of the markers of renal injury in ureterolithiasis may be used as diagnostic criteria for renal injury.

Background: Studies in chronic kidney disease populations suggest that the non-glomerular filtration rate (GFR) determinants of serum levels of the low-molecular-weight protein filtration markers cystatin C, β 2 -microglobulin (B2M), and beta-trace protein (BTP) are less affected by age, sex, and ethnicity than those of creatinine., Study Design: Cross-sectional study., Setting & Participants: Predominantly elderly participants selected from the Age, Gene/Environment Susceptibility Kidney Study (AGES-Kidney; N=683; mean [SD] age, 79 [4] years; GFR, 62 [17]mL/min/1.73 m 2 ) and from the Multi-Ethnic Study of Atherosclerosis Kidney Study (MESA-Kidney; N=273; mean [SD] age, 70.5 [9] years; GFR, 73 [19]mL/min/1.73 m 2 )., Predictors: Demographic and clinical factors hypothesized to be associated with conditions affecting non-GFR determinants of the filtration markers., Outcomes: Measured GFRs and estimated GFRs (eGFRs) based on creatinine, cystatin C, B2M, and BTP levels (eGFR cr, eGFR cys , eGFR B2M , and eGFR BTP , respectively). Residual associations of factors with eGFR after accounting for measured GFR as the parameter of interest., Results: eGFR cys , eGFR B2M , and eGFR BTP had significantly less strong residual associations with age and sex than eGFR cr in both AGES-Kidney and MESA-Kidney and were not associated with ethnicity (black vs white) in MESA-Kidney. After adjusting for age, sex, and ethnicity, residual associations with most clinical factors were smaller than observed with age and sex. eGFR cys and eGFR B2M , but not eGFR BTP , had significant residual associations with C-reactive protein levels in both studies., Limitations: Small sample size may limit power to detect associations. Participants may be healthier than the general population., Conclusions: Similar to previous studies in chronic kidney disease, in community-dwelling elders, cystatin C, B2M, and BTP levels are less affected than creatinine level by age and sex and are not affected by ethnicity. Both cystatin C and B2M levels may be affected by inflammation. These findings are important for the development and use of GFR estimating equations based on low-molecular-weight serum proteins throughout the range in GFRs., (Copyright © 2017 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Purpose of Review: Allergen extracts are still widely used in allergy diagnosis as they are regarded as sensitive screening tools despite the fact that they may lack some minor allergens. Another drawback of extracts is their low specificity, which is due to the presence of cross-reactive allergens. Progress in allergen identification has disclosed a number of allergenic molecules of homologous sequence and structure which are present in different animal species. This review summarizes recent advances in mammalian and fish allergen identification and focuses on their clinical relevance., Recent Findings: Serum albumins and parvalbumins are well-known animal panallergens. More recently several members of the lipocalin family were found to be cross-reactive between furry animals whereas in fish, additional allergens, enolase, aldolase and collagen, were found to be important and cross-reactive allergens. New epidemiological studies have analysed the prevalence and clinical relevance of mammalian and fish components. Primary sensitization can be distinguished from cross-sensitization by using marker allergens. Although substantial progress has been made in allergen identification, only few markers are commercially available for routine clinical practice.